TW201329067A - Urea compounds as GKA activators - Google Patents

Urea compounds as GKA activators Download PDF

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TW201329067A
TW201329067A TW101146267A TW101146267A TW201329067A TW 201329067 A TW201329067 A TW 201329067A TW 101146267 A TW101146267 A TW 101146267A TW 101146267 A TW101146267 A TW 101146267A TW 201329067 A TW201329067 A TW 201329067A
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pyridyl
methyl
phenyl
fluoro
alkyl
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TW101146267A
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Chinese (zh)
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Jonathan B Houze
Paul Dransfield
Vatee Pattaropong
Xiaohui Du
Zice Fu
Su-Jen Lai
Jae-Hyeon Park
Xian-Yun Jiao
Todd J Kohn
Thomas Daniel Aicher
Steven Armen Boyd
Josef Bencsik
Kevin Ronald Condroski
Ronald Jay Hinklin
Christopher F Kraser
Scott Pratt
Ajay Singh
Steven Mark Wenglowsky
Mark Laurence Boys
Mark Joseph Chicarelli
Peter J Mohr
Mario G Cardozo
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Amgen Inc
Array Biopharma Inc
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Publication of TW201329067A publication Critical patent/TW201329067A/en

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Abstract

The present invention relates to compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain glucokinase activators of Formula l useful in the treatment of diseases and disorders that would benefit from activation of glucokinase.

Description

作為GKA活化劑之脲化合物 Urea compound as a GKA activator

本發明係關於新穎化合物、包含該等化合物之醫藥組合物、製備該等化合物之方法及該等化合物於療法中之用途。更特定言之，本發明係關於適用於治療將受益於葡糖激酶活化之疾病及病症的某些葡糖激酶活化劑。 The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds, methods of preparing such compounds, and the use of such compounds in therapy. More specifically, the invention relates to certain glucokinase activators useful in the treatment of diseases and conditions that would benefit from glucokinase activation.

葡糖激酶(己糖激酶IV或D)為在與肝臟及胰臟β細胞中之葡萄糖利用及代謝相關之血糖調控方面起重要作用的糖解酶。充當葡萄糖感應器，葡糖激酶控制血漿葡萄糖含量。葡糖激酶在降低血漿葡萄糖含量方面起雙重作用：肝細胞中葡萄糖介導之酶活化促進肝臟葡萄糖吸收及肝糖合成，而在胰臟β細胞中最終誘導胰島素分泌。此兩種作用繼而降低血漿葡萄糖含量。 Glucokinase (hexose kinase IV or D) is a glycolytic enzyme that plays an important role in the regulation of blood glucose associated with glucose utilization and metabolism in liver and pancreatic beta cells. Acting as a glucose sensor, glucokinase controls plasma glucose levels. Glucokinase plays a dual role in reducing plasma glucose levels: glucose-mediated enzyme activation in hepatocytes promotes hepatic glucose uptake and hepatic glucose synthesis, while insulin secretion is ultimately induced in pancreatic beta cells. These two effects in turn reduce plasma glucose levels.

臨床證據已顯示活性降低及增強之葡糖激酶變異體分別與青年成年期發病型糖尿病(MODY2)及嬰兒持續高胰島素性低血糖症(PHHI)相關。又，已報導非胰島素依賴性糖尿病(NIDDM)患者具有不當的低葡糖激酶活性。此外，在飲食性或遺傳性糖尿病動物模型中葡糖激酶之過度表現預防、改善或逆轉疾病之病理性症狀的進程。出於此等原因，製藥工業已尋求活化葡糖激酶之化合物。 Clinical evidence has shown that decreased activity and enhanced glucokinase variants are associated with young adult onset diabetes (MODY2) and infants with persistent hyperinsulinemia (PHHI). Furthermore, patients with non-insulin dependent diabetes mellitus (NIDDM) have been reported to have inappropriate low glucosidase activity. Furthermore, overexpression of glucokinase in an animal model of diet or hereditary diabetes prevents, improves or reverses the progression of pathological symptoms of the disease. For these reasons, the pharmaceutical industry has sought to activate compounds of glucokinase.

2007年5月10日公開之國際專利申請公開案第WO 2007/OS3345號揭示在3位上具有亞甲基氧基連接之芳族基團且在胺基上具有雜芳基 環(諸如噻唑基或1,2,4-噻二唑基)之某些2-胺基吡啶衍生物作為葡糖激酶活化劑。 International Patent Application Publication No. WO 2007/OS3345, issued May 10, 2007, discloses an aromatic group having a methyleneoxy group attached at the 3-position and a heteroaryl group on the amine group. Certain 2-aminopyridine derivatives of the ring (such as thiazolyl or 1,2,4-thiadiazolyl) act as glucokinase activators.

現已發現吡啶基脲適用作葡糖激酶活化劑。已發現此等化合物中之某些化合物具有突出的特性組合，尤其使其適於口服使用來控制血漿葡萄糖含量。 Pyridyl urea has been found to be useful as a glucokinase activator. Certain of these compounds have been found to have outstanding combinations of properties, particularly making them suitable for oral use to control plasma glucose levels.

本發明包含一類適用於治療疾病(諸如糖尿病)之新穎化合物。因此，本發明亦包含含有該等化合物之醫藥組合物、使用本發明之化合物及組合物治療糖尿病之方法，及適用於製備本發明化合物之中間物及製程。 The invention encompasses a novel class of compounds suitable for use in the treatment of diseases such as diabetes. Accordingly, the present invention also encompasses pharmaceutical compositions containing such compounds, methods of using the compounds and compositions of the present invention to treat diabetes, and intermediates and processes suitable for use in preparing the compounds of the present invention.

本發明化合物係由以下通式結構表示： The compounds of the invention are represented by the following general structure:

及其醫藥學上可接受之鹽；其中G、P、R1、R2及R3定義於下文。 And pharmaceutically acceptable salts thereof; wherein G, P, R 1 , R 2 and R 3 are as defined below.

前述內容僅概述本發明之某些態樣且不欲或不應將其解釋為以任何方式限制本發明。本文所列舉之所有專利、專利申請案及其他公開案藉此以全文引用的方式併入。 The foregoing is merely illustrative of some aspects of the invention and is not intended to All patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety.

本發明之一個態樣係關於具有式I之通式結構的化合物： One aspect of the invention pertains to compounds having the general structure of formula I:

其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基(oxo)或鹵基之取代基取代；R2為H、烷基或鹵基；R3為H、鹵基、鹵烷基、烷氧基羰基、胺基羰基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環未經取代或經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環基環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、-NRR'、烷基-NRR'或 RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基取代基未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；G為C-Q或N；L為O、S、CH2或CH2O；Q為H或-L-R5；且P為H或-L-R6；其限制條件為：當Q為H時，則P為-L-R6，或當Q為-L-R5時，則P為H；當G為N時，則P為-L-R6；其他限制條件為，當R3為H，R1為甲基，R2為H，L為O，且P為H時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基； 其他限制條件為，當R3為Br，R1為甲基，R2為H，L為O，且P為H時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當R3為H，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為鹵基；其他限制條件為，當R3為溴，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為氯；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，R2為H，R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且G為CH時，R1不為苯基或第三丁基；其他限制條件為，當R2為H，R3為2-吡啶硫基，P為2-乙基-3-吡啶氧基，且G為CH時，R1不為4-甲基-2-咪唑基甲基；其他限制條件為，當R1為甲基，R2為H，G為N，且P為2-甲基-3-吡啶氧基時，R3不為4-甲基苯基、2,4-二甲基苯基或1,2-二羥基-2-苯基乙基；及其醫藥學上可接受之鹽。 Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or one or two independently selected from hydroxy, alkoxy, alkyl, oxo or halogen Substituted by a substituent; R 2 is H, alkyl or halo; R 3 is H, halo, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or -S(O)n; n is 0, 1 or 2; R 4 is alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkenyl, alkoxy Carbocarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, aralkenyl, arylalkynyl , cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl or heterocyclylcarbonylalkyl; Wherein the ring in R 4 is unsubstituted or substituted with from 1 to 3 substituents independently selected from the group consisting of H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, fluorenyl Alkylsulfonyl, heterocyclyl, aminosulfonyl, alkylaminosulfonyl, cyano, alkoxycarbonyl, carboxyl, amine, RR'N-alkyl, alkoxyalkyl , hydroxyalkyl or R a R b NC(=O), wherein R a is alkyl and R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a And R b together with nitrogen forms an unsubstituted or alkyl-substituted heterocyclyl ring; R 5 is aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclyl, wherein R 5 is not Substituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, cyano, alkoxycarbonyl, carboxy, decyl, cycloalkyl, Heterocyclyl, hydroxyalkyl, alkoxyalkyl, pendant oxy, -NRR', alkyl-NRR' or R a R b NC(=O), wherein R a is alkyl and R b is alkoxy Alkyl or aminoalkyl; wherein R and R' are H, alkyl, aryl, heterocyclyl, heterocyclylalkyl or naphthenic Wherein the heterocyclylalkyl, cycloalkyl and heterocyclyl substituents are unsubstituted or are independently selected from the group consisting of alkyl, alkoxy, hydroxy, halo, haloalkyl, cyano Or a substituent of a carboxy group; or R' and R may form a heterocyclic group together with N; R 6 is an aryl group, an aralkyl group, a heterocyclic group, a heterocyclic alkyl group or a cycloalkyl group, wherein each of the aforementioned rings is not Substituted or substituted with from 1 to 4 substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, cyano , cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; G is CQ or N; L is O, S, CH 2 Or CH 2 O; Q is H or -LR 5 ; and P is H or -LR 6 ; the constraint is: when Q is H, then P is -LR 6 , or when Q is -LR 5 P is H; when G is N, then P is -LR 6 ; other restrictions are: when R 3 is H, R 1 is methyl, R 2 is H, L is O, and P is H, then R 5 is not [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, Isoquinolin-5-yl, isoquinolin-6-yl, quin Porphyrin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2 -Methyl-1-oxooxy-1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6- , 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo -1,2-dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; Other restrictions are: when R 3 is Br, R 1 is methyl, R 2 is H, L is O, and P is H, then R 5 is not 5,7-difluoro-1,3,4- Trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl Keto-1-oxy-1,2-dihydro-isoquinolin-6-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazol-4-yl, R 1 is A Base, R 2 is H, L is O, and when P is H, then R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are when R 3 is 1-methyl- 1H-pyrazol-5-yl, R 1 is methyl, R 2 is H, L is O, and when P is H, then R 5 is not 2-A -1-la-oxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinoline Polin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl; other restrictions are, when R 3 is H, R 1 is methyl, When L is O, P is H, and R 5 is 5-quinolyl, R 2 is not a halogen; other restrictions are: when R 3 is bromine, R 1 is methyl, L is O, and P is H. And when R 5 is 5-quinolyl, R 2 is not chlorine; other restrictions are, when L is O, R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl Or 2,6-dimethyl-3-pyridyl, R 2 is H, R 3 is 2-pyridylthio, bromo, methoxyethoxy or trifluoromethyl, and when G is CH, R 1 Not phenyl or tert-butyl; other restrictions are, when R 2 is H, R 3 is 2-pyridylthio, P is 2-ethyl-3-pyridinyloxy, and G is CH, R 1 is not 4-methyl-2-imidazolylmethyl; other restrictions are when R 1 is methyl, R 2 is H, G is N, and P is 2-methyl-3-pyridinyloxy R 3 is not 4-methylphenyl, 2,4-dimethylphenyl or 1,2-dihydroxy-2-phenylethyl; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R1為H、C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥 基烷氧基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy alkoxy-C 1-6 alkyl, C 6-10 aryl, C 6- a 10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group-C 1-6 alkyl group, wherein the aryl or heterocyclic ring is unsubstituted or via one or Substituted by two substituents independently selected from C 1-6 alkyl, hydroxy, pendant oxy or halo; and pharmaceutically acceptable salts thereof.

在另一實施例中，R1為H、甲基、乙基、丙基、異丙基、第三丁基、烯丙基、三氟-乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、羥基乙氧基乙基、胺基乙基、苯基、苯基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、4-甲基咪唑基甲基、咪唑基甲基、1-甲基-咪唑基甲基、1,5-二甲基吡唑基甲基、2-甲基噻唑基甲基、5-甲基-異噁唑基甲基、嗎啉-4-基乙基、嗎啉-4-基甲基、四氫哌喃乙基或四氫呋喃基乙基；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, allyl, trifluoro-ethyl, methoxy, methoxyethyl, Hydroxyethyl, hydroxypropyl, 2,3-dihydroxypropyl, hydroxyethoxyethyl, aminoethyl, phenyl, phenylethyl, 2-hydroxyphenylmethyl, 3-hydroxyphenyl Methyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, pyridylmethyl, 6-methyl-2-oxooxy-1,2-dihydropyridylmethyl, 4-methyl Methyl imidazolylmethyl, imidazolylmethyl, 1-methyl-imidazolylmethyl, 1,5-dimethylpyrazolylmethyl, 2-methylthiazolylmethyl, 5-methyl-isoxine Azylmethyl, morpholin-4-ylethyl, morpholin-4-ylmethyl, tetrahydropyranylethyl or tetrahydrofuranylethyl; and pharmaceutically acceptable salts thereof.

在另一實施例中，R1為2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、4-甲基咪唑-2-基甲基、咪唑-5-基甲基、1-甲基咪唑-5-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑-5-基甲基、5-甲基異噁唑-3-基、6-甲基-2-側氧基-1,2-二氫吡啶-3-基甲基或嗎啉-4-基乙基；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-methylimidazol-2-ylmethyl, imidazolium-5-ylmethyl , 1-methylimidazolium-5-ylmethyl, 1,5-dimethylpyrazol-4-ylmethyl, 2-methylthiazol-5-ylmethyl, 5-methylisoxazole-3 a group, 6-methyl-2-oxooxy-1,2-dihydropyridin-3-ylmethyl or morpholin-4-ylethyl; and pharmaceutically acceptable salts thereof.

在另一實施例中，R1為甲基、乙基或羥基乙基；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is methyl, ethyl or hydroxyethyl; and the pharmaceutically acceptable salts thereof.

在另一實施例中，R2為H、甲基、氯或氟；及其醫藥學上可接受之鹽。 In another embodiment, R 2 is H, methyl, chloro or fluoro; and pharmaceutically acceptable salts thereof.

在另一實施例中，R2為H；及其醫藥學上可接受之鹽。 In another embodiment, R 2 is H; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為-S(O)nR4，且n為0、1或2；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is -S(O) n R 4 and n is 0, 1 or 2; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為-SR4；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is -SR 4 ; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R4為C1-6烷基、C1-6羥基烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C3-6環烷基-C1-6烷基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基或C1-6羥基烷基；及其醫藥學上可接受之鹽。 In another embodiment, R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 2 -6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl- C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 membered heterocyclic, C 6-10 aryl-C 1-6 alkane , C 6-10 aryl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-6 alkyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 member Heterocyclylcarbonyl-C 1-6 alkyl; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 4 is unsubstituted or 1-3 independently selected from the group consisting of Substitution: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1- 6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclic, amine, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl or C 1-6 hydroxyalkyl And its pharmaceutically acceptable salts.

在另一實施例中，R3為甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、(4-哌啶基)硫基、(1-異丙基哌啶-4-基)硫基、(1-甲基羰基哌啶-4-基)硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基哌啶-4-基)硫基、(1-異丙基羰基哌啶-4-基)硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio , 3,4-dihydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl) a thio group, (2-hydroxy-2-methylbutyl)thio group, (4-methylpiperazin-1-yl)-carbonylmethylthio group, (morpholin-4-yl)carbonylmethylthio group, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1- (tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentane Thiothio, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, (4-piperidinyl)thio, (1-isopropylpiperyl) Pyridin-4-yl)thio, (1-methylcarbonylpiperidin-4-yl)thio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonate) Mercaptopiperidin-4-yl)thio, (1-isopropylcarbonylpiperidin-4-yl)thio, 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1- ( Oxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4- Thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3- Methyl isoxazolo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-piperidin-4-ylthio; and pharmaceutically acceptable salts thereof.

在另一實施例中，R3為甲氧基丙基亞磺醯基、甲氧基丙基磺醯基、1-(第三丁氧基羰基)哌啶-4-基亞磺醯基、2-吡啶基亞磺醯基、1-(第三丁氧基羰基)哌啶-4-基磺醯基或2-吡啶基磺醯基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is methoxypropylsulfinyl, methoxypropylsulfonyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfinyl, 2-pyridylsulfinyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfonyl or 2-pyridylsulfonyl; and pharmaceutically acceptable salts thereof.

在另一實施例中，R3為-OR4；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is -OR 4 ; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為甲氧基乙氧基或2-甲基-3-吡啶氧基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is methoxyethoxy or 2-methyl-3-pyridyloxy; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為C1-6鹵烷基、C1-6烷氧基羰基、胺基羰基、C1-6烷基、C1-6羥基烷基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基或4-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基或C1-6羥基烷基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 Alkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic group, C 6-10 aryl-C 1-6 alkyl group, C 6-10 aryl-C 2-6 alkenyl group, C 6-10 aryl group- C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkyne Or a heterocyclic group -C 1-6 alkyl or 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 4 Substituted unsubstituted or substituted with 1-3 substituents independently selected from: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1- 6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, C 1-6 aminoalkyl, C 1-6 alkane -C 1-6 alkyl group or C 1-6 hydroxyalkyl; and the pharmaceutically acceptable salt thereof

在另一實施例中，R3為甲基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、羥基乙基、羥基丁基、2-羥基-2-甲基丁基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基丙烯-1-基、甲氧基戊炔-1-基、乙氧基羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、乙氧基羰基丙基、羧基丙基、4,5-二羥基戊基、丙烯-2- 基、羥基丁炔基、2-環丙基乙烯基、2-乙氧基乙烯基、3,3-二甲基丁烯-1-基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、4-哌啶基甲基、嗎啉-4-基甲基、四氫哌喃-4-基甲基、四氫哌喃-4-基乙基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、環己基甲基、環己基乙基、環丙基、環己基、環戊基、環庚基、環戊烯基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己-1-烯基、環庚烯基，四氫哌喃-4-基、3,6-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、1-羥基乙基-4-吡唑基、1-甲氧基乙基-4-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、2,4-二甲基-5-噻唑基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基， 2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、吡嗪-2-基、噠嗪-4-基、3-苯并噻吩基、咪唑并[1,2-a]吡啶基或2-甲基苯并噁唑-5-基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is methyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methylbutyl, trifluoromethyl, hydroxyethyl, Hydroxybutyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, methoxypropyl , methoxybutyl, methoxypentyl, methoxypropen-1-yl, methoxypentyn-1-yl, ethoxycarbonyl, N-methyl-N-(methoxyethyl) Aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, ethoxycarbonylpropyl, carboxypropyl, 4,5-dihydroxypentyl, propylene-2- , hydroxybutynyl, 2-cyclopropylvinyl, 2-ethoxyvinyl, 3,3-dimethylbuten-1-yl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1-phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 4-piperidyl Pyridylmethyl, morpholin-4-ylmethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylethyl, 3-(2,2-dimethyl-1,3 -dioxalan-4-yl)propyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, Hexyl, cyclopentyl, cycloheptyl, cyclopentenyl, cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohex-1-enyl, cycloheptane Alkenyl, tetrahydropyran-4-yl, 3,6-dihydropyran-4-yl, 1,4-dioxaspiro[4.5]dec-7-ene-8-yl, 1,1- Dioxylyltetrahydro-2H-thiopiperazin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl -1,2,3,6-tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxy Carbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxy Carbonyl-piperidin-4-yl, 1-(dimethylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-Dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 2-methylsulfonyl Phenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonylaminophenyl, 3-methyl Aminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-cyano-3-methoxybenzene , 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-difluoromethoxy Phenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethyl Oxyphenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyridyl Azyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-methoxyethyl- 4-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 2,4-dimethyl-5-thiazolyl, 1-methyl-5 -Imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl- 4-pyridyl, 2-methyl-3-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl , 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 5-fluoro-2-methoxy-4-pyridyl, 3-fluoro-4-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy-4-pyridyl, 2-methyl 5-ylpyridyl, 3-methoxy-5-pyridyl, 2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5 Pyridyl, 2-cyano-4-pyridyl, 2-cyano-5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 3-methylsulfonyl-5-pyridyl, 2-oxooxy-1,2-dihydropyridin-3-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-cyano-5-pyrimidinyl, pyrazin-2-yl, pyridazin-4-yl, 3- Benzothiophenyl, imidazo[1,2-a]pyridyl or 2-methylbenzoxazol-5-yl; and pharmaceutically acceptable salts thereof.

在另一實施例中，R3為H或溴；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is H or bromine; and a pharmaceutically acceptable salt thereof.

在另一實施例中，G為CH；及其醫藥學上可接受之鹽。 In another embodiment, G is CH; and a pharmaceutically acceptable salt thereof.

在另一實施例中，G為C-Q；Q為H；P為-L-R6；且R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；及其醫藥學上可接受之鹽。 In another embodiment, G is CQ; Q is H; P is -LR 6 ; and R 6 is 5-membered nitrogen-containing heterocyclic group, 5-membered oxygen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 6 An oxygen-containing heterocyclic group, a phenyl group, a benzyl group, a 9-membered bicyclic nitrogen-containing heterocyclic group, a 10-membered bicyclic oxygen-containing heterocyclic group or a 10-membered bicyclic nitrogen-containing heterocyclic group, wherein R 6 is unsubstituted or subjected to one or Substituted by a plurality of substituents independently selected from the group consisting of C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, Carboxyl, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [ a 4-6 membered nitrogen-containing heterocyclyl]carbonyl group optionally substituted; and a pharmaceutically acceptable salt thereof.

在另一實施例中，G為C-Q；Q為H；P為-L-R6；且R6為四氫呋喃基、四氫哌喃基、3,4-二氫-2H-哌喃并[3,2-c]吡啶基、烷基、哌啶 基、吡啶基、吡唑基、苯基、喹啉基、1,2-二氫喹啉基、吡咯啶基、苄基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基或嘧啶基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 In another embodiment, G is CQ; Q is H; P is -LR 6 ; and R 6 is tetrahydrofuranyl, tetrahydropyranyl, 3,4-dihydro-2H-pyrano[3,2 -c]pyridyl, Alkyl, piperidinyl, pyridyl, pyrazolyl, phenyl, quinolyl, 1,2-dihydroquinolyl, pyrrolidinyl, benzyl, 5,6,7,8-tetrahydroquinoline , quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[ 3,4-b]pyridyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-a]pyridinyl or pyrimidinyl, wherein R 6 is unsubstituted or one or more Substituted independently of the following substituents: methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, ethoxycarbonyl, tert-butoxycarbonyl, carboxy, N-(A -N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof.

在另一實施例中，G為C-Q；Q為H；P為-L-R6；且R6為2-甲基-3-吡啶基、2-乙基-3-吡啶基、2-氰基-3-吡啶基、3-氯-4-氰基-5-吡啶基，1,3,5-三甲基-4-吡唑基、1,3,4-三甲基-5-吡唑基、1-乙基-5-吡唑基、1-乙基-4-氯-5-吡唑基，四氫呋喃-3-基、1-BOC-吡咯啶-3-基、四氫-2H-哌喃-4-基、3-氟-四氫-2H-哌喃-4-基、3-甲基-四氫-2H-哌喃-4-基、3-乙基-四氫-2H-哌喃-4-基、1-第三丁氧基羰基哌啶-4-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基-5-乙氧基羰基苯基、2-乙基苯基、2-甲基-5-羧基苯基、3-氯-2-氰基苯基、2-氰基-6-三氟甲基苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基) 胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、苄基，3-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、5,6,7,8-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、喹喏啉-5-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-4-基、1-甲基-1H-吲唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、6,7-二氫-5H-環戊烷并[b]吡啶-5-基、烷-4-基、3,4-二氫-2H-哌喃并[3,2-c]吡啶-4-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基或4-氯-5-甲基-6-嘧啶基；及其醫藥學上可接受之鹽。 In another embodiment, G is CQ; Q is H; P is -LR 6 ; and R 6 is 2-methyl-3-pyridyl, 2-ethyl-3-pyridyl, 2-cyano- 3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 1,3,5-trimethyl-4-pyrazolyl, 1,3,4-trimethyl-5-pyrazolyl , 1-ethyl-5-pyrazolyl, 1-ethyl-4-chloro-5-pyrazolyl, tetrahydrofuran-3-yl, 1-BOC-pyrrolidin-3-yl, tetrahydro-2H-peri喃-4-yl, 3-fluoro-tetrahydro-2H-pyran-4-yl, 3-methyl-tetrahydro-2H-pyran-4-yl, 3-ethyl-tetrahydro-2H-piperidin Butan-4-yl, 1-tert-butoxycarbonylpiperidin-4-yl, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2, 4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3 -methoxyphenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6 -fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyl-5-ethyl Oxycarbonylcarbonylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl, 3-chloro-2-cyanophenyl, 2-cyano-6-trifluoromethylphenyl, 2 -methyl-5-[N-(A -N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5- [N-(Methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, benzyl , 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 5,6,7,8- Tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, quinoxalin-5-yl, 3-methyl-1H-indole Zin-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, [1 , 2,4]triazolo[4,3-a]pyridin-8-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl, Alkyl-4-yl, 3,4-dihydro-2H-piperazino[3,2-c]pyridin-4-yl, 1-methyl-2-oxooxy-1,2-dihydroquinoline -6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxo-1,2-dihydro Quinoline-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinoline-6 -yl, 2-methyl-1-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7 -difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl Keto-2-oxo-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 1 -methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridine-6- A 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl or 4-chloro-5-methyl-6-pyrimidinyl group; and a pharmaceutically acceptable salt thereof.

在另一實施例中，L為O；及其醫藥學上可接受之鹽。 In another embodiment, L is O; and a pharmaceutically acceptable salt thereof.

在另一實施例中，G為C-Q；Q為-L-R5；P為H；且R5為5員雜環基、6員雜環基、苯基、苯基-C1-6烷基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基烷基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基； 及其醫藥學上可接受之鹽。 In another embodiment, G is CQ; Q is -LR 5 ; P is H; and R 5 is a 5-membered heterocyclic group, a 6-membered heterocyclic group, a phenyl group, a phenyl-C 1-6 alkyl group, a 9-membered nitrogen-containing heterocyclic group or a 10-membered nitrogen-containing heterocyclic group wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, or halo , pendant oxy, hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxyalkyl-C 1-6 alkyl Aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl And its pharmaceutically acceptable salts.

在另一實施例中，G為C-Q；Q為-L-R5；P為H；且R5為吡啶基、吡唑基、吡咯啶基、苯基、苄基、喹啉基、1,2-二氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、嘧啶基或1,2,3,4-四氫喹啉基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：氟、氯、氰基、甲氧基、三氟甲基、乙氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基、側氧基、甲基、乙基或丁氧基羰基；及其醫藥學上可接受之鹽。 In another embodiment, G is CQ; Q is -LR 5 ; P is H; and R 5 is pyridinyl, pyrazolyl, pyrrolidinyl, phenyl, benzyl, quinolinyl, 1,2- Dihydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H- Pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, pyrimidinyl or 1,2,3,4- Tetrahydroquinolyl, wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, cyano, methoxy, trifluoromethyl, ethoxycarbonyl, carboxy , N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl) An aminocarbonyl group, (1-methylpyrazin-4-yl)carbonyl, pendant oxy, methyl, ethyl or butoxycarbonyl; and pharmaceutically acceptable salts thereof.

在另一實施例中，G為C-Q；Q為-L-R5；P為H；且R5為2-甲基-3-吡啶基、2-乙基-3-吡啶基、2,6-二甲基-3-吡啶基、2-氰基-3-吡啶基、3-氯-4-氰基-5-吡啶基、1,3,5-三甲基-4-吡唑基、1,3,4-三甲基-5-吡唑基、1-乙基-5-吡唑基、苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基-5-乙氧基羰基苯基、2-乙基苯基、2-甲基-5-羧基苯基、3-氯-2-氰基苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、苄基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、喹喏啉-5-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4- 基、1-甲基-1H-吲唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、4-氯-5-甲基-6-嘧啶基或5,6,7,8-四氫喹啉-5-基；及其醫藥學上可接受之鹽。 In another embodiment, G is CQ; Q is -LR 5 ; P is H; and R 5 is 2-methyl-3-pyridyl, 2-ethyl-3-pyridyl, 2,6-di Methyl-3-pyridyl, 2-cyano-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 1,3,5-trimethyl-4-pyrazolyl, 1, 3,4-Trimethyl-5-pyrazolyl, 1-ethyl-5-pyrazolyl, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorobenzene Base, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4- Difluoro-3-methoxyphenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-6-fluorophenyl, 3 -chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyl -5-ethoxycarbonylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl, 3-chloro-2-cyanophenyl, 2-methyl-5-[N-( Methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5 -[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, Benzyl, 5-quinolyl, 6-quinoline , 7-quinolyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, quin Porphyrin-5-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, [ 1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl -2-Sideoxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1, 4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl-1 -Sideoxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6- ,5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl- 2-Phenoxy-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1 , 2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 1-methyl-1H-pyrazole [3,4-b]pyridin-3-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H- Imidazo[4,5-b]pyridine-6-yl, 4-chloro 5-5-methyl-6-pyrimidinyl or 5,6,7,8-tetrahydroquinolin-5-yl; and pharmaceutically acceptable salts thereof.

本發明之另一態樣係關於具有式IIa及式IIb之通式結構的化合物： 其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧 基或鹵基之取代基取代；R3為H、鹵基、鹵烷基、烷氧基羰基、胺基羰基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-C1-6烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、RR'N-、RR'N-C1-6烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'獨立地為H、烷基、芳基、雜環基、雜環基烷基或環烷基(其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代)；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、 鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；L為O、S、CH2或CH2O；Q為-L-R5；且P為-L-R6；其限制條件為，當R3為H，R1為甲基，且L為O時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，L為O，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，L為O，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，L為O，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，且R3為2-吡啶硫基、溴、甲氧基乙氧基 或三氟甲基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基，L為O，且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基；及其醫藥學上可接受之鹽。 Another aspect of the invention pertains to compounds having the general structure of formula IIa and formula IIb: Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or substituted by one or two independently selected from hydroxy, alkoxy, alkyl, pendant or halo groups. Substituent; R 3 is H, halo, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or -S ( O)n; n is 0, 1 or 2; R 4 is alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkenyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl , alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, aralkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, ring An alkylalkynyl, heterocyclylalkyl or heterocyclylcarbonylalkyl group; wherein the ring in R 4 is 1-3 independent Substituted with a substituent selected from the group consisting of H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, fluorenyl, alkylsulfonyl, heterocyclyl, aminosulfonyl , alkylaminosulfonyl, cyano, alkoxycarbonyl, carboxyl, amine, RR'NC 1-6 alkyl, alkoxyalkyl, hydroxyalkyl or R a R b NC(=O) Wherein R a is alkyl and R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a and R b together with nitrogen form unsubstituted or alkyl a substituted heterocyclic ring; R 5 is aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclyl, wherein R 5 is unsubstituted or substituted with from 1 to 3 substituents independently selected from : alkyl, alkoxy, hydroxy, halo, haloalkyl, cyano, alkoxycarbonyl, carboxy, fluorenyl, cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, side oxygen a radical, RR'N-, RR'NC 1-6 alkyl or R a R b NC(=O), wherein R a is alkyl and R b is alkoxyalkyl or aminoalkyl; R' is independently H, alkyl, aryl, heterocyclic, heterocyclylalkyl or cycloalkyl (wherein the heterocyclylalkyl, ring And the heterocyclyl ring are unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, cyano or carboxy; or R' and R The heterocyclic group may be formed together with N; R 6 is an aryl group, an aralkyl group, a heterocyclic group, a heterocyclic alkyl group or a cycloalkyl group, wherein each of the aforementioned rings is unsubstituted or independently selected from 1 to 4 Substituted for the following: alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, cyano, cycloalkyl, heterocyclyl, hydroxyalkyl , alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; L is O, S, CH 2 or CH 2 O; Q is -LR 5 ; and P is -LR 6 ; The limitation is that when R 3 is H, R 1 is a methyl group, and L is O, then R 5 is not a [1,2,4]triazolo[4,3-a]pyridine-8-yl group, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinolin-6-yl, 2-side Oxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxooxy -1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5- Chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are When R 3 is Br, L is O, and R 1 is a methyl group, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5, 7-Difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl-1-yloxy-1,2-di Hydrogen-isoquinolin-6-yl; other restrictions: when R 3 is 1-methyl-1H-pyrazol-4-yl, L is O, and R 1 is methyl, then R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions: when R 3 is 1-methyl-1H-pyrazol-5-yl, L is O, and R 1 is methyl, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo- 1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl; other restrictions are, when L is O, R 6 is 2-ethyl-3-pyridyl, 3-pyridyl or 2-methyl-2,6-di 3-pyridyl group, and R 3 is 2-pyridyl group, bromo, methoxy, ethoxy or trifluoromethyl when, R 1 is not phenyl or tert-butyl; additional proviso that when R 3 is 2-pyridylthio, L is O, and when R 6 is 2-ethyl-3-pyridyl, R 1 is not 4-methyl-2-imidazolylmethyl; and pharmaceutically acceptable Accept the salt.

本發明之另一態樣係關於具有式III之通式結構的化合物： Another aspect of the invention pertains to compounds having the general structure of formula III:

其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、鹵基、C1-6鹵烷基、C1-6烷氧基羰基、胺基羰基、C1-6烷基、C1-6羥基烷基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、胺基磺醯基、C1-6烷基胺基磺醯 基、氰基、羧基、RR'N-C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)-，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5-6員雜環；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、氰基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、C1-6烷基-NRR'、胺基磺醯基、C1-6烷基胺基磺醯基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基(其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基取代)；或R'及R可與N一起形成5-10員雜環基；且其中R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員 含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基；及其醫藥學上可接受之鹽。 Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 alkyl, 5-10 membered heterocyclic or 5-10 membered heterocyclyl-C 1-6 alkyl, wherein the aryl or hetero The cyclo ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant oxy or halo; wherein R 3 is -XR 4 , halo, C 1- 6 haloalkyl, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 1-6 alkoxycarbonyl-C 1-6 alkane , C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic ring , C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 naphthenic -C 1-6 alkyl group, C 3-6 cycloalkyl, -C 2-6 alkenyl, C 3-6 alkynyl -C 2-6 cycloalkyl group, a heterocyclic -C 1-6 alkyl group or a 4-10 membered heterocyclic carbonyl group -C 1-6 alkyl; wherein R 3 is of the aryl group, cycloalkyl, cycloalkenyl or heterocyclyl ring is unsubstituted or 1-3 substituents independently selected from the group consisting of C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, aminosulfonyl, C 1-6 Alkylaminosulfonyl, cyano, carboxyl, RR'NC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl or R a R b NC (=O)-, wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl Or a C 1-6 alkyl-C 1-6 aminoalkyl group, or a 5-6 member heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein X Is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1- 6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl , aminocarbonyl -C 1-6 alkyl, C 1-6 alkylamine -C 1-6 alkyl-carbonyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 membered heterocyclyl, C 6-10 aryl group -C 1- 6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3- 6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl -C 1-6 alkyl; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 4 is unsubstituted or substituted with from 1 to 3 substituents independently selected from: C 1 -6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy a carbonyl group, a carboxyl group, 5-16 membered heterocyclyl, cyano, amino, C 1-6 aminoalkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 alkyl-NRR', aminosulfonyl, C 1-6 alkylaminosulfonyl or R a R b NC(=O), wherein R a Is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C a 1-6 aminoalkyl group, or wherein R a and R b together with a nitrogen form an unsubstituted or substituted C 1-6 alkyl group a 5- or 6-membered heterocyclic ring; wherein R and R' are independently H, C 1-6 alkyl, phenyl, 5-10 membered heterocyclyl, 5-10 membered heterocyclyl-C 1-6 alkyl or C 3-6 cycloalkyl (wherein the heterocyclyl-C 1-6 alkyl, phenyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl ring are unsubstituted or via C 1-6 An alkyl group, a C 1-6 alkoxy group, a hydroxyl group, a halogen group, a C 1-6 haloalkyl group, a cyano group or a carboxy group); or R' and R together with N form a 5-10 membered heterocyclic group; Wherein R 6 is a 5-membered nitrogen-containing heterocyclic group, a 5-membered oxygen-containing heterocyclic group, a 6-membered nitrogen-containing heterocyclic group, a 6-membered oxygen-containing heterocyclic group, a phenyl group, a benzyl group, and a 9-membered bicyclic nitrogen-containing heterocyclic group. a 10 membered bicyclic oxygen-containing heterocyclic group or a 10-membered bicyclic nitrogen-containing heterocyclic group wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano , halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; the limitation is When R 3 is 2-pyridylthio, bromo, methoxyethoxy or trifluoro Methyl, and when R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridinyl, R 1 is not phenyl or the third Butyl; other restrictions: when R 3 is 2-pyridylthio and R 6 is 2-ethyl-3-pyridyl, R 1 is not 4-methyl-2-imidazolylmethyl; A pharmaceutically acceptable salt.

在另一實施例中，R1為甲基、乙基、丙基、烯丙基、第三丁基、三氟-乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、羥基乙氧基乙基、BOC-胺基乙基、胺基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、苯乙基、嗎啉-4-基乙基、2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑-5-基甲基、1-甲基-咪唑-4-基甲基、1-甲基-咪唑-5-基甲基、4-甲基-咪唑-2-基甲基、5-甲基-咪唑-2-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑基-5-甲基、5-甲基-異噁唑-3-基甲基或苯基；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is methyl, ethyl, propyl, allyl, tert-butyl, trifluoro-ethyl, methoxy, methoxyethyl, hydroxyethyl, hydroxypropyl Base, 2,3-dihydroxypropyl, hydroxyethoxyethyl, BOC-aminoethyl, aminoethyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxy- Phenylmethyl, 4-fluorophenylmethyl, phenethyl, morpholin-4-ylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 6-A 2-yloxy-1,2-dihydropyridylmethyl, imidazolyl-5-ylmethyl, 1-methyl-imidazol-4-ylmethyl, 1-methyl-imidazole-5-yl Methyl, 4-methyl-imidazol-2-ylmethyl, 5-methyl-imidazol-2-ylmethyl, 1,5-dimethylpyrazol-4-ylmethyl, 2-methylthiazole 5-methyl, 5-methyl-isoxazol-3-ylmethyl or phenyl; and pharmaceutically acceptable salts thereof.

在另一實施例中，R1為甲基或乙基；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is methyl or ethyl; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為-SR4；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is -SR 4 ; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、4-甲氧基-2-甲基-丁-2-基硫基、4-羥基-2-甲基-丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、 羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、(4-哌啶基)硫基、(1-異丙基哌啶-4-基)硫基、(1-甲基羰基哌啶-4-基)硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, 4-methoxy 2-methyl-butan-2-ylthio, 4-hydroxy-2-methyl-butan-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutylthio, carboxyethylsulfide , (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl)thio, (2-hydroxy-2-methylbutyl) Thio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1-tert-butoxycarbonylpiperidin-4- Methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(tetrahydro-2H-pyran-4-yl) Sulfuryl, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylthio, 4-hydroxycyclohexylthio, cyclopentyl Alkenylthio, phenylthio, benzylthio, 2-pyridylthio, (4-piperidinyl)thio, (1-isopropylpiperidin-4-yl)thio, (1-methyl Carbopiperidin-4-yl)thio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1 -isopropyl carbonyl (piperidin-4-ylthio), 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1- (5-chloropyrimidin-2-yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazine-2) -yl)piperidin-4-yl)thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridine-4 a thiol group or a tetrahydro-2H-piperidin-4-ylthio group; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為溴、甲基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、羥基乙基、羥基丁基、2-羥基-2-甲基丁基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基丙烯-1-基、5-甲氧基戊炔-1-基、乙氧基羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、乙氧基羰基乙基、乙氧基羰基丙基、乙氧基羰基丁基、羧基丙基、4,5-二羥基戊基、丙烯-2-基、4-羥基丁炔-1-基、4-甲氧基丁炔-1-基、2-環丙基乙烯基、2-乙氧基乙烯基、3,3-二甲基丁烯-1-基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、4-哌啶基甲基、嗎啉-4-基甲基、四氫哌喃-4-基甲基、四氫哌喃- 4-基乙基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、環己基甲基、環己基乙基、環丙基、環己基、環戊基、環庚基、環戊烯基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、環庚烯基，四氫哌喃-4-基、3,6-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-(第三丁氧基羰基)-5,6-二氫-2H-吡啶-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基、1-(N,N-二甲基胺基羰基)-5,6-二氫-2H-吡啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、1-羥基乙基-4-吡唑基、1-甲氧基乙基-4-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、2,4-二甲基-5-噻唑基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、 3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、吡嗪-2-基、噠嗪-4-基、3-苯并噻吩基、咪唑并[1,2-a]吡啶-3-基或2-甲基苯并噁唑-5-基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is bromo, methyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methylbutyl, trifluoromethyl, hydroxyethyl Base, hydroxybutyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, methoxy Propyl, methoxybutyl, methoxypentyl, methoxypropen-1-yl, 5-methoxypentyn-1-yl, ethoxycarbonyl, N-methyl-N- (A Oxyethyl)aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl , carboxypropyl, 4,5-dihydroxypentyl, propen-2-yl, 4-hydroxybutyn-1-yl, 4-methoxybutyn-1-yl, 2-cyclopropylvinyl, 2-ethoxyvinyl, 3,3-dimethylbuten-1-yl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy- 2-phenylethyl, phenylvinyl, 1-phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 4-piperidylmethyl, morpholin-4-ylmethyl, tetra Hydropyran-4-ylmethyl, tetrahydropyran-4-ylethyl, 3-(2,2-dimethyl- 1,3-Dioxalan-4-yl)propyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclopentenyl, cyclohexyl Alkenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, cycloheptenyl, tetrahydropyran-4-yl, 3,6-dihydropyran 4-yl, 1,4-dioxaspiro[4.5]dec-7-ene-8-yl, 1,1-dioxoisyltetrahydro-2H-thiopiperazin-4-yl, 1- (t-butoxycarbonyl)-5,6-dihydro-2H-pyridin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1 -methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(Methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1 a -butoxycarbonyl-piperidin-4-yl group, 1-(dimethylaminocarbonyl)-piperidin-4-yl, 1-(N,N-dimethylaminocarbonyl)-5, 6-Dihydro-2H-pyridin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-trifluoro Methylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 2-methylsulfonylphenyl, 3-methyl Nonylphenyl, 4-methylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonylaminophenyl, 3-methylaminosulfonylphenyl , 3-cyanophenyl, 4-cyanophenyl, 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl) Phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-difluoromethoxyphenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorobenzene , 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 5-benzodioxolyl, 1-methyl-3 -pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl 4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-methoxyethyl-4-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl 5-pyrazolyl, 2,4-dimethyl-5-thiazolyl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 2-pyridine , 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-trifluoromethyl-5 -pyridyl, 2-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridine , 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 5-fluoro-2-methoxy-4-pyridyl, 3-fluoro-4-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy-4-pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5- Pyridyl, 2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2 -cyano-5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 3-methylsulfonate Mercapto-5-pyridyl, 2-oxo-1,2-dihydropyridin-3-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 5-pyrimidinyl, 2 -amino-5-pyrimidinyl, 2-cyano-5-pyrimidinyl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, imidazo[1,2-a]pyridine 3-yl or 2-methylbenzoxazol-5-yl; and pharmaceutically acceptable salts thereof.

在另一實施例中，其中R6為四氫呋喃基、四氫哌喃基、3,4-二氫-2H-哌喃并[3,2-c]吡啶基、烷基、吡咯啶基、哌啶基、吡啶基、吡唑基、苯基、苄基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、6,7-二氫-5H-環戊烷并[b]吡啶基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基或嘧啶基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 In another embodiment, wherein R 6 is tetrahydrofuranyl, tetrahydropyranyl, 3,4-dihydro-2H-piperido[3,2-c]pyridinyl, Alkyl, pyrrolidinyl, piperidinyl, pyridyl, pyrazolyl, phenyl, benzyl, quinolyl, 1,2-dihydroquinolinyl, 5,6,7,8-tetrahydroquinoline , quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 6,7-dihydro -5H-cyclopenta[b]pyridinyl, 1H-pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a a pyridyl or pyrimidinyl group, wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl , ethoxycarbonyl, tert-butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N- (Methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof.

在另一實施例中，R6為2-甲基-3-吡啶基、2-乙基-3-吡啶基、2-氰基-3-吡啶基、3-氯-4-氰基-5-吡啶基，1,3,5-三甲基-4-吡唑基、1,3,4-三甲基-5-吡唑基、1-乙基-5-吡唑基、1-乙基-4-氯-5-吡唑基，四氫呋喃-3-基、1-BOC-吡咯啶-3-基、四氫-2H-哌喃-4-基、3-氟- 四氫-2H-哌喃-4-基、3-甲基-四氫-2H-哌喃-4-基、3-乙基-四氫-2H-哌喃-4-基、1-第三丁氧基羰基哌啶-4-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基-5-乙氧基羰基苯基、2-乙基苯基、2-甲基-5-羧基苯基、3-氯-2-氰基苯基、2-氰基-6-三氟甲基苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、苄基，3-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、5,6,7,8-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、喹喏啉-5-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-4-基、1-甲基-1H-吲唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、6,7-二氫-5H-環戊烷并[b]吡啶-5-基、烷-4-基、3,4-二氫-2H-哌喃并[3,2-c]吡啶-4-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基或4-氯-5-甲基-6-嘧啶基；及其醫藥 學上可接受之鹽。 In another embodiment, R 6 is 2-methyl-3-pyridyl, 2-ethyl-3-pyridyl, 2-cyano-3-pyridyl, 3-chloro-4-cyano-5 -pyridyl, 1,3,5-trimethyl-4-pyrazolyl, 1,3,4-trimethyl-5-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-B 4-chloro-5-pyrazolyl, tetrahydrofuran-3-yl, 1-BOC-pyrrolidin-3-yl, tetrahydro-2H-pyran-4-yl, 3-fluoro-tetrahydro-2H- Piperazin-4-yl, 3-methyl-tetrahydro-2H-piperidin-4-yl, 3-ethyl-tetrahydro-2H-pyran-4-yl, 1-tert-butoxycarbonylpipe Pyridin-4-yl, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluoro Phenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 2,6-dichlorophenyl , 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethyl Phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-ethylphenyl, 2- Methyl-5-carboxyphenyl, 3-chloro-2-cyanophenyl, 2-cyano-6-trifluoromethylphenyl, 2-methyl-5-[N-(methyl)-N -(methoxyethyl)amino group Phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylamine Ethylethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, benzyl, 3-quinolinyl, 5-quinolinyl, 6-quinolyl, 7-quinolyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 6,6-di Methyl-5,6,7,8-tetrahydroquinolin-5-yl, quinoxalin-5-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H-indole Zin-4-yl, 1-methyl-1H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, [1,2,4]triazolo[4,3-a Pyridine-8-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl, Alkyl-4-yl, 3,4-dihydro-2H-piperazino[3,2-c]pyridin-4-yl, 1-methyl-2-oxooxy-1,2-dihydroquinoline -6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxo-1,2-dihydro Quinoline-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinoline-6 -yl, 2-methyl-1-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7 -difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl Keto-2-oxo-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 1 -methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridine-6- A 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl or 4-chloro-5-methyl-6-pyrimidinyl group; and a pharmaceutically acceptable salt thereof.

本發明之另一態樣係關於具有式IV之通式結構的化合物： Another aspect of the invention pertains to compounds having the general structure of formula IV:

其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基-C1-6烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、C1-6鹵烷基、C1-6烷氧基羰基、胺基羰基、C1-6烷基、C1-6羥基烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、雜環基-C1-6烷基、C2-6羥基炔基、C1-6烷氧基-C2-6炔基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中 Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基(其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之取代基取代)；或R'及R可與N一起形成5-10員雜環基；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、胺基磺醯基、C1-6烷基胺基磺醯基、C1-6烷氧基羰基、羧基、氰基、5-16員雜環基、胺基、RR'N-C1-6烷基-、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；且其中R5為5員含氮雜環基、6員含氮雜環基、苯基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基 羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為H，R1為甲基時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；及其醫藥學上可接受之鹽。 Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1 a -6 alkyl group, a C 6-10 aryl group, a C 6-10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group-C 1-6 alkyl group, wherein The aryl or heterocyclyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant or halo; wherein R 3 is -XR 4 , H , halo, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1 -6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1 -6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, heterocyclyl-C 1- 6 alkyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 2-6 alkynyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3 -6 cycloalkyl-C 2-6 alkynyl, 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 Substituted unsubstituted or substituted with 1-3 substituents independently selected from: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1- 6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, C 1-6 aminoalkyl, C 1-6 alkane Oxy-C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, RR 'NC 1-6 alkyl-, aminosulfonyl, C 1-6 alkylamine Sulfosyl, cyano or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1- a 6 alkyl group, a C 1-6 aminoalkyl group or a C 1-6 alkyl-C 1-6 aminoalkyl group, or wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkane a 5- or 6-membered heterocyclic ring substituted; wherein R and R' are independently H, C 1-6 alkyl, phenyl, 5-10 membered heterocyclic, 5-10 membered heterocyclyl-C 1-6 An alkyl group or a C 3-6 cycloalkyl group (wherein the heterocyclic group -C 1-6 alkyl group, phenyl group, C 3-6 cycloalkyl group and 5-10 membered heterocyclyl ring are unsubstituted or subjected to 1 -3 substituents independently selected from C 1-6 alkoxy , C 1-6 alkoxy, hydroxy, halo, C 1-6 haloalkyl, cyano or carboxyl substituents); or R 'and R may form a 5-10 membered heterocyclic group together with N; Wherein X is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl -C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 membered heterocyclic, C 6-10 aryl-C 1-6 Alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 Cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl- C 1-6 alkyl; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 4 is unsubstituted or substituted with from 1 to 3 substituents independently selected from: C 1- 6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl , acyl group sulfo, C 1-6 alkyl sulfonic acyl group, C 1-6 alkoxy, Group, carboxy, cyano, 5-16 membered heterocyclyl, amino, RR'NC 1-6 alkyl -, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 hydroxyalkyl Or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1- 6 aminoalkyl or C 1-6 alkyl-C 1-6 aminoalkyl, or 5 or 6 members wherein R a and R b together with nitrogen form unsubstituted or substituted C 1-6 alkyl a heterocyclic ring; and wherein R 5 is a 5-membered nitrogen-containing heterocyclic group, a 6-membered nitrogen-containing heterocyclic group, a phenyl group, a 9-membered nitrogen-containing heterocyclic group or a 10-membered nitrogen-containing heterocyclic group, wherein R 5 is unsubstituted or Substituted by one or more substituents independently selected from C 1-6 alkyl, cyano, halo, pendant oxy, hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1 -6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; the limitation is that when R 3 is H and R 1 is methyl, then R 5 is not [ 1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, isoquinoline-5 - base, different Quinoline-6-yl, quinoline-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxo-1,2-dihydro Quinoline-6-yl, 2-methyl-1-oxooxy-1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-di Methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5- b] Pyridin-6-yl; other restrictions are, when R 3 is Br and R 1 is methyl, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2 -Sideoxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquine Polin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl or 2-methyl-1-side Oxy-1,2-dihydro-isoquinolin-6-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazol-4-yl and R 1 is methyl R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are, when R 3 is 1-methyl-1H-pyrazol-5-yl, and R 1 is methyl, then R 5 is not methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl, 5,7-difluoro-1,4 Methyl-2-oxo-1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl; Its pharmaceutically acceptable salt.

在另一實施例中，R1為甲基、乙基、丙基、烯丙基、三氟-乙基、甲氧基乙基、羥基乙基、羥基丙基、羥基乙氧基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、嗎啉-4-基乙基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑基甲基、1-甲基-咪唑基甲基、2-甲基噻唑基甲基或5-甲基-異噁唑基甲基；及其醫藥學上可接受之鹽。 In another embodiment, R 1 is methyl, ethyl, propyl, allyl, trifluoro-ethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, hydroxyethoxyethyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, morpholin-4-ylethyl, pyridylmethyl, 6-A 2-yloxy-1,2-dihydropyridylmethyl, imidazolylmethyl, 1-methyl-imidazolylmethyl, 2-methylthiazolylmethyl or 5-methyl-isoxan Zozolylmethyl; and pharmaceutically acceptable salts thereof.

在另一實施例中，其中R1為甲基或乙基；及其醫藥學上可接受之 鹽。 In another embodiment, wherein R 1 is methyl or ethyl; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為-SR4；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is -SR 4 ; and a pharmaceutically acceptable salt thereof.

在另一實施例中，R3為甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio , 3,4-dihydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl) a thio group, (2-hydroxy-2-methylbutyl)thio group, (4-methylpiperazin-1-yl)-carbonylmethylthio group, (morpholin-4-yl)carbonylmethylthio group, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1- (tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentane Thiothio, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, (4-piperidinyl)thio, (1-isopropyl) Piperidin-4-ylthio, (1-methylcarbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl) Mercapto)piperidin-4-ylthio, (1-isopropylcarbonyl)piperidin-4-ylthio, 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1- ( Oxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4- Thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3- Methyl isoxazolo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-piperidin-4-ylthio; and pharmaceutically acceptable salts thereof.

在另一實施例中，R3為溴、甲基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、羥基乙基、羥基丁基、2-羥基-2-甲基丁基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基丙烯-1-基、甲氧基戊炔-1-基、乙氧基羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、乙氧基羰基丙基、羧基丙基、4,5-二羥基戊基、丙烯-2-基、羥基丁炔基、2-環丙基乙烯基、2-乙氧基乙烯基、3,3-二甲基丁烯-1-基、1-(1-羥基環戊基)乙炔基、苯基乙 基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、4-哌啶基甲基、嗎啉-4-基甲基、四氫哌喃-4-基甲基、四氫哌喃-4-基乙基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、環己基甲基、環己基乙基、環丙基、環己基、環戊基、環庚基、環戊烯基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、環庚烯基，四氫哌喃-4-基、3,6-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、3-環丁基-4-吡唑基、1-羥基乙基-4-吡唑基、1-甲氧基乙基-4-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、2,4-二甲基-5-噻唑基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡 啶基、2-甲基-3-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、吡嗪-2-基、噠嗪-4-基、3-苯并噻吩基、咪唑并[1,2-a]吡啶基或2-甲基苯并噁唑-5-基；及其醫藥學上可接受之鹽。 In another embodiment, R 3 is bromo, methyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methylbutyl, trifluoromethyl, hydroxyethyl Base, hydroxybutyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, methoxy Propyl, methoxybutyl, methoxypentyl, methoxypropen-1-yl, methoxypentyn-1-yl, ethoxycarbonyl, N-methyl-N-(methoxy Ethyl)aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, ethoxycarbonylpropyl, carboxypropyl, 4,5-dihydroxypentyl, propylene- 2-yl, hydroxybutynyl, 2-cyclopropylvinyl, 2-ethoxyvinyl, 3,3-dimethylbuten-1-yl, 1-(1-hydroxycyclopentyl)acetylene Base, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1-phenylvinyl, benzene Ethyl ethynyl, pyridin-2-ylmethyl, 4-piperidylmethyl, morpholin-4-ylmethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylethyl , 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl, cyclohexyl , cyclohexylethyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, cyclopentenyl, cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-third -cyclohexenyl, cycloheptenyl, tetrahydropyran-4-yl, 3,6-dihydropyran-4-yl, 1,4-dioxaspiro[4.5]indole-7-ene -8-yl, 1,1-dioxy-ionic tetrahydro-2H-thiopiperazin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4- 1,1-methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridine-4 -yl, 1-(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridine-4- , 1-tert-butoxycarbonyl-piperidin-4-yl, 1-(dimethylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylbenzene Base, 4-methylphenyl, 2,4-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylbenzene Base, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonyl Aminophenyl, 3-methylaminosulfonylphenyl, 3-cyanophenyl, 4-cyano Phenyl, 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-difluoromethoxyphenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2, 4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4- Pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro- Ethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-methoxyethyl-4-pyrazolyl, 1-methyl 5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 2,4-dimethyl-5-thiazolyl, 1-methyl-5-imidazolyl, 3,5-di Methyl-isoxazol-4-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-4-pyridyl, 2-methyl 3-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3 -pyridyl, 2-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 5-fluoro-2-methoxy-4- Pyridyl, 3-fluoro-4-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy-4-pyridyl, 2-methoxy-5-pyridyl, 3-methoxy 5-5-pyridyl, 2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridine , 2-cyano-5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 3- Methylsulfonyl-5-pyridyl, 2-oxooxy-1,2-dihydropyridin-3-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 5-pyrimidine , 2-amino-5-pyrimidinyl, 2-cyano-5-pyrimidinyl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, imidazo[1,2- a] pyridyl or 2-methylbenzoxazol-5-yl; and pharmaceutically acceptable salts thereof.

在另一實施例中，R5為吡啶基、吡唑基、苯基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基或嘧啶基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 In another embodiment, R 5 is pyridyl, pyrazolyl, phenyl, quinolinyl, 1,2-dihydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl, quinacrid Lolinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[3,4- b] pyridyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-a]pyridinyl or pyrimidinyl, wherein R 5 is unsubstituted or independently selected from one or more Substituted by the following substituents: methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, ethoxycarbonyl, butoxycarbonyl, carboxy, N-(methyl)-N-( Methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyridyl) Carbazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof.

在另一實施例中，R5為2-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2-乙基-3-吡啶基、2-氰基-3-吡啶基、3-氯-4-氰基-5-吡啶基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟- 3-甲氧基苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基-5-乙氧基羰基苯基、2-乙基苯基、2-甲基-5-羧基苯基、3-氯-2-氰基苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、5,6,7,8-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、喹喏啉-5-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基或4-氯-5-甲基-6-嘧啶基；及其醫藥學上可接受之鹽。 In another embodiment, R 5 is 2-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 2-cyano-3- Pyridyl, 3-chloro-4-cyano-5-pyridyl, 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, phenyl, 2,6 -difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3- Chloro-2-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-methoxyphenyl, 2 -methoxyphenyl, 4-methoxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl, 3-chloro 2-cyanophenyl, 2-methyl-5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N, N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl- 5-(1-methylpyrazin-4-yl)carbonyl)phenyl, 5-quinolyl, 6-quinolinyl, 7-quinolyl, 8-quinolinyl, 5-chloro-6-quinaline Lolinyl, 5,6,7,8-tetrahydrogen啉-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, quinoxalin-5-yl, 3-methyl-1H-indazole-4 -yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, [1,2,4]triazolo[4,3-a]pyridine- 8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6- , 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydro Quinoline-6-yl, 2-oxo-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxo-1,2-dihydroquinolin-6-yl, 5,7-Difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl -2-Sideoxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-di Hydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl , 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, imidazo[1, 2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl or 4-chloro -5-methyl-6-pyrimidinyl; and its medicinal Acceptance of salt.

本發明之另一態樣係關於具有式Ia之通式結構的化合物： 其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基或鹵基之取代基取代；R2為H、烷基或鹵基；R3為H、鹵基、烷氧基羰基、胺基羰基、氰基、氰基烷基、烷基羰基、雜環基羰基、烷基胺基羰基、烯基、炔基、羥基烯基、烷氧基烷氧基烷基、芳氧基烯基、烷氧基羰基烷基、烷基磺醯基烷基、烷基磺醯基烯基、烷基磺醯基炔基、雜環基炔基、雜環基羰基烷基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、鹵烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環未經取代或經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環基環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經 取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、-NRR'、烷基-NRR'或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；G為C-Q或N；L為O、S、CH2或CH2O；Q為H或-L-R5；且P為H或-L-R6；其限制條件為：(i)當Q為H時，則P為-L-R6，或(ii)當Q為-L-R5時，則P為H；(iii)當G為N時，則P為-L-R6；其他限制條件為，當R3為H，R1為甲基，R2為H，L為O，且P為H時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2- 二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，R1為甲基，R2為H，L為O，且P為H時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當R3為H，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為鹵基；其他限制條件為，當R3為溴，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為氯；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，R2為H，R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且G為CH時，R1不為苯基或第三丁基；其他限制條件為，當R2為H，R3為2-吡啶硫基，P為2-乙基-3-吡啶氧基，且G為CH時，R1不為4-甲基-2-咪唑基甲基；其他限制條件為，當R1為甲基，R2為H，G為N，且P為2-甲基-3-吡啶氧基時，R3不為4-甲基苯基或2,4-二甲基苯基或1,2-二羥基-2-苯基乙基； 及其醫藥學上可接受之鹽。 Another aspect of the invention pertains to compounds having the general structure of formula Ia: Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or substituted by one or two independently selected from hydroxy, alkoxy, alkyl, pendant or halo groups. Substituent; R 2 is H, alkyl or halo; R 3 is H, halo, alkoxycarbonyl, aminocarbonyl, cyano, cyanoalkyl, alkylcarbonyl, heterocyclylcarbonyl, alkyl Aminocarbonyl, alkenyl, alkynyl, hydroxyalkenyl, alkoxyalkoxyalkyl, aryloxyalkenyl, alkoxycarbonylalkyl, alkylsulfonylalkyl, alkylsulfonyl Alkyl, alkylsulfonylalkynyl, heterocyclylalkynyl, heterocyclylcarbonylalkyl, alkoxyalkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or -S(O ) n; n is 0, 1 or 2; R 4 is an alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl , alkoxyalkenyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl , aralkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl or heterocyclylcarbonylalkyl; wherein the ring in R 4 is unsubstituted Or substituted with 1-3 substituents independently selected from the group consisting of H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, decyl, alkylsulfonyl, heterocycle Base, aminosulfonyl, alkylaminosulfonyl, cyano, alkoxycarbonyl, carboxyl, amine, RR'N-alkyl, alkoxyalkyl, hydroxyalkyl or R a R b NC(=O), wherein R a is alkyl and R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a and R b are formed together with nitrogen a substituted or alkyl-substituted heterocyclyl ring; R 5 is aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclyl, wherein R 5 is unsubstituted or 1-3 independently Substituted by a substituent selected from the group consisting of alkyl, alkoxy, hydroxy, halo, haloalkyl A cyano group, an alkoxycarbonyl group, a carboxyl group, acyl, cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, oxo, -NRR ', an alkyl group -NRR' or R a R b NC (=O), wherein R a is alkyl and R b is alkoxyalkyl or aminoalkyl; wherein R and R' are H, alkyl, aryl, heterocyclyl, heterocyclylalkyl or a cycloalkyl group, wherein the heterocyclylalkyl, cycloalkyl and heterocyclyl rings are unsubstituted or 1-3 independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, Substituted with a substituent of a cyano group or a carboxyl group; or R' and R may form a heterocyclic group together with N; R 6 is an aryl group, an aralkyl group, a heterocyclic group, a heterocyclic group alkyl group or a cycloalkyl group, wherein each of the foregoing The ring is unsubstituted or substituted with from 1 to 4 substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, Cyano, cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; G is CQ or N; L is O, S, CH 2 or CH 2 O; Q is H or -LR 5 ; and P is H or -LR 6 ; the limiting conditions are: (i) when Q is H, then P is - LR 6 , or (ii) when Q is -LR 5 , then P is H; (iii) when G is N, then P is -LR 6 ; other restrictions are, when R 3 is H, R 1 is Methyl, R 2 is H, L is O, and when P is H, then R 5 is not [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl- 2-sided oxy-1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6-yl, 2-sided oxy-1, 2-Dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxooxy-1,2- Dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2- side Oxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are, when R 3 is Br, R 1 is Methyl, R 2 is H, L is O, and when P is H, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxo-1,2- Dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7 -difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl-1-sidedoxy-1,2- Dihydro-isoquinolin-6-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazol-4-yl, R 1 is methyl, R 2 is H, L is O, and When P is H, then R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are, when R 3 is 1-methyl-1H-pyrazole-5-yl, R 1 is Methyl, R 2 is H, L is O, and when P is H, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5, 7-Difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxooxy-1,2- Dihydroquinolin-6-yl; other restrictions are: when R 3 is H, R 1 is methyl, L is O, P is H, and R 5 is 5-quinolyl, R 2 is not halogen Other restrictions: when R 3 is bromine, R 1 is methyl, L is O, P is H, and R 5 is 5-quinolyl, R 2 is not chlorine; other restrictions are when L is O, R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridyl, R 2 is H, and R 3 is 2- Pyridylthio, bromo, methoxyethoxy or trifluoromethyl, and when G is CH, R 1 is not phenyl or tert-butyl; other restrictions are, when R 2 is H, R 3 is 2-pyridylthio, P is 2-ethyl-3-pyridinyloxy And when G is CH, R 1 is not 4-methyl-2-imidazolylmethyl; other restrictions are: when R 1 is methyl, R 2 is H, G is N, and P is 2-A When 3-pyridyloxy, R 3 is not 4-methylphenyl or 2,4-dimethylphenyl or 1,2-dihydroxy-2-phenylethyl; and pharmaceutically acceptable Accept the salt.

在另一實施例中，R1為H、C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代。 In another embodiment, R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy alkoxy-C 1-6 alkyl, C 6-10 aryl, C 6- a 10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group-C 1-6 alkyl group, wherein the aryl or heterocyclic ring is unsubstituted or via one or Two substituents independently selected from C 1-6 alkyl, hydroxy, pendant oxy or halo are substituted.

在另一實施例中，R1為H、甲基、乙基、丙基、異丙基、第三丁基、烯丙基、三氟乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、胺基乙基、苯基、苯基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、4-甲基咪唑基甲基、咪唑基甲基、1-甲基-咪唑基甲基、1,5-二甲基吡唑基甲基、2-甲基噻唑基甲基、5-甲基-異噁唑基甲基、嗎啉-4-基乙基、嗎啉-4-基甲基、四氫哌喃乙基或四氫呋喃基乙基。 In another embodiment, R 1 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, allyl, trifluoroethyl, methoxy, methoxyethyl, hydroxy Ethyl, hydroxypropyl, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, aminoethyl, phenyl, phenylethyl, 2-hydroxyphenyl Methyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, pyridylmethyl, 6-methyl-2-oxo-1,2-dihydro Pyridylmethyl, 4-methylimidazolylmethyl, imidazolylmethyl, 1-methyl-imidazolylmethyl, 1,5-dimethylpyrazolylmethyl, 2-methylthiazolylmethyl , 5-methyl-isoxazolylmethyl, morpholin-4-ylethyl, morpholin-4-ylmethyl, tetrahydropyranylethyl or tetrahydrofuranylethyl.

在另一實施例中，R1為2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、4-甲基咪唑-2-基甲基、咪唑-5-基甲基、1-甲基咪唑-5-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑-5-基甲基、5-甲基異噁唑-3-基、6-甲基-2-側氧基-1,2-二氫吡啶-3-基甲基或嗎啉-4-基乙基。 In another embodiment, R 1 is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-methylimidazol-2-ylmethyl, imidazolium-5-ylmethyl , 1-methylimidazolium-5-ylmethyl, 1,5-dimethylpyrazol-4-ylmethyl, 2-methylthiazol-5-ylmethyl, 5-methylisoxazole-3 -yl, 6-methyl-2-oxooxy-1,2-dihydropyridin-3-ylmethyl or morpholin-4-ylethyl.

在另一實施例中，R1為甲基、乙基或羥基乙基。 In another embodiment, R 1 is methyl, ethyl or hydroxyethyl.

在另一實施例中，R2為H、甲基、氯或氟。 In another embodiment, R 2 is H, methyl, chloro or fluoro.

在另一實施例中，R2為H。 In another embodiment, R 2 is H.

在另一實施例中，R3為-S(O)nR4，且n為0、1或2。 In another embodiment, R 3 is -S(O) n R 4 and n is 0, 1, or 2.

在另一實施例中，R3為-SR4。 In another embodiment, R 3 is -SR 4 .

在另一實施例中，R3為-OR4。 In another embodiment, R 3 is -OR 4 .

在另一實施例中，R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷 基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C3-6環烷基-C1-6烷基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基或C1-6羥基烷基。 In another embodiment, R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1 -6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1 -6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 membered heterocyclic, C 6-10 Aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-6 alkyl, 5-10 membered heterocyclyl-C 1- a 6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 4 is unsubstituted or passed through 1-3 Substituted independently of the following substituents: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkane Sulfosyl, C 1-6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclyl, amine, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl Or C 1-6 hydroxyalkyl.

在另一實施例中，R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、 (1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基。 In another embodiment, R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2-di Hydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanylmethoxy , methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutylsulfur Base, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl)thio, (2-hydroxy- 2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1- Third butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(tetrahydrogen) -2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylthio , 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, 2-chloro- 4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidyl) Pyridin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-methylcarbonyl)piperidine 4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1-isopropyl Carbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylthio, 1-( Dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidine-4 -yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1 -(Tertibutoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-pyran-4 -ylthio.

在另一實施例中，R3為甲氧基丙基亞磺醯基、甲氧基丙基磺醯基、1-(第三丁氧基羰基)哌啶-4-基亞磺醯基、2-吡啶基亞磺醯基、1-(第三丁氧基羰基)哌啶-4-基磺醯基或2-吡啶基磺醯基。 In another embodiment, R 3 is methoxypropylsulfinyl, methoxypropylsulfonyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfinyl, 2-pyridylsulfinyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfonyl or 2-pyridylsulfonyl.

在另一實施例中，R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基或3-氧雜環丁烷基甲氧基。 In another embodiment, R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2-di Hydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy or 3-oxetanylmethoxy .

在另一實施例中，R3為甲氧基乙氧基或2-甲基-3-吡啶氧基。 In another embodiment, R 3 is methoxyethoxy or 2-methyl-3-pyridinyloxy.

在另一實施例中，R3為甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基) 哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基。 In another embodiment, R 3 is methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio , 3,4-dihydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl) Sulfuryl, (2-hydroxy-2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl) Carboxymethylthio, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-pyran-4-yl) Methylthio, 1-(tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3, 4-dihydroxycyclopentylthio, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, 2-chloro-4-pyridylthio, 4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidin-4-yl-2 -pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-methylcarbonyl)piperidin-4-ylthio 1-(Tertibutoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1-isopropylcarbonyl)piperidin-4- Thiothio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylthio, 1-(dimethylaminocarbonyl) Piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)thio, ( 1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1-(t-butoxy) Carbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-piperidin-4-ylthio.

在另一實施例中，R3為H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環。 In another embodiment, R 3 is H, halo, cyano, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl Carbonyl, 4-10 membered heterocyclylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Hydroxyalkyl, C 2-6 hydroxyalkenyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy -C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 Alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1 -6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 2-6 alkenyl, C 1-6 alkylsulfonyl-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic, C 6-10 aryl-C 1-6 alkyl , C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 naphthenic -C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl or 4-10 member heterocyclylcarbonyl -C 1-6 Group; wherein R 3 is of the aryl group, cycloalkyl, cycloalkenyl or heterocyclyl ring unsubstituted or substituted by 1-3 substituents independently selected from the substituents: C 1-6 alkyl, halo , C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5- 10 membered heterocyclic group, amino group, C 1-6 aminoalkyl group, C 1-6 alkoxy-C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 1-6 haloalkoxy group, RR'NC 1-6 alkyl-, aminosulfonyl, C 1-6 alkylaminosulfonyl, cyano or R a R b NC(=O), wherein R a is C 1-6 alkane group and R b is C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl -C 1-6 alkyl group A group, or wherein R a and R b together with a nitrogen form a 5- or 6-membered heterocyclic ring which is unsubstituted or substituted with a C 1-6 alkyl group.

在另一實施例中，R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三 氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、 嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基或環己基甲基。 In another embodiment, R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methyl Butyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2-hydroxyl -2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1,2- Dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxymethoxy Methyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, propylene- 2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy-2-methyl Propylene, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxyvinyl, 2- Hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxyethyl)aminocarbonyl , N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonylmethyl, ethoxycarbonyl Propyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, carboxyethyl, carboxypropyl Base, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxy-2-methyl Propoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyn-1-yl, cyclopentylene Methyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonylpropyl, methyl Mercaptobutyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1-phenylethylene , phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinylmethyl, 1-piperidyl Pyridylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-ylmethyl, 4- Methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1,1-dioxyl) Thiomorpholyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3-yl)methyl , tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran-3-ylmethyl , 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl, 1 , 3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]hept-1-yl Base, 2-oxa-6-azaspiro[3.3]hept-6-yl , 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy-cyclopentylmethyl, 1,1 - a di-oxy-cyclopentylpropyl group, a 1-(hydroxycyclopentyl)methyl group, a 1-(methoxycyclopentyl)methyl group, a 1-(methoxycyclopentyl)bromomethyl group, Cyclohexylmethyl or cyclohexylmethyl.

在另一實施例中，R3為環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基或1,4-二氧雜螺[4.5]癸-7-烯-7-基。 In another embodiment, R 3 is cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2-oxocyclobutyl, 3 -hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl)-cyclobutyl, 3-hydroxyl Methyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxymethylcyclopentyl, 4-hydroxyl Methylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-oxo-cyclopentyl, 3-oxo-cyclopentyl, 2-(N- Ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl, cycloheptyl, cyclopentenyl , 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentenyl, 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-side Oxy-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-en-1-yl, cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl -cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4-hydroxymethyl-cyclohexenyl, 4-(2-hydroxy-2-yl) Ethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-fluoro-azetidin-1- Cyclocarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl)cyclohexenyl, cycloheptenyl or 1,4-dioxaspiro[4.5 ] 癸-7-ene-7-yl.

在另一實施例中，R3為3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基或1-(二甲基胺基羰基)-哌啶-4-基。 In another embodiment, R 3 is 3-hydroxy-3-oxetanyl, 2-tetrahydro-furanyl, 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl- 2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3-tetrahydro-furanyl, 2-oxopyrrolidin-1-yl, tetrahydrogen Piperazin-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxyl Tetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydropyran-2-yl, 3,6-dihydropyran 4-yl, 3,6-dihydropentan-5-yl, 5,6-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-Dimethyl-3,6-dihydro-2H-piperidin-4-yl, 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl, 3, 4-2H-dihydropyran-4-yl, 1,4-dioxaspiro[4.5]decan-7-en-8-yl, 1,1-di-oxy-isothiazolidine-2-yl 1,1-Dioxylyltetrahydro-2H-thiopiperazin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1- Methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1 -(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(A Carbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl or 1-(dimethylaminocarbonyl)-piperidine- 4-based.

在另一實施例中，R3為苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N- 甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基或5-苯并二氧雜環戊烯基。 In another embodiment, R 3 is phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-trifluoromethylbenzene Base, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonylphenyl, 3 -methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonylamino Phenyl, 3-methylaminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6 -methoxyphenyl, 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(di Methylaminocarbonyl)phenyl, 4-(dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl 4-ethylaminocarbonylphenyl, 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N -Methylaminocarbonyl)phenyl, 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-benzene Base, 3-( N-methoxyethyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethyl Aminocarbonylphenyl, 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethyl Aminocarbonylphenyl, 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl- Phenyl, 1,2-dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-yl Carbonyl)phenyl, 3-(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl , 3-(4-morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methyl Oxyphenyl, 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonyl Phenyl, 4-methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3- Difluoromethoxy Phenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethyl Oxyphenyl or 5-benzodioxolyl.

在另一實施例中，R3為1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥 基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基或3-甲基-1,2,4-噁二唑-5-基。 In another embodiment, R 3 is 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 1,3, 5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2,2,2-trifluoroethyl ]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxycarbonylmethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-ring Butyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyrazolyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl 4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxyethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl , 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl-5-pyrazolyl, 3-methylaminocarbonyl-pyrazole-5-yl, 3- Dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyrazol-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2- Methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl 5-5-imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 1-methyl-triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxyl Propyl-triazine-4 -yl, 1-hydroxybutyl-triazin-4-yl, 2-cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophene -5-yl, 2-(N-methoxyethyl-N-methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophene-5 -yl, 2-(2-hydroxy-2-methylethyl)thiophen-5-yl or 3-methyl-1,2,4-oxadiazol-5-yl.

在另一實施例中，R3為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲 基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基或2-(1-咪唑基)吡啶-4-基。 In another embodiment, R 3 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5-pyridyl, 2-difluoromethyl-5-pyridyl , 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methyl Oxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2-methoxy-4-pyridyl, 3-fluoro-4- Pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy-4-pyridyl, 2-methoxy-5 -pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy-4-pyridyl, 5-fluoro-2-hydroxyethoxy 4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy-5-pyridyl, 2-ethoxy-5- Pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-(1,1,1-trifluoroethoxy)-5- Pyridyl, 2-cyclopropylmethoxy-5-pyridyl, 2-(Methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl, 2-fluoro-4 -pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano-5-pyridyl , 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5-pyridyl, 3- Cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2-sided oxy- 1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxooxy-1,2- Dihydropyridin-5-yl, 1-isopropyl-2-yloxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy-1,2-dihydro Pyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2-dihydropyridine-4 -yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl, 3-methylamine Carbocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl-5-pyridyl, 2- Sulfosylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonylaminoethylcarbonyl- 5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethylaminocarbonyl-5-pyridyl , 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4-pyridyl, 4-fluoro-2 Methylaminocarbonylamino-5-pyridyl or 2-(1-imidazolyl)pyridin-4-yl.

在另一實施例中，R3為5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基或噠嗪-4-基。 In another embodiment, R 3 is 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy 5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethoxy-5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl 4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylaminocarbonylpyrimidin-5-yl, pyrazin-2-yl or pyridazin-4-yl.

在另一實施例中，R3為3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧 基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基。 In another embodiment, R 3 is 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-sided oxy-dihydro-5-fluorenyl, 6-fluorenyl , 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6-fluorenyl, imidazo[1,2-a]pyridin-3-yl , imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, 1,1-di-oxy-2-methyl-3,4-di Hydrogen-2H-benzo[b][1,4,5]oxathiazolidine-8-yl, benzoxazol-5-yl, benzoxazol-6-yl, 1,1-dioxy 3-,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridin-8-yl, 4-methyl-5-oxooxy-3,4-dihydro Benzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazol-5-yl, 2-ethylbenzoxazol-5-yl, 2 -isopropyl benzoxazol-5-yl, 2-oxo-2(3H)-benzo[d]oxazol-5-yl, benzothiazol-5-yl, benzothiazole-6- Base, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5-oxazolyl, 1-methyl-6-carbazolyl, 2- Methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4-yl, 1,5-dimethyl-2,3-dihydro-1H -pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2-a 3-oxo-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2-methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2- b][1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzo [d][1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxazol-5-yl,[1,2,4] Triazolo[4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2, 4] Triazolo[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl.

在另一實施例中，R3為H或溴。 In another embodiment, R 3 is H or bromine.

在另一實施例中，G為CH；及其醫藥學上可接受之鹽。 In another embodiment, G is CH; and a pharmaceutically acceptable salt thereof.

在另一實施例中，G為C-Q；Q為H；且P為-L-R6。 In another embodiment, G is CQ; Q is H; and P is -LR 6.

在另一實施例中，R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基；其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基。 In another embodiment, R 6 is a 5-membered nitrogen-containing heterocyclic group, oxygen-containing heterocyclic five, six nitrogen-containing heterocyclic group, oxygen-containing 6-membered heterocyclic group, phenyl, benzyl, 9 Bicyclic nitrogen-containing heterocyclic group, 10-membered bicyclic oxygen-containing heterocyclic group or 10-membered bicyclic nitrogen-containing heterocyclic group; wherein R 6 is unsubstituted or substituted by one or more substituents independently selected from: C 1- 6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkane Aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic group] Carbonyl.

在另一實施例中，R6為四氫呋喃基、四氫哌喃基、3,4-二氫-2H-哌喃并[3,2-c]吡啶基、烷基、哌啶基、吡啶基、吡唑基、苯基、喹啉基、1,2-二氫喹啉基、吡咯啶基、苄基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基或嘧啶基；其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰 基、(1-甲基吡嗪-4-基)羰基或側氧基。 In another embodiment, R 6 is tetrahydrofuranyl, tetrahydropyranyl, 3,4-dihydro-2H-piperido[3,2-c]pyridinyl, Alkyl, piperidinyl, pyridyl, pyrazolyl, phenyl, quinolyl, 1,2-dihydroquinolyl, pyrrolidinyl, benzyl, 5,6,7,8-tetrahydroquinoline , quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[ 3,4-b]pyridyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-a]pyridinyl or pyrimidinyl; wherein R 6 is unsubstituted or via one or more Substituted independently of the following substituents: methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, ethoxycarbonyl, tert-butoxycarbonyl, carboxy, N-(A -N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl)aminocarbonyl, (1-Methylpyrazin-4-yl)carbonyl or pendant oxy group.

在另一實施例中，R6為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基或2,5-二側氧基-吡咯啶-1-基。 In another embodiment, R 6 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl, 1-Boc-piperidin-4-yl, hexahydrofuran [2,3-b]furan-3-yl or 2,5-di-oxy-pyrrolidin-1-yl.

在另一實施例中，R6為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧 基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基或3-(3-氟-5-甲氧基苯基)-5-吡啶基。 In another embodiment, R 6 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-di Methyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5 -dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl- 6-Methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2- Hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)- 3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoro Methyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridine , 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl , 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4- Pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3- Chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4- Fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine- 5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl-2-oxopyridine-5-yl, 2-methyl-6-oxopyridine 4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl Keto-6-oxypyridine-5-yl, 1-isopropyl-2-poxypyridin-5-yl, 1,2-dimethyl-6-oxo-pyridin-3-yl, 1 -methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl) -4-pyridyl , 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl or 3-(3-fluoro-5-methoxyphenyl )-5-pyridyl.

在另一實施例中，R6為5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基或噠嗪-3-基。 In another embodiment, R 6 is 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidine- 5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyridyl Pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl or pyridazin-3-yl.

在另一實施例中，R6為1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基或1-乙基四唑-2-基。 In another embodiment, R 6 is 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1 -ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1 Methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl or 1-ethyltetrazol-2-yl.

在另一實施例中，R6為苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基- 5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基或3-(2-甲基-1,2,4-噁二唑-3-基)苯基。 In another embodiment, R 6 is phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2, 5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorobenzene Base, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylbenzene , 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro- 5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyl Phenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5- Methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2 ,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5- Carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2- Cyanophenyl, 4-cyanophenyl, 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2- Cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyano Phenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano -6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)amino Carbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-di Methyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-( 1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl) ke-N-methylamino)carbonyl)benzene , 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclobutyl)aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro- 5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-(( 2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1) -methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazine- 4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazole- 4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyridyl) Zin-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4 -yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl- Piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl- Pyridin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-? Phenyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl Phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl or 3-(2-methyl-1,2,4-oxo Zyrid-3-yl)phenyl.

在另一實施例中，R6為5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫唑啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基。 In another embodiment, R 6 is 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4- Quinolinyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4- Tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxaline-5-yl, 1 - pendant oxy-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H- Oxazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4 ,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2- Dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-sided oxy-dihydroquinolin-1-yl, 2- Methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydro Quinoline-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxo-l,2-dihydrooxalin-6-yl, 5,7-difluoro- 1-methyl-2-oxo-4-ene Methyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6- , 8-isoquinolyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3, 4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4 -b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a Pyridine-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl , 3-methylisoxazo[5,4-b]pyridin-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl- 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-pyrano[2,3 -b]pyridine-5-yl or 5- alkyl.

在另一實施例中，L為O。 In another embodiment, L is O.

在另一實施例中，G為C-Q；Q為-L-R5；且P為H。 In another embodiment, G is CQ; Q is -LR 5 ; and P is H.

在另一實施例中，R5為5員雜環基、6員雜環基、苯基、苯基-C1-6烷基、9員含氮雜環基或10員含氮雜環基；其中R5未經取代或經一或 多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基烷基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基。 In another embodiment, R 5 is 5-membered heterocyclic group, a 6-membered heterocyclic group, a phenyl group, a phenyl -C 1-6 alkyl group, 9 nitrogen-containing heterocyclic nitrogen-containing heterocyclic group or 10 Wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, halo, pendant oxy, hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxyalkyl -C 1-6 alkyl aminocarbonyl, aminocarbonyl C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl.

在另一實施例中，R5為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R5未經取代或經一或多個獨立地選自以下之取代基取代：氟、氯、氰基、甲氧基、三氟甲基、乙氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基、側氧基、甲基、乙基或丁氧基羰基。 In another embodiment, R 5 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, 2,5 - Bi-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1,2-dihydroquinolinyl, 5,6,7,8-tetra Hydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridyl, isoquinolinyl, 1H-pyridyl Zizo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazolo[5,4-b]pyridine , [1,2,4]triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridinyl, 3, 4-dihydro-2H-piperacino[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, methoxy, trifluoromethyl, ethoxycarbonyl, carboxy , N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl) Aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl, pendant oxy, methyl, ethyl or butoxycarbonyl.

在另一實施例中，R5為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基或2,5-二側氧基-吡咯啶-1-基。 In another embodiment, R 5 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl, 1-Boc-piperidin-4-yl, hexahydrofuran [2,3-b]furan-3-yl or 2,5-di-oxy-pyrrolidin-1-yl.

在另一實施例中，R5為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3- 吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基或3-(3-氟-5-甲氧基苯基)-5-吡啶基。 In another embodiment, R 5 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-di Methyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5 -dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl- 6-Methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2- Hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)- 3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoro Methyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl , 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl , 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4- Pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3- Chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4- Fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine- 5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl-2-oxopyridine-5-yl, 2-methyl-6-oxopyridine 4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl Keto-6-oxypyridine-5-yl, 1-isopropyl-2-poxypyridin-5-yl, 1,2-dimethyl-6-oxo-pyridin-3-yl, 1 -methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl) -4-pyridine , 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl or 3-(3-fluoro-5-methoxyphenyl )-5-pyridyl.

在另一實施例中，R5為5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基或噠嗪-3-基。 In another embodiment, R 5 is 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidine- 5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyridyl Pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl or pyridazin-3-yl.

在另一實施例中，R5為1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5- 吡唑基、1-甲基-3-環丙基-5-吡唑基或1-乙基四唑-2-基。 In another embodiment, R 5 is 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1 -ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1 -Methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl or 1-ethyltetrazol-2-yl.

在另一實施例中，R5為苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基 羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基或3-(2-甲基-1,2,4-噁二唑-3-基)苯基。 In another embodiment, R 5 is phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2, 5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorobenzene Base, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylbenzene , 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro- 5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyl Phenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5- Methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2 ,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5- Carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2- Cyanophenyl, 4-cyanophenyl, 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2- Cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyano Phenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano -6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)amino Carbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-di Methyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-( 1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl) ke-N-methylamino)carbonyl)benzene , 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclobutyl)aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro- 5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-(( 2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1) -methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazine- 4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazole- 4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyridyl) Zin-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4 -yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl- Piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl- Pyridin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-? Phenyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl Phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl or 3-(2-methyl-1,2,4-oxo Zyrid-3-yl)phenyl.

在另一實施例中，R5為5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二 氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基。 In another embodiment, R 5 is 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4- Quinolinyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4- Tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxaline-5-yl, 1 - pendant oxy-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H- Oxazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4 ,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2- Dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-sided oxy-dihydroquinolin-1-yl, 2- Methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydro Quinoline-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro- 1-methyl-2-oxo-4-ene Methyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6- , 8-isoquinolyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3, 4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4 -b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a Pyridine-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl , 3-methylisoxazo[5,4-b]pyridin-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl- 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-pyrano[2,3 -b]pyridine-5-yl or 5- alkyl.

本發明之另一態樣係關於具有式IIc及式IId之通式結構的化合物： 其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基或鹵基之取代基取代； R3為H、鹵基、烷氧基羰基、胺基羰基、氰基、氰基烷基、烷基羰基、雜環基羰基、烷基胺基羰基、烯基、炔基、羥基烯基、烷氧基烷氧基烷基、芳氧基烯基、烷氧基羰基烷基、烷基磺醯基烷基、烷基磺醯基烯基、烷基磺醯基炔基、雜環基炔基、雜環基羰基烷基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、鹵烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-C1-6烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、RR'N-、RR'N-C1-6烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'獨立地為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基； R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；L為O、S、CH2或CH2O；Q為-L-R5；且P為-L-R6；其限制條件為，當R3為H，R1為甲基，且L為O時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，L為O，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，L為O，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，L為O，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡 啶基或2,6-二甲基-3-吡啶基，且R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基，L為O，且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基。 Another aspect of the invention pertains to compounds having the general structure of formula IIc and formula IId: Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or substituted by one or two independently selected from hydroxy, alkoxy, alkyl, pendant or halo groups. Substituent; R 3 is H, halo, alkoxycarbonyl, aminocarbonyl, cyano, cyanoalkyl, alkylcarbonyl, heterocyclylcarbonyl, alkylaminocarbonyl, alkenyl, alkynyl, hydroxy Alkenyl, alkoxyalkoxyalkyl, aryloxyalkenyl, alkoxycarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, alkylsulfonylalkynyl, hetero Cycloalkynyl, heterocyclylcarbonylalkyl, alkoxyalkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or -S(O)n; n is 0, 1 or 2; R 4 is an alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxy, alkenyl, alkoxy Carbocarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, aralkenyl, arylalkynyl a cycloalkylalkyl group, a cycloalkylalkenyl group, a cycloalkylalkynyl group, a heterocyclylalkyl group or a heterocyclic carbonylalkyl group; wherein the ring in R 4 is independently substituted with from 1 to 3 Substituent: H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, fluorenyl, alkylsulfonyl, heterocyclyl, aminosulfonyl, alkylaminosulfonate Anthracenyl, cyano, alkoxycarbonyl, carboxy, amine, RR'NC 1-6 alkyl, alkoxyalkyl, hydroxyalkyl or R a R b NC(=O), wherein R a is an alkane And R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a and R b together with nitrogen form an unsubstituted or alkyl substituted heterocycle; 5 is an aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclic group wherein R 5 is unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy Base, hydroxy, halo, haloalkyl, cyano, alkoxycarbonyl, carboxyl, fluorenyl , cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, pendant oxy, RR'N-, RR'NC 1-6 alkyl or R a R b NC(=O), wherein R a Is alkyl and R b is alkoxyalkyl or aminoalkyl; wherein R and R' are independently H, alkyl, aryl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein The heterocyclylalkyl, cycloalkyl and heterocyclyl rings are unsubstituted or substituted with from 1 to 3 independently selected from alkyl, alkoxy, hydroxy, halo, halo, cyano or carboxy Substituent; or R' and R may form a heterocyclic group together with N; R 6 is aryl, aralkyl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein each of the foregoing rings is unsubstituted or 1-4 substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, cyano, cycloalkyl ,heterocyclyl, hydroxyalkyl, alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; L is O, S, CH 2 or CH 2 O; Q is -LR 5 And P is -LR 6 ; the restriction is that when R 3 is H, R 1 is methyl, and L is O, then R 5 is not [1,2,4]triazole [4,3- a] Pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6 -yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl -1-Sideoxy-1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5 -Chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions That is, when R 3 is Br, L is O, and R 1 is a methyl group, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5 ,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl-1-sidedoxy-1,2- Dihydro-isoquinolin-6-yl; other restrictions are: when R 3 is 1-methyl-1H-pyrazol-4-yl, L is O, and R 1 is methyl, then R 5 is not 1-ethyl -1H- pyrazol-5-yl; additional proviso that when R 3 is 1-methyl -1H- pyrazol-5-yl, L When O, and R 1 is methyl, then R 5 is not methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl, 5,7-difluoro-1,4 - dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl ; other restrictions: when L is O, R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridyl, and R 3 When it is 2-pyridylthio, bromo, methoxyethoxy or trifluoromethyl, R 1 is not phenyl or tert-butyl; other restrictions are, when R 3 is 2-pyridylthio, L When O is, and R 6 is 2-ethyl-3-pyridyl, R 1 is not 4-methyl-2-imidazolylmethyl.

本發明之另一態樣係關於具有式IIIa之通式結構的化合物： Another aspect of the invention pertains to compounds having the general structure of formula IIIa:

其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜 環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、胺基磺醯基、C1-6烷基胺基磺醯基、氰基、羧基、RR'N-C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)-，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5-6員雜環；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、氰基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、C1-6烷基-NRR'、胺基磺醯基、C1-6烷基胺基磺醯基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基，其中該等雜環基-C1-6烷基、苯基、C3-6 環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成5-10員雜環基；且其中R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基。 Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 alkyl, 5-10 membered heterocyclic or 5-10 membered heterocyclyl-C 1-6 alkyl, wherein the aryl or hetero The cycloalkyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant oxy or halo; wherein R 3 is -XR 4 , H, halo, cyanide , C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkenyl, C 2-6 Alkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy- C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl -C 1-6 alkyl, C 1-6 alkylamino -C 1-6 alkyl group, C 1-6 alkylsulfonyl group -C 1-6 alkyl, C 1-6 alkylsulfonyl group -C 2-6 alkenyl group, C 1-6 alkyl sulfo Mercapto-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1 -6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3 -6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl or a 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 is unsubstituted or independently selected from 1 to 3 Substituted by the following substituents: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, aminosulfonyl, C 1-6 alkylaminosulfonyl, Cyano, carboxyl, RR'NC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl or R a R b NC(=O)-, wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl Or a C 1-6 alkyl-C 1-6 aminoalkyl group, or a 5-6 member heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein X Is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1 -6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl , C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 naphthenic , C 5-6 cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 Aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2 -6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein the aryl, cycloalkyl, ring in R 4 The alkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 Alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclyl, cyano, amino, C 1-6 aminoalkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 alkyl-NRR', aminosulfonyl, C 1-6 alkylaminosulfonyl or R a R b NC(=O), wherein R a is C 1- 6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 amine An alkyl group, or a 5- or 6-membered heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein R and R' are independently H, C 1-6 alkane a phenyl group, a 5-10 membered heterocyclic group, a 5-10 membered heterocyclyl-C 1-6 alkyl group or a C 3-6 cycloalkyl group, wherein the heterocyclic group is a C 1-6 alkyl group, Phenyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl ring are unsubstituted or 1-3 independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo Substituted with a substituent of a C 1-6 haloalkyl group, a cyano group or a carboxy group; or R' and R together with N form a 5-10 membered heterocyclic group; and wherein R 6 is a 5-membered nitrogen-containing heterocyclic group, 5-membered oxygen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 6-membered oxygen-containing heterocyclic group, phenyl group, benzyl group, 9-membered bicyclic nitrogen-containing heterocyclic group, 10 membered bicyclic oxygen-containing heterocyclic group or 10 members double a cyclic nitrogen-containing heterocyclic group wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1- 6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; the limitation is that when R 3 is 2-pyridylthio, bromine , methoxyethoxy or trifluoromethyl, and when R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridinyl R 1 is not a phenyl group or a tert-butyl group; other restrictions are that when R 3 is 2-pyridylthio group and R 6 is 2-ethyl-3-pyridyl group, R 1 is not 4-methyl group 2-imidazolylmethyl.

在另一實施例中，R1為甲基、乙基、丙基、烯丙基、第三丁基、三氟-乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、BOC-胺基乙基、胺基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、苯乙基、嗎啉-4-基乙基、2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑-5-基甲基、1-甲基-咪唑-4-基甲基、1-甲基-咪唑-5-基甲基、4-甲基-咪唑-2-基甲基、5-甲基-咪唑-2-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑基-5-甲基、5-甲基-異噁唑-3-基甲基或苯基。 In another embodiment, R 1 is methyl, ethyl, propyl, allyl, tert-butyl, trifluoro-ethyl, methoxy, methoxyethyl, hydroxyethyl, hydroxypropyl Base, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, BOC-aminoethyl, aminoethyl, 2-hydroxyphenylmethyl, 3-hydroxyl Phenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, phenethyl, morpholin-4-ylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4 -pyridylmethyl, 6-methyl-2-oxooxy-1,2-dihydropyridylmethyl, imidazo-5-ylmethyl, 1-methyl-imidazol-4-ylmethyl, 1 -methyl-imidazol-5-ylmethyl, 4-methyl-imidazol-2-ylmethyl, 5-methyl-imidazol-2-ylmethyl, 1,5-dimethylpyrazole-4- Methyl, 2-methylthiazolyl-5-methyl, 5-methyl-isoxazol-3-ylmethyl or phenyl.

在另一實施例中，R1為甲基或乙基。 In another embodiment, R 1 is methyl or ethyl.

在另一實施例中，R3為-SR4。 In another embodiment, R 3 is -SR 4 .

在另一實施例中，R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基。 In another embodiment, R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2-di Hydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanylmethoxy , methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutylsulfur Base, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl)thio, (2-hydroxy- 2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1- Third butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(tetrahydrogen) -2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylthio , 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, 2-chloro- 4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidyl) Pyridin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-methylcarbonyl)piperidine 4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1-isopropyl Carbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylthio, 1-( Dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidine-4 -yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1 -(Tertibutoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-pyran-4 -ylthio.

在另一實施例中，R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基或3-氧雜環丁烷基甲氧基。 In another embodiment, R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2-di Hydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy or 3-oxetanylmethoxy .

在另一實施例中，R3為甲氧基羰基甲硫基、甲氧基羰基乙硫基、 甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基。 In another embodiment, R 3 is methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio , 3,4-dihydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl) Sulfuryl, (2-hydroxy-2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl) Carboxymethylthio, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-pyran-4-yl) Methylthio, 1-(tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3, 4-dihydroxycyclopentylthio, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, 2-chloro-4-pyridylthio, 4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidin-4-yl-2 -pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-methylcarbonyl)piperidin-4-ylthio , 1-(Tertibutoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1-isopropylcarbonyl)piperidine-4 -ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylthio, 1-(dimethylaminocarbonyl) Piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1-(third butoxy Alkylcarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-piperidin-4-ylthio.

在另一實施例中，R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥 基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基申基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧 雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基或1,1-二側氧基-環戊基甲基。 In another embodiment, R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methyl Butyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2-hydroxyl -2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1,2- Dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxymethoxy Methyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, propylene- 2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy-2-methyl Propylene, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxyvinyl, 2- Hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxyethyl)aminocarbonyl , N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonylmethyl, ethoxycarbonyl Propyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, carboxyethyl, carboxypropyl Base, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxy-2-methyl Propoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyn-1-yl, cyclopentylene Methyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonylpropyl, methyl Mercaptobutyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1-phenylethylene , phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinylmethyl, 1-piperidyl Pyridylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-ylmethyl, 4- Methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinyl, (1,1-dioxy) Thiomorpholyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3-yl)methyl , tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran-3-ylmethyl , 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl, 1 , 3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]hept-1-yl Base, 2-oxa-6-azaspiro[3.3]hept-6-yl Group, 3-benzyloxy - cyclobutylmethyl, cyclobutylmethyl 3-hydroxy, 3-hydroxy-3-methyl - cyclobutylmethyl-oxo or 1,1 - cyclopentylmethyl.

在另一實施例中，R3為1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基或1,4-二氧雜螺[4.5]癸-7-烯-7-基。 In another embodiment, R 3 is 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1 -(methoxycyclopentyl)bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxyl ring Butyl, 2-oxocyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2- Methyl ethyl)-cyclobutyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3, 3-dihydroxymethylcyclopentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3- Sideoxy-cyclopentyl, 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-yl -cyclohexyl, cycloheptyl, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentenyl, 4,4-bis(hydroxymethyl) ring Pent-2-en-1-yl, 3-sided oxy-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-en-1-yl, ring Alkenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4-hydroxymethyl- Cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl)cyclohexenyl 4-(3-Fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl)cyclohexenyl , cycloheptenyl or 1,4-dioxaspiro[4.5]dec-7-ene-7-yl.

在另一實施例中，R3為3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二 氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基或1-(二甲基胺基羰基)-哌啶-4-基。 In another embodiment, R 3 is 3-hydroxy-3-oxetanyl, 2-tetrahydro-furanyl, 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl- 2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3-tetrahydro-furanyl, 2-oxopyrrolidin-1-yl, tetrahydrogen Piperazin-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxyl Tetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydropyran-2-yl, 3,6-dihydropyran 4-yl, 3,6-dihydropentan-5-yl, 5,6-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-Dimethyl-3,6-dihydro-2H-piperidin-4-yl, 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl, 3, 4-2H-dihydropyran-4-yl, 1,4-dioxaspiro[4.5]decan-7-en-8-yl, 1,1-di-oxy-isothiazolidine-2-yl 1,1-Dioxylyltetrahydro-2H-thiopiperazin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1- Methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1 -(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(A Carbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl or 1-(dimethylaminocarbonyl)-piperidine- 4-based.

在另一實施例中，R3為苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥 基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基或5-苯并二氧雜環戊烯基。 In another embodiment, R 3 is phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-trifluoromethylbenzene Base, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonylphenyl, 3 -methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonylamino Phenyl, 3-methylaminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6 -methoxyphenyl, 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(di Methylaminocarbonyl)phenyl, 4-(dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl 4-ethylaminocarbonylphenyl, 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N -Methylaminocarbonyl)phenyl, 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-benzene Base, 3-( N-methoxyethyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethyl Aminocarbonylphenyl, 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethyl Aminocarbonylphenyl, 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl- Phenyl, 1,2-dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-yl Carbonyl)phenyl, 3-(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl , 3-(4-morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methyl Oxyphenyl, 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonyl Phenyl, 4-methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3- Difluoromethoxy Phenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethyl Oxyphenyl or 5-benzodioxolyl.

在另一實施例中，R3為1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基。 In another embodiment, R 3 is 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 1,3, 5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2,2,2-trifluoroethyl ]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxycarbonylmethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-ring Butyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyrazolyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl 4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxyethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl , 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl-5-pyrazolyl, 3-methylaminocarbonyl-pyrazole-5-yl, 3- Dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyrazol-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2- Methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl 5-5-imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 1-methyl-triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxyl Propyl-triazine-4 -yl, 1-hydroxybutyl-triazin-4-yl, 2-cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophene -5-yl, 2-(N-methoxyethyl-N-methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophene-5 -yl, 2-(2-hydroxy-2-methylethyl)thiophen-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl.

在另一實施例中，R3為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3- 三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶 基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基。 In another embodiment, R 3 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5-pyridyl, 2-difluoromethyl-5-pyridyl , 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methyl Oxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2-methoxy-4-pyridyl, 3-fluoro-4- Pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy-4-pyridyl, 2-methoxy-5 -pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy-4-pyridyl, 5-fluoro-2-hydroxyethoxy 4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy-5-pyridyl, 2-ethoxy-5- Pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-(1,1,1-trifluoroethoxy)-5- Pyridyl, 2-cyclopropylmethoxy-5-pyridyl 2-(Methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl, 2-fluoro-4 -pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano-5-pyridyl , 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5-pyridyl, 3- Cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2-sided oxy- 1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxooxy-1,2- Dihydropyridin-5-yl, 1-isopropyl-2-yloxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy-1,2-dihydro Pyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2-dihydropyridine-4 -yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl, 3-methylamine Carbocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl-5-pyridyl, 2- Methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonylaminoethylcarbonyl -5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethylaminocarbonyl-5-pyridine , 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4-pyridyl, 4-fluoro- 2-Methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl.

在另一實施例中，R3為5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基。 In another embodiment, R 3 is 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy 5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethoxy-5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl 4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylaminocarbonylpyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl.

在另一實施例中，R3為3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并 [3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基。 In another embodiment, R 3 is 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-sided oxy-dihydro-5-fluorenyl, 6-fluorenyl , 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6-fluorenyl, imidazo[1,2-a]pyridin-3-yl , imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, 1,1-di-oxy-2-methyl-3,4-di Hydrogen-2H-benzo[b][1,4,5]oxathiazolidine-8-yl, benzoxazol-5-yl, benzoxazol-6-yl, 1,1-dioxy 3-,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridin-8-yl, 4-methyl-5-oxooxy-3,4-dihydro Benzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazol-5-yl, 2-ethylbenzoxazol-5-yl, 2 -isopropyl benzoxazol-5-yl, 2-oxo-2(3H)-benzo[d]oxazol-5-yl, benzothiazol-5-yl, benzothiazole-6- Base, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5-oxazolyl, 1-methyl-6-carbazolyl, 2- Methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4-yl, 1,5-dimethyl-2,3-dihydro-1H -pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2-a 3-oxo-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2-methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2- b][1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzo [d][1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxazol-5-yl,[1,2,4] Triazolo[4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2, 4] Triazolo[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl.

在另一實施例中，R6為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基。 In another embodiment, R 6 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, 2,5 - Bi-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1,2-dihydroquinolinyl, 5,6,7,8-tetra Hydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridyl, isoquinolinyl, 1H-pyridyl Zizo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazolo[5,4-b]pyridine , [1,2,4]triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridinyl, 3, 4-dihydro-2H-piperacino[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, Ethoxycarbonyl, tert-butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-( Methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy group.

在另一實施例中，R6為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基或2,5-二側氧基-吡咯啶-1-基。 In another embodiment, R 6 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl, 1-Boc-piperidin-4-yl, hexahydrofuran [2,3-b]furan-3-yl or 2,5-di-oxy-pyrrolidin-1-yl.

在另一實施例中，R6為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟 甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基或3-(3-氟-5-甲氧基苯基)-5-吡啶基。 In another embodiment, R 6 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-di Methyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5 -dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl- 6-Methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2- Hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)- 3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoro Methyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridine , 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl , 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4- Pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3- Chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4- Fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine- 5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl-2-oxopyridine-5-yl, 2-methyl-6-oxopyridine 4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl Keto-6-oxypyridine-5-yl, 1-isopropyl-2-poxypyridin-5-yl, 1,2-dimethyl-6-oxo-pyridin-3-yl, 1 -methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl) -4-pyridyl , 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl or 3-(3-fluoro-5-methoxyphenyl )-5-pyridyl.

在另一實施例中，R6為5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基或噠嗪-3-基。 In another embodiment, R 6 is 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidine- 5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyridyl Pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl or pyridazin-3-yl.

在另一實施例中，R6為1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基或1-乙基四唑-2-基。 In another embodiment, R 6 is 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1 -ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1 Methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl or 1-ethyltetrazol-2-yl.

在另一實施例中，R6為苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3- 甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧 基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基或3-(2-甲基-1,2,4-噁二唑-3-基)苯基。 In another embodiment, R 6 is phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2, 5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorobenzene Base, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylbenzene , 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro- 5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyl Phenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5- Methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2 ,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5 -carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2 - cyanophenyl, 4-cyanophenyl, 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2 -Cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6- Cyanophenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano 6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl , 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)amine Phenylcarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N- Dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5- (1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-iso) propyl-N-methylamino)carbonyl)benzene , 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclobutyl)aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro- 5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-(( 2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1) -methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazine- 4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazole- 4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyridyl) Zin-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4 -yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl- Piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl- Pyridin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-? Phenyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl Phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl or 3-(2-methyl-1,2,4-oxo Zyrid-3-yl)phenyl.

在另一實施例中，R6為5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異 喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基。 In another embodiment, R 6 is 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4- Quinolinyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4- Tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxaline-5-yl, 1 - pendant oxy-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H- Oxazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4 ,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2- Dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-sided oxy-dihydroquinolin-1-yl, 2- Methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydro Quinoline-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro- 1-methyl-2-oxo-4-ene Methyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6- , 8-isoquinolyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3, 4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4 -b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a Pyridine-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl , 3-methylisoxazo[5,4-b]pyridin-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl- 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-pyrano[2,3 -b]pyridine-5-yl or 5- alkyl.

本發明之另一態樣係關於具有式IVa之通式結構的化合物： Another aspect of the invention pertains to compounds having the general structure of formula IVa:

其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基-C1-6烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基 磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基，其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成5-10員雜環基；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經 取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、胺基磺醯基、C1-6烷基胺基磺醯基、C1-6烷氧基羰基、羧基、氰基、5-16員雜環基、胺基、RR'N-C1-6烷基-、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；且其中R5為5員含氮雜環基、6員含氮雜環基、苯基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為H，R1為甲基時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，且R1為甲基時， 則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基。 Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1 a -6 alkyl group, a C 6-10 aryl group, a C 6-10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group-C 1-6 alkyl group, wherein The aryl or heterocyclyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant or halo; wherein R 3 is -XR 4 , H , halo, cyano, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, Aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkenyl , C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl, C 1- 6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl -C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl -C 1-6 alkyl, C 1-6 alkyl -C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl group -C 1-6 alkyl, C 1-6 alkylsulfonyl group -C 2-6 alkenyl group, C 1-6 alkyl Sulfonyl-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl Or a 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 is unsubstituted or independently selected from 1 to 3 Substituted from the following substituents: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkyl sulfonium , C 1-6 alkoxycarbonyl, carboxy, 5-10 membered heterocyclyl, amine, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1 -6 hydroxyalkyl, C 1-6 haloalkoxy, RR 'NC 1-6 alkyl-, aminosulfonyl, C 1-6 alkylaminosulfonyl, cyano or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 aminoalkyl, or wherein R a and R b together with nitrogen form unsubstituted or substituted C 1-6 alkyl Or a 6-membered heterocyclic ring; wherein R and R' are independently H, C 1-6 alkyl, phenyl, 5-10 membered heterocyclic, 5-10 membered heterocyclyl-C 1-6 alkyl or C a 3-6 cycloalkyl group, wherein the heterocyclic group -C 1-6 alkyl group, phenyl group, C 3-6 cycloalkyl group and 5-10 membered heterocyclic ring are unsubstituted or 1-3 independent Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo, C 1-6 haloalkyl, cyano or carboxy; or R' and R may form together with N a 5-10 membered heterocyclic group; wherein X is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy- C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl- C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 Heterocyclyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3- 6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3- 6 cycloalkyl, -C 2-6 alkynyl, -C 1-6 5-10 membered heterocyclyl, or 5-10 membered heterocyclyl alkyl carbonyl group -C 1-6 alkyl; wherein the aryl of R 4 in The cyclo, cycloalkyl, cycloalkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, halo, C1-6 haloalkyl , hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylamine Sulfosyl, C 1-6 alkoxycarbonyl, carboxyl, cyano, 5-16 membered heterocyclyl, amine, RR'NC 1-6 alkyl-, C 1-6 alkoxy-C 1 -6 alkyl, C 1-6 hydroxyalkyl or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy a base-C 1-6 alkyl group, a C 1-6 aminoalkyl group or a C 1-6 alkyl-C 1-6 aminoalkyl group, or wherein R a and R b together with nitrogen form an unsubstituted or via a C 1-6 alkyl substituted 5- or 6-membered heterocyclic ring; and wherein R 5 is a 5-membered nitrogen-containing heterocyclic group, a 6-membered nitrogen-containing heterocyclic group, a phenyl group, a 9-membered nitrogen-containing heterocyclic group or a 10-membered azetidin group, wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group substituted: C 1-6 alkyl, cyano, halo, oxo Hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy -C 1-6 alkyl aminocarbonyl, C 1- 6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; the limitation is when When R 3 is H and R 1 is methyl, then R 5 is not [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxo- 1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6-yl, 2-oxo-1,2-dihydroquinoline -6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxo-1,2-dihydro-isoquinoline -6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1-methyl-1H - oxazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are, when R 3 is Br and R 1 is methyl, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl Keto-2-oxo-4-trifluoromethyl-1,2-dihydroquine Polin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl or 2-methyl-1-side Oxy-1,2-dihydro-isoquinolin-6-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazol-4-yl and R 1 is methyl R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are, when R 3 is 1-methyl-1H-pyrazol-5-yl, and R 1 is methyl, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo- 1,2-Dihydroquinolin-6-yl or 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl.

在另一實施例中，R1為甲基、乙基、丙基、烯丙基、第三丁基、三氟-乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、BOC-胺基乙基、胺基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、苯乙基、嗎啉-4-基乙基、2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑-5-基甲基、1-甲基-咪唑-4-基甲基、1-甲基-咪唑-5-基甲基、4-甲基-咪唑-2-基甲基、5-甲基-咪唑-2-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑基-5-甲基、5-甲基-異噁唑-3-基甲基或苯基。 In another embodiment, R 1 is methyl, ethyl, propyl, allyl, tert-butyl, trifluoro-ethyl, methoxy, methoxyethyl, hydroxyethyl, hydroxypropyl Base, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, BOC-aminoethyl, aminoethyl, 2-hydroxyphenylmethyl, 3-hydroxyl Phenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, phenethyl, morpholin-4-ylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4 -pyridylmethyl, 6-methyl-2-oxooxy-1,2-dihydropyridylmethyl, imidazo-5-ylmethyl, 1-methyl-imidazol-4-ylmethyl, 1 -methyl-imidazol-5-ylmethyl, 4-methyl-imidazol-2-ylmethyl, 5-methyl-imidazol-2-ylmethyl, 1,5-dimethylpyrazole-4- Methyl, 2-methylthiazolyl-5-methyl, 5-methyl-isoxazol-3-ylmethyl or phenyl.

在另一實施例中，R1為甲基或乙基。 In another embodiment, R 1 is methyl or ethyl.

在另一實施例中，R3為-SR4。 In another embodiment, R 3 is -SR 4 .

在另一實施例中，R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基 甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基。 In another embodiment, R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2-di Hydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanylmethoxy , methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutylsulfur Base, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl)thio, (2-hydroxy- 2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1- Third butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(tetrahydrogen) -2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylthio , 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, 2-chloro- 4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidyl) Pyridin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-methylcarbonyl)piperidine 4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1-isopropyl Carbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylthio, 1-( Dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidine-4 -yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1 -(Tertibutoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-pyran-4 -ylthio.

在另一實施例中，R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基或3-氧雜環丁烷基甲氧基。 In another embodiment, R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2-di Hydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy or 3-oxetanylmethoxy .

在另一實施例中，R3為甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1- 異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基。 In another embodiment, R 3 is methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio , 3,4-dihydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl) Sulfuryl, (2-hydroxy-2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl) Carboxymethylthio, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-pyran-4-yl) Methylthio, 1-(tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3, 4-dihydroxycyclopentylthio, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridylthio, 2-chloro-4-pyridylthio, 4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidin-4-yl-2 -pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-methylcarbonyl)piperidin-4-ylthio , 1-(Tertibutoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, (1-isopropylcarbonyl)piperidine-4 -ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylthio, 1-(dimethylaminocarbonyl) Piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1-(third butoxy Alkylcarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-piperidin-4-ylthio.

在另一實施例中，R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲 基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基或1,1-二側氧基-環戊基甲基。 In another embodiment, R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methyl Butyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2-hydroxyl -2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1,2- Dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxymethoxy Methyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, propylene- 2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy-2-methyl Propylene, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxyvinyl, 2- Hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxyethyl)aminocarbonyl , N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonylmethyl, ethoxycarbonyl Propyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, carboxyethyl, carboxypropyl Base, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxy-2-methyl Propoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyn-1-yl, cyclopentylene Methyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonylpropyl, methyl Mercaptobutyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1-phenylethylene , phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinylmethyl, 1-piperidyl Pyridylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-ylmethyl, 4- Methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1,1-dioxyionyl) Thiomorpholyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3-yl)methyl , tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran-3-ylmethyl , 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl, 1 , 3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]hept-1-yl Base, 2-oxa-6-azaspiro[3.3]hept-6-yl Group, 3-benzyloxy - cyclobutylmethyl, cyclobutylmethyl 3-hydroxy, 3-hydroxy-3-methyl - cyclobutylmethyl-oxo or 1,1 - cyclopentylmethyl.

在另一實施例中，R3為1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3- 羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基或1,4-二氧雜螺[4.5]癸-7-烯-7-基。 In another embodiment, R 3 is 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1 -(methoxycyclopentyl)bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxyl ring Butyl, 2-oxocyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2- Methyl ethyl)-cyclobutyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3, 3-dihydroxymethylcyclopentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3- Sideoxy-cyclopentyl, 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-yl -cyclohexyl, cycloheptyl, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentenyl, 4,4-bis(hydroxymethyl) ring Pent-2-en-1-yl, 3-sided oxy-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-en-1-yl, ring Alkenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4-hydroxymethyl- Cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl)cyclohexenyl 4-(3-Fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl)cyclohexenyl , cycloheptenyl or 1,4-dioxaspiro[4.5]dec-7-ene-7-yl.

在另一實施例中，R3為3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基或1-(二甲基胺基羰基)-哌啶-4-基。 In another embodiment, R 3 is 3-hydroxy-3-oxetanyl, 2-tetrahydro-furanyl, 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl- 2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3-tetrahydro-furanyl, 2-oxopyrrolidin-1-yl, tetrahydrogen Piperazin-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxyl Tetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydropyran-2-yl, 3,6-dihydropyran 4-yl, 3,6-dihydropentan-5-yl, 5,6-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-Dimethyl-3,6-dihydro-2H-piperidin-4-yl, 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl, 3, 4-2H-dihydropyran-4-yl, 1,4-dioxaspiro[4.5]decan-7-en-8-yl, 1,1-di-oxy-isothiazolidine-2-yl 1,1-Dioxylyltetrahydro-2H-thiopiperazin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1- Methylsulfonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1 -(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(A Carbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl or 1-(dimethylaminocarbonyl)-piperidine- 4-based.

在另一實施例中，R3為苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基- 3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基或5-苯并二氧雜環戊烯基。 In another embodiment, R 3 is phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-trifluoromethylbenzene , 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonylphenyl, 3 -methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonylamino Phenyl, 3-methylaminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6 -methoxyphenyl, 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(di Methylaminocarbonyl)phenyl, 4-(dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl 4-ethylaminocarbonylphenyl, 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N -Methylaminocarbonyl)phenyl, 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-benzene Base, 3- (N-methoxyethyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethyl Aminocarbonylphenyl, 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethyl Aminocarbonylphenyl, 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl -phenyl, 1,2-dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1- Phenylcarbonyl)phenyl, 3-(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)benzene , 3-(4-morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6- Methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonyl Phenylphenyl, 4-methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3 -difluoromethoxy Phenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethyl Oxyphenyl or 5-benzodioxolyl.

在另一實施例中，R3為1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟- 乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基。 In another embodiment, R 3 is 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 1,3, 5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2,2,2-trifluoroethyl ]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxycarbonylmethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-ring Butyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyrazolyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl 4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxyethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl , 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl-5-pyrazolyl, 3-methylaminocarbonyl-pyrazole-5-yl, 3- Dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyrazol-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2- Methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl 5-5-imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 1-methyl-triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxyl Propyl-triazine- 4-yl, 1-hydroxybutyl-triazin-4-yl, 2-cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy- Thiophen-5-yl, 2-(N-methoxyethyl-N-methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophene- 5-Based, 2-(2-hydroxy-2-methylethyl)thiophen-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl.

在另一實施例中，R3為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺 醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基。 In another embodiment, R 3 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5-pyridyl, 2-difluoromethyl-5-pyridyl , 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methyl Oxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2-methoxy-4-pyridyl, 3-fluoro-4- Pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy-4-pyridyl, 2-methoxy-5 -pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy-4-pyridyl, 5-fluoro-2-hydroxyethoxy 4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy-5-pyridyl, 2-ethoxy-5- Pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-(1,1,1-trifluoroethoxy)-5- Pyridyl, 2-cyclopropylmethoxy-5-pyridyl, 2-(Methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl, 2-fluoro-4 -pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano-5-pyridyl , 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5-pyridyl, 3- Cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2-sided oxy- 1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxooxy-1,2- Dihydropyridin-5-yl, 1-isopropyl-2-yloxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy-1,2-dihydro Pyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2-dihydropyridine-4 -yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl, 3-methylamine Carbocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl-5-pyridyl, 2- Sulfosylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonylaminoethylcarbonyl- 5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethylaminocarbonyl-5-pyridyl , 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4-pyridyl, 4-fluoro-2 Methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl.

在另一實施例中，R3為5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基。 In another embodiment, R 3 is 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy 5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethoxy-5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl 4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylaminocarbonylpyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl.

在另一實施例中，R3為3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并 [1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基。 In another embodiment, R 3 is 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-sided oxy-dihydro-5-fluorenyl, 6-fluorenyl , 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6-fluorenyl, imidazo[1,2-a]pyridin-3-yl , imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, 1,1-di-oxy-2-methyl-3,4-di Hydrogen-2H-benzo[b][1,4,5]oxathiazolidine-8-yl, benzoxazol-5-yl, benzoxazol-6-yl, 1,1-dioxy 3-,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridin-8-yl, 4-methyl-5-oxooxy-3,4-dihydro Benzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazol-5-yl, 2-ethylbenzoxazol-5-yl, 2 -isopropyl benzoxazol-5-yl, 2-oxo-2(3H)-benzo[d]oxazol-5-yl, benzothiazol-5-yl, benzothiazole-6- Base, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5-oxazolyl, 1-methyl-6-carbazolyl, 2- Methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4-yl, 1,5-dimethyl-2,3-dihydro-1H -pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2-a 3-oxo-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2-methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2- b][1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzo [d][1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxazol-5-yl,[1,2,4] Triazolo[4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2, 4] Triazolo[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl.

在另一實施例中，R5為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R5未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、 甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基。 In another embodiment, R 5 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, 2,5 - Bi-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1,2-dihydroquinolinyl, 5,6,7,8-tetra Hydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridyl, isoquinolinyl, 1H-pyridyl Zizo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazolo[5,4-b]pyridine , [1,2,4]triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridinyl, 3, 4-dihydro-2H-piperacino[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, Ethoxycarbonyl, tert-butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-( Methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy group.

在另一實施例中，R5為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基或2,5-二側氧基-吡咯啶-1-基。 In another embodiment, R 5 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl, 1-Boc-piperidin-4-yl, hexahydrofuran [2,3-b]furan-3-yl or 2,5-di-oxy-pyrrolidin-1-yl.

在另一實施例中，R5為2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側 氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基或3-(3-氟-5-甲氧基苯基)-5-吡啶基。 In another embodiment, R 5 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl- 5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-di Methyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5 -dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl- 6-Methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2- Hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)- 3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoro Methyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridine , 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl , 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4- Pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3- Chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4- Fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine- 5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl-2-oxopyridine-5-yl, 2-methyl-6-oxopyridine 4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl Keto-6-oxypyridine-5-yl, 1-isopropyl-2-poxypyridin-5-yl, 1,2-dimethyl-6-oxo-pyridin-3-yl, 1 -methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl) -4-pyridyl , 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl or 3-(3-fluoro-5-methoxyphenyl )-5-pyridyl.

在另一實施例中，R5為5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基或噠嗪-3-基。 In another embodiment, R 5 is 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidine- 5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyridyl Pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl or pyridazin-3-yl.

在另一實施例中，R5為1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基或1-乙基四唑-2-基。 In another embodiment, R 5 is 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1 -ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1 Methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl or 1-ethyltetrazol-2-yl.

在另一實施例中，R5為苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2- 氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基) 苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基或3-(2-甲基-1,2,4-噁二唑-3-基)苯基。 In another embodiment, R 5 is phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2, 5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorobenzene Base, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylbenzene , 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro- 5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyl Phenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5- Methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2 ,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5- Carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2- Cyanophenyl, 4-cyanophenyl, 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2- Cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyano Phenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano -6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)amino Carbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-di Methyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-( 1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl) ke-N-methylamino)carbonyl)benzene , 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclobutyl)aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro- 5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-(( 2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1) -methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazine- 4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazole- 4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyridyl) Zin-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4 -yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl- Piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl- Pyridin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-? Phenyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl Phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl or 3-(2-methyl-1,2,4-oxo Zyrid-3-yl)phenyl.

在另一實施例中，R5為5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基。 In another embodiment, R 5 is 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4- Quinolinyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4- Tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxaline-5-yl, 1 - pendant oxy-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H- Oxazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4 ,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2- Dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-sided oxy-dihydroquinolin-1-yl, 2- Methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydro Quinoline-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro- 1-methyl-2-oxo-4-ene Methyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6- , 8-isoquinolyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3, 4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4 -b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a Pyridine-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl , 3-methylisoxazo[5,4-b]pyridin-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl- 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-pyrano[2,3 -b]pyridine-5-yl or 5- alkyl.

此處列舉本發明之一些特定實施例：1.一種式Ia化合物， 其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基或鹵基之取代基取代；R2為H、烷基或鹵基；R3為H、鹵基、烷氧基羰基、胺基羰基、氰基、氰基烷基、烷基羰基、雜環基羰基、烷基胺基羰基、烯基、炔基、羥基烯基、烷氧基烷氧基烷基、芳氧基烯基、烷氧基羰基烷基、烷基磺醯基烷基、烷基磺醯基烯基、烷基磺醯基炔基、雜環基炔基、雜環基羰基烷基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、鹵烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環未經取代或經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧 基、胺基、RR'N-烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環基環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、-NRR'、烷基-NRR'或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；G為C-Q或N；L為O、S、CH2或CH2O；Q為H或-L-R5；且P為H或-L-R6；其限制條件為：(iv)當Q為H時，則P為-L-R6，或(v)當Q為-L-R5時，則P為H；(vi)當G為N時，則P為-L-R6；其他限制條件為，當R3為H，R1為甲基，R2為H，L為O，且P為H 時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，R1為甲基，R2為H，L為O，且P為H時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當R3為H，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為鹵基；其他限制條件為，當R3為溴，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為氯；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，R2為H，R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且G為CH時，R1不為苯基或第三丁基；其他限制條件為，當R2為H，R3為2-吡啶硫基，P為2-乙基-3-吡啶 氧基，且G為CH時，R1不為4-甲基-2-咪唑基甲基；其他限制條件為，當R1為甲基，R2為H，G為N，且P為2-甲基-3-吡啶氧基時，R3不為4-甲基苯基或2,4-二甲基苯基或1,2-二羥基-2-苯基乙基；及其醫藥學上可接受之鹽。 Specific examples of the invention are listed herein: 1. A compound of formula Ia, Wherein: R1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkyl , cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, wherein cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl or The cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or substituted one or two substituents independently selected from hydroxy, alkoxy, alkyl, pendant or halo groups. Substituted; R2 is H, alkyl or halo; R3 is H, halo, alkoxycarbonyl, aminocarbonyl, cyano, cyanoalkyl, alkylcarbonyl, heterocyclylcarbonyl, alkylaminocarbonyl , alkenyl, alkynyl, hydroxyalkenyl, alkoxyalkoxyalkyl, aryloxyalkenyl, alkoxycarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, alkane Alkylsulfonylalkynyl, heterocyclylalkynyl, heterocyclylcarbonylalkyl, alkoxyalkynyl, hydroxyalkynyl or -XR4; X is a bond, -O- or -S(O)n; Is 0, 1 or 2; R4 is alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, Oxykenyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, aromatic Alkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl or heterocyclylcarbonylalkyl; wherein the ring in R4 is unsubstituted or - 3 substituents independently selected from the group consisting of H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, fluorenyl, alkylsulfonyl, heterocyclyl, amine Sulfosyl, alkylaminosulfonyl, cyano, alkoxycarbonyl, carboxyl, amine, RR'N-alkyl, alkoxyalkyl, hydroxyalkyl or RaRbNC(=O), wherein Ra is an alkyl group and Rb is an alkyl group, an alkoxyalkyl group, an aminoalkyl group or an alkylaminoalkyl group, or a heterocyclic ring in which Ra and Rb together with a nitrogen form an unsubstituted or alkyl group. R5 is aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclyl, wherein R5 is unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy Base, hydroxyl, halo, haloalkyl, cyano, alkoxy Carbocarbonyl, carboxy, fluorenyl, cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, pendant oxy, -NRR', alkyl-NRR' or RaRbNC (=O), wherein Ra is an alkane And Rb is alkoxyalkyl or aminoalkyl; wherein R and R' are H, alkyl, aryl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein the heterocycloalkyl The base, cycloalkyl and heterocyclyl rings are unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, cyano or carboxy; or R 'and R together with N form a heterocyclic group; R6 is aryl, aralkyl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein each of the foregoing rings is unsubstituted or independently from 1 to 4 Substituted with a substituent selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, cyano, cycloalkyl, heterocyclyl, hydroxy Alkyl, alkoxyalkyl, NR'R', CH2NRR', pendant oxy or fluorenyl; G is CQ or N; L is O, S, CH2 or CH2O; Q is H or -L-R5; P is H or -L-R6; the limiting conditions are: (iv) when Q is H, then P is -L-R6, or (v) when Q is -L-R5 Then P is H; (vi) When G is N, then P is -L-R6; other restrictions are: when R3 is H, R1 is methyl, R2 is H, L is O, and P is H , R5 is not [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl , isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6-yl, 2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-2- Sideoxy-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxooxy-1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl -2-Sideoxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5, 7-Difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl -3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are: when R3 is Br, R1 is methyl, R2 is H, L is O, and P is H, then R5 is not Is 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2 - oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxo-oxyl-1, 2-Dihydroquinolin-6-yl or 2-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl; other limiting bars Therefore, when R3 is 1-methyl-1H-pyrazol-4-yl, R1 is methyl, R2 is H, L is O, and P is H, then R5 is not 1-ethyl-1H-pyridyl Zyrid-5-yl; other restrictions are: when R3 is 1-methyl-1H-pyrazol-5-yl, R1 is methyl, R2 is H, L is O, and P is H, then R5 is not Is 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2 -dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl; other restrictions are when R3 is H and R1 is A a group, L is O, P is H, and when R5 is a 5-quinolyl group, R2 is not a halogen group; other restrictions are: when R3 is bromine, R1 is a methyl group, L is O, and P is H, and When R5 is 5-quinolyl, R2 is not chlorine; other restrictions are, when L is O, R6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6- Dimethyl-3-pyridyl, R2 is H, R3 is 2-pyridylthio, bromo, methoxyethoxy or trifluoromethyl, and when G is CH, R1 is not phenyl or tributyl Other restrictions: when R2 is H, R3 is 2-pyridylthio, P is 2-ethyl-3-pyridyloxy, and when G is CH, R1 is not 4-methyl-2-imidazole Methyl group; other limits The conditions are such that when R1 is methyl, R2 is H, G is N, and P is 2-methyl-3-pyridinyloxy, R3 is not 4-methylphenyl or 2,4-dimethyl Phenyl or 1,2-dihydroxy-2-phenylethyl; and pharmaceutically acceptable salts thereof.

2.如技術方案1之化合物，其中R1為H、C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；及其醫藥學上可接受之鹽。 2. A compound according to claim 1, wherein R1 is H, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 Aminoalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 hydroxyalkoxy-C1-6 alkyl, C6-10 aryl, C6-10 aryl-C1-6 alkyl, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclyl-C1-6 alkyl group, wherein the aryl or heterocyclic ring is unsubstituted or is independently selected from C1-6 alkyl, one or two, Substituted by a substituent of a hydroxyl group, a pendant oxy group or a halogen group; and a pharmaceutically acceptable salt thereof.

3.如技術方案1之化合物，其中R1為H、甲基、乙基、丙基、異丙基、第三丁基、烯丙基、三氟乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、胺基乙基、苯基、苯基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、4-甲基咪唑基甲基、咪唑基甲基、1-甲基-咪唑基甲基、1,5-二甲基吡唑基甲基、2-甲基噻唑基甲基、5-甲基-異噁唑基甲基、嗎啉-4-基乙基、嗎啉-4-基甲基、四氫哌喃乙基或四氫呋喃基乙基；及其醫藥學上可接受之鹽。 3. A compound according to claim 1 wherein R1 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, allyl, trifluoroethyl, methoxy, methoxyethyl , hydroxyethyl, hydroxypropyl, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, aminoethyl, phenyl, phenylethyl, 2-hydroxyl Phenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, pyridylmethyl, 6-methyl-2-oxo-1,2- Dihydropyridylmethyl, 4-methylimidazolylmethyl, imidazolylmethyl, 1-methyl-imidazolylmethyl, 1,5-dimethylpyrazolylmethyl, 2-methylthiazolyl Methyl, 5-methyl-isoxazolylmethyl, morpholin-4-ylethyl, morpholin-4-ylmethyl, tetrahydropyranylethyl or tetrahydrofuranylethyl; and its medicinal Acceptable salt.

4.如技術方案1之化合物，其中R1為2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、4-甲基咪唑-2-基甲基、咪唑-5-基甲基、1-甲基咪唑-5-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑-5-基甲基、5-甲基異噁唑-3-基、6-甲基-2-側氧基-1,2-二氫吡啶-3-基甲基或嗎啉-4-基乙基；及其醫藥學上可接受之鹽。 4. A compound according to claim 1, wherein R1 is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-methylimidazol-2-ylmethyl, imidazole-5-yl Methyl, 1-methylimidazolium-5-ylmethyl, 1,5-dimethylpyrazol-4-ylmethyl, 2-methylthiazol-5-ylmethyl, 5-methylisoxazole 3-yl, 6-methyl-2-oxooxy-1,2-dihydropyridin-3-ylmethyl or morpholin-4-ylethyl; and pharmaceutically acceptable salts thereof.

5.如技術方案1之化合物，其中R1為甲基、乙基或羥基乙基；及 其醫藥學上可接受之鹽。 5. The compound of claim 1 wherein R1 is methyl, ethyl or hydroxyethyl; Its pharmaceutically acceptable salt.

6.如技術方案1之化合物，其中R2為H、甲基、氯或氟；及其醫藥學上可接受之鹽。 6. A compound according to claim 1 wherein R2 is H, methyl, chloro or fluoro; and a pharmaceutically acceptable salt thereof.

7.如技術方案1之化合物，其中R2為H；及其醫藥學上可接受之鹽。 7. A compound according to claim 1 wherein R2 is H; and a pharmaceutically acceptable salt thereof.

8.如技術方案1之化合物，其中R3為-S(O)nR4，且n為0、1或2；及其醫藥學上可接受之鹽。 8. A compound according to claim 1 wherein R3 is -S(O)nR4 and n is 0, 1 or 2; and a pharmaceutically acceptable salt thereof.

9.如技術方案1之化合物，其中R3為-SR4；及其醫藥學上可接受之鹽。 9. A compound according to claim 1 wherein R3 is -SR4; and a pharmaceutically acceptable salt thereof.

10.如技術方案1之化合物，其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C3-6環烷基-C1-6烷基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基或C1-6羥基烷基；及其醫藥學上可接受之鹽。 10. The compound according to claim 1, wherein R4 is C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy -C2-6 alkenyl, C1-6 alkoxycarbonyl-C1-6 alkyl, C1-6 carboxyalkyl, aminocarbonyl-C1-6 alkyl, C1-6 alkylaminocarbonyl-C1- 6 alkyl, C6-10 aryl, C3-6 cycloalkyl, C5-6 cycloalkenyl, 5-10 membered heterocyclic, C6-10 aryl-C1-6 alkyl, C6-10 aryl- C2-6 alkenyl, C3-6 cycloalkyl-C1-6 alkyl, 5-10 membered heterocyclyl-C1-6 alkyl or 5-10 membered heterocyclylcarbonyl-C1-6 alkyl; wherein R4 The aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, halo, C1-6 halo Alkyl, hydroxy, C1-6 alkoxy, C1-6 fluorenyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclic, amine, C1- 6 aminoalkyl, C1-6 alkoxy-C1-6 alkyl or C1-6 hydroxyalkyl; and pharmaceutically acceptable salts thereof.

11.如技術方案1之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲 硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 11. The compound of claim 1 wherein R3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2 -dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanyl Oxy, methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxy Butylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl) A Sulfuryl, (3-hydroxy-3-methylbutyl)thio, (2-hydroxy-2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl) )-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl) Methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylthio, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridine Sulfuryl, 2-chloro-4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1 -Methylcarbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio (1-Isopropylcarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4- Thiothio group, 1-(dimethylaminocarbonyl)piperidin-4-yl , 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl) Piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl)thio, 1-(t-butoxycarbonyl)pyrrolidin-3- Thiothio group, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H-piperidin-4-ylthio; and pharmaceutically acceptable salts thereof .

12.如技術方案1之化合物，其中R3為甲氧基丙基亞磺醯基、甲氧基丙基磺醯基、1-(第三丁氧基羰基)哌啶-4-基亞磺醯基、2-吡啶基亞磺醯基、1-(第三丁氧基羰基)哌啶-4-基磺醯基或2-吡啶基磺醯基；及其醫藥學上可接受之鹽。 12. The compound of claim 1, wherein R3 is methoxypropylsulfinyl, methoxypropylsulfonyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfinium a 2-pyridylsulfinyl group, a 1-(t-butoxycarbonyl)piperidin-4-ylsulfonyl group or a 2-pyridylsulfonyl group; and a pharmaceutically acceptable salt thereof.

13.如技術方案1之化合物，其中R3為-OR4；及其醫藥學上可接受之鹽。 13. The compound of claim 1 wherein R3 is -OR4; and a pharmaceutically acceptable salt thereof.

14.如技術方案1之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基或3-氧雜環丁烷基甲氧基；及其醫藥學上可接受之鹽。 14. A compound according to claim 1 wherein R3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2 -dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy or 3-oxetanyl Oxyl; and pharmaceutically acceptable salts thereof.

15.如技術方案1之化合物，其中R3為H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；及其醫藥學上可接受之鹽。 15. The compound of claim 1, wherein R3 is H, halo, cyano, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C2-6 Hydroxyalkenyl, C2-6 hydroxyalkynyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy -C2-6 alkenyl, C1-6 alkoxy-C2-6 alkynyl, C6-10 aryloxy-C2-6 alkenyl, C1-6 alkoxycarbonyl-C1-6 alkyl, C1-6 Carboxyalkyl, aminocarbonyl-C1-6 alkyl, C1-6 alkylaminocarbonyl-C1-6 alkyl, C1-6 alkylsulfonyl-C1-6 alkyl, C1-6 alkyl sulfonate Mercapto-C2-6 alkenyl, C1-6 alkylsulfonyl-C2-6 alkynyl, C6-10 aryl, C3-6 cycloalkyl, C5-6 cycloalkenyl, 4-10 membered heterocyclic ring , C6-10 aryl-C1-6 alkyl, C6-10 aryl-C2-6 alkenyl, C6-10 aryl-C2-6 alkynyl, C3-6 cycloalkyl-C1-6 alkyl , C3-6 cycloalkyl-C2-6 alkenyl, C3-6 cycloalkyl-C2-6 alkynyl, heterocyclyl-C1-6 alkyl, heterocyclyl-C2-6 alkynyl or 4-10 a heterocyclic carbonyl-C1-6 alkyl group; wherein the aryl group and ring in R3 The cyclo, cycloalkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, halo, C1-6 haloalkyl, hydroxy, C1-6 Alkoxy, C1-6 fluorenyl, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, C1-6 aminoalkyl, C1- 6 alkoxy-C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkoxy, RR'N-C1-6 alkyl-, aminosulfonyl, C1-6 alkylamino Sulfonyl, cyano or RaRbNC(=O) wherein Ra is C1-6 alkyl and Rb is C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 aminoalkyl Or a C1-6 alkyl-C1-6 aminoalkyl group, or a 5- or 6-membered heterocyclic ring wherein Ra and Rb together with nitrogen form an unsubstituted or C1-6 alkyl group; and pharmaceutically acceptable Salt.

16.如技術方案1之化合物，其中R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基 丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎 啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基、1,4-二氧雜螺 [4.5]癸-7-烯-7-基，3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基 胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯 基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基- 5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基，3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、 2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基；及其醫藥學上可接受之鹽。 16. The compound of claim 1 wherein R3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2 -methylbutyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2 -hydroxy-2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1, 2-dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl , 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxy Methoxymethyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, Propen-2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1- Hydroxy-2-methylpropenyl, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxy Vinyl, 2-hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxy Ethyl)aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonyl , ethoxycarbonylpropyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, Carboxyethyl, carboxypropyl, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2- Hydroxy-2-methylpropoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyne-1- Base, cyclopentylmethyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonyl Base, methylsulfonyl butyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1-phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinyl , 1-piperidinylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-yl Methyl, 4-methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1,1 -dioxy-ionic thiomorpholinyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3 -yl)methyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran- 3-ylmethyl, 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl , propyl, 1,3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]g -1-ylmethyl, 2-oxa-6-azaspiro[ 3.3] Hept-6-ylmethyl, 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy-ring Amylmethyl, 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1-(methoxy Cyclopentyl)bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2- Oxyl cyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl) -cyclobutyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxymethyl Cyclopentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3-sided oxy-ring Pentyl, 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl, Cycloheptyl, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentyl , 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-oxo-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-ene-1- , cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4- Hydroxymethyl-cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl) Cyclohexenyl, 4-(3-fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl) Cyclohexenyl, cycloheptenyl, 1,4-dioxaspiro[4.5]dec-7-ene-7-yl, 3-hydroxy-3-oxetanyl, 2-tetrahydro-furan Base, 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl-2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3 -tetrahydro-furanyl, 2-oxopyryrrolidin-1-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5, 5-tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxytetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran- 3-yl, tetrahydropyran-2-yl, 3,6-dihydropyran-4-yl, 3,6-dihydropentan-5- ,5,6-dihydro-2H-piperidin-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-dimethyl-3,6-dihydro-2H -piperidin-4-yl, 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl, 3,4-2H-dihydropyran-4-yl, 1,4 -Dioxaspiro[4.5]dec-7-ene-8-yl, 1,1-di-oxo-isothiazolidin-2-yl, 1,1-dioxoisyltetrahydro-2H-thio Piperazin-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,3,6-tetrahydro Pyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxycarbonyl)-1,2,3,6- Tetrahydropyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1- (dimethylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonate Nonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methyl Alkylsulfonylaminophenyl, 3-methyl Aminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6-methoxyphenyl, 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(dimethylaminocarbonyl)benzene , 4-(dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl, 4-ethylamino Carbonyl phenyl, 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N-methylaminocarbonyl) Phenyl, 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-phenyl, 3-(N- Methoxyethyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethylamino Carbonyl phenyl, 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethylamino Carbonyl phenyl, 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl-phenyl 1,2-dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-ylcarbonyl)benzene , 3-(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl, 3- (4-morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methoxybenzene , 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonylphenyl, 4-methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3-difluoromethyl Oxyphenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4- Dimethoxyphenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4 -pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2 , 2,2-trifluoroethyl]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxy Carbonylmethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-cyclobutyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyridyl Azyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxy Ethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl 5-pyrazolyl, 3-methylaminocarbonyl-pyrazol-5-yl, 3-dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyridyl Zyrid-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2-methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazole-4-yl, 1-methyl -Triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxypropyl-triazin-4-yl, 1-hydroxybutyl-triazin-4-yl, 2- Cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophen-5-yl, 2-(N-methoxyethyl-N- Methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophen-5-yl, 2-(2-hydroxy-2-methylethyl) Pheno-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5 -pyridyl, 2-difluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl , 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2- Methoxy-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-B Oxy-4-pyridyl, 2-methoxy-5-pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy- 4-pyridyl, 5-fluoro-2-hydroxyethoxy-4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy 5-ylpyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-( 1,1,1-trifluoroethoxy)-5-pyridyl, 2-cyclopropylmethoxy 5-5-pyridyl, 2-(methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl , 2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano 5-ylpyridyl, 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5 Pyridyl, 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2-sided oxy-1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxooxy 1,2-dihydropyridin-5-yl, 1-isopropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxo- 1,2-dihydropyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2 -dihydropyridin-4-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl , 3-methylaminocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl- 5-pyridyl, 2-methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonyl Aminoethylaminocarbonyl-5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethyl Aminocarbonyl-5-pyridyl, 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4- Pyridyl, 4-fluoro-2-methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl, 5-pyrimidinyl, 2-amino-5-pyrimidinyl , 2-cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethyl Oxy-5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl-4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylamine Carboylpyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-sided oxy-dihydro 5-5-fluorenyl, 6-fluorenyl, 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6- Mercapto, imidazo[1,2-a]pyridin-3-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridine-6-yl, 1 , 1-di-oxo-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-8-yl, benzoxazole-5- Benzo, benzoxazole-6-yl, 1,1-di-oxy-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine-8-yl 4-methyl-5-oxooxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazole- 5-yl, 2-ethylbenzoxazol-5-yl, 2-isopropylbenzoxazol-5-yl, 2-sided oxy-2(3H)-benzo[d]oxazole- 5-yl, benzothiazol-5-yl, benzothiazole-6-yl, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5 -carbazolyl, 1-methyl-6-oxazolyl, 2-methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4- 1,1,5-Dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-benzoisoxazole-5-yl, 2-methyl 3-oxo-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2-methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2 -b][1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzene And [d][1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxazol-5-yl, [1,2,4 Triazolo[4,3-a]pyridin-5-yl,[1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2 , 4] Triazolo[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl; and its medicine A salt that is acceptable for learning.

17.如技術方案1之化合物，其中R3為H或溴；及其醫藥學上可接受之鹽。 17. The compound of aspect 1, wherein R 3 is H or bromine; and the pharmaceutically acceptable salts thereof.

18.如技術方案1之化合物，其中G為CH；及其醫藥學上可接受之鹽。 18. The compound of claim 1 wherein G is CH; and a pharmaceutically acceptable salt thereof.

19.如技術方案1之化合物，其中G為C-Q；Q為H；P為-L-R6；且R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜 環基]羰基；及其醫藥學上可接受之鹽。 19. The compound of claim 1, wherein G is CQ; Q is H; P is -LR 6 ; and R 6 is a 5-membered nitrogen-containing heterocyclic group, a 5-membered oxygen-containing heterocyclic group, and a 6-membered nitrogen-containing heterocyclic ring. a 6-membered oxygen-containing heterocyclic group, a phenyl group, a benzyl group, a 9-membered bicyclic nitrogen-containing heterocyclic group, a 10-membered bicyclic oxygen-containing heterocyclic group or a 10-membered bicyclic nitrogen-containing heterocyclic group in which R 6 is unsubstituted or Substituted by one or more substituents independently selected from C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxy Carbonyl group, carboxyl group, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl group, C 1-6 alkylaminocarbonyl group, C 1-6 alkylamino group-C 1-6 alkylamino group Carbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; and pharmaceutically acceptable salts thereof.

20.如技術方案1之化合物，其中G為C-Q；Q為H；P為-L-R6；且R6為四氫呋喃基、四氫哌喃基、3,4-二氫-2H-哌喃并[3,2-c]吡啶基、烷基、哌啶基、吡啶基、吡唑基、苯基、喹啉基、1,2-二氫喹啉基、吡咯啶基、苄基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基或嘧啶基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 20. The compound of claim 1, wherein G is CQ; Q is H; P is -LR 6 ; and R 6 is tetrahydrofuranyl, tetrahydropyranyl, 3,4-dihydro-2H-pyrano[ 3,2-c]pyridyl, Alkyl, piperidinyl, pyridyl, pyrazolyl, phenyl, quinolyl, 1,2-dihydroquinolyl, pyrrolidinyl, benzyl, 5,6,7,8-tetrahydroquinoline , quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[ 3,4-b]pyridyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-a]pyridinyl or pyrimidinyl, wherein R 6 is unsubstituted or one or more Substituted independently of the following substituents: methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, ethoxycarbonyl, tert-butoxycarbonyl, carboxy, N-(A -N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof.

21.如技術方案1之化合物，其中G為C-Q；Q為H；P為-L-R6；且R6為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲 基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧 基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、 2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧 基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 21. The compound of aspect 1, wherein G is CQ; Q is H; P is -LR 6; and R 6 is benzyl, tetrahydropyran-4-yl, 3-fluoro - tetrahydropyran -4 -yl, 1-Boc-piperidin-4-yl, hexahydrofuro[2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridine , 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridine , 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-di Methyl-3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-B 3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-iso Propyl-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl 5-ylpyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxyl Propyl-5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl , 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3- Trifluoromethyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3 -pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5- Pyridyl, 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2 -Cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridine , 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5- 3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine-5-yl, 1,3-dimethyl-2- Sideoxypyridin-5-yl, 1-methyl-2-oxoylpyridin-5-yl, 2-methyl-6-oxo-pyridin-4-yl, 1-ethyl-2-oxo Pyridyl-5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl-6-oxopyridine-5-yl, 1 -different Propyl-2-p-oxypyridin-5-yl, 1,2-dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-sideoxy Pyridin-4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylamino) Carbonyl)-6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl 4-Chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidine-5 -yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazine-5-yl, 2-dimethylaminocarbonyl - pyrazin-5-yl, pyridazin-3-yl, 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5- Pyrazolyl, 1-ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5- Pyrazolyl, 1-methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazole-2- Base, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2 , 3-difluorobenzene , 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3- Dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5 -trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxy Phenyl, 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylamine Sulfosyl-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylbenzene Base, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5- Methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2- Ethylphenyl, 2-methyl-5-carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2- Fluoro-5-aminocarbonylphenyl, 2-cyanophenyl, 4-cyano , 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3 ,6-dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro 2-cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)amino Carbonyl]phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl- 5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl Carbonyl)phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl Phenyl, 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropyl) Methyl))aminocarbonyl)phenyl, 2-fluoro-5-(cyclo) Base)) aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl) Phenyl, 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5 -((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro- 5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-(( 1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5- ((1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro- 5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5- (1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2- Fluoro-5-(1-ethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl , 2-fluoro-5-(4-morpholinyl))aminocarbonyl)phenyl, 2-fluoro-5-((4- Polinylethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2- Methyl-1-tetrazolyl)phenyl, 3-(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolinyl, 6-quinolinyl, 7 -quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4-quinolinyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinoline ,5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7, 8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxalin-5-yl, 1-o-oxo-isoindol-4-yl, 1-sided oxy-isoindole啉-6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, 1, 3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1 , 2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-sided oxy-1,2 -dihydroquinolin-6-yl, 4-oxo-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5,7- Fluorine-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxo 1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6 -yl,5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquine Lolinyl, 6-isoquinolyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-B -1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl -1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazole And [3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H -imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl, 3-methylisoxazole[5,4 -b]pyridin-4-yl,[1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H- Pyrazolo[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof.

22.如技術方案1之化合物，其中L為O；及其醫藥學上可接受之鹽。 22. The compound of claim 1 wherein L is O; and a pharmaceutically acceptable salt thereof.

23.如技術方案1之化合物，其中G為C-Q；Q為-L-R5；P為H；且R5為5員雜環基、6員雜環基、苯基、苯基-C1-6烷基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基烷基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基； 及其醫藥學上可接受之鹽。 23. The compound of claim 1, wherein G is CQ; Q is -LR 5 ; P is H; and R 5 is a 5-membered heterocyclic group, a 6-membered heterocyclic group, a phenyl group, a phenyl-C 1-6 An alkyl group, a 9 membered nitrogen-containing heterocyclic group or a 10 membered nitrogen-containing heterocyclic group, wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, cyano , halo, pendant oxy, hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxyalkyl-C 1- 6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic ring a carbonyl group; and a pharmaceutically acceptable salt thereof.

24.如技術方案1之化合物，其中G為C-Q；Q為-L-R5；P為H；且R5為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R5未經取代或經一或多個獨立地選自以下之取代基取代：氟、氯、氰基、甲氧基、三氟甲基、乙氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基、側氧基、甲基、乙基或丁氧基羰基；及其醫藥學上可接受之鹽。 24. The compound of claim 1, wherein G is CQ; Q is -LR 5 ; P is H; and R 5 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl , hexahydrofuro[2,3-b]furanyl, 2,5-di-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1 , 2-dihydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazole [4,3-a]pyridyl, isoquinolyl, 1H-pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5 -a]pyridyl, isoxazolo[5,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydro -3H-pyrazolo[3,4-b]pyridinyl, 3,4-dihydro-2H-piperido[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, methoxy, trifluoromethyl, ethoxycarbonyl, carboxy , N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl) An aminocarbonyl group, (1-methylpyrazin-4-yl)carbonyl, pendant oxy, methyl, ethyl or butoxycarbonyl; and pharmaceutically acceptable salts thereof.

25.如技術方案1之化合物，其中G為C-Q；Q為-L-R5；P為H；且R5為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶 基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙 基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯 基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三 唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 25. The compound of aspect 1, wherein G is CQ; Q is -LR 5; P is H; and R 5 is benzyl, tetrahydropyran-4-yl, 3-fluoro - tetrahydropyran -4 -yl, 1-Boc-piperidin-4-yl, hexahydrofuro[2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridine , 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridine , 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-di Methyl-3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-B 3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-iso Propyl-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl 5-ylpyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxyl Propyl-5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl , 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3- Trifluoromethyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3 -pyridyl, 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5- Pyridyl, 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2 -Cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridine , 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5- 3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine-5-yl, 1,3-dimethyl-2- Sideoxypyridin-5-yl, 1-methyl-2-oxoylpyridin-5-yl, 2-methyl-6-oxo-pyridin-4-yl, 1-ethyl-2-oxo Pyridyl-5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl-6-oxopyridine-5-yl, 1 -different Propyl-2-p-oxypyridin-5-yl, 1,2-dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-sideoxy Pyridin-4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylamino) Carbonyl)-6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl 4-Chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidine-5 -yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazine-5-yl, 2-dimethylaminocarbonyl - pyrazin-5-yl, pyridazin-3-yl, 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5- Pyrazolyl, 1-ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5- Pyrazolyl, 1-methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazole-2- Base, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2 , 3-difluorobenzene , 2,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3- Dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5 -trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxy Phenyl, 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylamine Sulfosyl-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylbenzene Base, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5- Methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2- Ethylphenyl, 2-methyl-5-carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2- Fluoro-5-aminocarbonylphenyl, 2-cyanophenyl, 4-cyano , 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3 ,6-dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro 2-cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)amino Carbonyl]phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl- 5-[N-(methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl Carbonyl)phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl Phenyl, 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropyl) Methyl))aminocarbonyl)phenyl, 2-fluoro-5-(cyclo) Base)) aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl) Phenyl, 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5 -((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro- 5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-(( 1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5- ((1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro- 5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5- (1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2- Fluoro-5-(1-ethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl , 2-fluoro-5-(4-morpholinyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-? Polinylethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2- Methyl-1-tetrazolyl)phenyl, 3-(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolinyl, 6-quinolinyl, 7 -quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4-quinolinyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinoline ,5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7, 8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxalin-5-yl, 1-o-oxo-isoindol-4-yl, 1-sided oxy-isoindole啉-6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, 1, 3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1 , 2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-sided oxy-1,2 -dihydroquinolin-6-yl, 4-oxo-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5,7- Fluorine-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxo 1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6 -yl,5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquine Lolinyl, 6-isoquinolyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-B -1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl -1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazole And [3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H -imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl, 3-methylisoxazole[5,4 -b]pyridin-4-yl,[1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H- Pyrazolo[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof.

26.一種式IIc及式IId化合物， 其中： R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基或鹵基之取代基取代；R3為H、鹵基、烷氧基羰基、胺基羰基、氰基、氰基烷基、烷基羰基、雜環基羰基、烷基胺基羰基、烯基、炔基、羥基烯基、烷氧基烷氧基烷基、芳氧基烯基、烷氧基羰基烷基、烷基磺醯基烷基、烷基磺醯基烯基、烷基磺醯基炔基、雜環基炔基、雜環基羰基烷基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、鹵烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-C1-6烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環 基、羥基烷基、烷氧基烷基、側氧基、RR'N-、RR'N-C1-6烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'獨立地為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；L為O、S、CH2或CH2O；Q為-L-R5；且P為-L-R6；其限制條件為，當R3為H，R1為甲基，且L為O時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，L為O，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6- 基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，L為O，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，L為O，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，且R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基，L為O，且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基；及其醫藥學上可接受之鹽。 26. A compound of formula IIc and formula IId, Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or substituted by one or two independently selected from hydroxy, alkoxy, alkyl, pendant or halo groups. Substituent; R 3 is H, halo, alkoxycarbonyl, aminocarbonyl, cyano, cyanoalkyl, alkylcarbonyl, heterocyclylcarbonyl, alkylaminocarbonyl, alkenyl, alkynyl, hydroxy Alkenyl, alkoxyalkoxyalkyl, aryloxyalkenyl, alkoxycarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, alkylsulfonylalkynyl, hetero Cycloalkynyl, heterocyclylcarbonylalkyl, alkoxyalkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or -S(O)n; n is 0, 1 or 2; R 4 is an alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxy, alkenyl, alkoxy Carbocarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, aralkenyl, arylalkynyl a cycloalkylalkyl group, a cycloalkylalkenyl group, a cycloalkylalkynyl group, a heterocyclylalkyl group or a heterocyclic carbonylalkyl group; wherein the ring in R 4 is independently substituted with from 1 to 3 Substituent: H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, fluorenyl, alkylsulfonyl, heterocyclyl, aminosulfonyl, alkylaminosulfonate Anthracenyl, cyano, alkoxycarbonyl, carboxy, amine, RR'NC 1-6 alkyl, alkoxyalkyl, hydroxyalkyl or R a R b NC(=O), wherein R a is an alkane And R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a and R b together with nitrogen form an unsubstituted or alkyl substituted heterocycle; 5 is an aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclic group wherein R 5 is unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy Base, hydroxy, halo, haloalkyl, cyano, alkoxycarbonyl, carboxyl, fluorenyl , cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, pendant oxy, RR'N-, RR'NC 1-6 alkyl or R a R b NC(=O), wherein R a Is alkyl and R b is alkoxyalkyl or aminoalkyl; wherein R and R' are independently H, alkyl, aryl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein The heterocyclylalkyl, cycloalkyl and heterocyclyl rings are unsubstituted or substituted with from 1 to 3 independently selected from alkyl, alkoxy, hydroxy, halo, halo, cyano or carboxy Substituent; or R' and R together with N form a heterocyclic group; R 6 is aryl, aralkyl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein each of the foregoing rings is unsubstituted or 1-4 substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, cyano, cycloalkyl ,heterocyclyl, hydroxyalkyl, alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; L is O, S, CH 2 or CH 2 O; Q is -LR 5 And P is -LR 6 ; the restriction is that when R 3 is H, R 1 is methyl, and L is O, then R 5 is not [1,2,4]triazole [4,3- a]pyridyl Pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6 -yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl -1-Sideoxy-1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5 -Chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions That is, when R 3 is Br, L is O, and R 1 is a methyl group, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5 ,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl-1-sidedoxy-1,2- Dihydro-isoquinolin-6-yl; other restrictions: when R 3 is 1-methyl-1H-pyrazol-4-yl, L is O, and R 1 is methyl, then R 5 is not 1-ethyl -1H- pyrazol-5-yl; additional proviso that when R 3 is 1-methyl -1H- pyrazol-5-yl, L When O, and R 1 is methyl, then R 5 is not methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl, 5,7-difluoro-1,4 - dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl ; other restrictions: when L is O, R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridyl, and R 3 When it is 2-pyridylthio, bromo, methoxyethoxy or trifluoromethyl, R 1 is not phenyl or tert-butyl; other restrictions are, when R 3 is 2-pyridylthio, L When O is, and R 6 is 2-ethyl-3-pyridyl, R 1 is not 4-methyl-2-imidazolylmethyl; and a pharmaceutically acceptable salt thereof.

27.一種式IIIa化合物， 27. A compound of formula IIIa,

其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6 烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、胺基磺醯基、C1-6烷基胺基磺醯基、氰基、羧基、RR'N-C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)-，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5-6員雜環；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下 之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、氰基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、C1-6烷基-NRR'、胺基磺醯基、C1-6烷基胺基磺醯基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基，其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成5-10員雜環基；且其中R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基；及其醫藥學上可接受之鹽。 Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 alkyl, 5-10 membered heterocyclic or 5-10 membered heterocyclyl-C 1-6 alkyl, wherein the aryl or hetero The cycloalkyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant oxy or halo; wherein R 3 is -XR 4 , H, halo, cyanide , C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkenyl, C 2-6 Alkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy- C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl -C 1-6 alkyl, C 1-6 alkylamino -C 1-6 alkyl group, C 1-6 alkylsulfonyl group -C 1-6 alkyl, C 1-6 alkylsulfonyl group -C 2-6 alkenyl group, C 1-6 alkyl sulfo Mercapto-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1 -6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3 -6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl or a 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 is unsubstituted or independently selected from 1 to 3 Substituted by the following substituents: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, aminosulfonyl, C 1-6 alkylaminosulfonyl, Cyano, carboxyl, RR'NC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl or R a R b NC(=O)-, wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl Or a C 1-6 alkyl-C 1-6 aminoalkyl group, or a 5-6 member heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein X Is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1 -6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl , C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 naphthenic , C 5-6 cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 Aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2 -6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein the aryl, cycloalkyl, ring in R 4 The alkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 Alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclyl, cyano, amino, C 1-6 aminoalkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 alkyl-NRR', aminosulfonyl, C 1-6 alkylaminosulfonyl or R a R b NC(=O), wherein R a is C 1- 6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 amine An alkyl group, or a 5- or 6-membered heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein R and R' are independently H, C 1-6 alkane a phenyl group, a 5-10 membered heterocyclic group, a 5-10 membered heterocyclyl-C 1-6 alkyl group or a C 3-6 cycloalkyl group, wherein the heterocyclic group is a C 1-6 alkyl group, Phenyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl ring are unsubstituted or 1-3 independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo Substituted with a substituent of a C 1-6 haloalkyl group, a cyano group or a carboxy group; or R' and R together with N form a 5-10 membered heterocyclic group; and wherein R 6 is a 5-membered nitrogen-containing heterocyclic group, 5-membered oxygen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 6-membered oxygen-containing heterocyclic group, phenyl group, benzyl group, 9-membered bicyclic nitrogen-containing heterocyclic group, 10 membered bicyclic oxygen-containing heterocyclic group or 10 members double a cyclic nitrogen-containing heterocyclic group wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1- 6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; the limitation is that when R 3 is 2-pyridylthio, bromine , methoxyethoxy or trifluoromethyl, and when R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridinyl R 1 is not a phenyl group or a tert-butyl group; other restrictions are that when R 3 is 2-pyridylthio group and R 6 is 2-ethyl-3-pyridyl group, R 1 is not 4-methyl group 2-imidazolylmethyl; and pharmaceutically acceptable salts thereof.

28.如技術方案27之化合物，其中R1為甲基、乙基、丙基、烯丙 基、第三丁基、三氟-乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、BOC-胺基乙基、胺基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、苯乙基、嗎啉-4-基乙基、2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑-5-基甲基、1-甲基-咪唑-4-基甲基、1-甲基-咪唑-5-基甲基、4-甲基-咪唑-2-基甲基、5-甲基-咪唑-2-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑基-5-甲基、5-甲基-異噁唑-3-基甲基或苯基；及其醫藥學上可接受之鹽。 28. The compound of aspect 27, wherein R 1 is methyl, ethyl, propyl, allyl, tert-butyl, trifluoromethyl - ethyl, methoxy, methoxyethyl, hydroxyethyl , hydroxypropyl, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, BOC-aminoethyl, aminoethyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, phenethyl, morpholin-4-ylethyl, 2-pyridylmethyl, 3-pyridyl , 4-pyridylmethyl, 6-methyl-2-oxooxy-1,2-dihydropyridylmethyl, imidazo-5-ylmethyl, 1-methyl-imidazole-4-yl , 1-methyl-imidazolium-5-ylmethyl, 4-methyl-imidazol-2-ylmethyl, 5-methyl-imidazol-2-ylmethyl, 1,5-dimethylpyrazole 4-methylmethyl, 2-methylthiazolyl-5-methyl, 5-methyl-isoxazol-3-ylmethyl or phenyl; and pharmaceutically acceptable salts thereof.

29.如技術方案27之化合物，其中R1為甲基或乙基；及其醫藥學上可接受之鹽。 29. aspect of Compound 27, wherein R 1 is methyl or ethyl; and the pharmaceutically acceptable salts thereof.

30.如技術方案27之化合物，其中R3為-SR4；及其醫藥學上可接受之鹽。 30. aspect of Compound 27, wherein R 3 is -SR 4; and a pharmaceutically acceptable salt thereof.

31.如技術方案27之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫 基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1, 2-dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanyl Methoxy, methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-di Hydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl)thio, (2 -hydroxy-2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1- (tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentane Thiothio group, 4-hydroxycyclohexylthio group, cyclopentenylthio group, phenylthio group, benzylthio group, 2-pyridyl group Sulfuryl, 2-chloro-4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1 -Methylcarbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio (1-Isopropylcarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4- Thiothio, 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidine-2) -yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidine-4 -yl)thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro -2H-piperidin-4-ylthio; and pharmaceutically acceptable salts thereof.

32.如技術方案27之化合物，其中R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基 胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側 氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基、1,4-二氧雜螺[4.5]癸-7-烯-7-基，3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4- 基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2- 甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧 基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙 基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基，3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并 [3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基；及其醫藥學上可接受之鹽。 32. aspect of Compound 27, wherein R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methylbutyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2-hydroxy-2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1 , 2-dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethyl) Oxy)ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methyl Pentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxy Methoxymethyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl , propen-2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy-2-methylpropenyl, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2- Ethoxyvinyl, 2-hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(A Oxyethyl)aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-tert-butoxy Carbonylmethyl, ethoxycarbonylpropyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl Base, carboxyethyl, carboxypropyl, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxy-2-methylpropoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyne- 1-yl, cyclopentylmethyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonate Propyl, methylsulfonyl butyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl , 1-phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinyl Methyl, 1-piperidinylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazine-1- Methyl, 4-methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1, 1-Dioxy-ionic thiomorpholinyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan- 3-yl)methyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran 3-ylmethyl, 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolane-4- Propyl, 1,3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3] Hept-1-ylmethyl, 2-oxa-6-aza [3.3] Hept-6-ylmethyl, 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy- Cyclopentylmethyl, 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1-(methoxy Cyclopentyl)bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2 - pendant oxycyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl )-cyclobutyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxy Methylcyclopentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3-sided oxy- Cyclopentyl, 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl , cycloheptyl, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclo Alkenyl, 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-oxo-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-ene-1 -yl, cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4 -hydroxymethyl-cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl) Cyclohexenyl, 4-(3-fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl Cyclohexenyl, cycloheptenyl, 1,4-dioxaspiro[4.5]decan-7-en-7-yl, 3-hydroxy-3-oxetanyl, 2-tetrahydro- Furanyl, 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl-2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3-tetrahydro-furanyl, 2-oxopyryrrolidin-1-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5 ,5-tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxytetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran 3-yl, tetrahydropyran-2-yl, 3,6-dihydropyran-4-yl, 3,6-dihydropentan- 5-yl, 5,6-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-dimethyl-3,6-dihydro -2H-piperidin-4-yl, 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl, 3,4-2H-dihydropyran-4-yl, 1 ,4-dioxaspiro[4.5]dec-7-ene-8-yl, 1,1-di-oxy-isothiazolidin-2-yl, 1,1-dioxoisyltetrahydro-2H- Thioppyran-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,3,6- Tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxycarbonyl)-1,2,3, 6-tetrahydropyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1-(Dimethylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl , 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methyl Sulfosylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3 -methylsulfonylaminophenyl, 3-methyl Aminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6-methoxyphenyl 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(dimethylaminocarbonyl) Phenyl, 4-(dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl, 4-ethylamine Phenylcarbonylphenyl, 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N-methylaminocarbonyl Phenyl, 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-phenyl, 3-(N -methoxyethyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethylamine Phenylcarbonylphenyl, 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethylamine Phenylcarbonylphenyl, 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl-benzene 1,2-Dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-ylcarbonyl) Phenyl, 3-(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl, 3 -(4-morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methoxy Phenyl, 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonylphenyl 4-methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3-difluoro Methoxyphenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4 -dimethoxyphenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl- 4-pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[ 2,2,2-trifluoroethyl]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-B Oxycarbonylmethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-cyclobutyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4 -pyrazolyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methyl Oxyethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-tri Fluoromethyl-5-pyrazolyl, 3-methylaminocarbonyl-pyrazol-5-yl, 3-dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino -pyrazol-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2-methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazole , 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 1 -methyl-triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxypropyl-triazin-4-yl, 1-hydroxybutyl-triazin-4-yl, 2-cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophen-5-yl, 2-(N-methoxyethyl- N-methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophen-5-yl, 2-(2-hydroxy-2-methyl-ethyl Thiophen-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl , 2-methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl- 5-pyridyl, 2-difluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridine , 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2 -methoxy-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2- Ethoxy-4-pyridyl, 2-methoxy-5-pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy 4-pyridyl, 5-fluoro-2-hydroxyethoxy-4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methyl Oxy-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2- (1,1,1-trifluoroethoxy)-5-pyridyl, 2-cyclopropyl 5-ylpyridyl, 2-(methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridine Base, 2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2- Cyano-5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl- 5-pyridyl, 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl , 2-oxooxy-1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2- side Oxy-1,2-dihydropyridin-5-yl, 1-isopropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy -1,2-dihydropyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1, 2-Dihydropyridin-4-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridine , 3-methylaminocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl 5-5-pyridyl, 2-methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonyl Aminoethylaminocarbonyl-5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethyl Aminocarbonyl-5-pyridyl, 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4 -pyridyl, 4-fluoro-2-methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl, 5-pyrimidinyl, 2-amino-5-pyrimidine , 2-cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoro Ethoxy-5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl-4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethyl Aminocarbonylpyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-sided oxy-di Hydrogen-5-fluorenyl, 6-fluorenyl, 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro -6-fluorenyl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridine-6- 1,1,1-dihydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazol-8-yl, benzoxazole -5-yl, benzoxazole-6-yl, 1,1-di-oxy-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine- 8-yl, 4-methyl-5-oxooxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzo Oxazol-5-yl, 2-ethylbenzoxazol-5-yl, 2-isopropylbenzoxazol-5-yl, 2-sided oxy-2(3H)-benzo[d] Oxazol-5-yl, benzothiazol-5-yl, benzothiazole-6-yl, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl 5-yloxazolyl, 1-methyl-6-oxazolyl, 2-methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole 4-yl, 1,5-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2 -methyl-3-oxo-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-o-oxy-benzo[d]isoxazole-5 -yl, 2-methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3 ,2-b][1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy -Benzo[d][1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxazol-5-yl,[1,2 , 4] Triazolo[4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1 , 2,4]triazolo[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl; and its medicine A salt that is acceptable for learning.

33.如技術方案27之化合物，其中R6為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 33. aspect of Compound 27, wherein R 6 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyran-yl, piperidinyl, hexahydro-furo [2,3-b] furanyl, 2,5-di-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1,2-dihydroquinolinyl, 5,6,7, 8-tetrahydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazole [5,4- b] pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridyl , 3,4-dihydro-2H-piperido[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, Ethoxycarbonyl, tert-butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-( Methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof.

34.如技術方案27之化合物，其中R6為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲 基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲 基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙 基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、 4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 34. The compound of aspect 27, wherein R 6 is benzyl, tetrahydropyran-4-yl, 3-fluoro - tetrahydro-pyran-4-yl, 1-Boc- piperidin-4-yl, six Hydrofuro[2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl 3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl 5-ylpyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl -5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridine , 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methyl Vinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl -5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-di Hydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridine , 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoromethyl-6-pyridyl, 3-tri Fluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridine , 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl 5-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3- Pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5- Pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3- Methyl-5-pyridyl, 1,4-dimethyl-2-oxopurin-5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl -2-Sideoxypyridin-5-yl, 2-methyl-6-oxooxypyridin-4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1 -Methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl-6-oxoxypyridin-5-yl, 1-isopropyl-2-isooxypyridine-5 -base 1,2-Dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinyl Methyl)-3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methyl Oxyphenyl)-5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidine-6- , 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4- Trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl, pyridazin-3-yl ,1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1-ethyl-4-bromo-5 -pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1-methyl-3-dimethyl Aminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazol-2-yl, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro -3-methoxyphenyl , 2,4-difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl , 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyl Sulfophenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro- 5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxy Carbocarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl , 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2-cyanobenzene Base, 4-cyanophenyl, 2-cyano-3-methylphenyl 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro 4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3 ,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2- Cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[( Isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(A Oxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl) -N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3 -((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl)phenyl, 2-fluoro-3-((ethyl Amino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl))aminocarbonyl)phenyl, 2-fluoro -5-(cyclobutyl))aminocarbonyl)phenyl, 2- -5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxy) Propyl))aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)amino Carbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)benzene , 2-chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)amine Carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl) Aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)amine Phenylcarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl)) Aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl-piperidine- 4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-morpholinyl )) Aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)phenyl , 2-chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl , 3-(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolinyl, 6-quinolyl, 7-quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4-quinolyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetra Hydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxalin-5-yl, 1-o-oxo-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl- 1H-carbazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-carbazole- 4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinoline-6 -yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4 -Phenoxy-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4- Dimethyl-2-sidedoxy- 1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5 ,7-Difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1 -Methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl , 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridine- 3-Based, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridine-3 -yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo [1,2-a]pyridine-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-methylisoxazo[5,4-b]pyridin-4-yl, [1,2,4] Triazolo[4,3-a]pyridin-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-Methyl-3,4-dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof.

35.一種式IVa化合物， 35. A compound of formula IVa,

其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基-C1-6烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環 未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基，其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之取代基取代； 或R'及R可與N一起形成5-10員雜環基；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、胺基磺醯基、C1-6烷基胺基磺醯基、C1-6烷氧基羰基、羧基、氰基、5-16員雜環基、胺基、RR'N-C1-6烷基-、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；且其中R5為5員含氮雜環基、6員含氮雜環基、苯基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為H，R1為甲基時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基- 2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；及其醫藥學上可接受之鹽。 Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1 a -6 alkyl group, a C 6-10 aryl group, a C 6-10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group-C 1-6 alkyl group, wherein The aryl or heterocyclyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant or halo; wherein R 3 is -XR 4 , H , halo, cyano, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, Aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkenyl , C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl, C 1- 6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl -C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl -C 1-6 alkyl, C 1-6 alkyl -C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl group -C 1-6 alkyl, C 1-6 alkylsulfonyl group -C 2-6 alkenyl group, C 1-6 alkyl Sulfonyl-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl Or a 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 is unsubstituted or independently selected from 1 to 3 Substituted from the following substituents: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkyl sulfonium , C 1-6 alkoxycarbonyl, carboxy, 5-10 membered heterocyclyl, amine, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1 -6 hydroxyalkyl, C 1-6 haloalkoxy, RR 'NC 1-6 alkyl-, aminosulfonyl, C 1-6 alkylaminosulfonyl, cyano or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 aminoalkyl, or wherein R a and R b together with nitrogen form unsubstituted or substituted C 1-6 alkyl Or a 6-membered heterocyclic ring; wherein R and R' are independently H, C 1-6 alkyl, phenyl, 5-10 membered heterocyclic, 5-10 membered heterocyclyl-C 1-6 alkyl or C a 3-6 cycloalkyl group, wherein the heterocyclic group -C 1-6 alkyl group, phenyl group, C 3-6 cycloalkyl group and 5-10 membered heterocyclic ring are unsubstituted or 1-3 independent Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo, C 1-6 haloalkyl, cyano or carboxy; or R' and R may form together with N a 5-10 membered heterocyclic group; wherein X is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy- C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl- C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 Heterocyclyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3- 6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3 -6 cycloalkyl-C 2-6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein R 4 The aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, halo, C1-6 halo Base, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkyl Aminosulfonyl, C 1-6 alkoxycarbonyl, carboxyl, cyano, 5-16 membered heterocyclic, amine, RR'NC 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkane Oxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 aminoalkyl, or wherein R a and R b together with nitrogen form unsubstituted or a 5- or 6-membered heterocyclic ring substituted with a C 1-6 alkyl group; and wherein R 5 is a 5-membered nitrogen-containing heterocyclic group, a 6-membered nitrogen-containing heterocyclic group, a phenyl group, a 9-membered nitrogen-containing heterocyclic group or 10 members. a nitrogen-containing heterocyclic group wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, halo, pendant oxy , hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1 a -6 alkylaminocarbonyl group, a C 1-6 alkylamino group-C 1-6 alkylaminocarbonyl group or a [substituted 4-6 member nitrogen-containing heterocyclic group]carbonyl group; When R 3 is H and R 1 is methyl, then R 5 is not [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy -1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6-yl, 2-oxo-1,2-dihydroquinoline啉-6-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxo-1,2-dihydro-isoquine Porphyrin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1-methyl- 1H-carbazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are when R 3 is Br and R 1 is methyl Then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxo-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1- Methyl-2-oxo-4-trifluoromethyl-1,2-dihydro Polin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl or 2-methyl-1-side Oxy-1,2-dihydro-isoquinolin-6-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazol-4-yl and R 1 is methyl R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are, when R 3 is 1-methyl-1H-pyrazol-5-yl, and R 1 is methyl, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo- 1,2-Dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl; and pharmaceutically acceptable salts thereof.

36.如技術方案35之化合物，其中R1為甲基、乙基、丙基、異丙基、第三丁基、烯丙基、三氟乙基、甲氧基乙基、羥基乙基、羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、胺基乙基、苯基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、嗎啉-4-基乙基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑基甲基、1-甲基-咪唑基甲基、2-甲基噻唑基甲基或5-甲基-異噁唑基甲基；及其醫藥學上可接受之鹽。 36. The compound of aspect 35, wherein R 1 is methyl, ethyl, propyl, isopropyl, tertiary butyl, allyl, trifluoroethyl, methoxyethyl, hydroxyethyl, Hydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, aminoethyl, phenyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenyl Methyl, 4-fluorophenylmethyl, morpholin-4-ylethyl, pyridylmethyl, 6-methyl-2-oxooxy-1,2-dihydropyridylmethyl, imidazolyl a group, 1-methyl-imidazolylmethyl, 2-methylthiazolylmethyl or 5-methyl-isoxazolylmethyl; and pharmaceutically acceptable salts thereof.

37.如技術方案35之化合物，其中R1為甲基或乙基；及其醫藥學上可接受之鹽。 37. The compound of aspect 35, wherein R 1 is methyl or ethyl; and the pharmaceutically acceptable salts thereof.

38.如技術方案35之化合物，其中R3為-SR4；及其醫藥學上可接受之鹽。 38. The compound of aspect 35, wherein R 3 is -SR 4; and a pharmaceutically acceptable salt thereof.

39.如技術方案35之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 39. The compound of aspect 35, wherein R 3 is methoxy propoxy, 2- (methoxy) propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1, 2-dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanyl Methoxy, methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-di Hydroxybutylthio, carboxyethylthio, (methylaminocarbonyl)methylthio, (dimethylaminocarbonyl)methylthio, (3-hydroxy-3-methylbutyl)thio, (2 -hydroxy-2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1-tert-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1- (tetrahydro-2H-piperidin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentane Thiothio group, 4-hydroxycyclohexylthio group, cyclopentenylthio group, phenylthio group, benzylthio group, 2-pyridyl group Sulfuryl, 2-chloro-4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1-hydroxyvinylpiperidin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1 -Methylcarbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio (1-Isopropylcarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4- Thiothio, 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidine-2) -yl)piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidine-4 -yl)thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro -2H-piperidin-4-ylthio; and pharmaceutically acceptable salts thereof.

40.如技術方案35之化合物，其中R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1- 羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙 基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基、1,4-二氧雜螺[4.5]癸-7-烯-7-基，3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基 四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧 基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻 吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧 基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基，3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡 啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基；及其醫藥學上可接受之鹽。 40. The compound of claim 35, wherein R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-methylbutyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2-hydroxy-2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1 , 2-dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethyl) Oxy)ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methyl Pentyl, 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxy Methoxymethyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl , propen-2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl 1-hydroxy-2-methylpropenyl, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2- Ethoxyvinyl, 2-hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(A Oxyethyl)aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-tert-butoxy Carbonylmethyl, ethoxycarbonylpropyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl Base, carboxyethyl, carboxypropyl, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxy-2-methylpropoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyne- 1-yl, cyclopentylmethyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonate Propyl, methylsulfonyl butyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl , 1-phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinyl Methyl, 1-piperidinylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazine-1- Methyl, 4-methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1, 1-Dioxy-ionic thiomorpholinyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan- 3-yl)methyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran 3-ylmethyl, 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolane-4- Propyl, 1,3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3] Hept-1-ylmethyl, 2-oxa-6-aza [3.3] Hept-6-ylmethyl, 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy- Cyclopentylmethyl, 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1-(methoxy Cyclopentyl)bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2 - pendant oxycyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl )-cyclobutyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxy Methylcyclopentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3-sided oxy- Cyclopentyl, 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl , cycloheptyl, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclo Alkenyl, 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-oxo-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-ene-1 -yl, cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4 -hydroxymethyl-cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl) Cyclohexenyl, 4-(3-fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl Cyclohexenyl, cycloheptenyl, 1,4-dioxaspiro[4.5]decan-7-en-7-yl, 3-hydroxy-3-oxetanyl, 2-tetrahydro- Furanyl, 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl-2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3-tetrahydro-furanyl, 2-oxopyryrrolidin-1-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5 ,5-tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxytetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran 3-yl, tetrahydropyran-2-yl, 3,6-dihydropyran-4-yl, 3,6-dihydropyran 5-5-yl, 5,6-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-dimethyl-3,6-di Hydrogen-2H-piperazin-4-yl, 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl, 3,4-2H-dihydropyran-4-yl, 1,4-Dioxaspiro[4.5]dec-7-ene-8-yl, 1,1-di-oxy-isothiazolidin-2-yl, 1,1-dioxoisyltetrahydro-2H -thiopipet-4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,3,6 -tetrahydropyridin-4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxycarbonyl)-1,2,3 ,6-tetrahydropyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl , 1-(dimethylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylbenzene , 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2- Methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonylaminophenyl, 3-methyl Aminosulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6-methoxyphenyl 4-cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(dimethylaminocarbonyl) Phenyl, 4-(dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl, 4-ethylamine Phenylcarbonylphenyl, 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N-methylaminocarbonyl Phenyl, 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-phenyl, 3-(N -methoxyethyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethylamine Phenylcarbonylphenyl, 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethylamine Phenylcarbonylphenyl, 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl-benzene 1,2-Dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-ylcarbonyl) Phenyl, 3-(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl, 3 -(4-morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methoxy Phenyl, 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonylphenyl 4-methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3-difluoro Methoxyphenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4 -dimethoxyphenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl- 4-pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[ 2,2,2-trifluoroethyl]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-B Carbocarbonylmethyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-cyclobutyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4- Pyrazolyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxy Benzyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoro Methyl-5-pyrazolyl, 3-methylaminocarbonyl-pyrazol-5-yl, 3-dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino- Pyrazol-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2-methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl , 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazol-4-yl, 1- Methyl-triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxypropyl-triazin-4-yl, 1-hydroxybutyl-triazin-4-yl, 2 -cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophen-5-yl, 2-(N-methoxyethyl-N -Methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophen-5-yl, 2-(2-hydroxy-2-methylethyl Thiophen-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl , 2-methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl- 5-pyridyl, 2-difluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridine , 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2 -methoxy-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2- Ethoxy-4-pyridyl, 2-methoxy-5-pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy 4-pyridyl, 5-fluoro-2-hydroxyethoxy-4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methyl Oxy-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2- (1,1,1-trifluoroethoxy)-5-pyridyl, 2-cyclopropyl 5-ylpyridyl, 2-(methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridine Base, 2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2- Cyano-5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl- 5-pyridyl, 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl , 2-oxooxy-1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2- side Oxy-1,2-dihydropyridin-5-yl, 1-isopropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy -1,2-dihydropyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1, 2-Dihydropyridin-4-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridine , 3-methylaminocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl 5-5-pyridyl, 2-methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonyl Aminoethylaminocarbonyl-5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethyl Aminocarbonyl-5-pyridyl, 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4 -pyridyl, 4-fluoro-2-methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl, 5-pyrimidinyl, 2-amino-5-pyrimidine , 2-cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoro Ethoxy-5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl-4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethyl Aminocarbonylpyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-sided oxy-di Hydrogen-5-fluorenyl, 6-fluorenyl, 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro- 6-fluorenyl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl 1,1-di-oxo-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-8-yl, benzoxazole- 5-yl, benzoxazole-6-yl, 1,1-di-oxy-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine-8 -yl, 4-methyl-5-oxooxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzone Zylo-5-yl, 2-ethylbenzoxazol-5-yl, 2-isopropylbenzoxazol-5-yl, 2-sided oxy-2(3H)-benzo[d] Zyrid-5-yl, benzothiazol-5-yl, benzothiazole-6-yl, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl 5-5-carbazolyl, 1-methyl-6-oxazolyl, 2-methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole- 4-yl, 1,5-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-benzoisoxazole-5-yl, 2- Methyl-3-oxo-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5- , 2-methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3, 2-b][1,4]thiazin-7-yl, 2-o-oxy-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sideoxy- Benzo[d][1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxazol-5-yl, [1,2, 4] Triazolo[4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1, 2,4]triazolo[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl; and its medicine A salt that is acceptable for learning.

41.如技術方案35之化合物，其中R5為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 41. The compound of aspect 35, wherein R 5 is a pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyran-yl, piperidinyl, hexahydro-furo [2,3-b] furanyl, 2,5-di-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1,2-dihydroquinolinyl, 5,6,7, 8-tetrahydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazole [5,4- b] pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridyl , 3,4-dihydro-2H-piperido[2,3-b]pyridinyl or An alkyl or pyrimidinyl group, wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, Ethoxycarbonyl, butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl -N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof.

42.如技術方案35之化合物，其中R5為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、 2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰 基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯 基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯 基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 42. The compound of aspect 35, wherein R 5 is benzyl, tetrahydropyran-4-yl, 3-fluoro - tetrahydro-pyran-4-yl, 1-Boc- piperidin-4-yl, six Hydrofurop[2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl 3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl 5-ylpyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl -5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridine , 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methyl Vinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl -5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-di Hydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridine , 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoromethyl-6-pyridyl, 3-tri Fluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridine , 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl 5-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3- Pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5- Pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3- Methyl-5-pyridyl, 1,4-dimethyl-2-oxopurin-5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl -2-Sideoxypyridin-5-yl, 2-methyl-6-oxooxypyridin-4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1 -Methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl-6-oxoxypyridin-5-yl, 1-isopropyl-2-isooxypyridine-5 -base 1,2-Dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinyl Methyl)-3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methyl Oxyphenyl)-5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidine-6- , 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4- Trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl, pyridazin-3-yl ,1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1-ethyl-4-bromo-5 -pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1-methyl-3-dimethyl Aminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazol-2-yl, phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro -3-methoxybenzene , 2,4-difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl , 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyl Sulfophenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro- 5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxy Carbocarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl , 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2-cyanobenzene Base, 4-cyanophenyl, 2-cyano-3-methylphenyl 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro 4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3 ,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2- Cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[( Isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(A Oxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl) -N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3 -((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl)phenyl, 2-fluoro-3-((ethyl Amino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl))aminocarbonyl)phenyl, 2-fluoro -5-(cyclobutyl))aminocarbonyl)phenyl, 2- -5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxy) Propyl))aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)amino Carbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)benzene , 2-chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)amine Carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl) Aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)amine Phenylcarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl)) Aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl-piperidine- 4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-morpholinyl )) Aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)benzene , 2-chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl , 3-(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolinyl, 6-quinolyl, 7-quinolinyl, 8-quinolinyl, 5-chloro-6-quinolinyl, 7-chloro-4-quinolyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetra Hydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxalin-5-yl, 1-o-oxo-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl- 1H-carbazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-carbazole- 4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinoline-6 -yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4 -Phenoxy-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4- Dimethyl-2-sidedoxy- 1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5 ,7-Difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1 -Methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl , 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridine- 3-Based, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridine-3 -yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo [1,2-a]pyridine-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-methylisoxazo[5,4-b]pyridin-4-yl, [1,2,4] Triazolo[4,3-a]pyridin-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-Methyl-3,4-dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof.

在式I內特別受關注之一系列特定化合物由如下化合物及其醫藥學上可接受之衍生物組成：1-(5-苄基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲； 1-甲基-3-(5-(1-甲基-1H-吡唑-4-基)-4-(喹啉-5-基氧基)吡啶-2-基)脲；1-甲基-3-(5-(1-甲基-1H-吡唑-5-基)-4-(喹啉-5-基氧基)吡啶-2-基)脲；1-(5-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；1-(4-(3-氯-2-氟苯氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-5-((3-甲氧基丙基)硫基)吡啶-2-基)-3-甲基脲；1-(5-(3-甲氧基丙硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲；1-(5-(4-甲氧基丁-2-基硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲；1-乙基-3-(5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基)脲；1-甲基-3-(4-(喹啉-5-基氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲；1-(5-(環戊-1-烯-1-基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-5-(1,4-二氧雜螺[4.5]癸-7-烯-8-基)吡啶-2-基)-3-甲基脲；(E)-1-(5-(2-環丙基乙烯基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲；1-(5-環庚基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲；1-(5-環戊基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-5-異丙基吡啶-2-基)-3-甲基脲；4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸乙酯；1-(4-(3-氯-2-氟苯氧基)-5-(3-(甲基磺醯基)苯基)吡啶-2-基)-3-甲基脲；1-(4-(3-氯-2-氟苯氧基)-5-(3,4-二甲氧基苯基)吡啶-2-基)-3-甲基脲；1-(4-(3-氯-2-氟苯氧基)-5-(3-甲氧基苯基)吡啶-2-基)-3-甲基脲；3-(4-(3-氯-2-氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N,N-二甲基苄醯胺；1-(4-(3-氯-2-氟苯氧基)-5-(4-甲氧基苯基)吡啶-2-基)-3-甲基脲；3-(4-(3-氯-2-氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基苯磺醯胺； (Z)-1-(4-(2,6-二氟苯氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-5-苯基吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-5-(4-甲氧基苯基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-6'-甲氧基-3,3'-聯吡啶-6-基)-3-甲基脲；N-(3-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)苯基)甲烷磺醯胺；1-(4-(2,6-二氟苯氧基)-5-(3-甲氧基苯基)吡啶-2-基)-3-甲基脲；1-(4-(3-氯-2-氟苯氧基)-2'-氰基-[3,4'-聯吡啶]-6-基)-3-甲基脲；1-(5-(3-(二氟甲基)-4-氟苯基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲；(S)-1-(6'-甲氧基-5-(5,6,7,8-四氫喹啉-5-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲；4-((6-(3-甲基脲基)-5-(喹啉-5-基氧基)吡啶-3-基)硫基)哌啶-1-甲酸第三丁酯；1-(5-((3-甲氧基丙基)硫基)-3-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；1-(3-(2-乙基吡啶-3-基氧基)-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲；1-(3-(2-乙基吡啶-3-基氧基)-5-(四氫-2H-哌喃-4-基硫基)吡啶-2-基)-3-甲基脲；1-(3-(2-乙基吡啶-3-基氧基)-5-(3-羥基-3-甲基丁硫基)吡啶-2-基)-3-甲基脲；1-(3-(2-乙基吡啶-3-基氧基)-5-(順-4-羥基環己基硫基)吡啶-2-基)-3-甲基脲；(S)-1-(5-(3-羥基-3-甲基丁硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；(S)-1-甲基-3-(5-((四氫-2H-哌喃-4-基)甲硫基)-3-(5,6,7,8-四氫喹啉-5- 基氧基)吡啶-2-基)脲；(S)-1-甲基-3-(5-(四氫-2H-哌喃-4-基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲；1-(5-(順-4-羥基環己基硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；(S)-1-(5-(環戊-3-烯基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；(R)-1-(5-(3-甲氧基丙硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲鹽酸鹽或(S)-1-(5-(3-甲氧基丙硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲鹽酸鹽之一；1-(5-(1-異丁醯基哌啶-4-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲；1-(3-(2-乙基吡啶-3-基氧基)-5-(1-(甲基磺醯基)哌啶-4-基硫基)吡啶-2-基)-3-甲基脲；4-(5-(1-乙基-1H-吡唑-5-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)-N,N-二甲基哌啶-1-甲醯胺；4-(5-(1-乙基-1H-吡唑-5-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)哌啶-1-甲酸甲酯；1-(5-(1-(5-氯吡嗪-2-基)哌啶-4-基硫基)-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲；1-(5-(順-3,4-二羥基環戊基硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；1-(3-(2-乙基吡啶-3-基氧基)-5-(反-4-羥基環己基硫基)吡啶-2-基)-3-甲基脲；1-(5-(環己基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲；1-(3-((2-乙基吡啶-3-基)氧基)-5-(苯基乙炔基)吡啶-2-基)-3-甲基脲； 1-(5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-5-(2-羥基乙基)吡啶-2-基)-3-甲基脲；1-(4-(2,6-二氟苯氧基)-2'-(三氟甲基)-3,4'-聯吡啶-6-基)-3-甲基脲；1-(5-環丙基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲；(S)-1-甲基-3-(5-(四氫-2H-哌喃-4-基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲；1-(3-((2-乙基吡啶-3-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲；及1-(5-環丙基-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲。在式I內特別受關注之一系列特定化合物由如下化合物及其醫藥學上可接受之衍生物組成：1-(3-(1-乙基-1H-吡唑-5-基)氧基)-(5-(3-羥基-3-甲基環丁基)-2-吡啶基)-3-甲基脲；1-(6'-(2-羥基-2-甲基丙氧基)-4-((5-甲基-3-吡啶基)氧基)-3,3'-聯吡啶-6-基)-3-甲基脲；1-(4-((5-甲氧基-3-吡啶基)氧基)-5-((3R)-四氫-2H-哌喃-3-基)-2-吡啶基)-3-甲基脲；1-(5-環丙基-4-((1,2-二甲基-6-側氧基-1,6-二氫-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(順-3-羥基環丁基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((1,2-二甲基-6-側氧基-1,6-二氫-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲氧基-3-吡啶基)氧基)-2-吡啶基)- 3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(2-羥基乙基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；或1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(四氫-2H-哌喃-4-基甲基)-2-吡啶基)-3-甲基脲。 A particular class of compounds of particular interest in Formula I consists of the following compounds and their pharmaceutically acceptable derivatives: 1-(5-benzyl-4-(2,6-difluorophenoxy)pyridine- 2-yl)-3-methylurea; 1-methyl-3-(5-(1-methyl-1H-pyrazol-4-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)urea; 1-methyl -3-(5-(1-methyl-1H-pyrazol-5-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)urea; 1-(5-(1- (2-methoxyethyl)-1H-pyrazol-4-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea; 1-(4- (3-chloro-2-fluorophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea; 1-(4-(2 ,6-difluorophenoxy)-5-((3-methoxypropyl)thio)pyridin-2-yl)-3-methylurea; 1-(5-(3-methoxypropane) Thio)-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea; 1-(5-(4-methoxybut-2-ylthio)-4 -(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea; 1-ethyl-3-(5-(3-methoxypropylthio)-4-(quinoline) -5-yloxy)pyridin-2-yl)urea; 1-methyl-3-(4-(quinolin-5-yloxy)-2'-(trifluoromethyl)-[3,4 '-Bipyridyl]-6-yl)urea; 1-(5-(cyclopent-1-en-1-yl)-4-(2,6-difluorophenoxy)pyridin-2-yl)- 3-methylurea; 1-(4-(2,6-difluorophenoxy)-5-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)pyridine-2 -yl)-3-methylurea; (E)-1-(5-(2-cyclopropylvinyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3 -methyl ; 1-(5-cycloheptyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea; 1-(5-cyclopentyl-4-(2, 6-difluorophenoxy)pyridin-2-yl)-3-methylurea; 1-(4-(2,6-difluorophenoxy)-5-isopropylpyridin-2-yl)- 3-methylurea; ethyl 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)butanoate; 1-(4-( 3-chloro-2-fluorophenoxy)-5-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-3-methylurea; 1-(4-(3-chloro-) 2-fluorophenoxy)-5-(3,4-dimethoxyphenyl)pyridin-2-yl)-3-methylurea; 1-(4-(3-chloro-2-fluorophenoxy) 5-(3-methoxyphenyl)pyridin-2-yl)-3-methylurea; 3-(4-(3-chloro-2-fluorophenoxy)-6-(3- Methylurea)pyridin-3-yl)-N,N-dimethylbenzylamine; 1-(4-(3-chloro-2-fluorophenoxy)-5-(4-methoxybenzene Pyridin-2-yl)-3-methylurea; 3-(4-(3-chloro-2-fluorophenoxy)-6-(3-methylureido)pyridin-3-yl)- N-methylbenzenesulfonamide; (Z)-1-(4-(2,6-difluorophenoxy)-5-(2-ethoxyvinyl)pyridin-2-yl)-3-methylurea; 1-(4- (2,6-difluorophenoxy)-5-phenylpyridin-2-yl)-3-methylurea; 1-(4-(2,6-difluorophenoxy)-5-(4 -Methoxyphenyl)pyridin-2-yl)-3-methylurea; 1-(4-(2,6-difluorophenoxy)-6'-methoxy-3,3'-linked Pyridine-6-yl)-3-methylurea; N-(3-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)benzene Methanesulfonamide; 1-(4-(2,6-difluorophenoxy)-5-(3-methoxyphenyl)pyridin-2-yl)-3-methylurea; (4-(3-Chloro-2-fluorophenoxy)-2'-cyano-[3,4'-bipyridyl]-6-yl)-3-methylurea; 1-(5-(3) -(Difluoromethyl)-4-fluorophenyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea; (S)-1-(6' -methoxy-5-(5,6,7,8-tetrahydroquinolin-5-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea; 4-( (6-(3-methylureido)-5-(quinolin-5-yloxy)pyridin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester; 1-(5-( (3-methoxypropyl)thio)-3-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea; 1-(3-(2-ethylpyridine)- 3-yloxy)-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea; 1-(3-(2-ethylpyridine) -3-yloxy)-5-(tetrahydro-2H-piperazin-4-ylthio)pyridin-2-yl)-3-methylurea; 1-(3-(2-ethylpyridine)- 3-yloxy)-5-(3-hydroxy-3-methylbutylthio)pyridin-2-yl)-3-methylurea; 1-(3-(2-ethylpyridin-3-yl) Oxy)-5-(cis-4-hydroxycyclohexylthio)pyridin-2-yl)-3-methylurea; (S)-1-(5-(3-hydroxy-3-methylbutylsulfuric) 3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea; (S)-1-methyl-3-( 5-((tetrahydro-2H-piperidin-4-yl)methylthio)-3-(5,6,7,8-tetrahydroquinolin-5- (oxy)pyridin-2-yl)urea; (S)-1-methyl-3-(5-(tetrahydro-2H-piperidin-4-ylthio)-3-(5,6,7 , 8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)urea; 1-(5-(cis-4-hydroxycyclohexylthio)-3-((S)-5,6, 7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea; (S)-1-(5-(cyclopent-3-enylthio)-3 -(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea; (R)-1-(5-(3-methoxypropane) Thio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea hydrochloride or (S)-1-(5) -(3-methoxypropylthio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea hydrochloride 1-(5-(1-Isobutylphosphazin-4-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea; 1-(3-(2-ethylpyridin-3-yloxy)-5-(1-(methylsulfonyl)piperidin-4-ylthio)pyridin-2-yl)-3-methyl 4-urea; 4-(5-(1-ethyl-1H-pyrazol-5-yloxy)-6-(3-methylureido)pyridin-3-ylthio)-N,N-di Methylpiperidine-1-carboxamide; 4-(5-(1-ethyl-1H-pyrazol-5-yloxy)-6-(3-methylureido)pyridin-3-ylsulfide Methyl) piperidine-1-carboxylate; 1-(5-(1-(5-chloropyrazin-2-yl)piperidin-4-yl) 3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea; 1-(5-(cis-3,4-dihydroxycyclopentylthio) )-3-((S)-5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea; 1-(3-(2-B) Pyridyl-3-yloxy)-5-(trans-4-hydroxycyclohexylthio)pyridin-2-yl)-3-methylurea; 1-(5-(cyclohexylmethyl)-3- ((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea; 1-(3-((2-ethylpyridin-3-yl)oxy)-5 -(phenylethynyl)pyridin-2-yl)-3-methylurea; 1-(5-(3-methoxypropylthio)-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea; 1-(4-(2,6) -difluorophenoxy)-5-(2-hydroxyethyl)pyridin-2-yl)-3-methylurea; 1-(4-(2,6-difluorophenoxy)-2'- (trifluoromethyl)-3,4'-bipyridin-6-yl)-3-methylurea; 1-(5-cyclopropyl-4-(2,6-difluorophenoxy)pyridine- 2-yl)-3-methylurea; (S)-1-methyl-3-(5-(tetrahydro-2H-piperidin-4-ylthio)-3-(5,6,7, 8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)urea; 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(4-hydroxy-4) -methylpentyl)pyridin-2-yl)-3-methylurea; and 1-(5-cyclopropyl-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl) -3-methylurea. A particular class of compounds of particular interest in Formula I consists of the following compounds and their pharmaceutically acceptable derivatives: 1-(3-(1-ethyl-1H-pyrazol-5-yl)oxy) -(5-(3-hydroxy-3-methylcyclobutyl)-2-pyridyl)-3-methylurea; 1-(6'-(2-hydroxy-2-methylpropoxy)- 4-((5-methyl-3-pyridyl)oxy)-3,3'-bipyridin-6-yl)-3-methylurea; 1-(4-((5-methoxy)- 3-pyridyl)oxy)-5-((3R)-tetrahydro-2H-pyran-3-yl)-2-pyridyl)-3-methylurea; 1-(5-cyclopropyl- 4-((1,2-dimethyl-6-oxooxy-1,6-dihydro-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; 1-(5 -(cis-3-hydroxycyclobutyl)-4-((5-methyl-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; 1-(5-(5, 6-Dihydro-2H-piperid-3-yl)-4-((5-methyl-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; 1-(5- (5,6-Dihydro-2H-pyran-3-yl)-4-((1,2-dimethyl-6-oxo-oxy-1,6-dihydro-3-pyridyl)oxy )-2-pyridyl)-3-methylurea; 1-(5-(5,6-dihydro-2H-piperidin-3-yl)-4-((5-methoxy-3-pyridine) Ethyl)-2-pyridyl)- 3-methylurea; 1-(5-(5,6-dihydro-2H-piperidin-3-yl)-4-((5-methyl-3-pyridyl)oxy)-2-pyridine 3-methylurea; 1-(5-(2-hydroxyethyl)-4-((5-methyl-3-pyridyl)oxy)-2-pyridyl)-3-methyl Urea; or 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(tetrahydro-2H-piperidin-4-ylmethyl)-2-pyridyl )-3-methylurea.

本發明之另一態樣係關於一種醫藥組合物，其包含式I-IV及式Ia、式IIc、式IId、式IIIa及式IVa化合物及醫藥學上可接受之稀釋劑或載劑。 Another aspect of the invention pertains to a pharmaceutical composition comprising a compound of Formulas I-IV and Formula Ia, Formula IIc, Formula IId, Formula IIIa and Formula IVa, and a pharmaceutically acceptable diluent or carrier.

本發明之另一態樣係關於任一上述實施例之化合物作為藥物之用途。 Another aspect of the invention pertains to the use of a compound of any of the above embodiments as a medicament.

本發明之另一態樣係關於任一上述實施例之化合物製造用於治療糖尿病之藥物的用途。 Another aspect of the invention is the use of a compound of any of the above embodiments for the manufacture of a medicament for the treatment of diabetes.

本發明化合物一般可具有若干不對稱中心且通常以外消旋混合物之形式描繪。本發明欲涵蓋外消旋混合物、部分外消旋混合物及各別對映異構體及非對映異構體。 The compounds of the invention may generally have several asymmetric centers and are typically depicted in the form of a racemic mixture. The present invention is intended to cover racemic mixtures, partial racemic mixtures, and individual enantiomers and diastereomers.

本發明包括所有醫藥學上可接受之經同位素標記之本發明化合物，其中一或多個原子經原子序數相同，但原子質量或質量數不同於自然界中占主導之原子質量或質量數的原子置換。 The invention includes all pharmaceutically acceptable isotope-labeled compounds of the invention wherein one or more atoms have the same atomic number, but the atomic mass or mass number differs from the atomic mass or mass number of the dominant atom in nature. .

適合包含於本發明化合物中之同位素的實例包括(但不限於)氫同位素，諸如2H及3H；碳同位素，諸如11C、13C及14C；氯同位素，諸如38Cl；氟同位素，諸如18F；碘同位素，諸如123I及125I；氮同位素，諸如13N及15N；氧同位素，諸如15O、17O及18O；磷同位素，諸如32P；及硫同位素，諸如35S。 Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, hydrogen isotopes such as 2 H and 3 H; carbon isotopes such as 11 C, 13 C and 14 C; chlorine isotopes such as 38 Cl; fluorine isotope, Such as 18 F; iodine isotopes such as 123 I and 125 I; nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 O, 17 O and 18 O; phosphorus isotopes such as 32 P; and sulfur isotopes such as 35 S.

某些經同位素標記之本發明化合物(例如併有放射性同位素者)適用於藥物及/或受質組織分佈研究。放射性同位素氚(亦即3H)及碳- 14(亦即14C)由於其易於併入及現成的偵測手段而尤其適用於達成此目的。 Certain isotopically-labeled compounds of the invention (e.g., with radioisotopes) are useful for drug and/or matrix distribution studies. The radioisotope iridium (also known as 3 H) and carbon-14 (ie 14 C) are particularly suitable for this purpose due to their ease of integration and ready-to-use detection means.

經諸如氘(亦即2H)之較重同位素取代可提供由較大代謝穩定性產生之某些治療優勢，例如活體內半衰期延長或劑量需求降低，且因此在一些情況下可能較佳。 Substitution with heavier isotopes such as hydrazine (i.e., 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances.

經正電子發射同位素(諸如11C、18F、15O及13N)取代可適用於正電子發射斷層攝影術(PET)研究，以檢查受質受體佔有率。 Substitution with positron-emitting isotopes (such as 11 C, 18 F, 15 O, and 13 N) can be applied to positron emission tomography (PET) studies to examine receptor receptor occupancy.

經同位素標記之本發明化合物一般可藉由熟習此項技術者已知之習知技術，或藉由與附隨實例及製備中所述製程類似之製程使用經同位素標記之適當試劑替代先前採用之未經標記試劑來製備。 Isotopically labeled compounds of the invention can generally be substituted for previously employed by conventional techniques known to those skilled in the art, or by procedures analogous to those described in the accompanying Examples and Preparations, using isotopically labeled appropriate reagents. Prepared by labeling reagents.

符合本發明之醫藥學上可接受之溶劑合物包括其中結晶化溶劑可經同位素取代(例如D2O、d6-丙酮、d6-DMSO)之溶劑合物。 Acceptable consistent with the present invention the pharmaceutically acceptable solvates include those wherein the solvent of crystallization may be isotopically substituted (e.g., D 2 O, d 6 - acetone, d 6 -DMSO) of the solvate.

本發明之特定實施例包括下文實例中所例示之化合物及其醫藥學上可接受之鹽、複合物、溶劑合物、多晶型物、立體異構體、代謝物、前藥及其他衍生物。除非另有規定，否則以下定義適用於說明書及申請專利範圍中所見之術語：術語「H」表示單一氫原子。此基團可連接於例如氧原子以形成羥基。 Particular embodiments of the invention include the compounds exemplified in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs and other derivatives . Unless otherwise specified, the following definitions apply to the terms used in the specification and patent application: the term "H" means a single hydrogen atom. This group may be attached to, for example, an oxygen atom to form a hydroxyl group.

單獨或在諸如「鹵烷基」及「烷基胺基」之其他術語內使用術語「烷基」時，其涵蓋具有一個至約十二個碳原子之直鏈或分支鏈基團。更佳烷基為具有一個至約六個碳原子之「低碳烷基」基團。該等基團之實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、己基及其類似基團。具有1個或2個碳原子之低碳烷基甚至更佳。術語「伸烷基」涵蓋橋連二價烷基，諸如亞甲基及伸乙基。 When the term "alkyl" is used alone or in other terms such as "haloalkyl" and "alkylamino", it encompasses straight or branched chain groups having from one to about twelve carbon atoms. More preferred alkyl groups are "lower alkyl" groups having from one to about six carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, pentyl, isopentyl, hexyl and the like. Group. A lower alkyl group having 1 or 2 carbon atoms is even more preferred. The term "alkylene" encompasses bridged divalent alkyl groups such as methylene and ethyl.

術語「烯基」涵蓋具有兩個至約十二個碳原子之直鏈或分支鏈 基團。更佳烯基為具有兩個至約六個碳原子之「低碳烯基」基團。該等基團之實例包括乙烯基、烯丙基及其類似基團。具有二至三個碳原子之低碳烯基甚至更佳。 The term "alkenyl" encompasses straight or branched chains having from two to about twelve carbon atoms. Group. More preferred alkenyl groups are "lower alkenyl" groups having from two to about six carbon atoms. Examples of such groups include vinyl groups, allyl groups, and the like. A lower alkenyl group having two to three carbon atoms is even more preferred.

術語「炔基」涵蓋具有兩個至約十二個碳原子之直鏈或分支鏈基團。更佳炔基為具有兩個至約六個碳原子之「低碳炔基」基團。該等基團之實例包括乙炔基及其類似基團。具有二至三個碳原子之低碳炔基甚至更佳。 The term "alkynyl" encompasses straight or branched chain groups having from two to about twelve carbon atoms. More preferred alkynyl groups are "lower alkynyl" groups having from two to about six carbon atoms. Examples of such groups include ethynyl groups and the like. A lower alkynyl group having two to three carbon atoms is even more preferable.

術語「鹵基」意謂鹵素，諸如氟、氯、溴或碘原子。 The term "halo" means a halogen such as a fluorine, chlorine, bromine or iodine atom.

術語「鹵烷基」涵蓋其中任何一或多個烷基碳原子經如上文所定義之鹵基取代之基團。特別涵蓋單鹵烷基、二鹵烷基及多鹵烷基，包括全鹵烷基。列舉一例，單鹵烷基在該基團內可具有碘、溴、氯或氟原子。二鹵烷基及多鹵烷基可具有兩個或兩個以上相同鹵原子或不同鹵基之組合。「低碳鹵烷基」涵蓋具有1-6個碳原子之基團。具有一至三個碳原子之低碳鹵烷基甚至更佳。鹵烷基之實例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基及二氯丙基。「全氟烷基」意謂所有氫原子經氟原子置換之烷基。實例包括三氟甲基及五氟乙基。 The term "haloalkyl" encompasses groups wherein any one or more alkyl carbon atoms are replaced by a halo group as defined above. Particularly contemplated are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups, including perhaloalkyl groups. As an example, a monohaloalkyl group may have an iodine, bromine, chlorine or fluorine atom in the group. The dihaloalkyl group and the polyhaloalkyl group may have two or more of the same halogen atoms or a combination of different halo groups. "Lower halohaloalkyl" encompasses groups having from 1 to 6 carbon atoms. A lower halogen haloalkyl group having one to three carbon atoms is even more preferred. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, Dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means an alkyl group in which all hydrogen atoms are replaced by a fluorine atom. Examples include trifluoromethyl and pentafluoroethyl.

術語「羥基烷基」意謂其中一或多個氫已經羥基置換之烷基。 The term "hydroxyalkyl" means an alkyl group in which one or more hydrogens have been replaced by a hydroxy group.

術語「羥基炔基」意謂其中一或多個氫已經羥基置換之炔基。 The term "hydroxyalkynyl" means an alkynyl group in which one or more hydrogens have been replaced by a hydroxy group.

術語「胺基烷基」意謂其中一或多個氫已經胺基置換之烷基。 The term "aminoalkyl" means an alkyl group in which one or more hydrogens have been replaced by an amine group.

術語「烷氧基」涵蓋各具有一個至約十個碳原子之烷基部分的直鏈或分支鏈含氧基團。更佳烷氧基為具有一至六個碳原子之「低碳烷氧基」基團。該等基團之實例包括甲氧基、乙氧基、丙氧基、丁氧基及第三丁氧基。具有一至三個碳原子之低碳烷氧基甚至更佳。 The term "alkoxy" encompasses a straight or branched chain oxygen-containing group each having an alkyl moiety of from one to about ten carbon atoms. More preferably, the alkoxy group is a "lower alkoxy group" having one to six carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. A lower alkoxy group having one to three carbon atoms is even more preferable.

術語「烷氧基烷基」涵蓋各具有一個至約十個碳原子之烷氧基部分的烷基。更佳烷氧基烷基為具有一至六個碳原子之「低碳烷氧基烷基」基團。該等基團之實例包括甲氧基甲基、乙氧基甲基及甲氧基乙基。 The term "alkoxyalkyl" embraces an alkyl group each having an alkoxy moiety of from one to about ten carbon atoms. More preferably, the alkoxyalkyl group is a "lower alkoxyalkyl" group having one to six carbon atoms. Examples of such groups include methoxymethyl, ethoxymethyl and methoxyethyl.

術語「烷氧基烯基」涵蓋各具有兩個至約十個碳原子之烷氧基部分的烯基。更佳烷氧基烯基為具有二至六個碳原子之「低碳烷氧基烯基」基團。該等基團之實例包括甲氧基乙烯基。 The term "alkoxyalkenyl" encompasses alkenyl groups each having an alkoxy moiety of two to about ten carbon atoms. More preferably, the alkoxyalkenyl group is a "lower alkoxyalkenyl" group having two to six carbon atoms. Examples of such groups include methoxyvinyl groups.

術語「烷氧基炔基」涵蓋各具有兩個至約十個碳原子之烷氧基部分的炔基。更佳烷氧基炔基為具有二至六個碳原子之「低碳烷氧基炔基」基團。該等基團之實例包括甲氧基乙炔基。 The term "alkoxyalkynyl" encompasses alkynyl groups each having an alkoxy moiety of two to about ten carbon atoms. More preferably, the alkoxyalkynyl group is a "lower alkoxyalkynyl" group having two to six carbon atoms. Examples of such groups include methoxyethynyl.

術語「羥基烷氧基烷基」涵蓋各具有一或多個羥基的一個至約十個碳原子之烷氧基烷基。更佳羥基烷氧基烷基為具有一至六個碳原子之「低碳羥基烷氧基烷基」基團。該等基團之實例包括羥基甲氧基甲基、羥基乙氧基甲基及羥基甲氧基乙基。 The term "hydroxyalkoxyalkyl" encompasses alkoxyalkyl groups each having one or more hydroxyl groups of from one to about ten carbon atoms. More preferred hydroxyalkoxyalkyl groups are "lower hydroxyalkoxyalkyl" groups having from one to six carbon atoms. Examples of such groups include hydroxymethoxymethyl, hydroxyethoxymethyl, and hydroxymethoxyethyl.

烷氧基可進一步經一或多個鹵原子(諸如氟、氯或溴)取代，得到「鹵烷氧基」基團。具有一至三個碳原子之低碳鹵烷氧基甚至更佳。該等基團之實例包括氟甲氧基、氯甲氧基、三氟甲氧基、三氟乙氧基、氟乙氧基及氟丙氧基。 The alkoxy group may be further substituted with one or more halogen atoms such as fluorine, chlorine or bromine to give a "haloalkoxy" group. A lower haloalkyloxy group having one to three carbon atoms is even more preferred. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

單獨或組合之術語「芳基」意謂含有一或兩個環之碳環芳族系統，其中該等環可以稠合方式連接在一起。術語「芳基」涵蓋芳族基團，諸如苯基、萘基、茚基、四氫萘基及茚滿基。更佳芳基為苯基。 The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, anthracenyl, tetrahydronaphthyl and indanyl. More preferably, the aryl group is a phenyl group.

該「芳基」基團可具有1至3個取代基，諸如低碳烷基、羥基、鹵基、鹵烷基、硝基、氰基、烷氧基及低碳烷基胺基。經-O-CH2-O-取代之苯基形成芳基苯并二氧雜環戊烯基取代基。 The "aryl" group may have 1 to 3 substituents such as a lower alkyl group, a hydroxyl group, a halogen group, a haloalkyl group, a nitro group, a cyano group, an alkoxy group and a lower alkylamino group. The phenyl group substituted with -O-CH 2 -O- forms an arylbenzodioxolyl substituent.

術語「雜環基」涵蓋飽和、部分飽和及不飽和含雜原子環基 團，其中該等雜原子可選自氮、硫及氧。雜環基不包括含有-O-O-、-O-S-或-S-S-部分之環。該「雜環基」基團可具有1至3個取代基，諸如羥基、Boc、鹵基、鹵烷基、氰基、低碳烷基、低碳芳烷基、側氧基、低碳烷氧基、胺基及低碳烷基胺基。 The term "heterocyclyl" encompasses saturated, partially saturated and unsaturated heteroatom-containing cyclic groups. a group wherein the heteroatoms can be selected from the group consisting of nitrogen, sulfur, and oxygen. The heterocyclic group does not include a ring containing a -O-O-, -O-S- or -S-S- moiety. The "heterocyclyl" group may have 1 to 3 substituents such as a hydroxyl group, a Boc group, a halogen group, a haloalkyl group, a cyano group, a lower alkyl group, a lower aralkyl group, a pendant oxy group, a lower carbene group. Oxyl, amine and lower alkylamino groups.

飽和雜環基團之實例包括含有1至4個氮原子之飽和3至6員雜單環基團[例如吡咯啶基、咪唑啶基、哌啶基、吡咯啉基、哌嗪基]；含有1至2個氧原子及1至3個氮原子之飽和3至6員雜單環基團[例如嗎啉基]；含有1至2個硫原子及1至3個氮原子之飽和3至6員雜單環基團[例如噻唑啶基]。部分飽和雜環基之實例包括二氫噻吩基、二氫哌喃基、二氫呋喃基及二氫噻唑基。 Examples of the saturated heterocyclic group include a saturated 3 to 6 membered heteromonocyclic group having 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; a saturated 3 to 6 membered heteromonocyclic group of 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms A heteromonocyclic group [e.g., thiazolidinyl]. Examples of the partially saturated heterocyclic group include a dihydrothiophenyl group, a dihydropiperidyl group, a dihydrofuranyl group, and a dihydrothiazolyl group.

不飽和雜環基團(亦稱為「雜芳基」基團)之實例包括含有1至4個氮原子之不飽和5至6員雜單環基，例如吡咯基、咪唑基、吡唑基、2-吡啶基、3-吡啶基、4-吡啶基、嘧啶基、吡嗪基、噠嗪基、三唑基[例如4H-1,2,4-三唑基、1H-1,2,3-三唑基、2H-1,2,3-三唑基]；含有氧原子之不飽和5至6員雜單環基團，例如哌喃基、2-呋喃基、3-呋喃基等；含有硫原子之不飽和5至6員雜單環基團，例如2-噻吩基、3-噻吩基等；含有1至2個氧原子及1至3個氮原子之不飽和5至6員雜單環基團，例如噁唑基、異噁唑基、噁二唑基[例如1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基]；含有1至2個硫原子及1至3個氮原子之不飽和5至6員雜單環基團，例如噻唑基、噻二唑基[例如1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基]。 Examples of the unsaturated heterocyclic group (also referred to as "heteroaryl" group) include an unsaturated 5 to 6 membered heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl group, imidazolyl group, pyrazolyl group. , 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [eg 4H-1,2,4-triazolyl, 1H-1,2, 3-Triazolyl, 2H-1,2,3-triazolyl]; an unsaturated 5 to 6 membered heteromonocyclic group containing an oxygen atom, such as a piperidyl group, a 2-furyl group, a 3-furyl group, etc. An unsaturated 5- to 6-membered heteromonocyclic group containing a sulfur atom, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5 to 6 members having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms a heteromonocyclic group such as oxazolyl, isoxazolyl, oxadiazolyl [eg 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- Oxadiazolyl]; an unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [eg 1,2,4-thio Diazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

該術語亦涵蓋其中雜環基團與芳基稠合/縮合之基團：含有1至5個氮原子之不飽和縮合雜環基團，例如吲哚基、異吲哚基、吲哚嗪基、苯并咪唑基、喹啉基、異喹啉基、吲唑基、苯并三唑基、四唑并噠嗪基[例如四唑并[1,5-b]噠嗪基]；含有1至2個氧原子及1至3個氮原 子之不飽和縮合雜環基團[例如苯并噁唑基、苯并噁二唑基]；含有1至2個硫原子及1至3個氮原子之不飽和縮合雜環基團[例如苯并噻唑基、苯并噻二唑基]；及含有1至2個氧或硫原子之飽和、部分不飽和及不飽和縮合雜環基團[例如苯并呋喃基、苯并噻吩基、2,3-二氫-苯并[1,4]二氧雜環己烯基及二氫苯并呋喃基]。較佳雜環基團包括5至10員稠合或非稠合基團。雜芳基之更佳實例包括喹啉基、異喹啉基、咪唑基、吡啶基、噻吩基、噻唑基、噁唑基、呋喃基及吡嗪基。其他較佳雜芳基為含有一或兩個選自硫、氮及氧之雜原子的5或6員雜芳基，其係選自噻吩基、呋喃基、吡咯基、吲唑基吡唑基、噁唑基、三唑基、咪唑基、吡唑基、異噁唑基、異噻唑基、吡啶基、哌啶基及吡嗪基。 The term also encompasses groups in which a heterocyclic group is fused/condensed with an aryl group: an unsaturated fused heterocyclic group containing from 1 to 5 nitrogen atoms, such as an indenyl group, an isodecyl group, a pyridazinyl group. , benzimidazolyl, quinolyl, isoquinolyl, oxazolyl, benzotriazolyl, tetrazolopyridazinyl [eg tetrazolo[1,5-b]pyridazinyl]; Up to 2 oxygen atoms and 1 to 3 nitrogen atoms Unsaturated condensed heterocyclic group [eg benzoxazolyl, benzooxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg benzene And thiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms [eg benzofuranyl, benzothienyl, 2, 3-Dihydro-benzo[1,4]dioxanyl and dihydrobenzofuranyl]. Preferred heterocyclic groups include 5 to 10 membered fused or non-fused groups. More preferred examples of the heteroaryl group include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. Other preferred heteroaryl groups are 5 or 6 membered heteroaryl groups containing one or two heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl pyrazolyl. , oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

非含氮雜芳基之特定實例包括哌喃基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、苯并呋喃基、苯并噻吩基及其類似基團。 Specific examples of the non-nitrogen-containing heteroaryl group include a piperidyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a benzofuranyl group, a benzothienyl group, and the like.

部分飽和及飽和雜環基之特定實例包括吡咯啶基、咪唑啶基、哌啶基、吡咯啉基、吡唑啶基、哌嗪基、嗎啉基、四氫哌喃基、噻唑啶基、二氫噻吩基、2,3-二氫-苯并[1,4]二噁烷基、吲哚啉基、異吲哚啉基、二氫苯并噻吩基、二氫苯并呋喃基、異烷基、烷基、1,2-二氫喹啉基、1,2,3,4-四氫-異喹啉基、1,2,3,4-四氫-喹啉基、2,3,4,4a,9,9a-六氫-1H-3-氮雜-茀基、5,6,7-三氫-1,2,4-三唑并[3,4-a]異喹啉基、3,4-二氫-2H-苯并[1,4]噁嗪基、苯并[1,4]二噁烷基、2,3-二氫-1H-1λ'-苯并[d]異噻唑-6-基、二氫哌喃基、二氫呋喃基及二氫噻唑基及其類似基團。 Specific examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, Dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxyl, porphyrin, isoindolyl, dihydrobenzothienyl, dihydrobenzofuranyl, iso alkyl, Alkyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4, 4a,9,9a-hexahydro-1H-3-aza-indenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3 ,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazole -6-yl, dihydropiperidyl, dihydrofuranyl and dihydrothiazolyl and the like.

「雜環」意謂包含至少一個碳原子及至少一個選自N、O及S之其他原子的環。申請專利範圍中可見之雜環之實例包括(但不限於)以下： "Heterocycle" means a ring containing at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles visible in the scope of the patent application include, but are not limited to, the following:

含氮雜環基及含氧雜環基在大多數狀況下不解自明。具有氮及氧或硫原子之雜環仍應定義為含氮雜環基。 The nitrogen-containing heterocyclic group and the oxygen-containing heterocyclic group are not self-evident in most cases. A heterocyclic ring having a nitrogen and an oxygen or sulfur atom should still be defined as a nitrogen-containing heterocyclic group.

單獨使用抑或與其他術語一起使用(諸如「羧基烷基」)之術語「羧基」表示-CO2H。 The term "carboxy" used alone or in conjunction with other terms (such as "carboxyalkyl") means -CO 2 H.

單獨使用抑或與其他術語一起使用(諸如「胺基羰基」)之術語「羰基」表示-(C=O)-。 The term "carbonyl" used alone or in conjunction with other terms (such as "aminocarbonyl") means -(C=O)-.

術語「羧基烷基」表示經羧基取代之烷基。 The term "carboxyalkyl" means an alkyl group substituted with a carboxy group.

術語「烷氧基羰基」表示酯基，其含有經烷氧基取代之羰基。 The term "alkoxycarbonyl" means an ester group containing a carbonyl group substituted with an alkoxy group.

術語「烷氧基羰基胺基烷基」意謂其中一或多個氫已經烷氧基羰基置換之胺基烷基。一個實例應為BOC-胺基甲基。 The term "alkoxycarbonylaminoalkyl" means an aminoalkyl group in which one or more hydrogens have been replaced by an alkoxycarbonyl group. An example would be BOC-aminomethyl.

術語「烷氧基羰基烷基」意謂其中一或多個氫已經烷氧基羰基置換之烷基。一個實例應為甲氧基羰基甲基。 The term "alkoxycarbonylalkyl" means an alkyl group in which one or more hydrogens have been replaced by an alkoxycarbonyl group. An example should be methoxycarbonylmethyl.

術語「胺基羰基」表示式-C(=O)NH2之醯胺基。 The term "aminocarbonyl" means an amidino group of the formula -C(=O)NH 2 .

術語「胺基羰基烷基」意謂其中一或多個氫已經胺基羰基置換之烷基。一個實例應為胺基羰基甲基。 The term "aminocarbonylalkyl" means an alkyl group in which one or more hydrogens have been replaced by an aminocarbonyl group. An example should be an aminocarbonylmethyl group.

術語「N-烷基胺基羰基」及「N,N-二烷基胺基羰基」表示分別獨立地經一或兩個烷基取代之胺基羰基。具有如上文所述之低碳烷基連接於胺基羰基的「低碳烷基胺基羰基」更佳。 The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" denote an aminocarbonyl group which is each independently substituted with one or two alkyl groups. A "lower alkylaminocarbonyl group" having a lower alkyl group bonded to an aminocarbonyl group as described above is more preferred.

術語「N-烷基胺基羰基烷基」及「N,N-二烷基胺基羰基烷基」表示分別獨立地經一或兩個烷基取代之烷基胺基羰基。具有如上文所述之烷基胺基羰基連接於低碳烷基的「低碳烷基胺基羰基烷基」更佳。 The terms "N-alkylaminocarbonylalkyl" and "N,N-dialkylaminocarbonylalkyl" denote alkylaminocarbonyl, each independently substituted with one or two alkyl groups. More preferably, the "lower alkylaminocarbonylalkyl group" having an alkylaminocarbonyl group as described above attached to a lower alkyl group.

術語「芳烷基」涵蓋經芳基取代之烷基。較佳芳烷基為具有芳基連接於具有一至六個碳原子之烷基的「低碳芳烷基」基團。連接於具有一至三個碳原子之烷基部分的「苯基」甚至更佳。該等基團之實例包括苄基、二苯基甲基及苯基乙基。該芳烷基中之芳基可另外經鹵基、烷基、烷氧基、鹵烷基及鹵烷氧基取代。 The term "aralkyl" embraces an alkyl group substituted with an aryl group. Preferred aralkyl groups are "lower arylalkyl" groups having an aryl group attached to an alkyl group having from one to six carbon atoms. A "phenyl group" attached to an alkyl moiety having one to three carbon atoms is even more preferable. Examples of such groups include benzyl, diphenylmethyl and phenylethyl. The aryl group in the aralkyl group may be additionally substituted with a halogen group, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group.

術語「芳烯基」涵蓋經芳基取代之烯基。較佳芳烯基為具有芳基連接於具有二至六個碳原子之烯基的「低碳芳烯基」基團。連接於具有一至三個碳原子之烷基部分的「苯基」甚至更佳。該等基團之實例包括苯基乙烯基。該芳烯基中之芳基可另外經鹵基、烷基、烷氧基、鹵烷基及鹵烷氧基取代。 The term "arylalkenyl" encompasses an alkenyl group substituted with an aryl group. Preferred aralkenyl groups are "lower aralkenyl" groups having an aryl group attached to an alkenyl group having two to six carbon atoms. A "phenyl group" attached to an alkyl moiety having one to three carbon atoms is even more preferable. Examples of such groups include phenylvinyl groups. The aryl group in the aralkenyl group may be additionally substituted with a halogen group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group.

術語「芳炔基」涵蓋經芳基取代之炔基。較佳芳炔基為具有芳基連接於具有二至六個碳原子之炔基的「低碳芳炔基」基團。連接於 具有二至三個碳原子之炔基部分的苯基甚至更佳。該等基團之實例包括苯基乙炔基。該芳炔基中之芳基可另外經鹵基、烷基、烷氧基、鹵烷基及鹵烷氧基取代。 The term "arylalkynyl" encompasses an alkynyl group substituted with an aryl group. Preferred aralkynyl groups are "lower carbon aralkynyl" groups having an aryl group attached to an alkynyl group having two to six carbon atoms. Connected to A phenyl group having an alkynyl moiety of two to three carbon atoms is even more preferable. Examples of such groups include phenylethynyl. The aryl group in the aralkynyl group may be additionally substituted with a halogen group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group.

術語「雜環基烷基」涵蓋經雜環基取代之烷基。較佳雜環基烷基為具有雜環基連接於具有一至六個碳原子之烷基的「低碳雜環基烷基」基團。連接於具有一至三個碳原子之烷基部分的5-10員雜環基甚至更佳。該雜環基烷基中之雜環基可另外經鹵基、烷基、烷氧基、鹵烷基及鹵烷氧基取代。 The term "heterocyclylalkyl" encompasses an alkyl group substituted with a heterocyclic group. Preferred heterocyclylalkyl groups are "lower heterocyclylalkyl" groups having a heterocyclic group attached to an alkyl group having from one to six carbon atoms. A 5-10 membered heterocyclic group attached to an alkyl moiety having one to three carbon atoms is even more preferred. The heterocyclic group in the heterocyclylalkyl group may be additionally substituted with a halogen group, an alkyl group, an alkoxy group, a halogenated alkyl group and a haloalkoxy group.

術語「烷基胺基」涵蓋「N-烷基胺基」及「N,N-二烷基胺基」，其中胺基分別經一個烷基及兩個獨立烷基取代。更佳烷基胺基為具有一至六個碳原子之一或兩個烷基連接於氮原子的「低碳烷基胺基」。具有一至三個碳原子之低碳烷基胺基甚至更佳。適合之烷基胺基可為單烷基胺基或二烷基胺基，諸如N-甲基胺基、N-乙基胺基、N,N-二甲基胺基、N,N-二乙基胺基及其類似基團。 The term "alkylamino" encompasses "N-alkylamino" and "N,N-dialkylamino" wherein the amine group is substituted by one alkyl group and two independent alkyl groups, respectively. More preferably, the alkylamino group is a "lower alkylamino group" having one to six carbon atoms or two alkyl groups bonded to a nitrogen atom. Even lower alkylamino groups having one to three carbon atoms are even more preferred. Suitable alkylamino groups may be monoalkylamino or dialkylamino groups such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-di Ethylamino group and the like.

術語「芳基胺基」表示已經一或兩個芳基取代之胺基，諸如N-苯基胺基。芳基胺基在該基團之芳基環部分上可進一步經取代。 The term "arylamino" means an amine group which has been substituted with one or two aryl groups, such as an N-phenylamino group. The arylamine group can be further substituted on the aryl ring portion of the group.

術語「雜芳基胺基」表示已經一或兩個雜芳基取代之胺基，諸如N-噻吩基胺基。「雜芳基胺基」基團在該基團之雜芳環部分上可進一步經取代。 The term "heteroarylamino" means an amine group which has been substituted with one or two heteroaryl groups, such as an N-thienylamino group. The "heteroarylamino" group can be further substituted on the heteroaryl ring portion of the group.

術語「雜芳氧基」涵蓋連接於氧原子的視情況經取代之如上文所定義之雜芳基。 The term "heteroaryloxy" embraces optionally substituted heteroaryl as defined above attached to an oxygen atom.

術語「環烷基」包括飽和碳環基團。較佳環烷基包括C3-C6環。更佳化合物包括環戊基、環丙基及環己基。 The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C 3 -C 6 cycloalkyl. More preferred compounds include cyclopentyl, cyclopropyl and cyclohexyl.

術語「環烷基烷基」涵蓋經環烷基取代之烷基。較佳環烷基烷基為具有C3-C6環烷基連接於具有一至六個碳原子之烷基的「低碳環烷基烷基」基團。連接於具有一至三個碳原子之烷基部分的環己基甚 至更佳。該等基團之實例包括環己基甲基。該環烷基烷基中之環烷基可另外經低碳烷基取代。 The term "cycloalkylalkyl" encompasses alkyl substituted by cycloalkyl. Preferred cycloalkylalkyl groups are "lower cycloalkylalkylalkyl" groups having a C 3 -C 6 cycloalkyl group attached to an alkyl group having from one to six carbon atoms. It is even more preferable to attach a cyclohexyl group to an alkyl moiety having one to three carbon atoms. Examples of such groups include cyclohexylmethyl. The cycloalkyl group in the cycloalkylalkyl group may be additionally substituted with a lower alkyl group.

術語「環烷基烯基」涵蓋經環烷基取代之烯基。較佳環烷基烯基為具有C3-C6環烷基連接於具有二至六個碳原子之烷基的「低碳環烷基烯基」基團。連接於具有二至三個碳原子之烯基部分的環己基甚至更佳。該等基團之實例包括環己基乙烯基。該環烷基烯基中之環烷基可另外經低碳烷基取代。 The term "cycloalkylalkenyl" encompasses a cycloalkyl substituted alkenyl group. Preferred cycloalkylalkenyl groups are "lower cycloalkylalkenyl" groups having a C 3 -C 6 cycloalkyl group attached to an alkyl group having from two to six carbon atoms. It is even more preferable to attach a cyclohexyl group having an alkenyl moiety having two to three carbon atoms. Examples of such groups include cyclohexylvinyl. The cycloalkyl group in the cycloalkylalkenyl group may be additionally substituted with a lower alkyl group.

術語「環烷基炔基」涵蓋經環烷基取代之炔基。較佳環烷基炔基為具有C3-C6環烷基連接於具有二至六個碳原子之炔基的「低碳環烷基炔基」基團。連接於具有二至三個碳原子之炔基部分的環己基甚至更佳。該等基團之實例包括環己基乙炔基。該環烷基炔基中之環烷基可另外經低碳烷基取代。 The term "cycloalkylalkynyl" encompasses alkynyl substituted by a cycloalkyl group. Preferred cycloalkylalkynyl groups are "lower cycloalkylalkynyl" groups having a C 3 -C 6 cycloalkyl group attached to an alkynyl group having two to six carbon atoms. A cyclohexyl group attached to an alkynyl moiety having two to three carbon atoms is even more preferable. Examples of such groups include cyclohexylethynyl. The cycloalkyl group in the cycloalkylalkynyl group may be additionally substituted with a lower alkyl group.

術語「環烯基」包括部分不飽和碳環基團。較佳環烯基包括C5-C6環。更佳化合物包括環戊烯基及環己烯基。 The term "cycloalkenyl" includes partially unsaturated carbocyclic groups. Preferred cycloalkenyl groups include C 5 -C 6 rings. More preferred compounds include cyclopentenyl and cyclohexenyl.

單獨使用抑或與其他術語相關聯(諸如烷基磺醯基)之術語「磺醯基」分別表示二價基團-SO2-。 Used alone or in connection with other terms associated with (such as an alkylsulfonyl group) The term "sulfonic acyl" each represent a divalent radical -SO 2 -.

術語「胺磺醯基」及「胺基磺醯基」表示經胺基取代之磺醯基，從而形成磺醯胺(-SO2NH2)。 The terms "amine sulfonyl" and "aminosulfonyl" refer to a sulfonyl group substituted with an amine group to form a sulfonamide (-SO 2 NH 2 ).

術語「烷基胺基磺醯基」包括「N-烷基胺基磺醯基」，其中胺磺醯基獨立地經一或兩個烷基取代。更佳烷基胺基磺醯基為具有一至六個碳原子之「低碳烷基胺基磺醯基」基團。具有一至三個碳原子之低碳烷基胺基磺醯基甚至更佳。該等低碳烷基胺基磺醯基之實例包括N-甲基胺基磺醯基及N-乙基胺基磺醯基。 The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" wherein the aminesulfonyl group is independently substituted with one or two alkyl groups. More preferably, the alkylaminosulfonyl group is a "lower alkylaminosulfonyl" group having one to six carbon atoms. A lower alkylaminosulfonyl group having one to three carbon atoms is even more preferred. Examples of such lower alkylaminosulfonyl groups include N-methylaminosulfonyl and N-ethylaminosulfonyl.

術語「烷基胺基烷基」包括「N-烷基胺基烷基」，其中烷基獨立地經烷基胺基取代。更佳烷基胺基烷基為具有一至六個碳原子之「低碳烷基胺基烷基」基團。 The term "alkylaminoalkyl" includes "N-alkylaminoalkyl" wherein the alkyl group is independently substituted with an alkylamino group. More preferred alkylaminoalkyl groups are "lower alkylaminoalkyl" groups having from one to six carbon atoms.

術語「烷基磺醯基」包括經烷基取代之磺醯基。更佳烷基磺醯基為具有一至六個碳原子之「低碳烷基磺醯基」基團。具有一至三個碳原子之低碳烷基磺醯基甚至更佳。該等低碳烷基磺醯基之實例包括甲基磺醯基及乙基磺醯基。 The term "alkylsulfonyl" includes alkyl substituted sulfonyl. More preferably, the alkylsulfonyl group is a "lower alkylsulfonyl" group having one to six carbon atoms. A lower alkyl sulfonyl group having one to three carbon atoms is even more preferred. Examples of such lower alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.

單獨或組合之「苯并基團」意謂當鄰接於另一環時形成苯樣環(例如伸四氫萘基、吲哚及其類似物)之二價基團C4H4=，其一種表現形式為-CH=CH-CH=CH-。 The "benzo group", alone or in combination, means a divalent group C 4 H 4 = which forms a benzene-like ring (for example, tetrahydronaphthyl, anthracene and the like) when adjacent to another ring, one of which The expression is -CH=CH-CH=CH-.

術語「側氧基」表示基團=O(如羰基中)。 The term "sideoxy" means a group = 0 (as in a carbonyl group).

術語「雜環基羰基烷基」涵蓋經雜環基羰基取代之烷基。較佳雜環基羰基烷基為具有雜環基羰基連接於具有一至六個碳原子之烷基的「低碳雜環基烷基烷基」基團。連接於羰基及具有一至三個碳原子之烷基部分的5-10員雜環基甚至更佳。該雜環基羰基烷基中之雜環基可另外經鹵基、烷基、烷氧基、鹵烷基及鹵烷氧基取代。 The term "heterocyclylcarbonylalkyl" encompasses an alkyl group substituted with a heterocyclylcarbonyl group. Preferred heterocyclylcarbonylalkyl groups are "lower heterocyclylalkylalkyl" groups having a heterocyclic carbonyl group attached to an alkyl group having from one to six carbon atoms. A 5-10 membered heterocyclic group attached to a carbonyl group and an alkyl moiety having one to three carbon atoms is even more preferred. The heterocyclic group in the heterocyclic carbonylalkyl group may be additionally substituted with a halogen group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group.

「醫藥學上可接受之鹽」意謂由習知方式製備之鹽，且為熟習此項技術者所熟知。「藥理學上可接受之鹽」包括無機酸及有機酸之鹼性鹽，該等酸包括(但不限於)鹽酸、氫溴酸、硫酸、磷酸、甲烷磺酸、乙烷磺酸、蘋果酸、乙酸、草酸、酒石酸、檸檬酸、乳酸、反丁烯二酸、丁二酸、順丁烯二酸、水楊酸、苯甲酸、苯乙酸、杏仁酸及其類似酸。當本發明化合物包括酸性官能基(諸如羧基)時，則羧基之適合醫藥學上可接受之陽離子對為熟習此項技術者所熟知且包括鹼金屬、鹼土金屬、銨、四級銨陽離子及其類似物。關於「藥理學上可接受之鹽」的其他實例，參見下文及Berge等人，J.Pharm.Sci.66：1(1977)。 "Pharmaceutically acceptable salt" means a salt prepared by conventional means and is well known to those skilled in the art. "Pharmacologically acceptable salts" include basic salts of inorganic acids and organic acids including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid. , acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When a compound of the invention includes an acidic functional group (such as a carboxy group), then a suitable pharmaceutically acceptable cation pair of a carboxy group is well known to those skilled in the art and includes alkali metal, alkaline earth metal, ammonium, quaternary ammonium cations and analog. For additional examples of "pharmacologically acceptable salts," see below and Berge et al, J. Pharm. Sci. 66:1 (1977).

「飽和、部分飽和或不飽和」包括氫飽和之取代基、氫完全不飽和之取代基及氫部分飽和之取代基。 "Saturated, partially saturated or unsaturated" includes a hydrogen-saturated substituent, a hydrogen-unsaturated substituent, and a hydrogen-saturated substituent.

「離去基」一般係指容易由親核試劑(諸如胺、硫醇或醇親核試 劑)置換之基團。該等離去基在此項技術中為熟知的。該等離去基之實例包括(但不限於)N-羥基丁二醯亞胺、N-羥基苯并三唑、鹵化物、三氟甲磺酸酯、甲苯磺酸酯及其類似物。適當時，本文中指示較佳離去基。 "Leaving group" generally means prone to nucleophilic reagents such as amines, thiols or alcohols. Agent) a group that is substituted. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxybutadienimide, N-hydroxybenzotriazole, halides, triflate, tosylate, and the like. Preferred leaving groups are indicated herein as appropriate.

「保護基」一般係指此項技術中熟知用於防止所選反應性基團(諸如羧基、胺基、羥基、巰基及其類似基團)發生不當反應(諸如親核反應、親電子反應、氧化、還原及其類似反應)之基團。適當時，本文中指示較佳保護基。胺基保護基之實例包括(但不限於)芳烷基、經取代之芳烷基、環烯基烷基及經取代之環烯基烷基、烯丙基、經取代之烯丙基、醯基、烷氧基羰基、芳烷氧基羰基、矽烷基及其類似基團。芳烷基之實例包括(但不限於)苄基、鄰甲基苄基、三苯甲基及二苯甲基，其可視情況經鹵素、烷基、烷氧基、羥基、硝基、醯胺基、醯基及其類似基團取代，及鹽，諸如鏻及銨鹽。芳基之實例包括苯基、萘基、茚滿基、蒽基、9-(9-苯基茀基)、菲基、四甲苯基(durenyl)及其類似基團。環烯基烷基或經取代之伸環烷基烷基之實例較佳具有6-10個碳原子，包括(但不限於)環己烯基甲基及其類似基團。適合之醯基、烷氧基羰基及芳烷氧基羰基包括苄氧基羰基、第三丁氧基羰基、異丁氧基羰基、苄醯基、經取代之苄醯基、丁醯基、乙醯基、三氟乙醯基、三氯乙醯基、酞醯基及其類似基團。可使用保護基之混合物保護同一胺基，諸如一級胺基可由芳烷基與芳烷氧基羰基兩者來保護。胺基保護基亦可與其所連接之氮一起形成雜環，例如1,2-雙(亞甲基)苯、鄰苯二醯亞胺基、丁二醯亞胺基、順丁烯二醯亞胺基及其類似物，且其中此等雜環基團可另外包括毗連芳基及環烷基環。另外，雜環基團可經單取代、二取代或三取代，諸如硝基鄰苯二醯亞胺基。亦可藉由形成加成鹽(諸如鹽酸鹽、甲苯磺酸鹽、三氟乙酸鹽及其類似物)保護胺基免於發生不當反應(諸如氧化)。許多胺基保 護基亦適合於保護羧基、羥基及巰基。舉例而言，芳烷基。烷基亦為用於保護羥基及巰基之適合基團，諸如第三丁基。 "Protecting group" generally refers to an unsuitable reaction (such as nucleophilic reaction, electrophilic reaction, oxidation) which is well known in the art for preventing the selection of selected reactive groups such as carboxyl groups, amine groups, hydroxyl groups, sulfhydryl groups and the like. , reduction and similar reactions) groups. Preferred protecting groups are indicated herein as appropriate. Examples of amine protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl, and substituted cycloalkenylalkyl, allyl, substituted allyl, hydrazine Alkyl, alkoxycarbonyl, aralkoxycarbonyl, decylalkyl and the like. Examples of aralkyl groups include, but are not limited to, benzyl, o-methylbenzyl, trityl, and diphenylmethyl, which may optionally be halogen, alkyl, alkoxy, hydroxy, nitro, decylamine. Substituents, thiol groups and the like, and salts, such as hydrazine and ammonium salts. Examples of the aryl group include a phenyl group, a naphthyl group, an indanyl group, an anthracenyl group, a 9-(9-phenylindenyl group), a phenanthryl group, a tetrarenyl group, and the like. Examples of cycloalkenylalkyl or substituted cycloalkylalkyl groups preferably have from 6 to 10 carbon atoms including, but not limited to, cyclohexenylmethyl and the like. Suitable fluorenyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, benzinyl, substituted benzinyl, butyl fluorenyl, ethyl fluorenyl , trifluoroethenyl, trichloroethane, fluorenyl and the like. The same amine group can be protected with a mixture of protecting groups, such as a primary amine group, which can be protected by both an aralkyl group and an aralkoxycarbonyl group. The amine protecting group may also form a heterocyclic ring together with the nitrogen to which it is attached, for example, 1,2-bis(methylene)benzene, phthalimido, butylimine, maleicene Amine groups and analogs thereof, and wherein such heterocyclic groups may additionally include a contiguous aryl group and a cycloalkyl ring. Further, the heterocyclic group may be mono-, di- or tri-substituted, such as a nitrophthalic acid imide group. The amine group can also be protected from inappropriate reactions (such as oxidation) by the formation of addition salts such as hydrochlorides, tosylates, trifluoroacetates, and the like. Many amines The protecting group is also suitable for protecting the carboxyl group, the hydroxyl group and the sulfhydryl group. For example, an aralkyl group. Alkyl groups are also suitable groups for protecting hydroxyl groups and mercapto groups, such as tert-butyl groups.

矽烷基保護基為視情況經一或多個烷基、芳基及芳烷基取代之矽原子。適合之矽烷基保護基包括(但不限於)三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、第三丁基二甲基矽烷基、二甲基苯基矽烷基、1,2-雙(二甲基矽烷基)苯、1,2-雙(二甲基矽烷基)乙烷及二苯基甲基矽烷基。胺基之矽烷化提供單矽烷基胺基或二矽烷基胺基。胺基醇化合物之矽烷化可產生N,N,O-三矽烷基衍生物。容易藉由用例如金屬氫氧化物或氟化銨試劑處理(作為個別反應步驟或在與醇基反應期間當場處理)自矽烷基醚官能基移除矽烷基官能基。適合之矽烷化劑為例如氯化三甲基矽烷、氯化第三丁基-二甲基矽烷、氯化苯基二甲基矽烷、氯化二苯基甲基矽烷或其與咪唑或DMF之組合產物。胺矽烷化及移除矽烷基保護基之方法為熟習此項技術者所熟知。自相應胺基酸、胺基酸醯胺或胺基酸酯製備此等胺衍生物之方法亦為熟習有機化學(包括胺基酸/胺基酸酯或胺基醇化學)技術者所熟知。 A decyl protecting group is a fluorene atom which is optionally substituted with one or more alkyl, aryl and aralkyl groups. Suitable decyl protecting groups include, but are not limited to, trimethyl decyl, triethyl decyl, triisopropyl decyl, tert-butyl dimethyl decyl, dimethyl phenyl decyl, 1 , 2-bis(dimethylalkylalkyl)benzene, 1,2-bis(dimethylalkylalkyl)ethane, and diphenylmethyldecylalkyl. The decylation of an amine group provides a monodecylamino group or a dialkylalkylamine group. The decanolation of an amino alcohol compound produces an N,N,O-tridecylalkyl derivative. It is readily removed from the decyl ether functional group by treatment with, for example, a metal hydroxide or ammonium fluoride reagent (as an individual reaction step or on-site treatment during reaction with an alcohol group). Suitable decylating agents are, for example, trimethyl decane chloride, tert-butyl-dimethyl decane chloride, phenyl dimethyl decane chloride, diphenylmethyl decane chloride or their imidazole or DMF. Combine the product. Amidoxime and methods for removing a decyl protecting group are well known to those skilled in the art. The preparation of such amine derivatives from the corresponding amino acids, amine amides or amino acid esters is also well known to those skilled in the art of organic chemistry, including amino acid/amino acid esters or amino alcohol chemistry.

在不會影響分子其餘部分之條件下移除保護基。此等方法在此項技術為熟知的且包括酸水解、氫解及其類似方法。較佳方法涉及移除保護基，諸如藉由在適合溶劑系統(諸如醇、乙酸及其類似物或其混合物)中利用鈀/碳氫解來移除苄氧基羰基。可在適合溶劑系統(諸如二噁烷或二氯甲烷)中利用無機酸或有機酸(諸如HCl或三氟乙酸)移除第三丁氧基羰基保護基。可容易地中和所得胺基鹽，產生游離胺。可在熟習此項技術者熟知之水解及氫解條件下移除羧基保護基，諸如甲基、乙基、苄基、第三丁基、4-甲氧基苯基甲基及其類似基團。 The protecting group is removed without affecting the rest of the molecule. Such methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like. A preferred method involves removal of the protecting group, such as by removal of the benzyloxycarbonyl group by palladium/hydrocarbon digestion in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. The third butoxycarbonyl protecting group can be removed using a mineral or organic acid such as HCl or trifluoroacetic acid in a suitable solvent system such as dioxane or dichloromethane. The resulting amine salt can be readily neutralized to yield the free amine. The carboxy protecting group can be removed under conditions of hydrolysis and hydrogenolysis well known to those skilled in the art, such as methyl, ethyl, benzyl, t-butyl, 4-methoxyphenylmethyl and the like. .

應注意，本發明化合物可含有可能以互變異構形式存在之基團，諸如環狀及非環狀脒基及胍基、經雜原子取代之雜芳基及其類似基團，例如，如以下實例中所說明： It should be noted that the compounds of the present invention may contain groups which may exist in tautomeric forms, such as cyclic and acyclic sulfhydryl groups and fluorenyl groups, heteroaryl substituted heteroaryl groups and the like, for example, as follows As explained in the example:

且儘管本文中命名、描述、展示及/或主張一種形式，但所有互變異構形式欲固有地包括於該名稱、描述、展示及/或主張中。 And, although a form is recited, described, shown, and/or claimed, all tautomeric forms are intended to be included in the name, description, display, and/or claim.

本發明亦涵蓋本發明化合物之前藥。前藥為在將前藥投與患者之後經活體內生理作用(諸如水解、代謝及其類似作用)化學改質為本發明化合物之活性或非活性化合物。製備及使用前藥中所涉及之適宜性及技術為熟習此項技術者所熟知。關於涉及酯之前藥的一般論述，參見Svensson及Tunek Drug Metabolism Reviews 165(1988)及Bundgaard Design of Prodrugs,Elsevier(1985)。經遮蔽之羧酸酯陰離子之實例包括多種酯，諸如烷基(例如甲基、乙基)、環烷基(例如環己基)、芳烷基(例如苄基、對甲氧基苄基)及烷基羰氧基烷基(例如特戊醯氧基甲基)。已將胺遮蔽為經芳基羰氧基甲基取代之衍生物，其係由酯酶活體內裂解，釋放游離藥物及甲醛(Bungaard J.Med.Chem.2503(1989))。又，含有酸性NH基團之藥物(諸如咪唑、醯亞胺、吲哚及其類似物)已經N-醯氧基甲基遮蔽(Bundgaard Design of Prodrugs,Elsevier(1985))。已將羥基遮蔽為酯及醚。EP 039,051(Sloan及Little,4/11/81)揭示曼尼希鹼(Mannich-base)異羥肟酸前藥、其製備及用途。 The invention also encompasses prodrugs of the compounds of the invention. A prodrug is an active or inactive compound that is chemically modified to a compound of the invention by in vivo physiological action (such as hydrolysis, metabolism, and the like) after administration of the prodrug to a patient. The suitability and techniques involved in the preparation and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrug-related drugs, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of blocked carboxylate anions include various esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and Alkylcarbonyloxyalkyl (e.g., p-pentyloxymethyl). The amine has been masked as an arylcarbonyloxymethyl substituted derivative which is cleaved in vivo by the esterase to release free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Further, drugs containing acidic NH groups such as imidazole, quinone imine, guanidine and the like have been masked by N-decyloxymethyl (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxyl groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

說明書及申請專利範圍含有使用語言「選自...及...」及「為...或...」之物質清單(有時稱作馬庫西群組(Markush group))。當本申請案中使用此語言時，除非另有規定，否則其意欲包括整個群組，或其任何單一成員，或其任何子組。此語言之使用僅出於簡寫之目的，且不欲以任何方式限制需要時個別要素或子組的移除。 The description and the scope of the patent application contain a list of substances (hereinafter referred to as Markush group) using the language "selected from... and..." and "for... or...". When the language is used in this application, it is intended to include the entire group, or any single member thereof, or any subgroup thereof, unless otherwise specified. This language is used for abbreviated purposes only and is not intended to limit the removal of individual features or sub-groups as needed.

效用及使用方法 Utility and method of use

本發明化合物可用作預防劑或治療劑以供治療由葡糖激酶活性 程度不足介導或可藉由活化葡糖激酶而治療之疾病或病症，包括(但不限於)糖尿病、葡萄糖耐受性異常、IFG(空腹葡萄糖異常)及IFG(空腹血糖異常)，以及其他疾病及病症，諸如下文所論述者。此外，本發明化合物亦可用於預防邊緣型葡萄糖耐受性異常、IFG(空腹葡萄糖異常)或IFG(空腹血糖異常)進展為糖尿病。 The compounds of the invention are useful as prophylactic or therapeutic agents for the treatment of glucokinase activity A disease or condition that is insufficiently mediated or that can be treated by activating glucokinase, including but not limited to diabetes, impaired glucose tolerance, IFG (fasting glucose abnormality), and IFG (fasting abnormal blood glucose), and other diseases And conditions, such as those discussed below. Furthermore, the compounds of the invention may also be used to prevent marginal glucose tolerance abnormalities, IFG (fasting glucose abnormalities) or IFG (fasting blood glucose abnormalities) progression to diabetes.

因此，本發明之另一態樣提供治療或預防本文所述之疾病或病狀之方法，其係藉由投與哺乳動物(諸如人類)治療有效量之式I化合物來達成。 Accordingly, another aspect of the invention provides a method of treating or preventing a disease or condition as described herein by administering to a mammal, such as a human, a therapeutically effective amount of a compound of formula I.

片語「治療有效量」意謂(i)治療或預防特定疾病、病狀或病症，(ii)減輕、改善或消除特定疾病、病狀或病症之一或多種症狀，或(iii)預防或延緩本文所述之特定疾病、病狀或病症之一或多種症狀發作的本發明化合物之量。 The phrase "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or condition, or (iii) preventing or An amount of a compound of the invention that delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

對應於此種量之式I化合物之量將視以下因素而變化，諸如特定化合物、疾病病狀及其嚴重性、需要治療之哺乳動物之特性(例如重量)，但仍可由熟習此項技術者例行確定。 The amount of the compound of formula I corresponding to such an amount will vary depending on such factors as the particular compound, the condition of the disease and its severity, the characteristics (e.g., weight) of the mammal in need of treatment, but still by those skilled in the art. Routine determination.

術語「治療」係指治療性治療與預防性措施，其中目的在於減緩(減輕)不當生理變化或病症。就本發明而言，有益或所要臨床結果包括(但不限於)症狀減輕、疾病程度減小、疾病病況穩定(亦即不惡化)、疾病進程延緩或減緩、疾病病況改善或緩和及病徵緩解(部分抑或完全)，該等結果為可偵測抑或不可偵測的。「治療」亦可意謂使存活時間與不接受治療之預期存活時間相比延長。需要治療者包括已患有病狀或病症者以及易患病狀或病症者或欲減緩或減輕病狀或病症者。 The term "treatment" refers to both therapeutic and prophylactic measures, with the aim of slowing (alleviating) inappropriate physiological changes or conditions. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, reduced symptoms, reduced disease levels, stable disease conditions (ie, no deterioration), delayed or slowed progression of the disease, improved or alleviated disease conditions, and symptomatic relief ( Partially or completely), the results are detectable or undetectable. "Treatment" can also mean prolonging the survival time compared to the expected survival time without treatment. Those in need of treatment include those already with the condition or disorder as well as those susceptible to the condition or disorder or who desire to slow or alleviate the condition or disorder.

如本文所用之術語「預防」意謂完全或部分預防如本文所述之疾病或病狀或其症狀發作、復發或擴散。 The term "prevention" as used herein means to completely or partially prevent the onset, recurrence or spread of a disease or condition, or a symptom thereof, as described herein.

如本文所用之術語「哺乳動物」係指患有本文所述之疾病或處 於顯現本文所述之疾病之風險下的溫血動物，且包括(但不限於)天竺鼠、犬、貓、大鼠、小鼠、倉鼠及靈長類動物，包括人類。 The term "mammal" as used herein refers to a disease or a place as described herein. Warm-blooded animals at risk of developing the diseases described herein, and include, but are not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

在某些實施例中，本發明方法適用於治療糖尿病。糖尿病為空腹血漿葡萄糖含量(靜脈血漿中之葡萄糖濃度)大於或等於126 mg/dL(在兩種情形下測試)且75 g口服葡萄糖耐受性測試(OGTT)之2小時血漿葡萄糖含量大於或等於200 mg/dL之病狀。其他典型症狀包括煩渴、貪食及多尿。 In certain embodiments, the methods of the invention are useful for treating diabetes. Diabetes is a fasting plasma glucose level (glucose concentration in venous plasma) greater than or equal to 126 mg/dL (tested in both cases) and a 2-hour plasma glucose content greater than or equal to 75 g oral glucose tolerance test (OGTT) The condition of 200 mg/dL. Other typical symptoms include polydipsia, bulimia and polyuria.

在某些實施例中，本發明方法適用於治療葡萄糖耐受性異常(IGT)之症候群。IGT係由空腹血漿葡萄糖含量小於126 mg/dL且2小時口服葡萄糖激發後含量大於140 mg/dL之表現診斷。 In certain embodiments, the methods of the invention are useful for treating a syndrome of glucose intolerance (IGT). IGT was diagnosed by a fasting plasma glucose content of less than 126 mg/dL and a dose of greater than 140 mg/dL after 2 hours of oral glucose challenge.

本發明化合物亦可用作糖尿病併發症之預防劑或治療劑，該等併發症為諸如(但不限於)神經病變、腎病變、視網膜病變、白內障、大血管病變、骨質減少、糖尿病高滲性昏迷、感染性疾病(例如呼吸道感染、泌尿道感染、胃腸道感染、皮膚軟組織感染、下肢感染等)、糖尿病性壞疽、口乾症、聽覺下降、腦血管疾病、周邊循環紊亂等。 The compound of the present invention can also be used as a prophylactic or therapeutic agent for diabetic complications such as, but not limited to, neuropathy, nephropathy, retinopathy, cataract, macrovascular disease, osteopenia, hyperosmolarity of diabetes. Coma, infectious diseases (such as respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, dry mouth, decreased hearing, cerebrovascular diseases, peripheral circulation disorders, etc.

本發明化合物亦可用作治療以下疾病及病症之預防劑或治療劑，諸如(但不限於)肥胖症、代謝症候群(X症候群)、高胰島素血症、高胰島素血症誘發之感覺障礙、異常脂蛋白血症(血液中之脂蛋白異常)(包括糖尿病性血脂異常)、高脂質血症、高脂蛋白血症(血液中之脂蛋白過量)(包括I型、II-a型(高膽固醇血症)、II-b型、III型、IV型(高三酸甘油酯血症)及V型(高三酸甘油酯血症))、低HDL含量、高LDL含量、動脈粥樣硬化及其後遺症、血管再狹窄、神經退化性疾病、抑鬱症、CNS病症、肝脂肪變性、骨質疏鬆症、高血壓、腎病(例如糖尿病性腎病變、腎小球腎炎、腎小球硬化、腎病症候群、高血壓性腎硬化、末期腎病症等)、心肌梗塞、心絞痛及腦血管疾病(例 如腦梗塞、腦中風)。 The compounds of the present invention are also useful as prophylactic or therapeutic agents for the treatment of diseases and conditions such as, but not limited to, obesity, metabolic syndrome (X syndrome), hyperinsulinemia, hyperinsulinemia-induced sensory disorders, abnormalities Lipoproteinemia (abnormal lipoproteins in the blood) (including diabetic dyslipidemia), hyperlipidemia, hyperlipoproteinemia (lipoprotein excess in the blood) (including type I, type II-a (high cholesterol) Blood), type II-b, type III, type IV (hyperglycerolemia) and type V (hyperglycerolemia), low HDL, high LDL, atherosclerosis and its sequelae , vascular restenosis, neurodegenerative diseases, depression, CNS disorders, hepatic steatosis, osteoporosis, hypertension, kidney disease (eg diabetic nephropathy, glomerulonephritis, glomerular sclerosis, renal syndrome, hypertension) Kidney cirrhosis, end stage renal disease, etc.), myocardial infarction, angina pectoris and cerebrovascular disease (eg Such as cerebral infarction, stroke.

本發明化合物可與一或多種其他藥物組合使用，例如由相同或不同作用機制起作用之化合物，諸如胰島素製劑、改良胰島素抗性之藥劑、α-葡糖苷酶抑制劑、雙胍、胰島素促泌素、二肽基肽酶IV(DPP IV)抑制劑、β-3促效劑、澱粉素促效劑(amylin agonist)、磷酸酪胺酸磷酸酯酶抑制劑、葡糖新生抑制劑、鈉-葡萄糖共轉運體抑制劑、用於糖尿病併發症之已知治療劑、抗高血脂劑、降血壓劑及抗肥胖劑。改良胰島素抗性之藥劑的一個實例為過氧化體增殖物活化受體γ(PPARγ)之促效劑。 The compounds of the invention may be used in combination with one or more other drugs, such as compounds that act by the same or different mechanisms of action, such as insulin preparations, agents that modify insulin resistance, alpha-glucosidase inhibitors, biguanides, insulin secretagogues. , dipeptidyl peptidase IV (DPP IV) inhibitor, beta-3 agonist, amylin agonist, phosphotyrosine phosphatase inhibitor, glucose stimulating inhibitor, sodium-glucose Co-transporter inhibitors, known therapeutic agents for diabetic complications, anti-hyperlipidemic agents, antihypertensive agents, and anti-obesity agents. An example of an agent that modifies insulin resistance is an agonist of peroxisome proliferator-activated receptor gamma (PPAR gamma).

投藥及醫藥組合物 Administration and pharmaceutical composition

一般而言，本發明化合物可由針對發揮類似效用之藥劑的公認投藥模式中之任一者以治療有效量投與。本發明化合物(亦即活性成分)之實際量將視眾多因素而定，諸如所治療疾病之嚴重性、個體之年齡及相對健康狀況、所用化合物之效能、投藥之途徑及形式及其他因素。 In general, the compounds of the invention may be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that exert similar utility. The actual amount of a compound of the invention (i.e., the active ingredient) will depend on a number of factors, such as the severity of the condition being treated, the age and relative health of the subject, the potency of the compound employed, the route and form of administration, and other factors.

式(I)化合物之治療有效量可在約0.1-1000毫克/天之範圍內。 A therapeutically effective amount of a compound of formula (I) can range from about 0.1 to 1000 mg/day.

一般而言，本發明化合物可以醫藥組合物形式由以下任一途徑投與：經口、全身(例如經皮、鼻內或經栓劑)或非經腸(例如肌肉內、靜脈內或皮下)投與。較佳投藥方式為使用可根據疾患程度作調整之便利日給藥方案經口投藥。組合物可採用錠劑、丸劑、膠囊、半固體、散劑、持續釋放調配物、溶液、懸浮液、酏劑、氣霧劑或任何其他適當組合物之形式。 In general, the compounds of the invention may be administered in the form of a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). versus. The preferred mode of administration is oral administration using a convenient daily dosing regimen that can be adjusted to the extent of the disorder. The compositions may take the form of a troche, a pill, a capsule, a semisolid, a powder, a sustained release formulation, a solution, a suspension, an elixirs, an aerosol, or any other suitable composition.

調配物之選擇視多種因素而定，諸如藥物投藥模式(例如對於經口投藥，呈錠劑、丸劑或膠囊形式之調配物較佳)及原料藥之生物可用性。最近，已基於可藉由增加表面積(亦即減小粒度)而增加生物可用性之原則開發尤其用於顯示較差生物可用性之藥物的醫藥調配物。 舉例而言，美國專利第4,107,288號描述具有尺寸在10至1,000 nm範圍內之粒子的醫藥調配物，其中活性物質負載於巨分子之交聯基質上。美國專利第5,145,684號描述醫藥調配物的製備，其中在表面改質劑存在下將原料藥粉碎成奈米粒子(平均粒度為400 nm)，接著分散於液體介質中，得到展現顯著較高生物可用性之醫藥調配物。 The choice of formulation will depend on a number of factors, such as the mode of administration of the drug (e.g., for oral administration, preferably in the form of a lozenge, pill or capsule) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed based on the principle of increasing bioavailability by increasing surface area (i.e., reducing particle size), particularly for pharmaceuticals that exhibit poor bioavailability. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles having a size in the range of 10 to 1,000 nm, wherein the active substance is supported on a crosslinked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the preparation of pharmaceutical formulations in which the drug substance is pulverized into nanoparticles (average particle size of 400 nm) in the presence of a surface modifying agent, followed by dispersion in a liquid medium, resulting in significantly higher bioavailability. Pharmaceutical formulations.

組合物一般包含本發明化合物與至少一種醫藥學上可接受之賦形劑的組合。可接受之賦形劑無毒，有助於投藥，且不會不利地影響本發明化合物之治療效益。該賦形劑可為熟習此項技術者一般可用之任何固體、液體、半固體賦形劑或在氣霧劑組合物之狀況下為氣體賦形劑。 The compositions generally comprise a combination of a compound of the invention and at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic benefit of the compounds of the invention. The excipient can be any solid, liquid, semi-solid excipient that is generally available to those skilled in the art or a gaseous excipient in the case of an aerosol composition.

固體醫藥賦形劑包括澱粉、纖維素、滑石、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻米、麵粉、白堊、矽膠、硬脂酸鎂、硬脂酸鈉、單硬脂酸甘油酯、氯化鈉、脫脂乳粉及其類似物。液體及半固體賦形劑可選自甘油、丙二醇、水、乙醇及各種油，包括石油、動物、植物或合成來源之油，例如花生油、大豆油、礦物油、芝麻油等。較佳液體載劑、尤其用於可注射溶液之液體載劑包括水、生理食鹽水、右旋糖水溶液及二醇。 Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, tannin, magnesium stearate, sodium stearate, glyceryl monostearate, chlorine Sodium, skim milk powder and the like. The liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, especially liquid carriers for injectable solutions, include water, physiological saline, aqueous dextrose, and diols.

壓縮氣體可用於分散呈氣霧劑形式之本發明化合物。適合於達成此目的之惰性氣體為氮氣、二氧化碳等。 Compressed gases can be used to disperse the compounds of the invention in the form of an aerosol. Suitable inert gases for this purpose are nitrogen, carbon dioxide, and the like.

其他適合醫藥賦形劑及其調配物描述於Remington's Pharmaceutical Sciences,Gennaro,A.R,(Mack Publishing Company，第18版，1995)中。 Other suitable pharmaceutical excipients and formulations thereof are described in Remington's Pharmaceutical Sciences, Gennaro, A.R, (Mack Publishing Company, 18th Ed., 1995).

調配物中化合物之含量可在熟習此項技術者所採用之全範圍內變化。以重量百分比(重量%)計，調配物通常含有基於總調配物約0.01-99.99重量%之本發明化合物，其餘為一或多種適合醫藥賦形劑。化合物較佳以約1-80重量%之含量存在。 The amount of the compound in the formulation can vary within the full range of those employed by those skilled in the art. The formulations typically contain from about 0.01% to about 99.99% by weight of the compound of the invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients, in weight percent (% by weight). The compound is preferably present in an amount of from about 1% to about 80% by weight.

組合 combination

儘管本發明化合物可以單獨活性醫藥劑形式投與，但其亦可與一或多種本發明化合物或其他藥劑組合使用。當以組合形式投與時，治療劑可調配成同時或在不同時間依序投與之各別組合物，或治療劑可以單一組合物形式給與。 While the compounds of the invention may be administered as a separate active pharmaceutical agent, they may also be employed in combination with one or more compounds of the invention or other agents. When administered in combination, the therapeutic agents can be formulated to be administered separately or sequentially at different times, or the therapeutic agents can be administered as a single composition.

片語「共同療法」(或「組合療法」)在定義本發明化合物及另一醫藥劑之使用時欲涵蓋在將提供藥物組合之有益作用的方案中以依序方式投與各藥劑，且亦欲涵蓋諸如以具有固定比率之此等活性劑的單一膠囊形式或以各藥劑之多個各別膠囊形式以實質上同時之方式共同投與此等藥劑。 The phrase "common therapy" (or "combination therapy"), when defining the use of a compound of the invention and another pharmaceutical agent, is intended to encompass the sequential administration of the agents in a regimen that would provide a beneficial effect of the combination of drugs, and Such agents are intended to be co-administered in a substantially simultaneous manner, such as in the form of a single capsule having such a fixed ratio of such active agents, or in a plurality of separate capsules of each agent.

特定言之，本發明化合物之投藥可與熟習此項技術者已知之預防或治療瘤形成之其他療法聯合，諸如與放射線療法或與細胞抑制劑或細胞毒性劑聯合。 In particular, administration of the compounds of the invention may be combined with other therapies known to those skilled in the art for preventing or treating neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.

若調配成固定劑量，則該等組合產物採用在已接受之劑量範圍內的本發明化合物。當組合調配物不適當時，式I化合物亦可與已知抗糖尿病劑依序投與。本發明在投藥順序方面不受限制；本發明化合物可在投與已知抗糖尿病劑之前、同時或之後投與。 If formulated as a fixed dose, such combination products employ a compound of the invention within the accepted dosage range. When the combination formulation is not suitable, the compound of formula I can also be administered sequentially with known anti-diabetic agents. The invention is not limited in the order of administration; the compounds of the invention may be administered prior to, concurrently with, or after administration of a known anti-diabetic agent.

若患者將要接受或正在接受多種醫藥活性化合物，則該等化合物可同時或依序投與。舉例而言，在錠劑之狀況下，活性化合物可存在於一個錠劑中或各別錠劑中，該等各別錠劑可一次性投與或以任何次序依序投與。另外，應瞭解，組合物可呈不同形式。舉例而言，一或多種化合物可經由錠劑傳遞，而另一種化合物經由注射投與或以糖漿形式經口投與。所有組合、傳遞方法及投藥順序均涵蓋在內。 If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously or sequentially. For example, in the case of a lozenge, the active compound may be presented in a lozenge or in separate lozenges, which may be administered in a single dose or sequentially in any order. Additionally, it should be understood that the compositions may take different forms. For example, one or more compounds can be delivered via a lozenge while another compound is administered via injection or orally in the form of a syrup. All combinations, delivery methods, and dosing sequences are covered.

本發明化合物可用於製造用以治療由GKA介導之疾病及/或病狀(諸如2型糖尿病)之藥物。 The compounds of the invention are useful in the manufacture of a medicament for the treatment of diseases and/or conditions mediated by GKA, such as type 2 diabetes.

本發明化合物可與其他醫藥活性化合物組合使用。應注意，術 語「醫藥活性化合物」可包括生物劑，諸如蛋白質、抗體及肽體。其他醫藥活性化合物之實例包括(但不限於)：(a)二肽基肽酶IV(DPP-IV)抑制劑，諸如維格列汀(Vildagliptin)(Novartis)、西他列汀(Sitagliptin)(Merck&Co.)、沙格列汀(Saxagliptin)(BMS)、阿格列汀(Allogliptin)(Takeda)；(b)胰島素增敏劑，包括(i)PPARγ促效劑，諸如格列酮(glitazone)(例如曲格列酮(troglitazone)、吡格列酮(pioglitazone)、依格列酮(edaglitazone)、羅格列酮(rosiglitazone)及其類似物)，及其他PPAR配位體，包括PPARα/γ雙重促效劑，諸如莫格列紮(muraglitazar)(BMS)及替格列紮(tesaglitazar)(AstraZeneca)，及PPARα促效劑，諸如非諾貝酸(fenofibric acid)衍生物(吉非羅齊(gemfibrozil)、氯貝特(clofibrate)、非諾貝特(fenofibrate)及苯紮貝特(bezafibrate))，(ii)雙胍，諸如二甲雙胍(metformin)及苯乙雙胍(phenformin)，及(iii)蛋白質酪胺酸磷酸酯酶-1B(PTP-1B)抑制劑；(c)胰島素或胰島素模擬物；(d)腸促胰島素(incretin)及腸促胰島素模擬物，諸如(i)艾塞那肽(Exenatide)，可獲自Amylin Pharmaceuticals，(i)澱粉素及澱粉素模擬物，諸如醋酸普蘭林肽(pramlintide acetate)，以Symlin®獲得，(iii)GLP-1、GLP-1模擬物及GLP-1受體促效劑，(iv)GIP、GIP模擬物及GIP受體促效劑；(e)磺醯基脲及其他胰島素促泌素，諸如甲苯磺丁脲(tolbutamide)、優降糖(glyburide)、甲磺吡脲(gliclazide)、吡磺環己脲(glipizide)、格列美脲(glimepiride)、美格替耐(meglitinide)及瑞格列奈(repaglinide)；(f)α-葡糖苷酶抑制劑(諸如醣祿(acarbose)及米格列醇(miglitol))；(g)升糖素受體拮抗劑；(h)PACAP、PACAP模擬物及PACAP受體促效劑；(i)膽固醇降低劑，諸如(i)HMG-CoA還原酶抑制劑(洛伐他汀(lovastatin)、辛伐他汀(simvastatin)、普伐他汀(pravastatin)、西立伐他汀(cerivastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、伊伐他汀(itavastatin)及 羅素他汀(rosuvastatin)及其他他汀(statin))，(ii)膽汁酸錯隔劑，諸如消膽胺(cholestyramine)、考來替潑(colestipol)及交聯葡聚糖之二烷基胺基烷基衍生物，(iii)菸鹼醇、菸鹼酸或其鹽，(iv)PPARα促效劑，諸如非諾貝酸衍生物(吉非羅齊、氯貝特、非諾貝特及苯紮貝特)，(v)PPARα/γ雙重促效劑，諸如莫格列紮(BMS)及替格列紮(AstraZeneca)，(vi)膽固醇吸收抑制劑，諸如β-植固醇(beta-sitosterol)及依折麥布(ezetimibe)，(vii)醯基CoA：膽固醇醯基轉移酶抑制劑，諸如阿伐麥布(avasimibe)，及(viii)抗氧化劑，諸如普羅布可(probucol)；(j)PPARδ促效劑，諸如來自GSK之GW-501516；(k)抗肥胖化合物，諸如氟苯丙胺(fenfluramine)、右旋氟苯丙胺(dexfenfluramine)、苯丁胺(phentemine)、諾美婷(sibutramine)、奧利司他(orlistat)、神經肽Y1或Y5拮抗劑、MTP抑制劑、角鯊烯合成酶抑制劑、脂加氧酶抑制劑、ACAT抑制劑、神經肽大麻素(Neuropeptide Cannabinoid)CB-1受體拮抗劑、CB-1受體反向促效劑及拮抗劑、脂肪酸氧化抑制劑、食慾抑制劑；(l)腎上腺素激導性受體促效劑、黑皮素(melanocortin)受體促效劑(詳言之，黑皮素-4受體促效劑)、胃內激素(ghrelin)拮抗劑及黑色素濃集激素(melanin-concentrating hormone，MCH)受體拮抗劑；(m)迴腸膽汁酸轉運體抑制劑；(n)欲用於發炎病狀之藥劑，諸如阿司匹靈(aspirin)、非類固醇消炎藥、糖皮質激素、阿紮非定(azalfidine)及選擇性環加氧酶-2抑制劑；(o)抗高血壓劑，諸如ACE抑制劑(依拉普利(enalapril)、賴諾普利(lisinopril)、卡托普利(captopril)、喹那普利(quinapril)、福辛普利(fosinoprol)、雷米普利(ramipril)、螺普利(spirapril)、群多普利(tandolapril))、血管收縮素-II(AT-1)受體阻斷劑(洛沙坦(losartan)、坎地沙坦(candesartan)、厄貝沙坦(irbesartan)、纈沙坦(valsartan)、替米沙坦(telmisartan)、普羅沙坦(eprosartan))、β阻斷劑及鈣通道阻斷劑；及(p)葡糖激酶活化劑 (GKA)；(q)可用於預防神經退化性病症、認知病症、延緩該等病症之進程或治療該等病症之藥劑或用於改善記憶力之藥物，諸如消炎藥、抗氧化劑、神經保護劑、麩胺酸受體拮抗劑、乙醯膽鹼酯酶抑制劑、丁醯膽鹼酯酶抑制劑、MAO抑制劑、多巴胺促效劑或拮抗劑、γ及β分泌酶抑制劑、類澱粉蛋白聚集抑制劑、類澱粉β肽、針對類澱粉β肽之抗體、乙醯膽鹼酯酶抑制劑、葡糖激酶活化劑、旨在調節GABA、NMDA、大麻素、AMPA、紅藻酸(kainate)、磷酸二酯酶(PDE)、PKA、PKC、CREB或益智系統之藥劑；(r)欲用於治療及預防骨髓產生減少、感染性疾病、激素依賴性病症、發炎疾病、HIV、過敏、白血球減少症及風濕病之白血球生長促進劑；(s)SGLT2抑制劑；(t)肝糖磷酸化酶抑制劑；(u)aP2抑制劑；(v)胺基肽酶N抑制劑；(w)血管肽酶抑制劑，如奈溶酶(neprilysin)抑制劑及/或ACE抑制劑或雙重NEP/ACE抑制劑；(x)用於提高生長激素含量及用於治療生長遲緩/侏儒症或代謝病症或病症為損傷之狀況或需要癒合之傷口或自手術恢復之哺乳動物患者的生長激素促泌素；(y)5-HT 3或5-HT 4受體調節劑(替加色羅(tegaserod)、西沙必利(cisapride)、去甲西沙必利(nor-cisapride)、倫紮必利(renzapride)、紮考必利(zacopride)、莫沙必利(mosapride)、普卡必利(prucalopride)、丁螺環酮(buspirone)、去甲西沙必利、西蘭司瓊(cilansetron)、雷莫司瓊(ramosetron)、阿紮司瓊(azasetron)、昂丹司瓊(ondansetron)等)；(Za)醛糖還原酶抑制劑；(Zb)山梨糖醇去氫酶抑制劑；(Zc)AGE抑制劑；(Zd)紅血球生成素促效劑，諸如EPO、EPO模擬物及EPO受體促效劑。本發明化合物亦可與GPR40促效劑組合使用。 The compounds of the invention may be used in combination with other pharmaceutically active compounds. It should be noted that the term "pharmaceutically active compound" may include biological agents such as proteins, antibodies, and peptibodies. Examples of other pharmaceutically active compounds include, but are not limited to: (a) dipeptidyl peptidase IV (DPP-IV) inhibitors, such as Vildagliptin (Novartis), sitagliptin (Sitagliptin) ( Merck & Co.), Saxagliptin (BMS), Allogliptin (Takeda); (b) Insulin sensitizers, including (i) PPAR gamma agonists, such as glitazone (eg troglitazone, pioglitazone, edaglitazone, rosiglitazone and its analogues), and other PPAR ligands, including PPARα/γ dual efficacies Agents such as mulglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARα agonists, such as fenofibric acid derivatives (gemfibrozil) , clofibrate, fenofibrate and bezafibrate, (ii) biguanides such as metformin and phenformin, and (iii) protein tyramine Acid phosphatase-1B (PTP-1B) inhibitor; (c) insulin or insulin mimetic; (d) incretin and incretin Was proposed, such as (i) Exenatide (Exenatide), available from Amylin Pharmaceuticals, (i) amylin and amylin mimetics such as pramlintide acetate (pramlintide acetate), to obtain Symlin ®, (iii) GLP-1, GLP-1 mimetic and GLP-1 receptor agonist, (iv) GIP, GIP mimetic and GIP receptor agonist; (e) sulfonyl urea and other insulin secretagogues, such as Tolbutamide, glyburide, gliclazide, glipizide, glimepiride, meglitinide, and reggae (repaglinide); (f) alpha-glucosidase inhibitors (such as acarbose and miglitol); (g) glycosaminoglycan receptor antagonists; (h) PACAP, PACAP Mimetic and PACAP receptor agonists; (i) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, pravastatin, Cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin and other statins (ii) bile acid spacers, such as cholestyramine, colestipol and dialkylaminoalkyl derivatives of crosslinked dextran, (iii) nicotine alcohol, Nicotinic acid or its salt, (iv) PPARα agonist, such as fenofibric acid derivatives (gefiprozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ double Agonists such as moglitaza (BMS) and AstraZeneca, (vi) cholesterol absorption inhibitors such as beta-sitosterol and ezetimibe, Vii) sulfhydryl-based CoA: cholesterol thiol transferase inhibitors, such as avasimibe, and (viii) antioxidants, such as probucol; (j) PPAR delta agonists, such as from GSK GW-501516; (k) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentemine, sibutramine, orlistat, neuropeptides Y1 or Y5 antagonist, MTP inhibitor, squalene synthetase inhibitor, lipoxygenase inhibitor, ACAT inhibitor, Neuropeptide Cannabinoid CB-1 receptor antagonist Agent, CB-1 receptor inverse agonist and antagonist, fatty acid oxidation inhibitor, appetite suppressant; (1) adrenergic receptor agonist, melanocortin receptor agonist (In other words, melanocortin-4 receptor agonist), ghrelin antagonist and melanin-concentrating hormone (MCH) receptor antagonist; (m) ileal bile acid transporter Inhibitors; (n) agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azalfidine and selective cyclooxygenase-2 Inhibitor; (o) antihypertensive agents, such as ACE inhibitors (enalapril, lisinopril, captopril, quinapril, fosin Fosinoprol, ramipril, spirapril, tandolapril, angiotensin-II (AT-1) receptor blocker (losartan) Losartan), candesartan, irbesartan, valsartan, telmisartan, eprosartan, beta blockers and calcium channels Blockers; and (p) glucokinase activators (GKA); (q) useful for preventing neurodegenerative disorders, cognitive disorders, delaying the progression of such disorders or treating such disorders or for improving memory Drugs, such as anti-inflammatory drugs, antioxidants, neuroprotective agents, glutamate receptor antagonists, acetylcholinesterase inhibitors, acetylcholinesterase inhibitors, MAO inhibitors, dopamine agonists or antagonists , γ and β secretase inhibitors, amyloid aggregation inhibitors, amyloid beta peptides, antibodies against amyloid beta peptides, acetylcholinesterase inhibitors, glucokinase activators, designed to regulate GABA, NMDA , cannabinoids, AMPA, kainate, phosphodiesterase (PDE), PKA, PKC, CREB or the system of the puzzle system; (r) intended to treat and prevent bone marrow production, infectious diseases, Hormone-dependent disease, inflammatory disease, HIV, allergy, leukopenia, and leukocyte growth promoter of rheumatism; (s) SGLT2 inhibitor; (t) hepatic glycophosphorylase inhibitor; (u) aP2 inhibitor; v) an aminopeptidase N inhibitor; (w) a vasopeptidase inhibitor, such as nepolytic enzyme (n Eprilysin) inhibitors and/or ACE inhibitors or dual NEP/ACE inhibitors; (x) for increasing growth hormone levels and for treating growth retardation/dwarfism or metabolic disorders or conditions as a condition of injury or wounds requiring healing Or growth hormone secretagogue in a mammalian patient recovered from surgery; (y) 5-HT 3 or 5-HT 4 receptor modulator (tegaserod, cisapride, normethacin) Nor-cisapride, renzapride, zacopride, mosapride, prucalopride, buspirone, armor Cisapride, cilansetron, ramosetron, azasetron, ondansetron, etc.; (Za) aldose reductase inhibitor; (Zb a sorbitol dehydrogenase inhibitor; (Zc) AGE inhibitor; (Zd) erythropoietin agonist, such as EPO, EPO mimetic, and EPO receptor agonist. The compounds of the invention may also be used in combination with GPR40 agonists.

本發明化合物亦可與FGF-21化合物組合使用，且尤其用於治療2型糖尿病。FGF-21化合物之實例揭示於美國專利第7,671,180號、美國專利第7,667,008號、美國專利第7,459,540號、美國專利第 7,696,172號、PCT申請公開案第WO 2010/042747號及PCT申請公開案第WO 2009/149171號中。 The compounds of the invention may also be used in combination with FGF-21 compounds, and in particular for the treatment of type 2 diabetes. Examples of FGF-21 compounds are disclosed in U.S. Patent No. 7,671,180, U.S. Patent No. 7,667,008, U.S. Patent No. 7,459,540, U.S. Patent No. No. 7,696,172, PCT Application Publication No. WO 2010/042747, and PCT Application Publication No. WO 2009/149171.

本發明化合物亦可與阿那白滯素(anakinra)組合使用，尤其用於治療2型糖尿病。 The compounds of the invention may also be used in combination with anakinra, especially for the treatment of type 2 diabetes.

在一個特定態樣中，本發明化合物可與二甲雙胍組合使用。 In one particular aspect, the compounds of the invention can be used in combination with metformin.

合成方法resolve resolution

本發明化合物可根據以下流程1-13之程序製備，其中取代基如上文針對式I-IV所定義，有註釋之處除外。 The compounds of the invention can be prepared according to the procedures of Schemes 1-13 below, wherein the substituents are as defined above for Formulas I-IV, except where noted.

本文中可使用以下縮寫： The following abbreviations can be used in this article:

吡啶基脲7可根據流程1中所陳述之方法製備。首先在約室溫之溫度下用諸如NaH之強鹼處理醇1，接著用2-鹵基-4-硝基吡啶2處理，得到吡啶基醚3。藉由在諸如Pd(dba)2之催化劑存在下，在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約90℃之溫度下，用諸如胺基甲酸第三丁酯之經取代胺基甲酸酯處理吡啶基醚3來製備吡啶基胺基甲酸酯4。在約室溫之溫度下用酸(較佳為TFA)處理吡啶-2-基胺基甲酸酯4，得到吡啶-2-胺5。藉由使吡啶-2-基胺5溴化，諸如用含Br2之AcOH處理來製備5-溴-吡啶-2-基胺6。在約室溫之溫度下用氯甲酸4-硝基苯酯處理5-溴-吡啶-2-胺6，繼而用經取代之胺處理，得到所要5-溴吡啶基脲7。 Pyridylurea 7 can be prepared according to the procedure set forth in Scheme 1. The alcohol 1 is first treated with a strong base such as NaH at about room temperature, followed by treatment with 2-halo-4-nitropyridine 2 to give the pyridyl ether 3 . By using, for example, an aminocarboxylic acid in the presence of a catalyst such as Pd(dba) 2 at a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of about 90 ° C The pyridyl carbamate 4 is prepared by treating the pyridyl ether 3 with a substituted urethane of tributyl ester. Treatment of pyridin-2-ylcarbamate 4 with an acid (preferably TFA) at about room temperature affords pyridin-2-amine 5 . Pyridin-2-ylamine 6 - pyridin-2-yl-amine by making 5 bromide, prepared as Br AcOH containing 5-bromo-2 of process. Treatment of 5-bromo-pyridin-2-amine 6 with 4-nitrophenyl chloroformate at about room temperature, followed by treatment with a substituted amine affords the desired 5-bromopyridylurea 7 .

4-經取代之2-吡啶基脲8可根據流程2中所陳述之方法製備。在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約90℃之溫度 下，藉助於諸如Pd2(dba)3之催化劑及5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑使吡啶基醚3與經取代之脲偶合，得到所要脲8。 4-Substituted 2-pyridylurea 8 can be prepared according to the procedure set forth in Scheme 2. At a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of about 90 ° C, by means of a catalyst such as Pd 2 (dba) 3 and 5-(di-t-butyl) Phosphyl)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole couples pyridyl ether 3 with a substituted urea to give the desired urea 8 .

用以製備4-經取代之2-吡啶基脲8之替代方法展示於流程3中。在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約90℃之溫度下，使用布赫瓦爾德化學法(Buchwald chemistry)[例如1,1'-聯萘-2-基二第三丁基膦及諸如Pd2(dba)3之鈀催化劑]使1-經取代之脲9與2-氯-4-硝基吡啶2組合，得到(4-硝基吡啶-2-基)脲11。在室溫下用諸如NaH之鹼處理醇R5-OH，接著冷卻至低於室溫、較佳為約0℃之溫度，接著在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約70℃之溫度下與(4-硝基吡啶-2-基)脲11組合，得到所要經取代之脲8。 An alternative method for preparing 4-substituted 2-pyridylurea 8 is shown in Scheme 3. At temperatures above room temperature, preferably above 50 ° C and more preferably at temperatures of about 90 ° C, Buchwald chemistry is used [eg 1,1 '-binaphthyl] 2-yldibutylphosphonium and a palladium catalyst such as Pd 2 (dba) 3 ] 1-substituted urea 9 is combined with 2-chloro-4-nitropyridine 2 to give (4-nitropyridine -2-yl)urea 11 . The alcohol R 5 -OH is treated with a base such as NaH at room temperature, followed by cooling to a temperature below room temperature, preferably about 0 ° C, followed by a temperature above room temperature, preferably above 50 ° C. The combination with (4-nitropyridin-2-yl)urea 11 at a temperature and more preferably at a temperature of about 70 ° C gives the desired urea 8 .

4,5-二取代之2-吡啶基脲13可根據流程4中所陳述之方法製備。使用鈴木偶合(Suzuki coupling)或類似Pd催化之化學法，在高於室溫之 溫度下、較佳在高於50℃之溫度下且更佳在約80℃之溫度下使1-(5-溴-吡啶-2-基)-3-經取代之脲與經取代之酸及諸如Pd(PPh3)4之催化劑組合，得到所要化合物13。 The 4,5-disubstituted 2-pyridylurea 13 can be prepared according to the procedure set forth in Scheme 4. Using Suzuki coupling or a Pd-like chemistry, 1-(5- is made at a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of about 80 ° C. Bromo-pyridin-2-yl)-3-substituted urea and substituted The combination of an acid and a catalyst such as Pd(PPh 3 ) 4 gives the desired compound 13 .

用以製備(5-溴-2-吡啶基)脲7之替代方法展示於流程5中。使(3-經取代之吡啶-2-基)脲8溴化，諸如藉由在0℃與室溫之間的溫度下用NBS處理，得到所要經取代之1-(5-溴-吡啶-2-基)-3-經取代之脲7。 An alternative method for preparing (5-bromo-2-pyridyl)urea 7 is shown in Scheme 5. The (3-substituted pyridin-2-yl)urea 8 is brominated, such as by treatment with NBS at a temperature between 0 ° C and room temperature to give the desired 1-(5-bromo-pyridine- 2-based)-3-substituted urea 7 .

(4,5-二取代之2-吡啶基)脲19可根據流程6中所陳述之方法製備。在約室溫之溫度下用諸如NBS於DMF中使吡啶基胺基甲酸酯4溴化， 得到5-溴吡啶基胺基甲酸酯15。藉由諸如在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約95℃之溫度下用鹼(例如DIEA)、Pd催化劑(例如Pd2dba3)、Xantphos及3-巰基丙酸甲酯處理溴代中間物來實現吡啶基環上之其他取代，得到巰基丙酸甲酯吡啶基胺基甲酸酯(X為S)16。可能對取代基進行修飾，諸如使巰基丙酸甲酯取代基轉化成醚17，諸如在約室溫之溫度下用例如2-甲基丙-2-醇鉀之鹼及經取代之烷基鹵化物(例如1-溴-3-甲氧基丙烷)處理，得到醚17。如流程1中所述來脫除保護基並使游離胺18轉化成脲。或者，使用流程8中所述之程序，依序用經取代之氯甲酸酯、經取代之胺處理醚17，得到所要脲19。 (4,5-Disubstituted 2-pyridyl)urea 19 can be prepared according to the procedure set forth in Scheme 6. Bromination of pyridyl carbamate 4 with, for example, NBS in DMF at a temperature of about room temperature affords 5-bromopyridylcarbamate 15 . By using a base such as DIEA, a Pd catalyst (e.g., Pd 2 dba 3 ), Xantphos, such as at a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of about 95 ° C The bromo intermediate is treated with methyl 3-mercaptopropionate to effect other substitutions on the pyridyl ring to give methyl mercaptopropionate pyridyl carbamate (X is S) 16 . It is possible to modify the substituents, such as converting the methyl mercaptopropionate substituent to ether 17 , such as by halogenation with a base such as potassium 2-methylpropan-2-olate and a substituted alkyl group at a temperature of about room temperature Treatment with a substance such as 1-bromo-3-methoxypropane affords the ether 17 . The protecting group is removed as described in Scheme 1 and the free amine 18 is converted to the urea. Alternatively, the ether 17 is treated sequentially with a substituted chloroformate or a substituted amine using the procedure described in Scheme 8 to provide the desired urea 19 .

3,5-二取代之2-吡啶基脲21可根據流程7中所陳述之方法製備。在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約60℃至約70℃之溫度下使異氰酸酯基乙烷與3,5-二取代之吡啶-2-胺20反應，得到脲21。 The 3,5-disubstituted 2-pyridylurea 21 can be prepared according to the procedure set forth in Scheme 7. Isocyanate ethane and 3,5-disubstituted pyridin-2- at a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of from about 60 ° C to about 70 ° C. The amine 20 is reacted to give the urea 21 .

3,5-經取代之2-吡啶基脲21可根據流程8中所陳述之方法製備。使經取代之吡啶-2-胺20與諸如氯甲酸4-硝基苯酯之氯甲酸酯反應，得到單胺基甲酸酯與雙胺基甲酸酯之混合物22。使胺基甲酸酯22與一級胺R1-NH2反應，得到所要脲21。 The 3,5-substituted 2-pyridylurea 21 can be prepared according to the procedure set forth in Scheme 8. The substituted pyridin-2-amine 20 is reacted with a chloroformate such as 4-nitrophenyl chloroformate to give a mixture of a monocarbamate and a bis-carbamate 22 . The carbamate 22 is reacted with a primary amine R 1 -NH 2 to give the desired urea 21 .

3,5-二取代之2-吡啶基脲21可根據流程9中所陳述之方法製備。在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約80℃之溫度下用吡啶-3-基酸及諸如Pd(PPh3)4之鈀催化劑處理經取代之1-(5-溴吡啶-2-基)-3-經取代之脲23，得到所要經取代之吡啶基脲24。 The 3,5-disubstituted 2-pyridylurea 21 can be prepared according to the procedure set forth in Scheme 9. Pyridin-3-yl at a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of about 80 ° C The substituted 1-(5-bromopyridin-2-yl)-3-substituted urea 23 is treated with an acid and a palladium catalyst such as Pd(PPh 3 ) 4 to give the pyridyl urea 24 to be substituted.

3,5-二取代之2-吡啶基脲25可根據流程10中所陳述之方法製備。在高於室溫之溫度下、較佳在高於50℃之溫度下且更佳在約95℃之溫度下用Xantphos、酯及諸如Pd2dba3之鈀催化劑處理1-(5-溴吡啶-2-基)- 3-甲基脲，得到所要吡啶基-酯25。 The 3,5-disubstituted 2-pyridylurea 25 can be prepared according to the procedure set forth in Scheme 10. Treatment of 1-(5-bromopyridine) with Xantphos, an ester and a palladium catalyst such as Pd 2 dba 3 at a temperature above room temperature, preferably at a temperature above 50 ° C and more preferably at a temperature of about 95 ° C 2-yl)- 3-methylurea gives the desired pyridyl-ester 25 .

3,5-二取代之2-吡啶基脲21可根據流程11中所陳述之方法製備。在約室溫之溫度下用諸如2-甲基丙-2-醇鉀之鹼及經取代之鹵化物處理吡啶基-酯25，得到所要經取代之吡啶基脲21。 The 3,5-disubstituted 2-pyridylurea 21 can be prepared according to the procedure set forth in Scheme 11. The pyridyl-ester 25 is treated with a base such as potassium 2-methylpropan-2-ol and a substituted halide at a temperature of about room temperature to give the pyridyl urea 21 to be substituted.

3,5-二取代之2-吡啶基脲21亦可根據流程12中所陳述之方法製備。諸如用酸(諸如HCl)使經保護之(羥基吡啶-2-基)脲26脫除保護基，得到羥基化合物27。在約室溫之溫度下用PPh3、DIAD及經取代之醇(R6-OH)處理羥基化合物27，得到3,5-二取代之化合物21。 The 3,5-disubstituted 2-pyridylurea 21 can also be prepared according to the procedure set forth in Scheme 12. Deprotection of the protected (hydroxypyridin-2-yl)urea 26 , such as with an acid such as HCl, affords the hydroxy compound 27 . The hydroxy compound 27 is treated with PPh 3 , DIAD and a substituted alcohol (R 6 -OH) at a temperature of about room temperature to give a 3,5-disubstituted compound 21 .

3,5-二取代之2-吡啶基脲21亦可根據流程13中所陳述之方法製備。在約室溫之溫度下使5-溴-2-氯-3-氟吡啶29、經取代之醇28及諸如Cs2CO3之鹼反應，得到5-溴-2-氯吡啶醇30。在高於室溫之溫度下、較佳在高於50℃之溫度下，醇30、Xantphos、諸如Pd2(dba)3之鈀催化劑及經取代之硫醇醚(R4XH，其中X為硫)得到2-氯-吡啶31。在約室溫之溫度下處理2-氯吡啶31、1-經取代之脲、5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑及諸如Pd2(dba)3之鈀催化劑，得到所要脲21。 The 3,5-disubstituted 2-pyridylurea 21 can also be prepared according to the procedure set forth in Scheme 13. 5-Bromo-2-chloro-3-fluoropyridine 29 , substituted alcohol 28 and a base such as Cs 2 CO 3 are reacted at about room temperature to give 5-bromo-2-chloropyridinol 30 . At a temperature above room temperature, preferably above 50 ° C, alcohol 30 , Xantphos, a palladium catalyst such as Pd 2 (dba) 3 and a substituted thiol ether (R 4 XH, where X is Sulfur) gives 2-chloro-pyridine 31 . Treatment of 2-chloropyridine 31 , 1-substituted urea, 5-(di-t-butylphosphino)-1',3',5'-triphenyl-1'H- at a temperature of about room temperature 1,4'-bipyrazole and a palladium catalyst such as Pd 2 (dba) 3 give the desired urea 21 .

亦咸信上述流程中所說明之化合物7、8、11、13、15、16、17、18、19、20、21、22、23、24、25、26、27、30及31(其中各式中之變數如針對式I所定義)為新穎的，且提供本發明之另一態樣。 Also known as compounds 7, 8, 11, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 30 and 31 (each of which is described in the above process) The variables in the formula are as defined for Formula I) are novel and provide another aspect of the invention.

流程1-13中所定義之起始化合物亦可存在呈經保護形式(必要時)及/或呈鹽形式之官能基，其限制條件為成鹽基團存在且以鹽形式反應為可能的。若有此需要，則一種式I-IV化合物可轉化成另一種式I-IV化合物或其N-氧化物；式I-IV化合物可轉化成鹽；式I-IV化合物之鹽可轉化成游離化合物或另一種鹽；及/或式I-IV異構化合物之混合物可分離成個別異構體。 The starting compounds defined in Schemes 1-13 may also be present in a protected form (if necessary) and/or in the form of a salt, with the proviso that the salt-forming group is present and reacted as a salt. If desired, a compound of formula I-IV can be converted to another compound of formula I-IV or an N-oxide thereof; a compound of formula I-IV can be converted to a salt; a salt of a compound of formula I-IV can be converted to free A compound or another salt; and/or a mixture of isomeric compounds of formula I-IV can be separated into individual isomers.

N-氧化物可以已知方式藉由在如二氯甲烷之惰性溶劑中，在約-10℃至35℃(諸如約0℃至室溫)之間的溫度下，使式I-IV化合物與過氧化氫或過酸(例如3-氯過氧-苯甲酸)反應而獲得。 The N-oxide can be compounded in a known manner by a compound of formula I-IV with a temperature between about -10 ° C and 35 ° C (such as about 0 ° C to room temperature) in an inert solvent such as dichloromethane. Obtained by the reaction of hydrogen peroxide or a peracid such as 3-chloroperoxy-benzoic acid.

若在式I-IV及式Ia、式IIc、式IId、式IIIa及式IVa化合物中或合成式I-IV及式Ia、式IIc、式IId、式IIIa及式IVa化合物中保護或需要保護 一或多個其他官能基，例如羧基、羥基、胺基或巰基，此係因為該等官能基不應參與反應，則在合成肽化合物以及頭孢菌素(cephalosporin)及青黴素(penicillin)以及核酸衍生物及糖中通常使用此等基團。 Protecting or requiring protection in the compounds of Formula I-IV and Formula Ia, Formula IIc, Formula IId, Formula IIIa and Formula IVa or in the synthesis of compounds of Formula I-IV and Formula Ia, Formula IIc, Formula IId, Formula IIIa and Formula IVa One or more other functional groups, such as a carboxyl group, a hydroxyl group, an amine group or a thiol group, because the functional groups are not involved in the reaction, in the synthesis of peptide compounds as well as cephalosporin and penicillin and nucleic acid derivatization These groups are commonly used in substances and sugars.

保護基可已存在於前驅物中且應保護相關官能基免於發生非所欲之二次反應，諸如醯化、醚化、酯化、氧化、溶劑分解及類似反應。保護基之一個特徵在於其使得自身易於通常藉由溶劑分解、還原、光解或亦藉由酶活性(例如在類似於生理條件之條件下)而移除(亦即無不當二次反應)且不存在於最終產物中。專家已知或可易於確定哪些保護基適合上文及下文所提及之反應。 The protecting group may already be present in the precursor and the relevant functional groups should be protected from undesired secondary reactions such as deuteration, etherification, esterification, oxidation, solvolysis and the like. A feature of a protecting group is that it facilitates its own removal, usually by solvolysis, reduction, photolysis or also by enzymatic activity (for example under conditions similar to physiological conditions) (ie without undue secondary reaction) and Not present in the final product. Experts are known or can readily determine which protecting groups are suitable for the reactions mentioned above and below.

該等保護基對該等官能基之保護、保護基自身及其移除反應描述於例如標準文獻著作中，諸如J.F.W.McOmie,「Protective Groups in Organic Chemistry」,Plenum Press,London and New York 1973；T.W.Greene,「Protective Groups in Organic Synthesis」,Wiley,New York 1981；「The Peptides」；第3卷(編者：E.Gross及J.Meienhofer),Academic Press,London and New York 1981；「Methoden der organischen Chemie」(Methods of organic chemistry),Houben Weyl，第4版，第15/1卷，Georg Thieme Verlag,Stuttgart 1974；H.-D.Jakubke及H.Jescheit,「Aminosäuren,Peptide,Proteine」(Amino acids,peptides,proteins),Verlag Chemie,Weinheim,Deerfield Beach及Basel 1982；及Jochen Lehmann,「Chemie der Kohlenhydrate：Monosaccharide und Derivate」(Chemistry of carbohydrates：monosaccharides and derivatives),Georg Thieme Verlag,Stuttgart 1974。 The protection of such protecting groups, the protecting groups themselves and their removal reactions are described, for example, in standard literature such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981; "The Peptides"; Volume 3 (Editor: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; "Methoden der organischen Chemie (Methods of organic chemistry), Houben Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, "Aminosäuren, Peptide, Proteine" (Amino acids, Peptides, proteins, Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

在必要時所進行的其他製程步驟中，起始化合物中不應參與反應之官能基可以未經保護形式存在或可例如由上文在「保護基」下所提及之一或多個保護基加以保護。接著根據彼處所述之一種方法完全 或部分移除保護基。 In other process steps carried out as necessary, the functional group of the starting compound which should not participate in the reaction may be present in unprotected form or may be, for example, one or more of the protecting groups mentioned above under "protecting groups" Protected. Then completely according to one of the methods described in the other Or partially remove the protecting group.

具有成鹽基團之式I-IV及式Ia、式IIc、式IId、式IIIa及式IVa化合物之鹽可以本身已知之方式製備。因此，可藉由用酸或用適合之陰離子交換試劑處理而獲得式I-IV化合物之酸加成鹽。具有兩個酸分子之鹽(例如式I-IV化合物之二鹵化物)亦可轉化成每個化合物具有一個酸分子之鹽(例如單鹵化物)；此可藉由加熱至熔融物，或例如藉由在高真空下於高溫(例如約130℃至約170℃)下以固體形式加熱來完成，式I-IV及式Ia、式IIc、式IId、式IIIa及式IVa化合物之每個分子放出一個酸分子。 Salts of the formula I-IV and the compounds of the formula Ia, the formula IIc, the formula IId, the formula IIIa and the formula IVa having a salt-forming group can be prepared in a manner known per se. Thus, the acid addition salts of the compounds of formula I-IV can be obtained by treatment with an acid or with a suitable anion exchange reagent. Salts having two acid molecules (e.g., dihalides of the compounds of formula I-IV) can also be converted to a salt (e.g., a monohalide) having one acid molecule per compound; this can be by heating to the melt, or for example Each of the compounds of Formula I-IV and Formula Ia, Formula IIc, Formula IId, Formula IIIa, and Formula IVa is completed by heating in solid form under high vacuum (eg, from about 130 ° C to about 170 ° C) under high vacuum. Release an acid molecule.

鹽通常可轉化成游離化合物，例如藉由用適合之鹼性試劑處理，例如用鹼金屬碳酸鹽、鹼金屬碳酸氫鹽或鹼金屬氫氧化物(通常為碳酸鉀或氫氧化鈉)處理。 The salt can usually be converted to the free compound, for example by treatment with a suitable alkaline reagent, for example with an alkali metal carbonate, an alkali metal hydrogencarbonate or an alkali metal hydroxide (usually potassium carbonate or sodium hydroxide).

此處所述之所有製程步驟可在已知反應條件下、較佳在特定提及之條件下，在不存在或通常存在溶劑或稀釋劑(較佳對所用試劑呈惰性且能夠溶解此等試劑)之情況下，在不存在或存在催化劑、冷凝劑或中和劑(例如離子交換劑，通常為陽離子交換劑，例如呈H+形式)之情況下，視反應及/或反應物之類型而定，在低溫、常溫或高溫下，例如在約-100℃至約190℃、較佳約-80℃至約150℃之範圍內，例如在約-80℃至約60℃下、在室溫下、在約-20℃至約40℃下或在所用溶劑之沸點下，在大氣壓下或在密閉容器中，適當時在一定壓力下，及/或在惰性氛圍中，例如在氬氣或氮氣下進行。 All of the process steps described herein can be carried out under known reaction conditions, preferably under specifically mentioned conditions, in the absence or presence of a solvent or diluent (preferably inert to the reagents employed and capable of dissolving such reagents) In the case of the absence or presence of a catalyst, a condensing agent or a neutralizing agent (for example an ion exchanger, usually a cation exchanger, for example in the form of H+), depending on the type of reaction and/or reactant At low temperature, normal temperature or elevated temperature, for example, in the range of about -100 ° C to about 190 ° C, preferably about -80 ° C to about 150 ° C, for example, at about -80 ° C to about 60 ° C, at room temperature At about -20 ° C to about 40 ° C or at the boiling point of the solvent used, at atmospheric pressure or in a closed vessel, suitably under a certain pressure, and / or in an inert atmosphere, such as under argon or nitrogen get on.

鹽可存在於所有起始化合物及過渡物質中，條件為此等物質含有成鹽基團。鹽亦可在該等化合物反應期間存在，其限制條件為不會因此而干擾反應。 Salts may be present in all starting compounds and transition materials, provided that such materials contain a salt-forming group. Salts may also be present during the reaction of such compounds with the proviso that they do not interfere with the reaction.

在某些狀況下，通常在氫化過程中，可達成立體選擇性反應，從而可例如較易回收個別異構體。 In some cases, it is common to have a stereoselective reaction during the hydrogenation process so that, for example, individual isomers can be recovered more easily.

除非製程之描述中另有規定，否則可自其中選擇適合於所述反應之溶劑的溶劑包括例如水；酯，通常為低碳烷酸低碳烷酯，例如乙酸乙酯；醚，通常為脂族醚，例如乙醚，或環醚，例如THF；液態芳族烴，通常為苯或甲苯；醇，通常為MeOH、EtOH或1-丙醇、2-丙醇；腈，通常為CH3CN；鹵化烴，通常為DCM；醯胺(acid amide)，通常為DMF；鹼，通常為雜環氮鹼，例如吡啶；羧酸，通常為低碳烷羧酸，例如AcOH；羧酸酐，通常為低碳烷酸酐，例如乙酸酐；環狀、直鏈或分支鏈烴，通常為環己烷、己烷或異戊烷；或此等溶劑之混合物，例如水溶液。該等溶劑混合物亦可用於處理，例如用於層析。 Unless otherwise specified in the description of the process, solvents from which a solvent suitable for the reaction can be selected include, for example, water; esters, typically lower alkyl alkanoates, such as ethyl acetate; ethers, usually fats a family ether, such as diethyl ether, or a cyclic ether, such as THF; a liquid aromatic hydrocarbon, typically benzene or toluene; an alcohol, typically MeOH, EtOH or 1-propanol, 2-propanol; a nitrile, typically CH 3 CN; Halogenated hydrocarbon, usually DCM; acid amide, usually DMF; base, usually a heterocyclic nitrogen base such as pyridine; carboxylic acid, usually a lower alkane carboxylic acid such as AcOH; carboxylic anhydride, usually low A carbonic acid anhydride such as acetic anhydride; a cyclic, linear or branched hydrocarbon, usually cyclohexane, hexane or isopentane; or a mixture of such solvents, such as an aqueous solution. These solvent mixtures can also be used for processing, for example for chromatography.

本發明亦關於彼等製程形式，其中吾人以可在任何階段作為過渡物質獲得之化合物起始且進行缺少之步驟，或在任何階段中斷該製程，或在反應條件下形成起始物質，或以反應性衍生物或鹽形式使用該起始物質，或產生可藉助於本發明製程獲得之化合物且當場處理該化合物。在較佳實施例中，吾人以產生上文描述為較佳之化合物的彼等起始物質起始。 The invention also relates to their process forms, wherein we start with a compound obtainable as a transitional material at any stage and carry out the missing steps, or interrupt the process at any stage, or form a starting material under the reaction conditions, or The starting material is used in the form of a reactive derivative or salt, or a compound obtainable by means of the process of the invention is produced and treated on the spot. In a preferred embodiment, we start with the starting materials which produce the compounds described above as preferred.

式I-IV化合物(包括其鹽)亦可以水合物形式獲得，或其晶體可包括例如用於結晶之溶劑(以溶劑合物形式存在)。 The compound of formula I-IV, including its salts, may also be obtained in the form of a hydrate, or the crystal thereof may include, for example, a solvent for crystallization (present in the form of a solvate).

新起始物質及/或中間物以及其製備製程同樣為本發明之主題。在較佳實施例中，使用能夠獲得較佳化合物之起始物質且選擇能夠獲得較佳化合物之反應條件。 The novel starting materials and/or intermediates and their preparation processes are also the subject of the present invention. In a preferred embodiment, a starting material capable of obtaining a preferred compound is used and the reaction conditions for obtaining a preferred compound are selected.

在製備起始物質中，必要時，應保護不參與反應之現有官能基。較佳保護基、其引入及其移除描述於上文或實例中。 In preparing the starting materials, if necessary, the existing functional groups which do not participate in the reaction should be protected. Preferred protecting groups, their introduction and their removal are described above or in the examples.

已知所有剩餘起始物質能夠根據已知製程製備，或可購得；詳言之，其可使用如實例中所述之製程製備。 All remaining starting materials are known to be prepared according to known processes, or are commercially available; in particular, they can be prepared using processes as described in the Examples.

本發明化合物一般可具有一或多個不對稱碳原子且因此能夠以 光學異構體形式存在且由此呈外消旋體及外消旋混合物、非外消旋混合物(scalemic mixture)、單一對映異構體、個別非對映異構體及非對映異構體混合物形式。光學異構體可藉由根據習知製程，例如藉由形成非對映異構體鹽、藉由用光學活性酸或鹼處理來解析外消旋混合物而獲得。適當酸之實例為酒石酸、二乙醯基酒石酸、二苄醯基酒石酸、二甲苯醯基酒石酸及樟腦磺酸，接著藉由結晶分離非對映異構體之混合物，繼而自此等鹽釋放光學活性鹼。一種用於分離光學異構體之不同製程涉及使用對掌性層析管柱，其經最佳選擇以使對映異構體之分離達到最大。另一可用方法涉及藉由使本發明化合物與呈活化形式之光學純酸或光學純之異氰酸酯反應來合成共價非對映異構體分子。所合成之非對映異構體可由習知方式(諸如層析、蒸餾、結晶或昇華)分離，接著進行水解以釋放出對映異構純之化合物。本發明之光學活性化合物可同樣藉由使用光學活性起始物質而獲得。此等異構體可呈游離酸、游離鹼、酯或鹽之形式。此等化合物之所有該等異構形式明確包括於本發明中。 The compounds of the invention may generally have one or more asymmetric carbon atoms and are therefore capable of The optical isomer form exists and thus is a racemate and a racemic mixture, a non-racemic mixture, a single enantiomer, an individual diastereomer and a diastereomer In the form of a mixture of bodies. Optical isomers can be obtained by resolution of the racemic mixture according to conventional procedures, for example by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of suitable acids are tartaric acid, dimercapto tartaric acid, dibenzylidene tartaric acid, xylyl tartaric acid and camphorsulfonic acid, followed by separation of the mixture of diastereomers by crystallization, followed by release of the optical from these salts. Active base. A different process for separating optical isomers involves the use of a pair of palm chromatography columns that are optimally selected to maximize separation of the enantiomers. Another useful method involves the synthesis of covalent diastereomeric molecules by reacting a compound of the invention with an optically pure acid or optically pure isocyanate in an activated form. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, followed by hydrolysis to liberate the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. All such isomeric forms of such compounds are expressly included in the present invention.

化合物亦可呈順-或反-或E-或Z-雙鍵異構形式。該等化合物之所有該等異構形式明確包括於本發明中。本文所述化合物之所有晶體形式均明確包括於本發明中。 The compounds may also be in the cis- or trans- or E- or Z-double bond isomeric form. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

環部分(例如苯基、噻吩基等)上之取代基可連接於特定原子，藉此其欲固定於彼原子；或可將該等取代基繪製成不連接於特定原子，藉此其欲連接在尚未經除H(氫)以外之原子取代的任何可用原子處。 a substituent on a ring moiety (e.g., phenyl, thienyl, etc.) may be attached to a particular atom, whereby it is intended to be attached to the other atom; or the substituents may be drawn not to a particular atom, thereby At any available atom that has not been replaced by an atom other than H (hydrogen).

本發明化合物可含有連接於另一環系統之雜環系統。該等雜環系統可經環系統中之碳原子或雜原子連接。 The compounds of the invention may contain a heterocyclic system attached to another ring system. The heterocyclic ring systems can be attached via carbon or heteroatoms in the ring system.

或者，本文所描繪之任一式之化合物可根據本文所描述之任一製程來合成。在本文所描述之製程中，步驟可以輪流次序進行，且必要時可在該等步驟之前或之後進行額外的保護/脫除保護基步驟。製 程可進一步包含使用適當反應條件，包括惰性溶劑、其他試劑(諸如鹼(例如LDA、DIEA、吡啶、K2CO3及其類似物))、催化劑及上述物質之鹽形式。中間物可在純化或未純化下當場分離或繼續使用。純化方法在此項技術中為已知的且包括例如結晶、層析(液相及氣相、模擬移動床(「SMB」))、萃取、蒸餾、濕磨、逆相HPLC及其類似方法。諸如溫度、持續時間、壓力及氛圍(惰性氣體、周圍環境)之反應條件在此項技術中為已知的且可作調整而適於反應。 Alternatively, a compound of any of the formulae described herein can be synthesized according to any of the processes described herein. In the processes described herein, the steps may be performed in a sequential order, and additional protection/deprotection steps may be performed before or after such steps as necessary. Process may further comprise use of appropriate reaction conditions, including inert solvents, additional reagents (such as a base (e.g., LDA, DIEA, pyridine, K 2 CO 3 and the like)), and a salt thereof of the form of the catalyst. The intermediate can be isolated or continued to be used on the spot with or without purification. Purification methods are known in the art and include, for example, crystallization, chromatography (liquid and gas phase, simulated moving bed ("SMB")), extraction, distillation, wet milling, reverse phase HPLC, and the like. Reaction conditions such as temperature, duration, pressure and atmosphere (inert gas, ambient) are known in the art and can be adapted to the reaction.

如熟練技術人員可瞭解，上述合成流程不欲包含可合成本申請案中描述及主張之化合物之所有方式的詳盡清單。其他方法將為一般技術者顯而易知。另外，上文所述之各種合成步驟可以輪流順序或次序進行以得到所要化合物。適用於合成本文所述之抑制劑化合物之合成化學轉化及保護基方法學(保護及脫除保護基)在此項技術中為已知的且包括例如以下文獻中所述者：諸如R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989)；T.W.Greene及P.G.M.Wuts,Protective Groups in Organic Synthesis，第3版，John Wiley and Sons(1999)；L.Fieser及M.Fieser,Fieser and Fieser's Reagents for Organic Synthesis,John Wiley and Sons(1994)；A.Katritzky及A.Pozharski,Handbook of Heterocyclic Chemistry，第2版(2001)；M.Bodanszky,A.Bodanszky：The practice of Peptiae Synthesis Springer-Verlag,Berlin Heidelberg 1984；J.Seyden-Penne：Reductions by the Alumino-and Borohydrides in Organic Synthesis，第2版，Wiley-VCH,1997；及L.Paquette編，Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)。 As the skilled artisan will appreciate, the above synthetic schemes are not intended to include an exhaustive list of all the ways in which the compounds described and claimed in this application can be synthesized. Other methods will be apparent to the average person. Additionally, the various synthetic steps described above can be carried out in sequential order or order to provide the desired compound. Synthetic chemical transformation and protecting group methodology (protection and removal of protecting groups) suitable for use in the synthesis of the inhibitor compounds described herein are known in the art and include, for example, those described in the literature: such as R. Larock , Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2nd ed. (2001); M. Bodanszky, A. Bodanszky: The practice of Peptiae Synthesis Springer-Verlag, Berlin Heidelberg 1984; J. Seyden-Penne: Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd Edition, Wiley-VCH, 1997; and L. Paquette, eds. Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995).

本發明化合物可藉由附加適當官能基以增強選擇性生物特性而加以改質。該等改質在此項技術中為已知的且包括增加生物穿透至特定生物代謝區(例如血液、淋巴系統、中樞神經系統)中、增加口服可 用性、增加溶解度以允許藉由注射投藥、改變代謝及改變排泄速率之改質。 The compounds of the invention may be modified by the addition of suitable functional groups to enhance selective biological properties. Such modifications are known in the art and include increased bioavailability into specific biological metabolic regions (eg, blood, lymphatic system, central nervous system), increased oral administration. Use, increase solubility to allow for administration by injection, altered metabolism, and altered excretion rate.

以下實例含有式I-IV化合物之製備方法的詳細描述。此等詳細描述處於範疇內，且用以例示構成本發明之一部分的上述一般合成程序。呈現此等詳細描述僅為達成說明性目的，且不欲限制本發明之範疇。 The following examples contain a detailed description of the preparation of the compounds of formula I-IV. These detailed descriptions are within the scope and are intended to illustrate the above-described general synthetic procedures that form part of the invention. The Detailed Description is presented for illustrative purposes only and is not intended to limit the scope of the invention.

實驗 experiment

除非另有註釋，否則所有物質均獲自商業供應商且未經進一步純化即使用。除非另有指示，否則所有份數均以重量計且溫度為攝氏度。所有微波輔助反應均使用來自BiotageTM之Smith SynthesizerTM進行。所有化合物均展示與其指定結構一致之NMR光譜。熔點係在Buchi裝置上測定且未經校正。MS數據係藉由電噴霧電離技術測定。如高效液相層析所測定，所有實例均純化至>90%純度。除非另有規定，否則反應均在室溫下操作。 All materials were obtained from commercial suppliers and used without further purification unless otherwise noted. Unless otherwise indicated, all parts are by weight and temperatures are in degrees Celsius. All microwave assisted reactions were carried out using the Smith Synthesizer TM from the Biotage TM performed. All compounds exhibited NMR spectra consistent with their assigned structure. Melting points were determined on a Buchi apparatus and were uncorrected. MS data was determined by electrospray ionization technique. All examples were purified to >90% purity as determined by high performance liquid chromatography. Unless otherwise specified, the reactions were all carried out at room temperature.

分析方法：Analytical method:

除非另有指示，否則HPLC分析係在Agilent Model 1100系統上使用在30℃下以約1.50 mL/min之流動速率操作的Agilent Technologies Zorbax SB-C8(5 μ)逆相管柱(4.6×150 mm)(Agilent Technologies,Santa Clara,CA)進行。移動相使用溶劑A(H2O/0.1% TFA)及溶劑B(ACN/0.1% TFA)，其中使用5%至100% ACN之11分鐘梯度。該梯度後繼之以2分鐘返回至5% ACN及約2.5分鐘再平衡(吹洗)。 Unless otherwise indicated, HPLC analysis was performed on an Agilent Model 1100 system using an Agilent Technologies Zorbax SB-C 8 (5 μ) reverse phase column operating at 30 ° C at a flow rate of approximately 1.50 mL/min (4.6 x 150). Mm) (Agilent Technologies, Santa Clara, CA). The mobile phase used solvent A (H 2 O/0.1% TFA) and solvent B (ACN/0.1% TFA) using an 11 minute gradient of 5% to 100% ACN. The gradient was then returned to 5% ACN in 2 minutes and rebalanced (purged) in about 2.5 minutes.

LC-MS方法： LC-MS method:

除非另有指示，否則樣品係在Agilent model-1100 LC-MSD系統上使用Agilent Technologies XDB-C8(3.5 μ)逆相管柱(4.6×75 mm)在30℃下操作。流動速率為恆定的且在約0.75 mL/min至約1.0 mL/min之範圍內。移動相使用溶劑A(H2O/0.1% HCO2H或TFA)與溶劑B (ACN/0.1% HCO2H或TFA)之混合物，其中使用10%至90%溶劑B之5分鐘梯度。該梯度後繼之以0.5分鐘時段-9分鐘時段返回至10%溶劑B及2.5分鐘10%溶劑B管柱再平衡(吹洗)。 Unless otherwise indicated, the use of sample-based Agilent Technologies XDB-C on Agilent model-1100 LC-MSD system 8 (3.5 μ) reverse phase column (4.6 × 75 mm) operating at 30 ℃. The flow rate is constant and is in the range of from about 0.75 mL/min to about 1.0 mL/min. The mobile phase used a mixture of solvent A (H 2 O/0.1% HCO 2 H or TFA) and solvent B (ACN/0.1% HCO 2 H or TFA) using a 5 minute gradient of 10% to 90% solvent B. The gradient was followed by a 0.5 minute period to 9 minutes period returning to 10% solvent B and 2.5 minutes 10% solvent B column re-equilibration (purging).

大多數分析使用具有單四極MSD(G6120)與多模式源(multi-mode source)之Agilent 1200 LCMS。移動相A由含有1% IPA及0.1%甲酸之H2O組成。移動相B由含有1% IPA及0.1%甲酸之ACN組成。分離以經3或5分鐘以5%移動相B開始且以95%移動相B結束之梯度使用Halo(Advanced Materials Technology)C18管柱(50×2.1 mm，2.7 μm粒度)進行。流速設定為1 ml/min且電離以正模式與負模式之ESI與APCI進行。 Most analyses used an Agilent 1200 LCMS with a single quadrupole MSD (G6120) and a multi-mode source. Mobile phase A consisted of H 2 O containing 1% IPA and 0.1% formic acid. Mobile phase B consisted of ACN containing 1% IPA and 0.1% formic acid. Separation was carried out using a Halo (Advanced Materials Technology) C18 column (50 x 2.1 mm, 2.7 μm particle size) starting with 3 or 5 minutes starting with 5% mobile phase B and ending with 95% mobile phase B. The flow rate was set to 1 ml/min and the ionization was performed in ESI and APCI in positive and negative modes.

製備型HPLC方法Preparative HPLC method

如有指示，本發明化合物係經由逆相HPLC使用以下條件純化：製備型HPLC方法1 製備型逆相HPLC係在30×250 mm Phenomenex Luna PFP(2)全氟苯基管柱PN上進行：OOG-4448-UO-AX，5 μm粒子，A=含0.1% TFA之水；B=含0.1% TFA之ACN。將該管柱及60吋、0.020內徑之不鏽鋼管段浸入45℃乙二醇浴中；流速=40 mL min-1；梯度：0→5分鐘：在10% B下等濃度沖提；5→60分鐘：線性梯度至55% B；60→70分鐘：在55% B下等濃度沖提；70.01分鐘步進至100% B，保持10分鐘；80.1分鐘步進至10% B；80分鐘結束。 As indicated, the compounds of the invention were purified via reverse phase HPLC using the following conditions: preparative HPLC method 1 preparative reverse phase HPLC on a 30 x 250 mm Phenomenex Luna PFP (2) perfluorophenyl column PN: OOG -4448-UO-AX, 5 μm particles, A = water with 0.1% TFA; B = ACN with 0.1% TFA. The column and the 60 吋, 0.020 inner diameter stainless steel pipe section were immersed in a 45 ° C ethylene glycol bath; flow rate = 40 mL min -1 ; gradient: 0 → 5 minutes: at 10% B under the same concentration; 5 → 60 minutes: linear gradient to 55% B; 60 → 70 minutes: 55% B at the same concentration; 70.01 minutes to 100% B for 10 minutes; 80.1 minutes to 10% B; 80 minutes to end .

製備型HPLC方法2 製備型逆相HPLC係在Waters Xterra製備型C18 MS上進行：由Vydac/The Separations Group裝填，50 mm×300 mm(PN PA0000-050730，10 μm粒度，球形，A=含0.1% TFA之水；B=10% TFE-0.1% TFA-89.9% ACN；來自設定為45℃之外部熱傳遞單元之乙二醇流過管柱夾套。將手動注射器進樣環路及柱前管道浸入熱傳遞浴中)；梯度：0→4分鐘，20 mL/min，25% B；4→5分鐘，20→100 mL/min，25% B；5→25分鐘，100 mL/min，線性梯度至55% B；25→35分鐘，100 mL/min，在55% B下等濃度沖提；35分鐘，步進至100% B，100 mL/min；35→50分鐘，100 mL/min，100% B；50分鐘，步進至25% B，100 mL/min；60分鐘結束。 Preparative HPLC Method 2 Preparative reverse phase HPLC was performed on a Waters Xterra preparative C18 MS: loaded by Vydac/The Separations Group, 50 mm x 300 mm (PN PA0000-050730, 10 μm particle size, spherical, A = 0.1) % TFA water; B = 10% TFE-0.1% TFA-89.9% ACN; ethylene glycol flowing through the column jacket from an external heat transfer unit set at 45 ° C. Manual syringe injection loop and column front Pipe immersed in heat transfer bath); Gradient: 0→4 minutes, 20 mL/min, 25% B; 4→5 minutes, 20→100 mL/min, 25% B; 5→25 minutes, 100 mL/min, Linear gradient to 55% B; 25→35 minutes, 100 mL/min, eluted at 55% B; 35 minutes, stepped to 100% B, 100 mL/min; 35→50 minutes, 100 mL/ Min, 100% B; 50 minutes, stepped to 25% B, 100 mL/min; 60 minutes ended.

製備型HPLC方法3 製備型逆相HPLC係在配備有Phenomenex Synergi C18管柱(部件號00F-4435-U0-AX)(150×30 mm，5 μm)或SiliaChom XT C18管柱(S/N 161915N091240)之Gilson GX-281上進行，其中在254 nm下進行UV偵測且使用含5-95% CH3CN之H2O(含0.1% TFA)以45 mL/min溶離11分鐘。該梯度後繼之以1分鐘返回至5% CH3CN。 Preparative HPLC Method 3 Preparative reverse phase HPLC with a Phenomenex Synergi C18 column (part number 00F-4435-U0-AX) (150 x 30 mm, 5 μm) or SiliaChom XT C18 column (S/N 161915 N091240) Gilson GX-281 was performed on UV detection at 254 nm and was dissolved at 45 mL/min for 11 minutes using H 2 O (containing 0.1% TFA) containing 5-95% CH 3 CN. The gradient of the subsequent return to 5% CH 3 CN to 1 minute.

製備型HPLC方法4 製備型逆相HPLC係在Shimadzu SIL-10AP自動注射器及配備有Phenomenex Synergi C18管柱(部件號00F-4436-U0-AX)(150×30 mm，10 μm)之Shimadzu FRC-10A溶離份收集器上進行，其中在254 nm下進行UV偵測且使用含5-100% CH3CN之水(含0.1% TFA)以35 mL/min溶離15分鐘。該梯度後繼之以1分鐘返回至5% CH3CN。 Preparative HPLC Method 4 Preparative reverse phase HPLC was performed on a Shimadzu SIL-10AP autoinjector and Shimadzu FRC equipped with a Phenomenex Synergi C18 column (part number 00F-4436-U0-AX) (150 x 30 mm, 10 μm) 10A from the upper parts of solvent for the collector, wherein a UV detector and using 5-100% CH 3 CN containing water (containing 0.1% TFA) at 35 mL / min eluting at 254 nm for 15 minutes. The gradient of the subsequent return to 5% CH 3 CN to 1 minute.

製備型HPLC方法5 製備型逆相HPLC係使用Phenomenex Gemini-NX C18 110A管柱(100×21 mm，5 μm)進行，其中在254 nm下進行UV偵測(Waters 2487或Waters PD)且使用含10-60%或10-90% CH3CN之水(含0.1% NH4OH)以44 mL/min溶離8分鐘。該梯度後繼之以2分鐘返回至10% CH3CN。 Preparative HPLC Method 5 Preparative reverse phase HPLC was performed using a Phenomenex Gemini-NX C18 110A column (100 x 21 mm, 5 μm) with UV detection at 254 nm (Waters 2487 or Waters PD) with 10-60% or 10-90% CH 3 CN water (containing 0.1% NH 4 OH) was dissolved at 44 mL/min for 8 minutes. The gradient of the subsequent return to 10% CH 3 CN 2 minutes.

質譜(MS)Mass spectrometry (MS)

除非另有指示，否則起始物質、中間物及/或例示性化合物之所有質譜數據以質量/電荷(m/z)報導，視電離模式(正模式或負模式)而定，具有(M+H+)或(M-H-)分子離子。所報導之分子離子係藉由電噴霧偵測方法獲得。如熟習此項技術者所瞭解，具有同位素原子(諸如溴及其類似物)之化合物係根據所偵測之同位素模式(isotopic pattern)報 導。或者，使用APCI作為質量偵測方法。 Unless otherwise indicated, all mass spectral data for the starting materials, intermediates, and/or exemplary compounds are reported in mass/charge (m/z), depending on the ionization mode (positive mode or negative mode), with (M+ H + ) or (MH - ) molecular ion. The reported molecular ions were obtained by electrospray detection. As is known to those skilled in the art, compounds having isotopic atoms such as bromine and the like are reported according to the detected isotopic pattern. Or, use APCI as a quality detection method.

製備1Preparation 1

2-乙基吡啶-3-醇 2-ethylpyridin-3-ol

步驟A：將乾燥管中之2-溴吡啶-3-醇(50 g，287 mmol)於Ac2O(150 mL)中之經攪拌懸浮液加熱至回流，維持3小時，接著冷卻至室溫。濃縮反應物以移除儘可能多的HOAc。在攪拌下，將反應物傾倒於100 g冰上。5分鐘後，逐份添加固體Na2CO3直至達到pH=7。將100 mL Et2O添加至混合物中且攪拌5分鐘。分離各層，且用4×100 mL MTBE萃取水相。用1×200 mL H2O及1×200 mL鹽水洗滌經合併之有機物。經MgSO4乾燥有機物，過濾且濃縮，得到粗乙酸2-溴吡啶-3-基酯(63 g，100%產率)。該物質未經任何進一步純化即用於下一反應中。 Step A : The 2-bromopyridin-3-ol (50 g, 287 mmol) in a dry tube was heated to reflux with a stirred suspension in Ac 2 O (150 mL) for 3 h then cooled to room temperature . The reactants were concentrated to remove as much HOAc as possible. The reaction was poured onto 100 g of ice with stirring. After 5 minutes, solid Na 2 CO 3 was added portionwise until pH = 7 was reached. 100 mL of Et 2 O was added to the mixture and stirred for 5 minutes. The layers were separated and the aqueous phase was extracted with 4×100 mL MTBE. Washed 1 × 200 mL H 2 O and 1 × 200 mL The combined organics with brine. The organics were dried over MgSO 4, filtered and concentrated to give crude 2-bromo-3-yl acetic acid ester (63 g, 100% yield). This material was used in the next reaction without any further purification.

步驟B：將乙酸2-溴吡啶-3-基酯(63 g，292 mmol)溶解於DMF(600 mL)中，且添加PdCl2(PPh3)2(10.2 g，14.6 mmol)及三丁基(乙烯基)錫烷(105 g，321 mmol)，且在145℃下加熱反應物3小時。冷卻反應物且分配於水與EtOAc之間，用H2O洗滌，經Na2SO4乾燥，過濾並濃縮。在矽膠上(含EtOAc之己烷)純化殘餘物，得到呈黃色油狀之2-乙烯基吡啶-3-基(30.0 g，63.0%產率)。 Step B : Dissolve 2-bromopyridin-3-yl acetate (63 g, 292 mmol) in DMF (600 mL) and add PdCl 2 (PPh 3 ) 2 (10.2 g, 14.6 mmol) and tributyl (Vinyl)stannane (105 g, 321 mmol) and the reaction was heated at 145 °C for 3 h. The reaction was cooled and partitioned between water and EtOAc, washed with H 2 O, dried over Na 2 SO 4, filtered and concentrated. The residue was purified with EtOAc EtOAc EtOAc EtOAc

步驟C：向帕爾容器(Parr vessel)中饋入乙酸2-乙烯基吡啶-3-基酯(30.0 g，184 mmol)、MeOH(200 mL)及10% Pd/C(4.9 g，4.6 mmol)。在30 psi H2壓力下震盪反應物2.5小時。接著經矽藻土過濾反應混合物，得到呈透明油狀之乙酸2-乙基吡啶-3-基酯。此物質未經任何進一步純化即用於下一反應中。 Step C : Feeding 2-vinylpyridin-3-yl acetate (30.0 g, 184 mmol), MeOH (200 mL) and 10% Pd/C (4.9 g, 4.6 mmol) to a Parr vessel. ). The reaction was shaken for 2.5 hours at 30 psi H 2 pressure. The reaction mixture was filtered through celite to give 2-ethylpyridin-3-yl acetate as a clear oil. This material was used in the next reaction without any further purification.

步驟D：將乙酸2-乙基吡啶-3-基酯(30 g，182 mmol)溶解於 MeOH(200 mL)中，且添加甲醇鈉(14.7 g，272.4 mmol)，且在60℃下加熱反應物2小時。冷卻反應物且濃縮，得到油狀物，將其分配於含15% MeOH之CH2Cl2與H2O(100 mL)之間且用含15% MeOH之CH2Cl2(3×75 mL)萃取。經Na2SO4乾燥，過濾且濃縮，得到呈白色固體狀之2-乙基吡啶-3-醇(16.0 g，71.5%產率)。 Step D : 2-ethylpyridin-3-yl acetate (30 g, 182 mmol) was dissolved in MeOH (200 mL) and sodium methoxide (14.7 g, 272.4 mmol) was added and heated at 60 ° C 2 hours. The reaction was cooled and concentrated to give an oil which was partitioned between 15% MeOH containing of CH 2 Cl 2 and H 2 O (100 mL) containing between 15% MeOH and the CH 2 Cl 2 (3 × 75 mL )extraction. Dried over Na 2 SO 4, filtered and concentrated to give a white solid of 2-ethyl-3-ol (16.0 g, 71.5% yield).

製備2Preparation 2

1,3,5-三甲基-1H-吡唑-4-醇 1,3,5-trimethyl-1H-pyrazol-4-ol

步驟A：將苯甲酸(136.1 g，1115 mmol)溶解於DMF(1200 mL)中，且添加KOH(62.54 g，1115 mmol)，且加熱反應物至50℃，維持1小時。緩慢添加3-氯戊烷-2,4-二酮(150 g，1115 mmol)，且在50℃下攪拌隔夜。冷卻混合物且傾倒至3.5 L H2O中，用Et2O(5×1 L)萃取，用飽和NH4Cl水溶液、鹽水及H2O(2×1 L)洗滌，經Na2SO4乾燥，過濾且濃縮，得到呈黃色油狀之苯甲酸2,4-二側氧基戊-3-基酯(224.9 g，1021 mmol，91.61%產率)。 Step A : Benzoic acid (136.1 g, 1115 mmol) was dissolved in DMF <RTI ID=0.0>(</RTI></RTI><RTIgt; 3-Chloropentan-2,4-dione (150 g, 1115 mmol) was added slowly and stirred at 50 ° C overnight. The mixture was cooled and poured into 3.5 LH 2 O in, (5 × 1 L) and extracted with Et 2 O, (2 × 1 L) was washed with 2 O 4 Cl aqueous saturated NH, brine and H, dried over Na 2 SO 4, Filtration and concentration gave 2,4-di-ethoxypentan-3-yl benzoate as a yellow oil (224.9 g, 1021 mmol, 91.61% yield).

步驟B：將苯甲酸2,4-二側氧基戊-3-基酯(224.9 g，1021 mmol)溶解於EtOH(2 L)中且在冰浴中冷卻。緩慢添加甲肼(108.2 ml，2042 mmol)，且在室溫下攪拌反應物隔夜。濃縮反應物且未經進一步純化即進行下一反應。 Step B : 2,4-Di-ethoxypentan-3-ylbenzoate (224.9 g, 1021 mmol) was dissolved in EtOH (2 L) and cooled in ice. Formazan (108.2 ml, 2042 mmol) was added slowly and the reaction was stirred at rt overnight. The reaction was concentrated and the next reaction was carried out without further purification.

步驟C：將粗苯甲酸1,3,5-三甲基-1H-吡唑-4-基酯(235.2 g，1021 mmol)溶解於EtOH(1 L)中。添加3 M NaOH(510.7 ml，1532 mmol)，且在室溫下攪拌反應物2小時。在真空中移除EtOH。用EtOAc(500 mL)萃取水層。用6 N HCl將水層中和至pH 8，且過濾所得固體，得到呈白色固體狀之1,3,5-三甲基-1H-吡唑-4-醇(62.9 g，48.8%產率)。 Step C : Crude benzoic acid 1,3,5-trimethyl-1H-pyrazol-4-yl ester (235.2 g, 1021 mmol) was dissolved in EtOH (1 L). 3 M NaOH (510.7 ml, 1532 mmol) was added and the mixture was stirred at room temperature for 2 hr. Remove EtOH in a vacuum. The aqueous layer was extracted with EtOAc (500 mL). The aqueous layer was neutralized to pH 8 with 6 N EtOAc and EtOAc (EtOAc md. ).

製備3Preparation 3

甲烷磺酸4-甲氧基丁-2-基酯 4-methoxybut-2-yl methanesulfonate

將4-甲氧基丁-2-醇(800 mg，7.68 mmol)溶解於CH2Cl2(50 mL)中，且添加NEt3(1285 μl，9.22 mmol)，且在室溫下攪拌。添加甲烷磺醯氯(599 μl，7.68 mmol)，且在室溫下攪拌20分鐘。將反應物分配於H2O與CH2Cl2之間，經Na2SO4乾燥，過濾且濃縮，得到呈透明無色油狀之甲烷磺酸4-甲氧基丁-2-基酯(1.3 g，7.13 mmol，92.9%產率)。 4-Methoxy-2-ol (800 mg, 7.68 mmol) was dissolved in CH 2 Cl 2 (50 mL) , and was added NEt 3 (1285 μl, 9.22 mmol ), and stirred at room temperature. Methanesulfonium chloride (599 μl, 7.68 mmol) was added and stirred at room temperature for 20 minutes. The reaction was partitioned between H 2 O and CH 2 Cl 2, dried over Na 2 SO 4, filtered and concentrated to give a clear colorless oil of methanesulfonic acid 4-methoxy-2-yl ester (1.3 g, 7.13 mmol, 92.9% yield).

製備4Preparation 4

4-甲基苯磺酸(R)-2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙酯 (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate

將(R)-2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙醇(5.00 g，34.2 mmol)溶解於CH2Cl2(50 mL)中，添加吡啶(11.1 ml，137 mmol)，且在冰浴中冷卻反應物。緩慢添加4-甲基苯-1-磺醯氯(8.48 g，44.5 mmol)，且在室溫下攪拌混合物隔夜。將反應物分配於1 N HCl與CH2Cl2之間，再次用1 N HCl、飽和NaHCO3、鹽水洗滌，經Na2SO4乾燥，過濾且濃縮。在矽膠上(5：1至3：1己烷：EtOAc)純化殘餘物，得到呈透明油狀之4-甲基苯磺酸(R)-2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙酯(8.89 g，29.6 mmol，86.5%產率)。 (R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (5.00 g, 34.2 mmol) was dissolved in CH 2 Cl 2 (50 mL) Pyridine (11.1 ml, 137 mmol) was added and the reaction was cooled in an ice bath. 4-Methylbenzene-1-sulfonium chloride (8.48 g, 44.5 mmol) was added slowly, and the mixture was stirred overnight at room temperature. The reaction was partitioned with 1 N HCl between CH 2 Cl 2, washed with saturated NaHCO 3, brine again with 1 N HCl,, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) 3-Dioxacyclo-4-yl)ethyl ester (8.89 g, 29.6 mmol, 86.5% yield).

經由製備4中之途徑，製備以下化合物： The following compounds were prepared via the route of Preparation 4:

製備6Preparation 6

5-氯喹啉-6-醇 5-chloroquinolin-6-ol

在10 mL DMF中組合喹啉-6-醇(0.500 g，3.44 mmol)及1-氯吡咯啶-2,5-二酮(0.483 g，3.62 mmol)，且在室溫下攪拌隔夜。加熱反應物至40℃，維持2天。將反應物傾倒至水(75 mL)中，接著用EtOAc(3×100 mL)萃取，用水(50 mL)、鹽水(50 mL)洗滌，經MgSO4乾燥，過濾且濃縮。在矽膠上(100% CH2Cl2)純化殘餘物，得到5-氯喹啉-6-醇(0.450 g，2.10 mmol，61.1%產率)。 Quinoline-6-ol (0.500 g, 3.44 mmol) and 1-chloropyrrolidine-2,5-dione (0.483 g, 3.62 mmol) were combined in 10 mL DMF and stirred at room temperature overnight. The reaction was heated to 40 ° C for 2 days. The reaction was poured into water (75 mL), followed by (3 × 100 mL) and extracted with EtOAc, and brine (50 mL) and washed with water (50 mL),, dried over MgSO 4, filtered and concentrated. On silica gel (100% CH 2 Cl 2) The residue was purified to give 5-chloro-quinolin-6-ol (0.450 g, 2.10 mmol, 61.1 % yield).

製備7Preparation 7

6-羥基-1-甲基喹啉-2(1H)-酮 6-hydroxy-1-methylquinoline-2(1H)-one

步驟A：在20 mL DMF中組合60% NaH(1.390 g，34.75 mmol)及6-羥基喹啉-2(1H)-酮(1.75 g，10.86 mmol)。在N2充氣下攪拌此物質30分鐘，隨後緩慢添加Me2SO4(2.569 ml，27.15 mmol)，且在室溫下攪拌反應物2小時。濃縮反應物且溶解於含0.1% MeOH之CH2Cl2(30 mL)中，且向此物質中添加10 mL EtOAc並過濾。濃縮濾液且在矽膠 上(1：1 EtOAc：CH2Cl2)純化，得到6-甲氧基-1-甲基喹啉-2(1H)-酮(1.57 g，7.468 mmol，68.77%產率)。 Step A : 60% NaH (1.390 g, 34.75 mmol) and 6-hydroxyquinolin-2(1H)-one (1.75 g, 10.86 mmol) were combined in 20 mL DMF. Was stirred under N 2 inflator substance for 30 minutes followed by slow addition of Me 2 SO 4 (2.569 ml, 27.15 mmol), and stirred at room temperature for 2 hours. The reaction was concentrated and dissolved in 0.1% MeOH containing of CH 2 Cl 2 (30 mL) , and to this was added 10 mL EtOAc and filtered material. The filtrate was concentrated on silica gel (1: 1 EtOAc: CH 2 Cl 2) to give 6-methoxy-1-methyl quinolin -2 (1H) - one (1.57 g, 7.468 mmol, 68.77 % yield ).

步驟B：將6-甲氧基-1-甲基喹啉-2(1H)-酮(1.57 g，8.30 mmol)溶解於75 mL CH2Cl2中且冷卻至-78℃，隨後添加1 M BBr3(24.9 ml，24.9 mmol)，且使反應物緩慢升溫至0℃。1小時後，向反應物中添加60 mL 2：1水：50% NaOH。經由添加濃鹽酸使pH值降至2且攪拌15分鐘。過濾固體，用CH2Cl2洗滌且乾燥，得到6-羥基-1-甲基喹啉-2(1H)-酮(1.33 g，91.5%產率)。 Step B : 6-Methoxy-1-methylquinolin-2(1H)-one (1.57 g, 8.30 mmol) was dissolved in 75 mL CH 2 Cl 2 and cooled to -78 ° C then 1 M BBr 3 (24.9 ml, 24.9 mmol), and the reaction was slowly warmed to 0 °C. After 1 hour, 60 mL of 2:1 water: 50% NaOH was added to the reaction. The pH was lowered to 2 via the addition of concentrated hydrochloric acid and stirred for 15 minutes. The solid was filtered, washed with CH 2 Cl 2 and dried to give 6-hydroxy-1-methyl-quinolin -2 (1H) - one (1.33 g, 91.5% yield).

遵循製備7中之程序，製備以下化合物： Following the procedure in Preparation 7, the following compounds were prepared:

製備9Preparation 9

5,7-二氟-6-羥基-4-(三氟甲基)喹啉-2(1H)-酮 5,7-difluoro-6-hydroxy-4-(trifluoromethyl)quinolin-2(1H)-one

步驟A：在室溫下，於50 mL DMF中緩慢組合NaH(於油中之60%分散液)(1.14 g，28.6 mmol)及2,6-二氟-4-硝基苯酚(5.0 g，28.6 mmol)。在室溫下攪拌此物質30分鐘，隨後緩慢添加碘甲烷(1.78 ml，28.6 mmol)。16小時後，緩慢添加0.25當量碘甲烷(0.445 mL)。次日早晨，將1 M NaOH(100 mL)添加至反應物中且攪拌30分鐘，隨後將反應物傾倒至含有EtOAc(300 mL)之分液漏斗中。用EtOAc(300 mL)萃 取水層。合併有機物，用1 M NaOH(100 mL)、H2O(2×100 mL)洗滌，且在減壓下濃縮，得到1,3-二氟-2-甲氧基-5-硝基苯(5.97 g，31.6 mmol，111%產率)，其按原樣使用。 Step A : Slowly combine NaH (60% dispersion in oil) (1.14 g, 28.6 mmol) and 2,6-difluoro-4-nitrophenol (5.0 g, 50 mL DMF) at room temperature. 28.6 mmol). This material was stirred at room temperature for 30 minutes, then iodomethane (1.78 ml, 28.6 mmol) was slowly added. After 16 hours, 0.25 equivalents of methyl iodide (0.445 mL) was slowly added. The next morning, 1 M NaOH (100 mL) was added to the mixture and stirred for 30 min then the mixture was poured to EtOAc (300 mL). The aqueous layer was extracted with EtOAc (300 mL). The organics were combined,, H 2 O (2 × 100 mL) and washed with 1 M NaOH (100 mL), and concentrated under reduced pressure to give 1,3-difluoro-2-methoxy-5-nitrobenzene ( 5.97 g, 31.6 mmol, 111% yield), which was used as is.

步驟B：將1,3-二氟-2-甲氧基-5-硝基苯(5.97 g，31.6 mmol)溶解於100 mL EtOH中，且將此物質抽真空並用N2回填三次，隨後添加10% Pd/C(3.36 g，3.16 mmol)。將反應物再次抽真空，但此時用H2回填三次。接著在H2氛圍下繼續反應，且次日早晨，過濾反應物，在減壓下濃縮，且在矽膠上用含10%己烷之CH2Cl2溶離來純化，獲得3,5-二氟-4-甲氧基苯胺(3.4 g，21.4 mmol，67.7%產率)。 Step B: 1,3-difluoro-2-methoxy-5-nitrobenzene (5.97 g, 31.6 mmol) was dissolved in 100 mL EtOH, and the substance of this evacuated and backfilled three times with N 2, followed by the addition 10% Pd/C (3.36 g, 3.16 mmol). The reaction was evacuated again, but this time backfilled with H 2 three times. Then the reaction was continued under H 2 atmosphere, and the next morning, the reaction was filtered, concentrated under reduced pressure, and purified hexane of from 10% CH 2 Cl 2 solution containing on silica gel to give 3,5-difluoro 4-Methoxyaniline (3.4 g, 21.4 mmol, 67.7% yield).

步驟C：在6 mL甲苯中組合3,5-二氟-4-甲氧基苯胺(0.500 g，3.14 mmol)、4,4,4-三氟-3-側氧基丁酸乙酯(0.868 g，4.71 mmol)及水(0.125 ml，6.91 mmol)，且反應燒瓶配備有冷凝器並在N2下加熱至回流。8小時後，在減壓下濃縮反應物。將所得殘餘物溶解於H2SO4(6 mL)中，且在密封容器中加熱至80℃。5小時後，冷卻反應物至室溫，且將其傾倒至200 mL水/冰漿液中，且向其中添加50% NaOH以達到pH=2。經由真空過濾收集所得白色固體，用水洗滌，且在真空烘箱中乾燥，得到5,7-二氟-6-羥基-4-(三氟甲基)喹啉-2(1H)-酮(0.716 g，2.57 mmol，81.7%產率)。(apci-負模式)(M-H)m/z=264.0。 Step C : Combine 3,5-difluoro-4-methoxyaniline (0.500 g, 3.14 mmol), 4,4,4-trifluoro-3-oxoethoxybutyrate (0.868) in 6 mL of toluene. g, 4.71 mmol) and water (0.125 ml, 6.91 mmol), and the reaction flask equipped with a condenser and heated to reflux under N 2. After 8 hours, the reaction was concentrated under reduced pressure. The resulting residue was dissolved in H 2 SO 4 (6 mL), and the heated to 80 deg.] C in a sealed vessel. After 5 hours, the reaction was cooled to room temperature and poured into a 200 mL water/ice slurry, and 50% NaOH was added thereto to reach pH=2. The resulting white solid was collected by vacuum filtration, washed with water and dried in vacuo to give 5,7-difluoro-6-hydroxy-4-(trifluoromethyl)quinolin-2(1H)-one (0.716 g , 2.57 mmol, 81.7% yield). (apci-negative mode) (MH) m/z = 264.0.

以下化合物均以類似方式使用適當α-酮酯製備。 The following compounds were all prepared in a similar manner using the appropriate alpha-ketoesters.

製備13Preparation 13

1-(2-甲氧基乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1H-pyrazole

在室溫下，於10 mL DMF中組合4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(5.0 g，25.77 mmol)、1-溴-2-甲氧基乙烷(4.298 g，30.92 mmol)及Cs2CO3(10.49 g，32.21 mmol)，且將反應物用N2充氣20分鐘，隨後將其密封，且在劇烈攪拌下加熱至100℃。繼續反應隔夜。用20 mL水稀釋反應物，接著用EtOAc(3×100 mL)萃取。接著用鹽水(3×50 mL)洗滌經合併之有機物，經MgSO4乾燥，過濾，且在真空中移除。藉由用含3%-5%丙酮之CH2Cl2進行層析來純化粗物質。合併所要溶離份，在減壓下移除，且在高真空下乾燥(產物稍有揮發)，得到1-(2-甲氧基乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(5.19，20.61 mmol，80.0%產率)。質譜(apci)m/z=253.1(M+H)。 Combining 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in 10 mL DMF at room temperature 2-yl)-1H-pyrazole (5.0 g, 25.77 mmol), 1-bromo-2-methoxyethane (4.298 g, 30.92 mmol) and Cs 2 CO 3 (10.49 g, 32.21 mmol), the reaction was inflated with N 2 for 20 minutes before it was sealed, and heated to 100 deg.] C under vigorous stirring. Continue to react overnight. The reaction was diluted with EtOAc (3×100 mL). Followed by brine (3 × 50 mL), the combined organics were washed dried over MgSO 4, filtered, and removed in vacuo. The crude material was purified by chromatography with CH 2 Cl 2 containing 3%-5% acetone. The desired fractions were combined, removed under reduced pressure and dried under high vacuum (yield slightly) to yield 1-(2-methoxyethyl)-4-(4,4,5,5- Methyl-1,3,2-dioxaboron -2-yl)-1H-pyrazole (5.19, 20.61 mmol, 80.0% yield). Mass spectrum (apci) m/z = 253.1 (M + H).

以下化合物係以相同方式使用適當起始物質製備。 The following compounds were prepared in the same manner using the appropriate starting materials.

製備15Preparation 15

1-(5-溴-4-氟吡啶-2-基)-3-甲基脲 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea

步驟A：在30 mL以N2充氣(15分鐘)之DME中組合1-甲基脲(1.69 g，22.8 mmol)及細粉狀磷酸三鉀(5.65 g，26.6 mmol)，且將此物質充氣5分鐘，隨後添加Pd2(dba)3(0.696 g，0.760 mmol)及1,1'-聯萘-2-基二第三丁基膦(1.21 g，3.04 mmol)，且將此物質再充氣5分鐘，隨後加熱反應物至60℃，維持1小時複合時段。此後，冷卻反應物至室溫，且添加2-氯-4-氟吡啶(2.0 g，15.2 mmol)。將此混合物用N2充氣1分鐘，隨後密封反應物且加熱至95℃隔夜。用150 mL 1：1 CH2Cl2：EtOAc稀釋反應物，接著過濾。依序用CH2Cl2及EtOAc(各約10 mL)洗滌濾餅，接著棄去。在真空中濃縮濾液，且用含20%丙酮之CH2Cl2對所得殘餘物進行層析。合併含產物之溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-氟吡啶-2-基)-3-甲基脲(1.31 g，7.59 mmol，49.9%產率)。 Step A : Combine 1-methylurea (1.69 g, 22.8 mmol) and finely powdered tripotassium phosphate (5.65 g, 26.6 mmol) in 30 mL of D 2 aerated (15 min) with N 2 and inflate the material. After 5 minutes, Pd 2 (dba) 3 (0.696 g, 0.760 mmol) and 1,1'-binaphthalen-2-yldi-tert-butylphosphine (1.21 g, 3.04 mmol) were added and the material was re-inflated. After 5 minutes, the reaction was then heated to 60 ° C for a one hour composite period. Thereafter, the reaction was cooled to room temperature and 2-chloro-4-fluoropyridine (2.0 g, 15.2 mmol) was added. The mixture was inflated with N 2 for 1 minute, and then the reaction was sealed and heated to 95 deg.] C overnight. With 150 mL 1: 1 CH 2 Cl 2: EtOAc reaction was diluted, followed by filtration. The filter cake was washed sequentially with CH 2 Cl 2 and EtOAc (about 10 mL each) and then discarded. The filtrate was concentrated in vacuo, and extracted with CH 20% acetone containing 2 Cl 2 The residue was chromatographed. The product-containing fractions were combined, dried with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj .

步驟B：在1 mL DMF中組合1-(4-氟吡啶-2-基)-3-甲基脲(0.100 g，0.591 mmol)及NBS(0,105 g，0.591 mmol)，且在室溫下攪拌此物 質隔夜。接著向反應物中添加6 mL水，且劇烈攪拌懸浮液30分鐘，隨後經由真空過濾收集固體，得到1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(0.106 g，0.427 mmol，72.3%產率)。質譜(apci)m/z=245.9,247.9(M+H)。 Step B : Combine 1-(4-fluoropyridin-2-yl)-3-methylurea (0.100 g, 0.591 mmol) and NBS (0, 105 g, 0.591 mmol) in 1 mL DMF and stir at room temperature This substance is overnight. Then 6 mL of water was added to the reaction, and the suspension was stirred vigorously for 30 minutes, then the solid was collected by vacuum filtration to give 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (0.106 g, 0.427 mmol, 72.3% yield). Mass spectrum (apci) m/z = 245.9, 247.9 (M+H).

製備16Preparation 16

1-(4-羥基-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea

步驟A：在室溫下，於10 mL DMA中組合NaH(於油中之60%分散液)(0.4837 g，12.09 mmol)及苯基甲醇(1.253 ml，12.09 mmol)。繼續去質子化40分鐘，隨後添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.0 g，8.063 mmol)。加熱反應物至80℃且攪拌隔夜。此後，用100 mL H2O稀釋反應物並劇烈攪拌，且形成白色沈澱物。經由真空過濾收集固體，且依序用10 mL H2O及20 mL Et2O洗滌。在真空烘箱中乾燥固體，得到1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(2.33 g，6.931 mmol，85.96%產率)。 Step A : NaH (60% dispersion in oil) (0.4837 g, 12.09 mmol) and phenylmethanol (1.253 ml, 12.09 mmol) were combined in 10 mL DMA at room temperature. Protonation was continued for 40 minutes followed by the addition of 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (2.0 g, 8.063 mmol). The reaction was heated to 80 ° C and stirred overnight. Thereafter, the reaction was diluted with 100 mL of H 2 O and stirred vigorously, and a white precipitate formed. The solid was collected via vacuum filtration and washed sequentially with 10 mL H 2 O and 20 mL Et 2 O. The solid was dried in a vacuum oven to give 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (2.33 g, 6. s.

步驟B：在20 mL二噁烷中組合1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(2.5 g，7.436 mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(2.321 g，11.15 mmol)及K2CO3(11.15 ml，22.31 mmol)，且將此物質用Ar充氣10分鐘。此後，添加PdCl2(dppf)．CH2Cl2(0.9109 g，1.115 mmol)，將反應物用Ar充氣10分鐘，密封，且加熱至100℃隔夜。用EtOAc(100 mL)稀釋反應物，且收集有機物。接著用EtOAc(2×100 mL)萃取水相，且用CH2Cl2(100 mL)萃取一次。接著經MgSO4乾燥經合併之有機物，過濾，且在真空中移除。在矽膠上 (含15-30%丙酮之CH2Cl2 w/0.5% NH4OH)純化所得粗物質，得到1-(4-(苄氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(1.359 g，4.028 mmol，54.17%產率)。 Step B : Combination of 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (2.5 g, 7.436 mmol), 1-methyl- in 20 mL of dioxane 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (2.321 g, 11.15 mmol) and K 2 CO 3 (11.15 ml, 22.31 mmol), and this material was inflated with Ar for 10 min. Thereafter, PdCl 2 (dppf) was added. CH 2 Cl 2 (0.9109 g, 1.115 mmol), the reaction was then swelled with Ar for 10 min, sealed and heated to 100 ° C overnight. The reaction was diluted with EtOAc (100 mL) and organic was collected. The aqueous phase was then extracted with EtOAc (2 × 100 mL), and extracted with CH 2 Cl 2 (100 mL) and extracted once. Dried over MgSO 4 and then the organics were combined, filtered, and removed in vacuo. On silica gel (acetone containing 15-30% CH 2 Cl 2 w / 0.5% NH 4 OH) resulting crude material was purified to give 1- (4- (benzyloxy) -5- (1-methyl -1H- Pyrazol-5-yl)pyridin-2-yl)-3-methylurea (1.359 g, 4.028 mmol, 54.17% yield).

步驟C：在6 mL 6 M HCl中組合1-(4-(苄氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.150 g，0.445 mmol)及2-胺基乙硫醇鹽酸鹽(0.0758 g，0.667 mmol)，且將此物質加熱至100℃。6小時後，反應完成且在冰浴中冷卻。向經攪拌之反應物中添加50% NaOH至pH=12，且在室溫下攪拌反應物20分鐘。接著用6 M HCl將pH值調整至3-4之間，且形成固體。經由真空過濾收集此固體且在真空烘箱中乾燥，得到1-(4-羥基-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.070 g，0.283 mmol，63.7%產率)。質譜(apci)m/z=248.1(M+H)。 Step C : Combining 1-(4-(benzyloxy)-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methyl in 6 mL of 6 M HCl Urea (0.150 g, 0.445 mmol) and 2-aminoethanethiol hydrochloride (0.0758 g, 0.667 mmol) were taken and heated to 100 °C. After 6 hours, the reaction was complete and cooled in an ice bath. To the stirred reaction was added 50% NaOH to pH = 12 and the reaction was stirred at room temperature for 20 min. The pH was then adjusted to between 3-4 with 6 M HCl and a solid formed. This solid was collected via vacuum filtration and dried in a vacuum oven to give 1-(4-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea (0.070 g, 0.283 mmol, 63.7% yield). Mass spectrum (apci) m/z = 248.1 (M+H).

製備17Preparation 17

1-(4-氟-2'-(三氟甲基)-3,4'-聯吡啶-6-基)-3-甲基脲 1-(4-Fluoro-2'-(trifluoromethyl)-3,4'-bipyridyl-6-yl)-3-methylurea

在含8 mL二噁烷之小瓶中組合1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(650 mg，2.62 mmol)、2-(三氟甲基)吡啶-4-基酸(750 mg，3.93 mmol)及K2CO3水溶液(3931 μl，7.86 mmol)。將Ar鼓泡通入此混合物中，持續5分鐘，繼而添加Pd(PPh3)4(303 mg，0.262 mmol)。將Ar鼓泡通入混合物中，再持續60秒，隨後將其密封且加熱至80℃，維持5小時。用CH2Cl2稀釋反應物且在二氧化矽管柱上(10-25%丙酮/CH2Cl2)純化，得到1-(4-氟-2'-(三氟甲基)-3,4'-聯吡啶-6-基)-3-甲基脲(230 mg，0.710 mmol，27.1%產率)。質譜(apci)m/z=315.1(M+H)。 Combine 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (650 mg, 2.62 mmol), 2-(trifluoromethyl)pyridine in a vial containing 8 mL of dioxane -4- base Acid (750 mg, 3.93 mmol) and aqueous K 2 CO 3 (3931 μl, 7.86 mmol). Ar was bubbled through this mixture for 5 minutes, followed by addition of Pd (PPh 3) 4 (303 mg, 0.262 mmol). Ar was bubbled through the mixture for an additional 60 seconds, then sealed and heated to 80 °C for 5 hours. Diluted with CH 2 Cl and the reaction (10-25% acetone / CH 2 Cl 2) was purified on a silicon dioxide column, to give 1- (4-fluoro-2 '- (trifluoromethyl) -3, 4'-Bipyridin-6-yl)-3-methylurea (230 mg, 0.710 mmol, 27.1% yield). Mass spectrum (apci) m/z = 315.1 (M+H).

製備18Preparation 18

2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苄腈 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)benzonitrile

將5-溴-2-甲氧基苄腈(1 g，4.8 mmol)、雙(頻哪醇根基)二硼(1.46 g，5.75 mmol)、PdCl2(dppf)2與CH2Cl2之複合物(0.39 g，0.48 mmol)及KOAc(1.43 g，14.6 mmol)於無水二噁烷(15 mL)中之經攪拌混合物用Ar淨化三次，且置於真空下三次。加熱混合物至90℃。21小時後，冷卻反應物至室溫，接著經矽藻土過濾。在減壓下移除有機溶劑，且在矽膠上(含0-25% EtOAc之己烷)純化殘餘物，得到呈白色固體狀之2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苄腈。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 7.90-7.99(2H,m),7.00(1H,d,J=8.4 Hz),3.96(3H,s),1.32(12H,s)。質譜(正模式)m/e：260.2(M+H)+。 Compound of 5-bromo-2-methoxybenzonitrile (1 g, 4.8 mmol), bis(pinacolyl)diboron (1.46 g, 5.75 mmol), PdCl 2 (dppf) 2 and CH 2 Cl 2 The mixture (0.39 g, 0.48 mmol) and EtOAc ( 1.43 g, 14.6 mmol) eluted with EtOAc (EtOAc) The mixture was heated to 90 °C. After 21 hours, the reaction was cooled to room temperature then filtered over EtOAc. The organic solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjj -tetramethyl-1,3,2-dioxaboron -2-yl)benzonitrile. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ ppm 7.90-7.99 (2H, m), 7.00 (1H, d, J = 8.4 Hz), 3.96 (3H, s), 1.32 (12H, s) . Mass spectrum (positive mode) m/e: 260.2 (M+H) + .

製備19Preparation 19

6-羥基-2-甲基異喹啉-1(2H)-酮 6-hydroxy-2-methylisoquinolin-1(2H)-one

在10 mL 2：1二噁烷：水中組合6-溴-2-甲基異喹啉-1(2H)-酮(1.00 g，4.20 mmol)及固體KOH(1.41 g，25.2 mmol)。將混合物用N2充氣10分鐘，隨後添加Pd2(dba)3(0)(0.385 g，0.420 mmol)及二第三丁基(2',4',6'-三異丙基聯苯-2-基)膦(0.357 g，0.840 mmol)，且將此物質用N2充氣30分鐘，隨後將其密封且加熱至100℃。8小時後，觀測到產物。用1 N NaOH(50 mL)稀釋反應物且用EtOAc(50 mL)及CH2Cl2(50 mL)萃取。接著用6 M HCl酸化剩餘水相，且經由真空過濾收集所得固體並用EtOAc(約10 mL)洗滌以去除顏色且剩餘亮白色固體。向水相中添加飽和量之固體NaCl且再次用EtOAc(2×100 mL)萃取，且經MgSO4乾燥經合併之有機物，過濾，且在真空中移除。接著將粗物質溶解於含1% MeOH之CH2Cl2中，屆時形成固體且經由真空過濾分離。合併固體，得到6-羥基-2-甲基異喹啉-1(2H)-酮(0.465 g，2.65 mmol，63.2%產率)。(apci)(M+H)m/z=176.1。 6-Bromo-2-methylisoquinolin-1(2H)-one (1.00 g, 4.20 mmol) and solid KOH (1.41 g, 25.2 mmol) were combined in 10 mL of 2:1 dioxane: water. The mixture was aerated with N 2 for 10 minutes, followed by the addition of Pd 2 (dba) 3 (0) (0.385 g, 0.420 mmol) and di-tert-butyl (2',4',6'-triisopropylbiphenyl- 2- yl) phosphine (0.357 g, 0.840 mmol), and this material inflated with N 2 for 30 minutes before it was sealed and heated to 100 ℃. After 8 hours, the product was observed. (50 mL) The reaction was diluted with 1 N NaOH and and (50 mL) and extracted with EtOAc (50 mL) CH 2 Cl 2. The remaining aqueous phase was then acidified with EtOAc (EtOAc) (EtOAc) (EtOAc) The amount of solid phase saturated NaCl and (2 × 100 mL) to the aqueous extracted again with EtOAc, dried over MgSO 4 and over the organics combined, filtered, and removed in vacuo. The crude material was then dissolved in of 1% MeOH in CH 2 Cl 2 in a solid form and then separated by vacuum filtration. The solids were combined to give 6-hydroxy-2-methylisoquinoline-1 (2H)-one (0.465 g, 2.65 mmol, 63.2% yield). (apci) (M+H) m/z = 176.1.

製備20Preparation 20

5-氯-6-羥基-1-甲基喹啉-2(1H)-酮 5-chloro-6-hydroxy-1-methylquinoline-2(1H)-one

在室溫下，於8 mL DMF中組合6-羥基-1-甲基喹啉-2(1H)-酮(0.700 g，4.00 mmol)及N-氯代丁二醯亞胺(0.560 g，4.20 mmol)，且在40℃下攪拌。2小時後反應完成。冷卻反應物至室溫，且向其中緩慢添加50 mL水，繼而添加8 mL EtOAc。攪拌混合物1小時，接著經由真空過濾分離所形成之所得固體，且用水(5 mL)、Et2O(5 mL)洗滌並在真空烘箱中乾燥隔夜，得到5-氯-6-羥基-1-甲基喹啉-2(1H)-酮(0.674 g，3.22 mmol，80.5%產率)。(apci-負模式)m/z=208.0,210.0(M-H)。 6-Hydroxy-1-methylquinoline-2(1H)-one (0.700 g, 4.00 mmol) and N-chlorobutanediamine (0.560 g, 4.20) were combined in 8 mL of DMF at room temperature. Mmmol) and stirred at 40 °C. The reaction was completed after 2 hours. The reaction was cooled to room temperature and 50 mL water was slowly added thereto, followed by 8 mL EtOAc. The mixture was stirred for 1 hour and then the resulting solid formed was isolated by vacuum filtration, and washed with water (5 mL), Et 2 O (5 mL) and dried overnight to give 5-chloro-6-hydroxy-1- vacuum oven Methylquinoline-2(1H)-one (0.674 g, 3.22 mmol, 80.5% yield). (apci-negative mode) m/z = 208.0, 210.0 (MH).

製備21Preparation 21

1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(1.00 g，2.79 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧硼)(1.418 g，5.58 mmol)、KOAc(1.096 g，11.17 mmol)及PdCl2(dppf)(0.228 g，0.279 mmol)於1,4-二噁烷(13.96 ml，2.79 mmol)中之混合物用N2脫氣，接著在100℃下攪拌隔夜。冷卻混合物至室溫，且添加20 mL 1 N HCl水溶液。用EtOAc(30 mL×4)萃取所得混合物。用無水Na2SO4乾燥經合併之萃取物且在真空中濃縮。藉由矽膠管柱，使用含0-100% EtOAc之己烷梯度純化殘餘物，得到313 mg 1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲。1H NMR(400 MHz,CDCl3)9.20(br s,1H),8.53(s,1H),8.48(s,1H),7.20(m,1H),7.04(m,2H),5.95(s,1H),2.83(d,J=4.0 Hz,3H),1.37(s,12H)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (1.00 g, 2.79 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron a mixture of (1.418 g, 5.58 mmol), KOAc (1.096 g, 11.17 mmol) and PdCl 2 (dppf) (0.228 g, 0.279 mmol) in 1,4-dioxane (13.96 ml, 2.79 mmol) 2 Degassing, followed by stirring at 100 ° C overnight. The mixture was cooled to room temperature and 20 mL of 1 N aqueous HCl was added. The resulting mixture was extracted with EtOAc (30 mL×4). 2 SO 4 dried and concentrated over anhydrous Na of the combined extracts in vacuo. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc 5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridin-2-yl)-3-methylurea. 1 H NMR (400 MHz, CDCl 3 ) 9.20 (br s, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 7.20 (m, 1H), 7.04 (m, 2H), 5.95 (s, 1H), 2.83 (d, J = 4.0 Hz, 3H), 1.37 (s, 12H).

製備22Preparation 22

(S)-6,6-二甲基-5,6,7,8-四氫喹啉-5-醇 (S)-6,6-Dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

在惰性氛圍下，於-20℃下在預冷卻容器中置放NaBH4(1.20 g，31.7 mmol)、CHCl3(150 mL)、EtOH(5.58 ml，95.0 mmol)及(四氫呋喃-2-基)甲醇(41.1 ml，422 mmol)，且攪拌混合物15分鐘。向混合物中添加鈷催化劑(0.103 g，0.148 mmol)於CHCl3(75 mL)中之溶液，且相繼添加含6,6-二甲基-7,8-二氫喹啉-5(6H)-酮(3.7 g，21.1 mmol)之 CHCl3(75 mL)，且在-20℃下攪拌混合物並緩慢升溫至室溫隔夜。用NH4Cl水溶液淬滅反應物，分離且濃縮。將殘餘物分配於Et2O與水之間，用水(×3)及鹽水(×2)洗滌，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含70%至100% EtOAc之己烷)純化殘餘物，得到(S)-6,6-二甲基-5,6,7,8-四氫喹啉-5-醇(688 mg，18.4%產率)。 NaBH 4 (1.20 g, 31.7 mmol), CHCl 3 (150 mL), EtOH (5.58 ml, 95.0 mmol) and (tetrahydrofuran-2-yl) were placed in a pre-cooled vessel at -20 ° C under an inert atmosphere. Methanol (41.1 ml, 422 mmol) and the mixture was stirred 15 min. A solution of a cobalt catalyst (0.103 g, 0.148 mmol) in CHCl 3 (75 mL) was added to the mixture, and the addition of 6,6-dimethyl-7,8-dihydroquinolin-5(6H)- CHCl -one (3.7 g, 21.1 mmol) of 3 (75 mL), and the mixture was stirred at -20 ℃ and slowly warmed to room temperature overnight. With aqueous NH 4 Cl The reaction was quenched, separated and concentrated. The residue was partitioned between Et 2 O and water, washed with water (× 3) and washed (× 2), brine, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc:EtOAc) Mg, 18.4% yield).

製備23Preparation 23

1-乙基-1H-吡唑-5-醇 1-ethyl-1H-pyrazole-5-ol

在1 L玻璃燒杯中，將草酸乙肼(54.30 g，361.7 mmol)與水(400 ml)組合。向所得漿液中添加50% w/v NaOH溶液(約60 ml)以將pH值調整至9.5(由pH計)。加熱混合物至40℃，且經1小時逐滴添加反-3-甲氧基丙烯酸甲酯(25.93 ml，241.1 mmol)。週期性地藉由添加50% w/v NaOH溶液將pH值調整至9.2-9.6之範圍。進料完成後，在40℃下再攪動混合物3小時，且不定時地將pH值調整至9.2-9.6之範圍。反應完成後，冷卻混合物至2℃且過濾。蒸發濾液至約150 ml體積，冷卻至5℃且再次過濾。接著用6 M HCl(約48 ml)將濾液酸化至pH 4-5且用6×200 ml 3：1 CHCl3/IPA混合物萃取。乾燥經合併之萃取物且蒸發至琥珀色油狀物，在矽膠上(20% MeOH/EtOAc)純化該油狀物，得到呈黃色固體狀之1-乙基-1H-吡唑-5-醇(18.25 g，162.8 mmol，67.50%產率)。 Ethyl oxalate (54.30 g, 361.7 mmol) was combined with water (400 ml) in a 1 L glass beaker. A 50% w/v NaOH solution (about 60 ml) was added to the resulting slurry to adjust the pH to 9.5 (by pH). The mixture was heated to 40 ° C and trans-3-methoxyethyl acrylate (25.93 ml, 241.1 mmol) was added dropwise over 1 hour. The pH was periodically adjusted to a range of 9.2-9.6 by the addition of a 50% w/v NaOH solution. After the completion of the feed, the mixture was further stirred at 40 ° C for 3 hours, and the pH was adjusted to a range of 9.2-9.6 from time to time. After the reaction was completed, the mixture was cooled to 2 ° C and filtered. The filtrate was evaporated to a volume of approximately 150 ml, cooled to 5 °C and filtered again. The filtrate was then acidified to pH 4-5 with 6 M HCl (~ 48 mL) and extracted with 6×200 mL 3:1 CHCl 3 /IPA mixture. The combined extracts were dried <RTI ID=0.0> (18.25 g, 162.8 mmol, 67.50% yield).

製備24Preparation 24

(R)-5,6,7,8-四氫喹啉-5-醇 (R)-5,6,7,8-tetrahydroquinolin-5-ol

在使用前，以N2充氣30分鐘將溶劑及所有液體試劑脫氣。向7,8-二氫喹啉-5(6H)-酮(20 g，136 mmol)於CH2Cl2(250 mL)中之溶液中添加NEt3(16 ml，136 mmol)及甲酸(7.0 ml，150 mmol)。在室溫下攪拌混合物5分鐘，且添加1R,2R-Ru催化劑(1.3 g，2.04 mmol)。在N2正壓下攪拌混合物隔夜。濃縮混合物，且將所獲得之棕色殘餘物溶解於CH2Cl2(5 mL)中並在矽膠上(100% EtOAc)純化，得到呈棕色固體狀之(R)-5,6,7,8-四氫喹啉-5-醇(18.5 g，91.2%產率)。 Before use, the pneumatic N 2 to 30 minutes all the liquid reagents and the solvent is degassed. Of NEt was added in one (20 g, 136 mmol) in CH 2 Cl 2 (250 mL) 3 (16 ml, 136 mmol) and formic acid (7.0 - To a solution of 7,8-dihydro-quinoline -5 (6H) Ml, 150 mmol). The mixture was stirred at room temperature for 5 minutes and 1R, 2R-Ru catalyst (1.3 g, 2.04 mmol) was added. The mixture was stirred overnight under N 2 positive pressure. The mixture was concentrated, and the brown residue obtained was dissolved in CH 2 Cl 2 (5 mL) and (100% EtOAc) was purified on silica, to give a brown solid of (R) -5,6,7,8 Tetrahydroquinolin-5-ol (18.5 g, 91.2% yield).

經由製備24中之途徑，使用適當催化劑製備以下化合物： The following compounds were prepared via the route in Preparation 24 using the appropriate catalyst:

製備28Preparation 28

4-氯-3-甲基異噁唑并[5,4-b]吡啶 4-chloro-3-methylisoxazo[5,4-b]pyridine

步驟A：向500 mL圓底燒瓶中添加米氏酸(meldrum's acid)(11.0 g，76.5 mmol)及原甲酸三甲酯(83.6 ml，765 mmol)。在回流(105℃) 下加熱無色溶液兩小時。添加3-甲基異噁唑-5-胺(7.50 g，76.5 mmol)於原甲酸三甲酯(83.6 ml，765 mmol)中之溶液，且幾乎立即形成沈澱物。再添加原甲酸三甲酯(50 mL)以有助攪拌。在回流下再加熱混合物2小時。移除熱且蒸發溶劑。使用甲苯使任何剩餘溶劑共沸。用Et2O濕磨粗固體，且移除固體，用Et2O洗滌並乾燥，得到玉色針狀晶體2,2-二甲基-5-((3-甲基異噁唑-5-基胺基)亞甲基)-1,3-二噁烷-4,6-二酮(12.4 g，64.3%產率)。 Step A : Meldrum's acid (11.0 g, 76.5 mmol) and trimethyl orthoformate (83.6 ml, 765 mmol) were added to a 500 mL round bottom flask. The colorless solution was heated under reflux (105 ° C) for two hours. A solution of 3-methylisoxazole-5-amine (7.50 g, 76.5 mmol) in trimethyl orthoformate (83.6 ml, 765 mmol) was added and a precipitate formed almost immediately. Additional trimethyl orthoformate (50 mL) was added to aid in agitation. The mixture was heated again under reflux for 2 hours. Heat is removed and the solvent is evaporated. Toluene was used to azeotropize any remaining solvent. The crude solid was wet-milled with Et 2 O, and the solid was removed, washed with Et 2 O and dried to give a crystal of crystals of 2,2-dimethyl-5-((3-methylisoxazole-5-). Amino)methylene)-1,3-dioxane-4,6-dione (12.4 g, 64.3% yield).

步驟B：在油浴中將陶氏導熱劑A(Dowtherm A)(5 mL)加熱至240℃。經15分鐘分數小份添加固體形式之2,2-二甲基-5-((3-甲基異噁唑-5-基胺基)亞甲基)-1,3-二噁烷-4,6-二酮(7.30 g，28.9 mmol)。在240℃下攪拌深色溶液5分鐘且冷卻至室溫。將粗物質溶解於MeOH中，吸收於二氧化矽上且在矽膠上(含0%至4% MeOH之EtOAc)純化，得到呈淺黃色固體狀之所要化合物。用100% EtOAc濕磨固體，且藉由過濾移出白色粉末並乾燥，得到3-甲基異噁唑并[5,4-b]吡啶-4-醇(1.08 g，25.0%產率)。 Step B : Dow Heat Conductor A (Dowtherm A) (5 mL) was heated to 240 ° C in an oil bath. Add 2,2-dimethyl-5-((3-methylisoxazol-5-ylamino)methylene)-1,3-dioxane-4 as a solid in 15 minute portions. , 6-diketone (7.30 g, 28.9 mmol). The dark solution was stirred at 240 ° C for 5 minutes and cooled to room temperature. The crude material was taken up in EtOAc EtOAc (EtOAc) The solid was triturated with 100% EtOAc and EtOAc (EtOAc)EtOAc.

步驟C：用磷醯三氯(3.354 ml，36.63 mmol)稀釋3-甲基異噁唑并[5,4-b]吡啶-4-醇(550 mg，3.663 mmol)，且加熱至100℃，維持1小時。冷卻反應物至室溫，且傾倒於100 g冰上並快速攪拌。用NaOH將pH值調整至7，且用CH2Cl2萃取，經Na2SO4乾燥，過濾並濃縮，得到4-氯-3-甲基異噁唑并[5,4-b]吡啶(576 mg，93.27%產率)及白色固體。 Step C : Dilute 3-methylisoxazo[5,4-b]pyridin-4-ol (550 mg, 3.663 mmol) with phosphonium trichloride (3.354 ml, 36.63 mmol) and heat to 100 ° C, Maintain for 1 hour. The reaction was cooled to room temperature and poured onto 100 g ice and stirred rapidly. The pH was adjusted with NaOH to 7, and extracted with CH 2 Cl 2, dried over Na 2 SO 4, filtered, and concentrated to give 4-chloro-3-methylisoxazolo [5,4-b] pyridine ( 576 mg, 93.27% yield) and white solid.

製備29Preparation 29

甲烷磺酸1-(四氫-2H-哌喃-4-基)乙酯 1-(tetrahydro-2H-piperazin-4-yl)ethyl methanesulfonate

步驟A：將四氫-2H-哌喃-4-甲醛(1.2 g，11 mmol)溶解於THF(70 mL)且在冰浴中冷卻。添加3 M溴化甲基鎂(3.5 ml，11 mmol)，且在室溫下攪拌反應物2小時，且用NH4Cl水溶液淬滅，用EtOAc萃取，經Na2SO4乾燥，過濾並濃縮，得到呈透明無色油狀之1-(四氫-2H-哌喃-4-基)乙醇(0.7 g，5.4 mmol，51%產率)。 Step A : Tetrahydro-2H-piperidin-4-carbaldehyde (1.2 g, 11 mmol) was dissolved in THF (EtOAc)EtOAc. Was added 3 M methyl magnesium bromide (3.5 ml, 11 mmol), and the reaction was stirred for 2 hours at room temperature, and extracted with EtOAc quenched with aqueous NH 4 Cl, dried over Na 2 SO 4, filtered and concentrated 1-(Tetrahydro-2H-pyran-4-yl)ethanol (0.7 g, 5.4 mmol, 51% yield) was obtained.

步驟B：將1-(四氫-2H-哌喃-4-基)乙醇(700 mg，5.38 mmol)溶解於CH2Cl2(50 mL)中，且添加NEt3(824 μl，5.91 mmol)。添加甲烷磺醯氯(477 μl，5.91 mmol)，且在室溫下攪拌反應物30分鐘。將反應物分配於水與CH2Cl2之間，乾燥，過濾且濃縮，得到呈透明無色油狀之甲烷磺酸1-(四氫-2H-哌喃-4-基)乙酯(1.05 g，5.04 mmol，93.8%產率)。 Step B: 1- (tetrahydro -2H--pyran-4-yl) ethanol (700 mg, 5.38 mmol) was dissolved in CH 2 Cl 2 (50 mL), and the added NEt 3 (824 μl, 5.91 mmol ) . Methanesulfonium chloride (477 μl, 5.91 mmol) was added and the reaction was stirred at room temperature for 30 min. The reaction was partitioned between water and CH 2 Cl 2, dried, filtered and concentrated to give a clear colorless oil of methanesulfonic acid l- (tetrahydro -2H--pyran-4-yl) ethyl ester (1.05 g , 5.04 mmol, 93.8% yield).

製備30Preparation 30

(反-4-碘環己氧基)三甲基矽烷 (trans-4-iodocyclohexyloxy)trimethyldecane

在N2下攪拌7-氧雜雙環[2.2.1]庚烷(2.79 ml，27.5 mmol)、NaI(4.12 g，27.5 mmol)及無水CH3CN(20 mL)。在室溫下，於快速攪拌下，緩慢添加氯三甲基矽烷(3.48 ml，27.5 mmol)。在室溫下攪拌混合物1小時，且在回流下加熱3小時。冷卻混合物至室溫，用己烷(5×30 mL)萃取且濃縮，得到呈透明無色油狀之(反-4-碘環己氧基)三甲基矽烷(4.8 g，16.1 mmol，58.5%產率)。 Was stirred under N 2 7- oxabicyclo [2.2.1] heptane (2.79 ml, 27.5 mmol), NaI (4.12 g, 27.5 mmol) and anhydrous CH 3 CN (20 mL). Chlorotrimethylnonane (3.48 ml, 27.5 mmol) was slowly added at room temperature with rapid stirring. The mixture was stirred at room temperature for 1 hour and heated under reflux for 3 hours. The mixture was cooled to room temperature, extracted with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjj Yield).

製備31Preparation 31

4-甲基苯磺酸環戊-3-烯基酯 4-methylbenzenesulfonic acid cyclopent-3-enyl ester

將環戊-3-烯醇(500 mg，5.9 mmol)溶解於CH2Cl2(30 ml)中，且 添加吡啶(0.57 mL，7.1 mmol)及TsC1(1.25 g，6.5 mmol)並攪拌反應物隔夜。濃縮反應物，且在矽膠上(100% CH2Cl2)純化殘餘物，得到呈灰色結晶固體狀之4-甲基苯磺酸環戊-3-烯基酯(1.3 g，91%產率)。 The cyclopent-3-enol (500 mg, 5.9 mmol) was dissolved in CH 2 Cl 2 (30 ml), and pyridine (0.57 mL, 7.1 mmol) and TsC1 (1.25 g, 6.5 mmol) Overnight. The reaction was concentrated, and the on silica gel (100% CH 2 Cl 2) Purification of the residue obtained as a gray crystalline solid of 4-methylbenzenesulfonic acid 3-enyl ester (1.3 g, 91% yield ).

製備32Preparation 32

5-溴-3-(2-甲基吡啶-3-基氧基)吡啶-2-胺 5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine

步驟A：向燒瓶中饋入2-甲基吡啶-3-醇(3.0 g，27.5 mmol)及DMF(100 mL)。添加NaH(0.760 g，30.2 mmol)且攪拌5分鐘。添加5-溴-3-硝基-2-氰基吡啶(6.26 g，27.5 mmol)且攪拌10分鐘。在劇烈攪拌下，將反應物傾倒至含有300 mL飽和NH4Cl及300 mL水之燒瓶中。過濾固體且在高真空下乾燥，得到呈淡褐色固體狀之5-溴-3-(2-甲基吡啶-3-基氧基)-2-氰基吡啶(7.78 g，97.6%產率)。 Step A : The flask was fed with 2-methylpyridin-3-ol (3.0 g, 27.5 mmol) and DMF (100 mL). NaH (0.760 g, 30.2 mmol) was added and stirred for 5 min. 5-Bromo-3-nitro-2-cyanopyridine (6.26 g, 27.5 mmol) was added and stirred for 10 min. Under vigorous stirring, the reaction was poured into a flask containing 300 mL of saturated NH 4 Cl and 300 mL water. The solid was filtered and dried <RTI ID=0.0> .

步驟B：向燒瓶中饋入5-溴-3-(2-甲基吡啶-3-基氧基)-2-氰基吡啶(60 g，207 mmol)及H2SO4(203 g，2068 mmol)。在室溫下攪拌反應物隔夜。小心添加水(500 mL)且使用50% NaOH中和至pH 5.0。用CH2Cl2及EtOAc萃取混合物，乾燥且濃縮，得到呈黃色固體狀之5-溴-3-(2-甲基吡啶-3-基氧基)吡啶醯胺(63.0 g，204 mmol，98.9%產率)。 Step B : Feed the flask with 5-bromo-3-(2-methylpyridin-3-yloxy)-2-cyanopyridine (60 g, 207 mmol) and H 2 SO 4 (203 g, 2068) Mm). The reaction was stirred at room temperature overnight. Water (500 mL) was carefully added and neutralized to pH 5.0 using 50% NaOH. With 2 Cl 2 and the mixture was extracted with EtOAc CH, dried and concentrated to give a yellow solid of 5-bromo-3- (2-methyl-pyridin-3-yloxy) pyridin-acyl amine (63.0 g, 204 mmol, 98.9 %Yield).

步驟C：向燒瓶中饋入2 M NaOH(256 ml，511 mmol)且冷卻至0℃。添加Br2(7.85 ml，153 mmol)且攪拌15分鐘。添加含5-溴-3-(2-甲基吡啶-3-基氧基)吡啶醯胺(31.5 g，102 mmol)之二噁烷(650 mL)，且在室溫下攪拌隔夜。用EtOAc及CH2Cl2萃取水層。用水、鹽水洗滌有機層，乾燥，濃縮且在矽膠上(含25-50-75-100% EtOAc之己烷)純化，得到呈黃色固體狀之5-溴-3-(2-甲基吡啶-3-基氧基)吡啶-2-胺(12 g， 43 mmol，41.9%產率)。 Step C : 2 M NaOH (256 ml, 511 mmol) was fed to the flask and cooled to 0 °C. Br 2 (7.85 ml, 153 mmol) was added and stirred for 15 min. Dioxane (650 mL) containing 5-bromo-3-(2-methylpyridin-3-yloxy)pyridiniumamine (31.5 g, 102 mmol) was added and stirred at room temperature overnight. CH 2 Cl 2 and EtOAc and the aqueous layer was extracted with. The organic layer was washed with EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3-yloxy)pyridin-2-amine (12 g, 43 mmol, 41.9% yield).

經由製備32中之途徑，製備以下化合物： The following compounds were prepared via the route in Preparation 32:

製備37Preparation 37

3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-胺 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine

步驟A：將2-乙基吡啶-3-醇(27.5 g，223 mmol)溶解於DMF(900 mL)且在冰浴中冷卻。逐份添加NaH(8.93 g，223 mmol)且在冰浴中 攪拌30分鐘。以一整份添加5-溴-3-硝基-2-氰基吡啶(50.9 g，223 mmol)且在冰浴中攪拌。1小時後，依序添加吡啶-2(1H)-硫酮(24.8 g，223 mmol)、NaH(8.93 g，223 mmol)，且在冰浴中攪拌反應物。1小時後，攪拌反應物隔夜，接著在真空中濃縮混合物至約300 mL，且在劇烈攪拌下傾倒至3L水中。用EtOAc(×3)萃取混合物，用水及鹽水(×2)洗滌，經Na2SO4乾燥，過濾且濃縮，得到呈深色油狀之3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)-2-氰基吡啶(81 g，242 mmol，108%產率)。 Step A : 2-Ethylpyridin-3-ol (27.5 g, 223 mmol) was dissolved in DMF (900 mL). NaH (8.93 g, 223 mmol) was added portion wise and stirred for 30 min. 5-Bromo-3-nitro-2-cyanopyridine (50.9 g, 223 mmol) was added in one portion and stirred in an ice-bath. After 1 h, pyridine-2(1H)-thione (24.8 g, 223 mmol), NaH (8.93 g, 223 mmol). After 1 hour, the reaction was stirred overnight, then the mixture was concentrated in vacuo to <RTI ID=0.0># </ RTI></RTI></RTI></RTI></RTI><RTIgt; Washed mixture was extracted with EtOAc (× 3), washed with water and brine (× 2), dried over Na 2 SO 4, filtered and concentrated to give a dark oil of 3- (2-ethyl-3-yloxy -5-(Pyridin-2-ylthio)-2-cyanopyridine (81 g, 242 mmol, 108% yield).

步驟B-C：遵循製備15步驟B及C中之步驟，合成3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-胺。 Step BC : Following the procedure in Preparation 15 Steps B and C, 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine was synthesized.

經由製備37中之途徑，製備以下化合物： The following compounds were prepared via the route in Preparation 37:

製備44Preparation 44

3-(2,6-二甲基吡啶-3-基氧基)-5-(三氟甲基)吡啶-2-胺 3-(2,6-dimethylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-amine

步驟A：將2,6-二甲基吡啶-3-醇(5.25 g，42.6 mmol)溶解於DMF(80 mL)中且冷卻至0℃。分數份添加NaH(1.16 g，48.4 mmol)，且攪拌混合物30分鐘。添加3-氯-5-(三氟甲基)-2-氰基吡啶(8.00 g，38.7 mmol)，使混合物升溫至室溫且攪拌隔夜。用EtOAc(300 ml)稀釋混合物，且用NaHCO3、水(3次)、鹽水洗滌，經Na2SO4乾燥，用Darco脫色，過濾並蒸發，得到呈淡棕色固體狀之3-(2,6-二甲基吡啶-3-基氧基)-5-(三氟甲基)-2-氰基吡啶(10.2 g，34.8 mmol，89.8%產率)。 Step A : 2,6-Dimethylpyridin-3-ol (5.25 g, 42.6 mmol) was dissolved in DMF (80 mL) and cooled to 0. NaH (1.16 g, 48.4 mmol) was added in portions and the mixture was stirred for 30 min. 3-Chloro-5-(trifluoromethyl)-2-cyanopyridine (8.00 g, 38.7 mmol) was added and the mixture was warmed to room temperature and stirred overnight. The mixture was diluted with EtOAc (300 ml), and washed with NaHCO 3, water (3x), washed with brine, dried over Na 2 SO 4, decolorized with Darco, filtered and evaporated to give a pale brown solid of 3- (2, 6-Dimethylpyridin-3-yloxy)-5-(trifluoromethyl)-2-cyanopyridine (10.2 g, 34.8 mmol, 89.8% yield).

步驟B-C：遵循製備15步驟B及C中之步驟，合成3-(2,6-二甲基吡啶-3-基氧基)-5-(三氟甲基)吡啶-2-胺。 Step BC : Following the procedure in Preparation 15 Steps B and C, 3-(2,6-dimethylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-amine was synthesized.

經由製備44中之途徑，製備以下化合物： The following compounds were prepared via the route of Preparation 44:

製備46Preparation 46

5-溴-3-(2-甲基吡啶-3-基氧基)吡嗪-2-胺 5-bromo-3-(2-methylpyridin-3-yloxy)pyrazin-2-amine

將2-甲基吡啶-3-醇(0.621 g，5.69 mmol)溶解於THF(10 mL)中且冷卻至0℃。添加NaH(0.228 g，5.69 mmol)，且攪拌反應物30分鐘。將3,5-二溴吡嗪-2-胺(1.2 g，4.75 mmol)溶解於THF(2 mL)中且添加至反應物中。加熱反應物至回流，維持2小時。添加DMF(4 mL)，且在回流下再加熱隔夜。冷卻反應物至室溫，用水(50 mL)稀釋且劇烈攪拌。過濾所得固體且用水洗滌，得到呈棕色固體狀之5-溴-3-(2-甲基吡啶-3-基氧基)吡嗪-2-胺(1.15 g，4.09 mmol，86.2%產率)。 2-Methylpyridin-3-ol (0.621 g, 5.69 mmol) was dissolved in THF (10 mL) and cooled to EtOAc. NaH (0.228 g, 5.69 mmol) was added and the reaction was stirred 30 min. 3,5-Dibromopyrazin-2-amine (1.2 g, 4.75 mmol) was dissolved in THF (2 mL) and added to the mixture. The reaction was heated to reflux for 2 h. DMF (4 mL) was added and heated at reflux overnight. The reaction was cooled to rt, diluted with water (50 mL) and stirring. The resulting solid was filtered and washed with w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ .

製備47Preparation 47

5-溴-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-胺 5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-amine

步驟A：將5,6,7,8-四氫喹啉-5-醇(2.85 g，19.1 mmol)、2-硝基吡啶-3-醇(2.68 g，19.1 mmol)、PPh3(6.8 g，26.0 mmol)溶解於THF(60 mL)中。緩慢添加DIAD(5.15 ml，26.0 mmol)，且在室溫下攪拌反應物隔夜。將反應物分配於水與EtOAc之間。用CH2Cl2萃取水層。經Na2SO4乾燥經合併之有機物，過濾且濃縮。在矽膠上(含25-50-100% EtOAc之己烷)純化殘餘物，得到6.0 g呈黃色油狀之粗5-(2-硝基吡啶-3-基氧基)-5,6,7,8-四氫喹啉。 Step A : 5,6,7,8-tetrahydroquinolin-5-ol (2.85 g, 19.1 mmol), 2-nitropyridin-3-ol (2.68 g, 19.1 mmol), PPh3 (6.8 g, 26.0 mmol) was dissolved in THF (60 mL). DIAD (5.15 ml, 26.0 mmol) was added slowly and the reaction was stirred at room temperature overnight. The reaction was partitioned between water and EtOAc. The aqueous layer was extracted with CH 2 Cl 2 . Dried over Na 2 SO 4 the combined the organics were filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAcjjjjjj , 8-tetrahydroquinoline.

步驟B：將5-(2-硝基吡啶-3-基氧基)-5,6,7,8-四氫喹啉(2.0 g，7.37 mmol)溶解於HOAc(50 mL)中。冷卻反應物至0℃，且添加鋅粉(2.41 g，36.9 mmol)並攪拌10分鐘。經矽藻土過濾反應物且用EtOAc洗滌。用NaHCO3中和濾液，用EtOAc(3×150 mL)及CH2Cl2(2×100 mL)萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(100% EtOAc至含5%氨化MeOH之CH2Cl2)純化殘餘物，得到呈淡棕色固體狀之3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-胺(0.642 g，2.66 mmol，36.1%產率)。 Step B : 5-(2-Nitropyridin-3-yloxy)-5,6,7,8-tetrahydroquinoline (2.0 g, 7.37 mmol) was dissolved in HOAc (50 mL). The reaction was cooled to 0 ° C and zinc powder (2.41 g, 36.9 mmol) was added and stirred for 10 min. The reaction was filtered through celite and washed with EtOAc. , And CH 2 Cl 2 (2 × 100 mL) and neutralized with NaHCO 3 and extracted filtrate with EtOAc (3 × 150 mL), dried over Na 2 SO 4, filtered and concentrated. On silica gel (100% EtOAc to a solution of CH 5% ammoniated MeOH 2 Cl 2) The residue was purified to give 3- (5,6,7,8-tetrahydro-5-yl as a light brown solid of Oxy)pyridin-2-amine (0.642 g, 2.66 mmol, 36.1% yield).

步驟C：將3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-胺(0.642 g，2.66 mmol)溶解於乙酸(20 mL)中。添加Br2(0.13 ml，2.66 mmol)，且在室溫下攪拌反應物10分鐘。添加水且用K2CO3中和反應物。用EtOAc萃取混合物，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含0%至3%氨化MeOH之EtOAc)純化殘餘物，得到呈黃色固體狀之5-溴-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-胺(0.723 g，2.15 mmol，80.6%產率)。 Step C : 3-(5,6,7,8-Tetrahydroquinolin-5-yloxy)pyridin-2-amine (0.642 g, 2.66 mmol) was dissolved in acetic acid (20 mL). Br 2 (0.13 ml, 2.66 mmol) was added and the mixture was stirred at room temperature for 10 min. Water was added and the reactants were neutralized with K 2 CO 3 . , The mixture was extracted with EtOAc and dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc (EtOAc) Pyridin-2-amine (0.723 g, 2.15 mmol, 80.6% yield).

遵循製備47中之程序，製備以下化合物： Following the procedure in Preparation 47, the following compounds were prepared:

製備50Preparation 50

5-(3-甲氧基丙硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-胺 5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-amine

步驟A：用二碳酸二第三丁酯(2.34 g，10.7 mmol)處理5-溴-3-(2-甲基吡啶-3-基氧基)吡啶-2-胺(1.0 g，3.57 mmol)於二噁烷(8 mL)及tBuOH(24 mL)中之溶液，且加熱至65℃隔夜。再添加二碳酸二第三丁酯(2.34 g，10.7 mmol)且加熱隔夜。再添加二碳酸二第三丁酯(2.34 g，10.7 mmol)且攪拌3天。冷卻混合物，分配於EtOAc與NaHCO3水溶液之間，用0.1 N NaOH洗滌，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含1：1 EtOAc之己烷)純化殘餘物，得到bis-Boc產物(1.53 g，3.19 mmol，89.2%產率)。 Step A : Treatment of 5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (1.0 g, 3.57 mmol) with dibutyl succinate (2.34 g, 10.7 mmol) A solution of dioxane (8 mL) and tBuOH (24 mL) was then warmed to 65 ° C overnight. Further, di-tert-butyl dicarbonate (2.34 g, 10.7 mmol) was added and heated overnight. Further, di-tert-butyl dicarbonate (2.34 g, 10.7 mmol) was added and stirred for 3 days. The mixture was cooled, partitioned between EtOAc and aqueous NaHCO 3, washed with 0.1 N NaOH, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc)

步驟B：將來自先前反應之bis-Boc產物(1.5 g，3.12 mmol)溶解於 二噁烷(30 mL)中。添加Xantphos(0.0903 g，0.156 mmol)及N-乙基-N-異丙基丙-2-胺(1.09 ml，6.25 mmol)，且使N2鼓泡通過反應物，持續5分鐘。添加Pd2dba3(0.0715 g，0.0781 mmol)及3-巰基丙酸甲酯(0.372 ml，3.43 mmol)，且將反應物傾沒於95℃油浴中並在N2下攪拌1小時。冷卻反應物至室溫，經矽藻土過濾且濃縮。在矽膠上(含2：1EtOAc之己烷)純化殘餘物，得到呈琥珀色油狀之3-(6-(雙(第三丁氧基羰基)胺基)-5-(2-甲基吡啶-3-基氧基)吡啶-3-基硫基)丙酸甲酯(1.6 g，3.08 mmol，98.6%產率)。 Step B : The bis-Boc product from the previous reaction (1.5 g, 3.12 mmol) was dissolved in dioxane (30 mL). Was added Xantphos (0.0903 g, 0.156 mmol) and N- ethyl -N- isopropyl-2-amine (1.09 ml, 6.25 mmol), and that the N 2 was bubbled through the reaction for 5 minutes. Pd 2 dba 3 (0.0715 g, 0.0781 mmol) and methyl 3-mercaptopropionate (0.372 ml, 3.43 mmol) were added, and the mixture was poured in a 95 ° C oil bath and stirred under N 2 for 1 hour. The reaction was cooled to rt, filtered over EtOAc (EtOAc)EtOAc. The residue was purified on EtOAc (EtOAc EtOAc) Methyl-3-methyloxy)pyridin-3-ylthio)propanoate (1.6 g, 3.08 mmol, 98.6% yield).

步驟C：將3-(6-(雙(第三丁氧基羰基)胺基)-5-(2-甲基吡啶-3-基氧基)吡啶-3-基硫基)丙酸甲酯(1.6 g，3.08 mmol)溶解於THF(20 mL)中，且使N2鼓泡通過，持續5分鐘。添加含1 M 2-甲基丙-2-醇鉀之THF(9.24 ml，9.24 mmol)，且攪拌反應物30秒。添加1-溴-3-甲氧基丙烷(0.435 ml，3.70 mmol)，且在室溫下攪拌反應物1小時，用NH4Cl水溶液淬滅，用EtOAc萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含75% EtOAc之己烷)純化殘餘物，得到呈油狀之5-(3-甲氧基丙硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基胺基甲酸第三丁酯(700 mg，1.73 mmol，56.1%產率)。 Step C : Methyl 3-(6-(bis(t-butoxycarbonyl)amino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (1.6 g, 3.08 mmol) was dissolved in THF (20 mL), and that the N 2 was bubbled through for 5 minutes. THF (9.24 ml, 9.24 mmol) containing 1 M 2-methylpropan-2-ol was added and the mixture was stirred for 30 s. L-bromo-3-methoxypropane (0.435 ml, 3.70 mmol), and stirred at room temperature for 1 hour, and extracted with EtOAc quenched with aqueous NH 4 Cl, dried over Na 2 SO 4, filtered And concentrated. The residue was purified on EtOAc (EtOAc EtOAc EtOAc) T-butyl 2-ylaminocarbamate (700 mg, 1.73 mmol, 56.1% yield).

步驟D：將5-(3-甲氧基丙硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基胺基甲酸第三丁酯(700 mg，1.73 mmol)溶解於CH2Cl2(20 mL)中，且添加少量MeOH(約1 mL)。添加含4 N HCl之二噁烷(8 mL)。4小時後，濃縮反應物以移除大部分HCl，分配於飽和NaHCO3水溶液與CH2Cl2之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含5%至10% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之5-(3-甲氧基丙硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-胺(370 mg，1.21 mmol，70.2%產率)。 Step D : tert-butyl 5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylcarbamate (700 mg, 1.73 mmol Dissolved in CH 2 Cl 2 (20 mL) with a small amount of MeOH (~1 mL). Dioxane (8 mL) containing 4 N HCl was added. After 4 hours, the reaction was concentrated to remove most of HCl, partitioned between 2 Cl 2 and saturated aqueous NaHCO 3 CH, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc) Pyridin-2-amine (370 mg, 1.21 mmol, 70.2% yield).

製備51Preparation 51

順-3-氟四氫-2H-哌喃-4-醇 Cis-3-fluorotetrahydro-2H-pentan-4-ol

將3-氟二氫-2H-哌喃-4(3H)-酮(1.0 g，8.47 mmol)置於THF(15 mL)中且冷卻至-78℃。逐滴添加含三異丁基硼氫化鋰(L-selectride)之THF(1 M，9.31 ml，9.31 mmol)，且攪拌反應物20分鐘。添加MeOH(1.03 ml，25.4 mmol)及NaOH(25.4 ml，25.4 mmol)，且在室溫下攪拌反應物30分鐘。將反應物置於冰浴上，繼而逐滴添加H2O2(2.88 ml，42.3 mmol)且攪拌反應物30分鐘。添加鹽水(24 mL)，且用EtOAc(2×50 mL)萃取反應物。分離有機部分，經MgSO4乾燥且濃縮，得到粗物質，藉由矽膠層析(5：1至3：1 CH2Cl2：EtOAc)純化該粗物質，得到呈透明油狀之(3S,4R)-3-氟四氫-2H-哌喃-4-醇(125 mg，12.3%產率)。 3-Fluorodihydro-2H-piperidin-4(3H)-one (1.0 g, 8.47 mmol) was taken in THF (15 mL) and cooled to -78. THF (1 M, 9.31 ml, 9.31 mmol) containing tri-isobutylborohydride (L-selectride) was added dropwise and the mixture was stirred for 20 min. MeOH (1.03 ml, 25.4 mmol) and NaOH (25.4 ml, 25.4 mmol) were then evaporated The reaction was placed on an ice bath, followed by dropwise added H 2 O 2 (2.88 ml, 42.3 mmol) and the reaction was stirred for 30 min. Brine (24 mL) was added and the EtOAc was evaporated. The organic portion was separated, dried over MgSO 4 dried and concentrated to give the crude material by silica gel chromatography (5: 1 to 3: 2 Cl 2 1 CH: EtOAc) of the crude material was purified, to give a clear oil of (3S, 4R 3-fluorotetrahydro-2H-pentan-4-ol (125 mg, 12.3% yield).

製備52Preparation 52

順-3-甲基四氫-2H-哌喃-4-醇 Cis-3-methyltetrahydro-2H-pentan-4-ol

步驟A：在N2下，在具有攪拌棒之小瓶中，將二氫-2H-哌喃-4(3H)-酮(2.5 g，24.97 mmol)及HMPA(4.344 ml，24.97 mmol)溶解於25 mL THF中。冷卻至0℃，且添加LDA(13.73 ml，27.47 mmol)並攪拌30分鐘。添加碘甲烷(2.337 ml，37.46 mmol)且在冰浴中攪拌，使冰浴本身逐漸升溫至室溫。16小時後，在攪拌下用25 mL己烷稀釋混合物。將此混合物添加至100 g二氧化矽管柱中且用Et2O溶離。濃縮此物質，得到3-甲基二氫-2H-哌喃-4(3H)-酮(5.0 g，35%醇)。此物質未經任何進一步純化即用於下一反應中。 Step A: Under N 2, of a vial with a stir bar, a dihydro -2H--pyran -4 (3H) - one (2.5 g, 24.97 mmol) and HMPA (4.344 ml, 24.97 mmol) was dissolved in 25 In mL THF. Cool to 0 ° C and add LDA (13.73 ml, 27.47 mmol) and stir for 30 min. Methyl iodide (2.337 ml, 37.46 mmol) was added and stirred in an ice bath, and the ice bath itself was gradually warmed to room temperature. After 16 hours, the mixture was diluted with 25 mL of hexane with stirring. This mixture was added to a 100 g cerium oxide column and dissolved with Et 2 O. This material was concentrated to give 3-methyldihydro-2H-pyran-4(3H)-one (5.0 g, 35% alcohol). This material was used in the next reaction without any further purification.

步驟B：將3-甲基二氫-2H-哌喃-4(3H)-酮(4.0 g，13.0 mmol，35%)置於THF(12 mL)中且冷卻至-78℃。逐滴添加含三異丁基硼氫化鋰之THF(1 M，23.3 ml，23.3 mmol)，且攪拌反應物20分鐘。添加MeOH(1.58 ml，38.9 mmol)及NaOH(38.9 ml，38.9 mmol)，且在室溫下攪拌反應物30分鐘。將反應物置於冰浴上，繼而逐滴添加H2O2(4.41 ml，64.8 mmol)，且攪拌反應物30分鐘。添加鹽水(24 mL)，且用EtOAc(2×50 mL)萃取反應物。在真空中濃縮直至粗混合物重2.0 g。在矽膠上使用純CH2Cl2至30% EtOAc/CH2Cl2矽膠之梯度純化，得到呈透明油狀之(3S,4R)-3-甲基四氫-2H-哌喃-4-醇(600 mg，5.17 mmol，39.8%)。 Step B : 3-Methyldihydro-2H-piperidin-4(3H)-one (4.0 g, 13.0 mmol, 35%) was taken in THF (12 mL) and cooled to -78. THF containing triisobutylborohydride (1 M, 23.3 ml, 23.3 mmol) was added dropwise and the mixture was stirred 20 min. MeOH (1.58 ml, 38.9 mmol) and NaOH (38.9 ml, 38.9 mmol) were added and the mixture was stirred at room temperature for 30 min. The reaction was placed on an ice bath, followed by dropwise added H 2 O 2 (4.41 ml, 64.8 mmol), and the reaction was stirred for 30 minutes. Brine (24 mL) was added and the EtOAc was evaporated. Concentrate in vacuo until the crude mixture weighed 2.0 g. On silica using pure CH 2 Cl 2 to 30% EtOAc / gradient of the silicone 2 Cl 2 CH, to give a clear oil of (3S, 4R) -3- methyl-tetrahydro-pyran-4-ol -2H- (600 mg, 5.17 mmol, 39.8%).

製備53Preparation 53

順-3-乙基四氫-2H-哌喃-4-醇 Cis-3-ethyltetrahydro-2H-pentan-4-ol

步驟A：在N2下，在具有攪拌棒之小瓶中，將二氫-2H-哌喃-4(3H)-酮(2.5 g，25.0 mmol)及HMPA(4.34 ml，25.0 mmol)溶解於25 mL無水THF中。冷卻至0℃，且添加LDA(16.2 ml，32.5 mmol)並攪拌30分鐘。添加碘乙烷(5.84 g，37.5 mmol)且在冰浴中攪拌，使冰浴本身逐漸升溫隔夜。用50 mL己烷稀釋混合物，且添加至100 g二氧化矽管柱中並用乙醚溶離。濃縮此混合物，得到呈透明油狀之3-乙基二氫-2H-哌喃-4(3H)-酮(500 mg，2.93 mmol)。此物質未經任何進一步純化即用於下一反應中。 Step A: Under N 2, of a vial with a stir bar, a dihydro -2H--pyran -4 (3H) - one (2.5 g, 25.0 mmol) and HMPA (4.34 ml, 25.0 mmol) was dissolved in 25 mL of anhydrous THF. Cool to 0 ° C and add LDA (16.2 mL, 32.5 mmol) and stir for 30 min. Iodoethane (5.84 g, 37.5 mmol) was added and stirred in an ice bath to gradually warm the ice bath itself overnight. The mixture was diluted with 50 mL of hexane and added to a 100 g ruthenium dioxide column and dissolved in diethyl ether. The mixture was concentrated to give 3-ethyldihydro-2H-pyran-4(3H)-one (500 mg, 2.93 mmol). This material was used in the next reaction without any further purification.

步驟B：將3-乙基二氫-2H-哌喃-4(3H)-酮(0.5 g，2.93 mmol)置於THF(4 mL)中且冷卻至-78℃。逐滴添加含三異丁基硼氫化鋰之THF(1 M，4.10 ml，4.10 mmol)，且攪拌反應物20分鐘。添加MeOH (0.356 ml，8.78 mmol)及NaOH(8.78 ml，8.78 mmol)，且在攪拌下經30分鐘使反應物升溫至室溫。將反應物回置於冰浴上，接著小心逐滴添加H2O2(0.995 ml，14.6 mmol)，且攪拌反應物30分鐘。接著添加鹽水(8 mL)，且用EtOAc(2×15 mL)萃取反應物。在真空中濃縮且在矽膠上依序用250 mL 25% EtOAc/己烷、250 mL 50% EtOAc/己烷溶離來純化。濃縮且置於高真空下20分鐘，獲得呈透明油狀之(3S,4R)-3-乙基四氫-2H-哌喃-4-醇(300 mg，78.8%產率)。 Step B : 3-Ethyldihydro-2H-piperidin-4(3H)-one (0.5 g, 2.93 mmol) was taken in THF (4 mL) and cooled to -78. THF containing triisobutylborohydride (1 M, 4.10 ml, 4.10 mmol) was added dropwise and the mixture was stirred for 20 min. MeOH (0.356 ml, 8.78 mmol) and NaOH (8.78 ml, 8.78 mmol) were added and the mixture was warmed to room temperature over 30 min with stirring. The reaction was placed back on an ice bath, followed by careful dropwise added H 2 O 2 (0.995 ml, 14.6 mmol), and the reaction was stirred for 30 min. Brine (8 mL) was then added and the EtOAc (2×15 mL) Concentrate in vacuo and purify on silica gel eluting sequentially with 250 mL 25% EtOAc / hexanes, 250 mL 50% EtOAc / hexane. Concentration and under high vacuum for 20 min afforded (3S,4R)-3-ethyltetrahydro-2H-pyran-4-ol (300 mg, 78.8% yield).

製備54Preparation 54

5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶 5-bromo-2-chloro-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridine

將1-乙基-1H-吡唑-5-醇(5.00 g，44.6 mmol)溶解於DMF(49.5 ml)中，且添加CsCO3(17.4 g，53.5 mmol)並攪拌漿液20分鐘。向漿液中添加5-溴-2-氯-3-氟吡啶(9.38 g，44.6 mmol)，且攪拌漿液隔夜。再添加9.00 g CsCO3(總共約1.80當量)，且加熱反應物至60℃並攪拌4.5小時。接著用水(200 mL)稀釋反應物，且用EtOAc(3×400 ml)萃取此混合物。用水(1×300 mL)、1 N LiCl溶液(1×300 mL)及鹽水(1×200 mL)洗滌經合併之有機層，且經MgSO4乾燥。在矽膠上(0%至70% EtOAc：己烷)純化粗物質，得到呈白色固體狀之5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶(9.00 g，29.7 mmol，66.7%產率)。1H NMR(400 MHz,DMSO-d 6)δ ppm 8.48(1H,d,J=2.2 Hz),8.01(1H,d,J=2.2 Hz),7.41(1H,d,J=2.2 Hz),5.87(1H,d,J=2.2 Hz),4.05(2H,q,J=7.2 Hz),1.33(3H,t,J=7.2 Hz)。質譜(ESI)m/z=301.9,303.9,305.8(M+H)。 1-ethyl -1 H - pyrazol-5-ol (5.00 g, 44.6 mmol) was dissolved in DMF (49.5 ml), and was added CsCO 3 (17.4 g, 53.5 mmol ) and the slurry was stirred for 20 min. To the slurry was added 5-bromo-2-chloro-3-fluoropyridine (9.38 g, 44.6 mmol), and the mixture was stirred overnight. Then add 9.00 g CsCO 3 (a total of about 1.80 eq.), And the reaction was heated to 60 deg.] C and stirred for 4.5 hours. The reaction was then diluted with water (2OmL) Washed with water (1 × 300 mL), 1 N LiCl solution (1 × 300 mL) and brine (1 × 200 mL) the combined organic layers were washed, and dried over MgSO 4. The crude material was purified on EtOAc (EtOAc:EtOAc) Oxy)pyridine (9.00 g, 29.7 mmol, 66.7% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.48 (1H, d, J = 2.2 Hz), 8.1 (1H, d, J = 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 5.87 (1H, d, J = 2.2 Hz), 4.05 (2H, q, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz). Mass Spectrum (ESI) m/z = 301.9, 303.9, 305.8 (M+H).

製備55Preparation 55

5-(6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基)戊-4-炔-1-醇 5-(6-chloro-5-((1-ethyl-1 H -pyrazol-5-yl)oxy)pyridin-3-yl)pent-4-yn-1-ol

將5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶(773 mg，2.55 mmol)、戊-4-炔-1-醇(0.236 ml，2.55 mmol)及NEt3(1.42 ml，10.2 mmol)添加至DMF(3.5 ml)中。接著在氮氣下添加CuI(15.0 mg，0.077 mmol)及A-Phos(20.0 mg，0.077 mmol)。加熱反應物至80℃且攪拌90分鐘。冷卻混合物且用EtOAc(200 mL)稀釋。用2 N HCl溶液(1×50 mL)、水(1×50 mL)、1 M LiCl溶液(1×50 mL)及鹽水(1×50 mL)萃取混合物。經MgSO4乾燥有機層，過濾且在減壓下濃縮。接著在矽膠上(35%至90% EtOAc：己烷)純化殘餘物，得到5-(6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基)戊-4-炔-1-醇(545 mg，1.78 mmol，69.8%產率)。1H NMR(400 MHz,DMSO-d 6)δ ppm 8.31(1H,d,J=2.0 Hz),7.65(1H,d,J=2.0 Hz),7.40(1H,d,J=2.0 Hz),5.83(1H,d,J=2.0 Hz),4.53(1H,t,J=5.2 Hz),4.04(2H,q,J=7.2 Hz),3.49(2H,q,J=6.1 Hz),2.46-2.50(2H,m),1.63-1.77(2H,m),1.32(3H,t,J=7.2 Hz)。質譜(ESI)m/z=306.0(M+H)。 5-Bromo-2-chloro-3-((1-ethyl-1 H -pyrazol-5-yl)oxy)pyridine (773 mg, 2.55 mmol), pent-4-yn-1-ol ( 0.236 ml, 2.55 mmol) and NEt 3 (1.42 ml, 10.2 mmol) were added to DMF (3.5 ml). CuI (15.0 mg, 0.077 mmol) and A-Phos (20.0 mg, 0.077 mmol) were then added under nitrogen. The reaction was heated to 80 ° C and stirred for 90 minutes. The mixture was cooled and diluted with EtOAc (200 mL). The mixture was extracted with 2 N HCl solution (1×50 mL), water (1×50 mL), 1 M LiCl solution (1×50 mL) and brine (1×50 mL). The organic layer was dried with MgSO 4 Next on silica gel (35% to 90% EtOAc: hexanes) the residue to give 5- (6-chloro-5 - ((1-ethyl -1 H - pyrazol-5-yl) oxy) pyridine -3-yl)pent-4-yn-1-ol (545 mg, 1.78 mmol, 69.8% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.31 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 5.83 (1H, d, J = 2.0 Hz), 4.53 (1H, t, J = 5.2 Hz), 4.04 (2H, q, J = 7.2 Hz), 3.49 (2H, q, J = 6.1 Hz), 2.46- 2.50 (2H, m), 1.63-1.77 (2H, m), 1.32 (3H, t, J = 7.2 Hz). Mass Spectrum (ESI) m/z = 306.0 (M+H).

遵循製備55中之程序，製備以下化合物： Following the procedure in Preparation 55, the following compounds were prepared:

製備57Preparation 57

2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)-5-(5-甲氧基戊-1-炔-1-基)吡啶 2-Chloro-3-((1-ethyl-1 H -pyrazol-5-yl)oxy)-5-(5-methoxypent-1-yn-1-yl)pyridine

將5-(6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基)戊-4-炔-1-醇(220 mg，0.720 mmol)溶解於THF(7 ml)中且冷卻至0℃。添加NaH(60%分散液)(32.0 mg，0.79 mmol)，且在0℃下攪拌混合物15分鐘。添加碘代甲烷(0.049 ml，0.79 mmol)，且經5.5小時使所得溶液緩慢升溫至室溫。用水淬滅反應物且用EtOAc(2×75 mL)萃取。用鹽水(1×30 mL)洗滌經合併之有機層且經MgSO4乾燥。在矽膠上(40%至100% EtOAc：己烷)純化粗物質，得到2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)-5-(5-甲氧基戊-1-炔-1-基)吡啶(99 mg，0.31 mmol，43%產率)。1H NMR(400 MHz,CDCl 3 )δ ppm 8.20(1H,d,J=2.0 Hz),7.42(1H,d,J=2.2 Hz),7.36(1H,d,J=2.0 Hz),5.66(1H,d,J=2.2 Hz),4.09(2H,q,J=7.2 Hz),3.47(2H,t,J=6.2 Hz),3.34(3H,s),2.49(2H,t,J=7.1 Hz),1.79-1.97(2H,m),1.43(3H,t,J=7.2 Hz)。質譜(ESI)m/z=320.0(M+H)。 5-(6-Chloro-5-((1-ethyl-1 H -pyrazol-5-yl)oxy)pyridin-3-yl)pent-4-yn-1-ol (220 mg, 0.720 Methyl) was dissolved in THF (7 mL) and cooled to 0 °C. NaH (60% dispersion) (32.0 mg, 0.79 mmol) was added and the mixture was stirred at 0 ° C for 15 min. Methyl iodide (0.049 ml, 0.79 mmol) was added, and the resulting solution was slowly warmed to room temperature over 5.5 hours. The reaction was quenched with EtOAc (EtOAc m. And dried combined organic layers were washed over with MgSO 4 brine (1 × 30 mL). The crude material was purified on silica gel (40% to 100%EtOAc:hexanes) to afford 2-chloro-3-((1-ethyl- 1H -pyrazol-5-yl)oxy)-5- (5 -Methoxypent-1-yn-1-yl)pyridine (99 mg, 0.31 mmol, 43% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.20 (1H, d, J = 2.0 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.36 (1H, d, J = 2.0 Hz), 5.66 ( 1H, d, J = 2.2 Hz), 4.09 (2H, q, J = 7.2 Hz), 3.47 (2H, t, J = 6.2 Hz), 3.34 (3H, s), 2.49 (2H, t, J = 7.1 Hz), 1.79-1.97 (2H, m), 1.43 (3H, t, J = 7.2 Hz). Mass Spectrum (ESI) m/z = 320.0 (M+H).

遵循製備57中之程序，製備以下化合物： Following the procedure in Preparation 57, the following compounds were prepared:

實例1Example 1

1-(5-溴-4-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

步驟A：將95% NaH(3.65 g，144 mmol)溶解於DMF(100 mL)中，且緩慢添加2-甲基吡啶-3-醇(15.0 g，137 mmol)，且在室溫下攪拌1小時。添加2-氯-4-硝基吡啶(22.9 g，144 mmol)且在室溫下攪拌2小時。將反應物傾倒至水中且用EtOAc(1 L)萃取，用水洗滌，經Na2SO4乾燥，過濾並濃縮，得到呈黃色固體狀之3-(2-氯吡啶-4-基氧基)-2-甲基吡啶(30 g，136 mmol，98.9%產率)。 Step A : Dissolve 95% NaH (3.65 g, 144 mmol) in DMF (100 mL) and slowly add 2-methylpyridin-3-ol (15.0 g, 137 mmol) and stir at room temperature 1 hour. 2-Chloro-4-nitropyridine (22.9 g, 144 mmol) was added and stirred at room temperature for 2 h. The reaction was poured into water and extracted with EtOAc (1 L), washed with water, dried over Na 2 SO 4, filtered, and concentrated to give a yellow solid of 3- (2-chloro-4-yloxy) - 2-methylpyridine (30 g, 136 mmol, 98.9% yield).

步驟B：將3-(2-氯吡啶-4-基氧基)-2-甲基吡啶(30 g，135 mmol)、胺基甲酸第三丁酯(39.8 g，339 mmol)及K3PO4(34.6 g，163 mmol)溶解於甲苯(600 mL)中且用N2脫氣。添加Pd(dba)2(7.81 g，13.6 mmol)且將反應物再用N2脫氣。添加經脫氣之水(150 mL)，且在90℃下加熱反應物隔夜。冷卻反應物且分配於水與EtOAc之間，用EtOAc(4×0.5 L)萃取，經Na2SO4乾燥，過濾並濃縮。在矽膠上(含25%至100% EtOAc之己烷)純化殘餘物，得到4-(2-甲基吡啶-3-基氧基)吡啶-2-基胺基甲酸第三丁酯(27 g，66%產率)。 Step B : 3-(2-Chloropyridin-4-yloxy)-2-methylpyridine (30 g, 135 mmol), tributyl carbamic acid (39.8 g, 339 mmol) and K 3 PO 4 (34.6 g, 163 mmol) was dissolved in toluene (600 mL) and treated with N 2 degassing. Was added Pd (dba) 2 (7.81 g , 13.6 mmol) and the reaction was again degassed N 2. Degassed water (150 mL) was added and the reaction was heated at 90 ° C overnight. The reaction was cooled and partitioned between water and EtOAc in, and extracted with EtOAc (4 × 0.5 L), dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc:EtOAc) , 66% yield).

步驟C：將4-(2-甲基吡啶-3-基氧基)吡啶-2-基胺基甲酸第三丁酯(27 g，89.60 mmol)溶解於CH2Cl2(250 mL)中，且添加TFA(150 mL)，且在室溫下攪拌反應物隔夜。濃縮反應物且分配於EtOAc與NaHCO3水溶液之間，經Na2SO4乾燥，過濾並濃縮。在矽膠上(含50%至100% EtOAc之己烷，繼之以含10%氨化MeOH之EtOAc)純化殘餘物，得到呈灰白色固體狀之4-(2-甲基吡啶-3-基氧基)吡啶-2-胺(13.30 g，66.10 mmol，73.77%產率)。 Step C: pyridin-2-yl-carbamic acid tert-butyl ester 4- (2-pyridin-3-yloxy) (27 g, 89.60 mmol) was dissolved in CH 2 Cl 2 (250 mL), the TFA (150 mL) was added and the mixture was stirred at room temperature overnight. The reaction was concentrated and partitioned between EtOAc and aqueous NaHCO 3, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc (EtOAc) Pyridin-2-amine (13.30 g, 66.10 mmol, 73.77% yield).

步驟D：將4-(2-甲基吡啶-3-基氧基)吡啶-2-胺(3.0 g，14.9 mmol)溶解於HOAc(50 mL)中。緩慢添加Br2(0.764 ml，14.9 mmol)，且在室溫下攪拌10分鐘。添加水(100 mL)，且使用飽和NaHCO3溶液中和HOAc。用EtOAc萃取混合物，經Na2SO4乾燥，過濾且濃縮。在矽膠上(100% EtOAc)純化殘餘物，得到呈白色固體狀之5-溴-4-(2-甲基吡啶-3-基氧基)吡啶-2-胺(2.74 g，9.78 mmol，65.6%產率)。 Step D : 4-(2-Methylpyridin-3-yloxy)pyridin-2-amine (3.0 g, 14.9 mmol) was dissolved in HOAc (50 mL). Br 2 (0.764 ml, 14.9 mmol) was added slowly and stirred at room temperature for 10 min. Water (100 mL), and saturated NaHCO 3 solution and HOAc. , The mixture was extracted with EtOAc and dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) %Yield).

步驟E：將5-溴-4-(2-甲基吡啶-3-基氧基)吡啶-2-胺(100 mg，0.357 mmol)溶解於THF(3 mL)中，且添加吡啶(86.4 μl，1.07 mmol)及氯甲酸4-硝基苯酯(144 mg，0.714 mmol)，且在室溫下攪拌。3小時後，添加CH2Cl2(3 mL)，再添加氯甲酸4-硝基苯酯，且在室溫下攪拌反應物。再過2小時後，添加含33%甲胺之EtOH(896 μl，7.14 mmol)，且在室溫下攪拌隔夜。將反應物分配於水與CH2Cl2之間，萃取(×2)，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含0%至2% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之1-(5-溴-4-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(90.1 mg，0.267 mmol，74.9%產率)。質譜(apci)m/z=337.0,339.0(M+H)。 Step E : Dissolve 5-bromo-4-(2-methylpyridin-3-yloxy)pyridin-2-amine (100 mg, 0.357 mmol) in THF (3 mL) and add pyridine (86.4 μl , 1.07 mmol) and 4-nitrophenyl chloroformate (144 mg, 0.714 mmol), and stirred at room temperature. After 3 hours, CH 2 Cl 2 (3 mL) was added and then 4-nitrophenyl chloroformate was added and the mixture was stirred at room temperature. After a further 2 hours, EtOH (896 μl, 7.14 mmol) containing EtOAc (EtOAc) The reaction was partitioned between water and CH 2 Cl 2, extracted (× 2), dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) 3-methylurea (90.1 mg, 0.267 mmol, 74.9% yield). Mass spectrum (apci) m/z = 337.0, 339.0 (M+H).

遵循實例1中之程序，製備以下化合物： Following the procedure in Example 1, the following compounds were prepared:

實例3Example 3

1-(5-苄基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-benzyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(50 mg，0.140 mmol)及Cs2CO3(136 mg，0.419 mmol)溶解於DMF(1.5 mL)及水(0.15 mL)中且用N2淨化。添加9-苄基-9-硼雙環[3.3.1]壬烷(838 μl，0.419 mmol)及PdCl2(dppf)．CH2Cl2(11.4 mg，0.0140 mmol)，且加熱反應物至60℃，維持45分鐘。冷卻反應物至室溫，分配於EtOAc與水之間，用鹽水洗滌，經Na2SO4乾燥，過濾並濃縮，且在矽膠上(含80% EtOAc之己烷)純化，得到呈白色固體狀之1-(5-苄基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(34.2 mg，0.0926 mmol，66.3%產率)。質譜(apci)m/z=370.1(M+H)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (50 mg, 0.140 mmol) and Cs 2 CO 3 (136 mg, 0.419 mmol) was dissolved in DMF (1.5 mL) and water (0.15 mL) and purged with the N 2. Add 9-benzyl-9-borobicyclo[3.3.1]nonane (838 μl, 0.419 mmol) and PdCl 2 (dppf). CH 2 Cl 2 (11.4 mg, 0.0140 mmol), and the reaction was heated to 60 ° C for 45 min. The reaction was cooled to rt, partitioned between EtOAc and water, washed with brine, dried over Na 2 SO 4, filtered and concentrated on silica gel and (80% EtOAc in hexanes's) to give a white solid 1-(5-Benzyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (34.2 mg, 0.0926 mmol, 66.3% yield). Mass spectrum (apci) m/z = 370.1 (M+H).

實例4Example 4

1-(4-(2,6-二氟苯氧基)-6'-甲基-3,3'-聯吡啶-6-基)-3-甲基脲鹽酸鹽 1-(4-(2,6-difluorophenoxy)-6'-methyl-3,3'-bipyridin-6-yl)-3-methylurea hydrochloride

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(50 mg，0.140 mmol)及6-甲基吡啶-3-基酸(38.2 mg，0.279 mmol)溶解於MeOCH2CH2OMe(2 mL)中，且添加2 M Na2CO3(209 μl，0.419 mmol)，且使氮氣鼓泡通過反應物，持續5分鐘。添加Pd(PPh3)4(32.3 mg，0.0279 mmol)，且加熱反應物至75℃隔夜。冷卻反應物至室溫，分配於水與EtOAc之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含2% MeOH之EtOAc)純化殘餘物，得到粗產物。將殘餘物溶解於 CH2Cl2中，添加含1 M HCl之Et2O(200 μL)且濃縮。將殘餘物溶解於少量CH2Cl2中且逐滴添加至劇烈攪拌之乙醚中，接著過濾，得到呈白色固體狀之1-(4-(2,6-二氟苯氧基)-6'-甲基-3,3'-聯吡啶-6-基)-3-甲基脲鹽酸鹽(25.9 mg，0.0637 mmol，45.6%產率)。質譜(apci)m/z=371.2(M+H-HCl)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (50 mg, 0.140 mmol) and 6-methylpyridin-3-yl Acid (38.2 mg, 0.279 mmol) was dissolved in MeOCH 2 CH 2 OMe (2 mL ) , and the added 2 M Na 2 CO 3 (209 μl, 0.419 mmol), and nitrogen was bubbled through the reaction for 5 minutes. Pd(PPh 3 ) 4 (32.3 mg, 0.0279 mmol) was added and the reaction was heated to 75 ° C overnight. The reaction was cooled to rt, partitioned between water and EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) The residue was dissolved in CH 2 Cl 2, was added Et 1 M HCl containing the 2 O (200 μL) and concentrated. The residue was dissolved in a small amount of CH 2 Cl 2 and added dropwise to vigorously stirring of diethyl ether, followed by filtration to give a white solid of 1- (4- (2,6-difluorophenoxy) -6 'Methyl-3,3'-bipyridin-6-yl)-3-methylurea hydrochloride (25.9 mg, 0.0637 mmol, 45.6% yield). Mass spectrum (apci) m/z = 371.2 (M+H-HCl).

實例5Example 5

1-甲基-3-(4-(2-甲基吡啶-3-基氧基)吡啶-2-基)脲 1-methyl-3-(4-(2-methylpyridin-3-yloxy)pyridin-2-yl)urea

步驟A：將NaH(1.07 g，42.3 mmol)溶解於DMF(25 mL)中，且緩慢添加3-羥基-2-甲基吡啶(4.40 g，40.3 mmol)並攪拌1小時。添加2-氯-4-硝基吡啶(6.71 g，42.3 mmol)，且攪拌反應物。將反應物分配於水與EtOAc之間，用水(1.5 L)洗滌，經Na2SO4乾燥，過濾且濃縮，得到呈黃色固體狀之2-氯-4-(2-甲基吡啶-3-基氧基)吡啶(8.0 g，89.9%產率)。 Step A : NaH (1.07 g, 42.3 mmol) was dissolved in DMF <RTI ID=0.0>(25</RTI><RTIgt; 2-Chloro-4-nitropyridine (6.71 g, 42.3 mmol) was added and the reaction was stirred. The reaction was partitioned between water and EtOAc, washed with water (1.5 L), dried over Na 2 SO 4, filtered and concentrated to give a yellow solid of 2-chloro-4- (2-methyl-3 Alkoxy)pyridine (8.0 g, 89.9% yield).

步驟B：將3-(2-氯吡啶-4-基氧基)-2-甲基吡啶(0.250 g，1.13 mmol)、1-甲基脲(0.101 g，1.36 mmol)及K3PO4(0.361 g，1.70 mmol)於2 ml DME中組合且用N2充氣5分鐘，隨後添加Pd2(dba)3(0.0519 g，0.0566 mmol)及5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑(0.115 g，0.227 mmol)，且將反應物再次用N2充氣5分鐘，隨後將其密封且加熱至90℃，維持3天。冷卻反應物且用CH2Cl2(75 mL)稀釋並過濾。濃縮濾液且在矽膠上(100% EtOAc)純化，得到1-甲基-3-(4-(2-甲基吡啶-3-基氧基)吡啶-2-基)脲(0.142 g，0.550 mmol，48.5%產率)。質譜(apci)m/z=259.1(M+H)。 Step B : 3-(2-Chloropyridin-4-yloxy)-2-methylpyridine (0.250 g, 1.13 mmol), 1-methylurea (0.101 g, 1.36 mmol) and K 3 PO 4 ( 0.361 g, 1.70 mmol) was combined in 2 ml DME and aerated with N 2 for 5 min, then Pd 2 (dba) 3 (0.0519 g, 0.0566 mmol) and 5-(di-t-butylphosphino)-1' , 3',5'-triphenyl-1 'H-1,4'-bipyrazole (0.115 g, 0.227 mmol), and the reaction was again inflated with N 2 for 5 minutes, then sealed and heated to 90 ° C, maintained for 3 days. The reaction was cooled and diluted with CH 2 Cl 2 (75 mL) and filtered. The filtrate was concentrated and purified on EtOAc (EtOAc EtOAc) , 48.5% yield). Mass spectrum (apci) m/z = 259.1 (M+H).

遵循實例5中之程序，在步驟B中使用5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑或1,1'-聯萘-2-基二第三丁基膦作為配位體製備以下化合物： Following the procedure in Example 5, using 5-(di-t-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole or 1,1'-Binaphthyl-2-yldi-tert-butylphosphine as a ligand to prepare the following compounds:

實例18Example 18

(R)-1-甲基-3-(4-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲 (R)-1-methyl-3-(4-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)urea

(S)-1-甲基-3-(4-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲 (S)-1-methyl-3-(4-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)urea

將1-甲基脲(1.07 g，14.4 mmol)、K3PO4(3.05 g，14.4 mmol)、1,1'-聯萘-2-基二第三丁基膦(0.382 g，0.959 mmol)及Pd2(dba)3(0.439 g，0.479 mmol)於10 mL DME中組合，用Ar充氣10分鐘，且在45℃下複合1小時，隨後添加5-(2-氯吡啶-4-基氧基)-5,6,7,8-四氫喹啉(2.5 g，9.59 mmol)，且將反應物再次用Ar充氣5分鐘，接著密封且維持於90℃下隔夜。用200 mL 1：1 CH2Cl2：EtOAc與20 mL MeOH稀釋反應物，進行音波處理，攪拌10分鐘，過濾且濃縮。在矽膠上(含80%至100% EtOAc之CH2Cl2至含3% MeOH之CH2Cl2)純化殘餘物，得到不純物質。將殘餘物溶解於CH2Cl2(約15 mL)中且用65 mL Et2O稀釋。添加己烷(20 mL)，且對溶液進行音波處理20分鐘，且過濾所得固體並乾燥，得到外消旋物質。藉由對掌性層析(管柱：OJH 20 mm×250 mm，流動速率：65 mL/min，含10% EtOH之超臨界CO2)分離外消旋物質，得到兩種對映異構體。對於第一溶離峰，質譜(apci)m/z=299.1(M+H)；且對於第二溶離峰，m/z=299.0(M+H)。 1-methylurea (1.07 g, 14.4 mmol), K 3 PO 4 (3.05 g, 14.4 mmol), 1,1'-binaphthalen-2-yldibutylphosphine (0.382 g, 0.959 mmol) And Pd 2 (dba) 3 (0.439 g, 0.479 mmol) were combined in 10 mL DME, aerated with Ar for 10 minutes, and compounded at 45 ° C for 1 hour, followed by the addition of 5-(2-chloropyridin-4-yloxy) 5,6,7,8-tetrahydroquinoline (2.5 g, 9.59 mmol), and the reaction was again inflated with Ar for 5 min, then sealed and maintained at 90 ° C overnight. With 200 mL 1: 1 CH 2 Cl 2: EtOAc 20 mL MeOH and the reaction was diluted with sonication performed, stirred for 10 minutes, filtered and concentrated. On silica gel (containing CH 80% to 100% EtOAc to a solution of 2 Cl 2 CH 3% MeOH of 2 Cl 2) The residue was purified to afford impure material. The residue was dissolved in CH 2 Cl 2 (about 15 mL) was diluted with 65 mL Et 2 O, and in. Hexane (20 mL) was added, and the solution was sonicated for 20 minutes, and the obtained solid was filtered and dried to give a racemic substance. Separation of racemic materials by palm chromatography (column: OJH 20 mm x 250 mm, flow rate: 65 mL/min, supercritical CO 2 with 10% EtOH) gave two enantiomers . For the first elution peak, mass spectrum (apci) m/z = 299.1 (M+H); and for the second elution peak, m/z = 299.0 (M+H).

實例19Example 19

1-(4-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(4-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

步驟A：將1-甲基脲(0.584 g，7.88 mmol)、K3PO4(2.01 g，9.46 mmol)、1,1'-聯萘-2-基二第三丁基膦(0.251 g，0.631 mmol)、Pd2(dba)3(0.289 g，0.315 mmol)組合，且將容器抽真空並用Ar回填， 隨後添加6 mL DME，且將反應物充氣15分鐘，隨後密封反應物，接著在45℃下攪拌1小時。添加2-氯-4-硝基吡啶(1.00 g，6.31 mmol)，且將反應物用Ar充氣5分鐘，隨後密封反應物且加熱至90℃隔夜。用1：1 EtOAc：CH2Cl2(150 mL)及20 mL MeOH稀釋反應物，接著音波處理5分鐘且過濾。在真空中濃縮濾液且在矽膠上(含25% EtOAc之CH2Cl2)純化殘餘物，得到呈黃橙色固體狀之1-甲基-3-(4-硝基吡啶-2-基)脲(0.813 g，4.14 mmol，65.7%產率)。 Step A : 1-methylurea (0.584 g, 7.88 mmol), K 3 PO 4 (2.01 g, 9.46 mmol), 1,1'-binaphthalen-2-yldibutylphosphine (0.251 g, 0.631 mmol), Pd 2 (dba) 3 (0.289 g, 0.315 mmol) combination, and the vessel was evacuated and backfilled with Ar, then 6 mL of DME was added and the reaction was aerated for 15 minutes, then the reaction was sealed, then at 45 Stir at ° C for 1 hour. 2-Chloro-4-nitropyridine (1.00 g, 6.31 mmol) was added, and the reaction was stirred with Ar for 5 min then the mixture was sealed and warmed to <RTIgt; With 1: 1 EtOAc: CH 2 Cl 2 (150 mL) and the reaction was diluted with 20 mL MeOH followed by sonication 5 minutes and filtered. The filtrate was concentrated in vacuo and the on silica (containing the CH 25% EtOAc 2 Cl 2) Purification of the residue, to give a yellow-orange solid of 1-methyl-3- (4-nitro-pyridin-2-yl) urea (0.813 g, 4.14 mmol, 65.7% yield).

步驟B：在2 mL DMF中組合2-乙基吡啶-3-醇(0.0942 g，0.765 mmol)及NaH(0.0306 g，0.765 mmol)。在室溫下攪拌此混合物30分鐘。冷卻反應物至0℃，接著添加1-甲基-3-(4-硝基吡啶-2-基)脲(0.150 g，0.765 mmol)，且在70℃下攪拌反應物隔夜。在室溫下，於攪拌下，將反應物緩慢添加至40 mL水中。用固體NaCl使水層飽和，接著用EtOAc(2×50 mL)萃取，經MgSO4乾燥，過濾且濃縮。在矽膠上(1：1 EtOAc：CH2Cl2)純化殘餘物，得到1-(4-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.076 g，0.279 mmol，36.5%產率)。質譜(apci)m/z=273.1(M+H)。 Step B : 2-Ethylpyridin-3-ol (0.0942 g, 0.765 mmol) and NaH (0.0306 g, 0.765 mmol) were combined in 2 mL DMF. The mixture was stirred at room temperature for 30 minutes. The reaction was cooled to 0.degree. C. then 1-methyl-3-(4-nitropyridin-2-yl)urea (0.150 g, 0.765 mmol). The reaction was slowly added to 40 mL of water with stirring at room temperature. With solid NaCl aqueous layer was saturated, then extracted with EtOAc (2 × 50 mL), dried over MgSO 4, filtered and concentrated. On silica gel (1: 1 EtOAc: CH 2 Cl 2) The residue was purified to give 1- (4- (2-ethyl-3-yloxy) pyridin-2-yl) -3-methyl-urea ( 0.076 g, 0.279 mmol, 36.5% yield). Mass spectrum (apci) m/z = 273.1 (M + H).

遵循實例19中之程序，製備以下化合物： Following the procedure in Example 19, the following compounds were prepared:

實例56Example 56

1-(5-溴-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea

將1-甲基-3-(4-(喹啉-5-基氧基)吡啶-2-基)脲(1.24 g，4.21 mmol)溶解於40 mL DMF中且冷卻至0℃，隨後以一整份添加NBS(0.750 g，4.21 mmol)，且在4℃下攪拌隔夜，接著在室溫下攪拌6小時。添加水(150 mL)及飽和NaHCO3(50 mL)，且經由真空過濾收集所形成之固體，用Et2O(50 mL)洗滌並在真空烘箱中乾燥，得到1-(5-溴-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(1.18 g，3.16 mmol，75.0%產率)。質譜(apci)m/z=372.9,374.9(M+H)。 1-Methyl-3-(4-(quinolin-5-yloxy)pyridin-2-yl)urea (1.24 g, 4.21 mmol) was dissolved in 40 mL DMF and cooled to 0 ° C then NBS (0.750 g, 4.21 mmol) was added in portions and stirred at 4 ° C overnight, then stirred at room temperature for 6 hours. Water (150 mL) and saturated NaHCO 3 (50 mL), and the solid formed was collected by vacuum filtration, (50 mL) and washed with Et 2 O and dried in a vacuum oven, to give 1- (5-bromo-4 -(Quinoline-5-yloxy)pyridin-2-yl)-3-methylurea (1.18 g, 3.16 mmol, 75.0% yield). Mass spectrum (apci) m/z = 372.9, 374.9 (M+H).

遵循實例56中之程序，製備以下化合物： Following the procedure in Example 56, the following compounds were prepared:

實例69Example 69

6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸鹼酸乙酯 Ethyl 6-(3-methylureido)-4-(quinolin-5-yloxy)nicotinate

步驟A：在35 mL DMF中組合喹啉-5-醇(5.0 g，34.4 mmol)及NaH (1.45 g，36.2 mmol)，且在室溫下攪拌1.5小時，隨後冷卻反應物至0℃，且緩慢添加4,6-二氯菸鹼酸乙酯(7.58 g，34.4 mmol)。在0℃下攪拌反應物4小時且升溫至室溫隔夜。用1：1飽和NaHCO3：水(300 mL)稀釋反應物且用EtOAc(3×250 mL)萃取。用水(200 mL)、鹽水(200 mL)洗滌經合併之有機物，經MgSO4乾燥，過濾且濃縮。在矽膠上(含10% EtOAc之CH2Cl2)純化殘餘物，得到6-氯-4-(喹啉-5-基氧基)菸鹼酸乙酯(9.09 g，23.8 mmol，69.0%產率)與4-氯-6-(喹啉-5-基氧基)菸鹼酸乙酯之10：1混合物。 Step A : Quinoline-5-ol (5.0 g, 34.4 mmol) and NaH (1.45 g, 36.2 mmol) were combined in 35 mL DMF and stirred at room temperature for 1.5 h then cooled to 0 ° C and Ethyl 4,6-dichloronicotinic acid (7.58 g, 34.4 mmol) was added slowly. The reaction was stirred at 0 °C for 4 h and warmed to rt overnight. Water (300 mL) and the reaction was diluted (3 × 250 mL) and extracted with EtOAc in: with 1: 1 saturated NaHCO 3. Washed with water (200 mL), brine (200 mL) The combined organics were washed, dried over MgSO 4, filtered and concentrated. On silica gel (containing the CH 10% EtOAc 2 Cl 2) Purification of the residue to give 6-chloro-4- (quinolin-5-yloxy) nicotinic acid ethyl ester (9.09 g, 23.8 mmol, 69.0 % yield Rate) a 10:1 mixture with 4-chloro-6-(quinolin-5-yloxy)nicotinic acid ethyl ester.

步驟B：將1-甲基脲(0.282 g，3.80 mmol)、K3PO4(0.969 g，4.56 mmol)、1,1'-聯萘-2-基二第三丁基膦(0.121 g，0.304 mmol)及Pd2(dba)3(0.139 g，0.152 mmol)於5 mL DME中組合，且用Ar充氣15分鐘並在55℃下攪拌1小時。此後，添加6-氯-4-(喹啉-5-基氧基)菸鹼酸乙酯(1.0 g，3.04 mmol)，且將反應物用Ar充氣5分鐘，隨後將其密封且加熱至90℃經週末。冷卻反應物且用1：1 EtOAc：CH2Cl2(100 mL)稀釋，進行音波處理，過濾並在真空中濃縮。在矽膠上(含75% EtOAc之CH2Cl2)純化殘餘物，得到6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸鹼酸乙酯(0.286 g，0.781 mmol，25.7%產率)。質譜(apci)m/z=367.0(M+H)。 Step B : 1-methylurea (0.282 g, 3.80 mmol), K 3 PO 4 (0.969 g, 4.56 mmol), 1,1'-binaphthalen-2-yldibutylphosphine (0.121 g, 0.304 mmol) and Pd 2 (dba) 3 (0.139 g, 0.152 mmol) were combined in 5 mL DME and was agitated with Ar for 15 min and stirred at 55 ° C for 1 hour. Thereafter, 6-chloro-4-(quinolin-5-yloxy)nicotinic acid ethyl ester (1.0 g, 3.04 mmol) was added, and the reaction was inflated with Ar for 5 min, then sealed and heated to 90. °C by the weekend. CH 2 Cl 2 (100 mL) was diluted, for sonication, filtered and concentrated in vacuo: The reaction was cooled and treated with 1: 1 EtOAc. On silica gel (containing the CH 75% EtOAc 2 Cl 2) The residue was purified to give 6- (3-methyl-ureido) -4- (quinolin-5-yloxy) nicotinic acid ethyl ester (0.286 g , 0.781 mmol, 25.7% yield). Mass spectrum (apci) m/z = 367.0 (M+H).

實例70Example 70

4-甲基-3-(2-(3-甲基脲基)吡啶-4-基氧基)苯甲酸 4-methyl-3-(2-(3-methylureido)pyridin-4-yloxy)benzoic acid

將4-甲基-3-(2-(3-甲基脲基)吡啶-4-基氧基)苯甲酸乙酯(0.200 g， 0.607 mmol)溶解於2 mL 1：1 MeOH：THF中，且在室溫下向其中添加2 M NaOH(1.52 ml，3.04 mmol)，且在室溫下攪拌此物質隔夜。濃縮反應物，接著將所得固體溶解於水中，且將pH值調整至約3-4。經由真空過濾收集所得固體且用Et2O洗滌。用Et2O濕磨固體且經由真空過濾收集固體，得到4-甲基-3-(2-(3-甲基脲基)吡啶-4-基氧基)苯甲酸(150 mg，80.3%產率)。質譜(apci)m/z=302.0(M+H)。 Ethyl 4-methyl-3-(2-(3-methylureido)pyridin-4-yloxy)benzoate (0.200 g, 0.607 mmol) was dissolved in 2 mL 1:1 MeOH:THF. 2 M NaOH (1.52 ml, 3.04 mmol) was added thereto at room temperature, and the mixture was stirred overnight at room temperature. The reactants were concentrated, then the resulting solid was dissolved in water and the pH was adjusted to about 3-4. The resulting solid was collected and washed with Et 2 O filtered through vacuo. And the solid was collected solid was triturated with Et 2 O via vacuum filtration to give 4-methyl-3- (2- (3-methyl-ureido) pyridin-4-yloxy) benzoic acid (150 mg, 80.3% yield rate). Mass spectrum (apci) m/z = 302.0 (M+H).

遵循實例70中之程序，製備以下化合物： Following the procedure in Example 70, the following compounds were prepared:

實例72Example 72

N-(2-甲氧基乙基)-N-甲基-6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸鹼醯胺 N-(2-methoxyethyl)-N-methyl-6-(3-methylureido)-4-(quinolin-5-yloxy)nicotinate

步驟A：將6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸鹼酸乙酯(0.250 g，0.682 mmol)溶解於THF(3 mL)中，且向反應物中緩慢添加2 M NaOH(1.02 ml，2.05 mmol)。攪拌反應物隔夜。濃縮反應物且用2 mL水稀釋，且向其中添加濃鹽酸直至pH值達到3-4。過濾固體且乾燥，得到6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸鹼酸(0.242 g，0.715 mmol，105%產率)。 Step A : Ethyl 6-(3-methylureido)-4-(quinolin-5-yloxy)nicotinate (0.250 g, 0.682 mmol) was dissolved in THF (3 mL) 2 M NaOH (1.02 ml, 2.05 mmol) was slowly added to the reaction. The reaction was stirred overnight. The reaction was concentrated and diluted with 2 mL of water, and concentrated hydrochloric acid was added to pH 3-4. The solid was filtered and dried to give 6-(3-methylureido)-4-(quinolin-5-yloxy)nicotinic acid (0.242 g, 0.715 mmol, 105% yield).

步驟B：在1 mL DMF中組合6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸 鹼酸(0.050 g，0.15 mmol)、HOBT-H2O(0.011 g，0.074 mmol)及EDCI(0.034 g，0.18 mmol)，且攪拌此物質2分鐘，隨後添加2-甲氧基-N-甲基乙胺(0.016 g，0.18 mmol)，且攪拌反應物4小時。濃縮反應物且在矽膠上(含1% MeOH之EtOAc)純化，得到N-(2-甲氧基乙基)-N-甲基-6-(3-甲基脲基)-4-(喹啉-5-基氧基)菸鹼醯胺(0.039 g，0.095 mmol，64%產率)。質譜(apci)m/z=410.0(M+H)。 Step B : Combination of 6-(3-methylureido)-4-(quinolin-5-yloxy)nicotinic acid (0.050 g, 0.15 mmol), HOBT-H 2 O (0.011) in 1 mL DMF g, 0.074 mmol) and EDCI (0.034 g, 0.18 mmol), and the material was stirred for 2 min then 2-methoxy-N-methylethylamine (0.016 g, 0.18 mmol). . The reaction was concentrated and purified on EtOAc (EtOAc EtOAcEtOAc) Porphyrin-5-yloxy)nicotinium amide (0.039 g, 0.095 mmol, 64% yield). Mass spectrum (apci) m/z = 410.0 (M+H).

遵循實例72中之程序，製備以下化合物： Following the procedure in Example 72, the following compounds were prepared:

實例74Example 74

N-(2-甲氧基乙基)-N,4-二甲基-3-(2-(3-甲基脲基)吡啶-4-基氧基)苄醯胺鹽酸鹽 N-(2-methoxyethyl)-N,4-dimethyl-3-(2-(3-methylureido)pyridin-4-yloxy)benzylamine hydrochloride

在室溫下，於1 mL DMF中組合4-甲基-3-(2-(3-甲基脲基)吡啶-4-基氧基)苯甲酸(0.025 g，0.083 mmol)、HOBT-H2O(0.019 g，0.12 mmol)及EDCI(0.019 g，0.100 mmol)且攪拌1分鐘，隨後添加2-甲氧基-N-甲基乙胺(0.015 g，0.17 mmol)且攪拌3小時。用水(10 mL)稀釋反應物且固體沈下(crash out)。攪拌反應物10分鐘，且經由真空過濾收集固體並用極少量水洗滌。將固體溶解於MeOH(1 mL)中，接著添 加含4 M HCl之二噁烷(3滴)，接著濃縮此溶液。將固體溶解於極少量CH2Cl2中，且向其中緩慢添加Et2O直至觀測到固體，再添加Et2O(總體積約10 mL)。經由真空過濾收集固體且用Et2O洗滌，獲得N-(2-甲氧基乙基)-N,4-二甲基-3-(2-(3-甲基脲基)吡啶-4-基氧基)苄醯胺鹽酸鹽(0.016 g，0.039 mmol，47%產率)。質譜(apci)m/z=373.1(M+H-HCl)。 4-methyl-3-(2-(3-methylureido)pyridin-4-yloxy)benzoic acid (0.025 g, 0.083 mmol), HOBT-H in 1 mL DMF at room temperature 2 O (0.019 g, 0.12 mmol ) and EDCI (0.019 g, 0.100 mmol) and stirred for 1 minute, followed by addition of 2-methoxy -N- methyl-ethylamine (0.015 g, 0.17 mmol) and stirred for 3 hours. The reaction was diluted with water (10 mL) and the solid was evaporated. The reaction was stirred for 10 min and the solid was collected via vacuum filtered and washed with water. The solid was dissolved in MeOH (1 mL) then EtOAc (3 mL). The solid was dissolved in a very small amount of CH 2 Cl 2 and Et 2 O was slowly added thereto until a solid was observed, and then Et 2 O (total volume of about 10 mL) was added. The solid was collected via vacuum filtration and washed with 2 O Et to give N- (2- methoxyethyl) -N, 4- dimethyl-3- (2- (3-methyl-ureido) pyridin-4 Benzyl)benzylguanamine hydrochloride (0.016 g, 0.039 mmol, 47% yield). Mass spectrum (apci) m/z = 373.1 (M+H-HCl).

遵循實例74中之程序，製備以下化合物： Following the procedure in Example 74, the following compounds were prepared:

實例78Example 78

1-(4-(2,6-二氟苯氧基)-5-(嘧啶-5-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(pyrimidin-5-yl)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.14 mmol)、嘧啶-5-基酸(0.035 g，0.28 mmol)及K2CO3(0.21 ml，0.42 mmol)於2 mL DME中組合且用N2充氣10分鐘，隨後添加Pd(PPh3)4(0.032 g，0.028 mmol)，且將反應物再次充氣5分鐘，隨後將其密封且加熱至80℃隔夜。冷卻反應物，且用1：1 EtOAc：CH2Cl2(50 mL)稀釋並過濾。濃縮濾液且在矽膠上(含25%至80% EtOAc之CH2Cl2)純化，得到1-(4-(2,6-二氟苯氧基)-5-(嘧啶-5-基)吡啶-2-基)-3-甲基脲(0.012 g，0.034 mmol，24%產率)。質譜(apci)m/z=358.0(M+H)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.050 g, 0.14 mmol), pyrimidin-5-yl Acid (0.035 g, 0.28 mmol) and K 2 CO 3 (0.21 ml, 0.42 mmol) were combined in 2 mL DME and treated with N 2 the inflator 10 minutes, followed by addition of Pd (PPh 3) 4 (0.032 g, 0.028 mmol), The reaction was again inflated for 5 minutes, then sealed and heated to 80 °C overnight. CH 2 Cl 2 (50 mL) was diluted and filtered: The reaction was cooled, and washed with 1: 1 EtOAc. The filtrate was concentrated on silica gel (containing CH 25% to 80% EtOAc of 2 Cl 2) to give 1- (4- (2,6-difluorophenyl) -5- (pyrimidin-5-yl) pyridine 2-yl)-3-methylurea (0.012 g, 0.034 mmol, 24% yield). Mass spectrum (apci) m/z = 358.0 (M+H).

遵循實例78中之程序，製備以下化合物： Following the procedure in Example 78, the following compounds were prepared:

實例106Example 106

1-(4-((1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基)氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-((1,4-Dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl)oxy)-5-(1-methyl-1H-pyrazole) -5-yl)pyridin-2-yl)-3-methylurea

步驟1：遵循實例56中之程序且以1-(4-(1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.230 g，0.680 mmol)為起始物，合成1-(5-溴-4-((1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基)氧基)吡啶-2-基)-3-甲基脲(0.220 g，0.422 mmol，62.1%產率)。 Step 1 : Following the procedure in Example 56 and using 1-(4-(1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy)pyridine-2- Synthesis of 1-(5-bromo-4-((1,4-dimethyl-2-oxo-oxyl-1,2-)-based 3-methylurea (0.230 g, 0.680 mmol) Dihydroquinolin-6-yl)oxy)pyridin-2-yl)-3-methylurea (0.220 g, 0.422 mmol, 62.1% yield).

步驟2：遵循實例78中之程序且以1-(5-溴-4-(1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.12 mmol)為起始物，合成1-(4-(1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.014 g，0.033 mmol，27%產率)。(apci)m/z=419.2(M+H)。 Step 2 : Following the procedure in Example 78 and using 1-(5-bromo-4-(1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy) Pyridin-2-yl)-3-methylurea (0.050 g, 0.12 mmol) was used as starting material to synthesize 1-(4-(1,4-dimethyl-2-oxooxy-1,2-di) Hydroquinolin-6-yloxy)-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea (0.014 g, 0.033 mmol, 27% yield) rate). (apci) m/z = 419.2 (M+H).

實例107Example 107

1-甲基-3-(5-(1-甲基-1H-咪唑-5-基)-4-(喹啉-5-基氧基)吡啶-2-基)脲 1-methyl-3-(5-(1-methyl-1H-imidazol-5-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)urea

將1-(5-溴-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.125 g，0.335 mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-咪唑(0.139 g，0.670 mmol)及K2CO3(0.670 ml，1.34 mmol)於2 mL二噁烷中組合且用Ar充氣2分鐘，隨後添加Pd(PPh3)4(0.0387 g，0.0335 mmol)。將反應物充氣5分鐘，密封，且加熱至90℃隔夜。向反應物中添加1-甲 基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-咪唑(0.139 g，0.670 mmol)、Pd2dba3(0.0153 g，0.0167 mmol)及XPHOS(0.0160 g，0.0335 mmol)，且將反應物充氣5分鐘，隨後密封，且加熱至95℃，維持2天。冷卻反應物至室溫，用CH2Cl2稀釋，且在矽膠上(含5% MeOH之CH2Cl2 w/0.5% NH4OH)純化，得到1-甲基-3-(5-(1-甲基-1H-咪唑-5-基)-4-(喹啉-5-基氧基)吡啶-2-基)脲(0.055 g，0.140 mmol，41.7%產率)。質譜(apci)m/z=375.0(M+H)。 1-(5-Bromo-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea (0.125 g, 0.335 mmol), 1-methyl-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-imidazole (0.139 g, 0.670 mmol) and K 2 CO 3 (0.670 ml, 1.34 mmol) were combined in 2 mL of dioxane and inflated with Ar for 2 min, then Pd(PPh 3 ) was added 4 (0.0387 g, 0.0335 mmol). The reaction was aerated for 5 minutes, sealed and heated to 90 °C overnight. Add 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborate to the reaction 2-yl)-1H-imidazole (0.139 g, 0.670 mmol), Pd 2 dba 3 (0.0153 g, 0.0167 mmol) and XPHOS (0.0160 g, 0.0335 mmol), and the reaction was inflated for 5 minutes, then sealed, and Heat to 95 ° C for 2 days. The reaction was cooled to room temperature, Cl 2 and diluted with CH 2, and purified on silica gel (CH 5% MeOH containing of 2 Cl 2 w / 0.5% NH 4 OH), to give 1-methyl-3- (5- ( 1-Methyl-1H-imidazol-5-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)urea (0.055 g, 0.140 mmol, 41.7% yield). Mass spectrum (apci) m/z = 375.0 (M+H).

遵循實例107中之程序，製備以下化合物： Following the procedure in Example 107, the following compounds were prepared:

實例109Example 109

3-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯 Methyl 3-(6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-ylthio)propanoate

在5 mL二噁烷中組合1-(5-溴-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.500 g，1.340 mmol)、3-巰基丙酸甲酯(0.3629 ml，3.349 mmol)、DIEA(0.9334 ml，5.359 mmol)、Pd2dba3(0.1227 g，0.1340 mmol)及Xantphos(0.1550 g，0.2679 mmol)。將此混合物用Ar充氣15分鐘，隨後將其密封且加熱至100℃隔夜。將反應物傾倒至EtOAc(150 mL)及水(50 mL)中且劇烈震盪，經MgSO4乾燥，過濾且濃縮。在 高真空下乾燥所得殘餘物，接著用2：1：1 CH2Cl2：EtOAc：Et2O濕磨，得到呈白色固體狀之3-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯(0.404 g，0.9795 mmol，73.11%產率)。質譜(apci)m/z=413.0(M+H)。 Combining 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea (0.500 g, 1.340 mmol), 3-mercapto group in 5 mL of dioxane Methyl propionate (0.3629 ml, 3.349 mmol), DIEA (0.9334 ml, 5.359 mmol), Pd 2 dba 3 (0.1227 g, 0.1340 mmol) and Xantphos (0.1550 g, 0.2679 mmol). The mixture was inflated with Ar for 15 minutes, then sealed and heated to 100 ° C overnight. The reaction was poured into EtOAc (150 mL) and water (50 mL) and shaken vigorously in, dried over MgSO 4, filtered and concentrated. The resultant was dried under high vacuum the residue, followed by 2: 1: 1 CH 2 Cl 2: EtOAc: Et 2 O triturated to give a white solid of 3- (6- (3-methyl-ureido) -4 Methyl (quinolin-5-yloxy)pyridin-3-ylthio)propanoate (0.404 g, 0.9795 mmol, 73.11% yield). Mass spectrum (apci) m/z = 413.0 (M+H).

遵循實例109中之程序，使用適當起始物質製備以下化合物： Following the procedure in Example 109, the following compounds were prepared using the appropriate starting materials:

實例118Example 118

1-(5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(3-methoxypropylthio)-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea

將3-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯 (0.075 g，0.18 mmol)懸浮於1 ml THF中，隨後使Ar鼓泡通過1分鐘。添加含1 M KOtBu之THF(0.55 ml，0.55 mmol)，且攪拌反應物30秒，隨後添加1-溴-3-甲氧基丙烷(0.042 g，0.27 mmol)。30分鐘後，用CH2Cl2稀釋反應物，且向其中添加約0.25 mL MeOH且所有固體均溶解。在矽膠上(含1：1 EtOAc：CH2Cl2至75% EtOAc之CH2Cl2 w/0.5% MeOH)純化此物質，得到1-(5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.038 g，0.093 mmol，51%產率)。質譜(apci)m/z=399.0(M+H)。 Methyl 3-(6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-ylthio)propanoate (0.075 g, 0.18 mmol) was suspended in 1 ml In THF, Ar was then bubbled through for 1 minute. 1 M KOtBu in THF (0.55 ml, 0.55 mmol) was added and the mixture was stirred for 30 s then then 1-bromo-3-methoxypropane (0.042 g, 0.27 mmol). After 30 min, diluted with CH 2 Cl reactants, and from about 0.25 mL MeOH was added thereto and all solids were dissolved. On silica gel (with 1: 1 EtOAc: 2 Cl 2 to 75% CH EtOAc of CH 2 Cl 2 w / 0.5% MeOH) This material was purified to give 1- (5- (3-methoxy-propylthio) - 4-(Quinolin-5-yloxy)pyridin-2-yl)-3-methylurea (0.038 g, 0.093 mmol, 51% yield). Mass spectrum (apci) m/z = 399.0 (M+H).

遵循實例118中之程序，製備以下化合物： Following the procedure in Example 118, the following compounds were prepared:

實例124Example 124

1-(5-(3-甲氧基丙硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(3-methoxypropylthio)-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea

步驟A：遵循實例118中之程序且以1-(5-溴-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.500 g，1.340 mmol)為起始物，合成3-(6-(3-甲基脲基)-4-(喹啉-6-基氧基)吡啶-3-基硫基)丙酸甲酯(0.518 g，1.218 mmol，90.93%產率)。 Step A : Following the procedure in Example 118 and using 1-(5-bromo-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea (0.500 g, 1.340 mmol) Starting material, methyl 3-(6-(3-methylureido)-4-(quinolin-6-yloxy)pyridin-3-ylthio)propanoate (0.518 g, 1.218 mmol, 90.93% yield).

步驟B：將3-(6-(3-甲基脲基)-4-(喹啉-6-基氧基)吡啶-3-基硫基)丙酸甲酯(0.150 g，0.364 mmol)懸浮於1 mL THF中且用Ar充氣2分鐘，隨後添加含1 M 2-甲基丙-2-醇鉀之THF(1.09 ml，1.09 mmol)且繼續充氣30秒，隨後添加含1-溴-3-甲氧基丙烷(0.0835 g，0.546 mmol)之0.5 mL THF。1.5小時後反應完成且用CH2Cl2稀釋，且在矽膠上(含95% EtOAc之CH2Cl2)純化，得到1-(5-(3-甲氧基丙硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.102 g，0.246 mmol，67.6%產率)。質譜(apci)m/z=399.0(M+H)。 Step B : Suspension of methyl 3-(6-(3-methylureido)-4-(quinolin-6-yloxy)pyridin-3-ylthio)propanoate (0.150 g, 0.364 mmol) In 1 mL of THF and aerated with Ar for 2 min, then THF (1.09 ml, 1.09 mmol) containing 1 M 2-methylpropan-2-ol was added and the aeration was continued for 30 s. - methoxypropane (0.0835 g, 0.546 mmol) in 0.5 mL THF. After 1.5 hours the reaction was complete and was diluted with CH 2 Cl 2, and purified on silica gel (2 Cl 2 containing the CH 95% EtOAc) to give 1- (5- (3-methoxy-propyl) -4- ( Quinoline-6-yloxy)pyridin-2-yl)-3-methylurea (0.102 g, 0.246 mmol, 67.6% yield). Mass spectrum (apci) m/z = 399.0 (M+H).

遵循實例124中之程序，製備以下化合物： Following the procedure in Example 124, the following compounds were prepared:

實例127Example 127

(S)-1-(5-(4-甲氧基丁-2-基硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲 (S)-1-(5-(4-methoxybut-2-ylthio)-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea

(R)-1-(5-(4-甲氧基丁-2-基硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲 (R)-1-(5-(4-methoxybutan-2-ylthio)-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea

將3-(6-(3-甲基脲基)-4-(喹啉-6-基氧基)吡啶-3-基硫基)丙酸甲酯(0.100 g，0.242 mmol)懸浮於2 mL THF中且用Ar充氣2分鐘，隨後添加含1 M 2-甲基丙-2-醇鉀之THF(0.727 ml，0.727 mmol)，且將此物質繼續充氣約45秒，隨後添加含甲烷磺酸4-甲氧基丁-2-基酯(0.0663 g，0.364 mmol)之0.5 mL THF。接著將反應物密封於Ar下且在室溫下繼續反應。4小時後，再添加含20 mg甲磺酸酯之0.25 mL THF，且在 室溫下繼續反應隔夜。用CH2Cl2(3 mL)稀釋反應物且在矽膠上(含90% EtOAc之CH2Cl2)純化，得到外消旋物質。藉由對掌性層析(管柱：OJ 20 mm×250 mm，流動速率：65 mL/min，含10% MeOH之超臨界CO2)分離外消旋物質。對於第一溶離峰，質譜(apci)m/z=413.1(M+H)；且對於第二溶離峰，m/z=413.0(M+H)。 Methyl 3-(6-(3-methylureido)-4-(quinolin-6-yloxy)pyridin-3-ylthio)propanoate (0.100 g, 0.242 mmol) was suspended in 2 mL In THF and aerated with Ar for 2 minutes, then THF (0.727 ml, 0.727 mmol) containing 1 M 2-methylpropan-2-ol was added, and the material was further inflated for about 45 seconds, followed by the addition of methanesulfonic acid. 4-Methoxybut-2-yl ester (0.0663 g, 0.364 mmol) in 0.5 mL THF. The reaction was then sealed under Ar and the reaction was continued at room temperature. After 4 hours, another 0.25 mL of THF containing 20 mg of the mesylate was added and the reaction was continued overnight at room temperature. Diluted with CH 2 Cl 2 (3 mL) and the reaction was purified on silica gel (2 2 Cl CH 90% EtOAc containing of), to give the racemic material. The racemic material was isolated by palm chromatography (column: OJ 20 mm x 250 mm, flow rate: 65 mL/min, supercritical CO 2 with 10% MeOH). For the first elution peak, mass spectrum (apci) m/z = 413.1 (M+H); and for the second elution peak, m/z = 413.0 (M+H).

實例128Example 128

(S)-1-(5-(3,4-二羥基丁硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲 (S)-1-(5-(3,4-dihydroxybutylthio)-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea

步驟A：將3-(6-(3-甲基脲基)-4-(喹啉-6-基氧基)吡啶-3-基硫基)丙酸甲酯(0.050 g，0.12 mmol)懸浮於1.0 mL THF中且用Ar充氣1分鐘，隨後依序添加含1 M 2-甲基丙-2-醇鉀之THF(0.36 ml，0.36 mmol)、4-甲基苯磺酸(S)-2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙酯(0.055 g，0.18 mmol)。2小時後，用CH2Cl2稀釋反應物且在矽膠上(含80% EtOAc之CH2Cl2)純化，得到(S)-1-(5-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.042 g，0.084 mmol，69%產率)。 Step A : Suspension of methyl 3-(6-(3-methylureido)-4-(quinolin-6-yloxy)pyridin-3-ylthio)propanoate (0.050 g, 0.12 mmol) Into 1.0 mL of THF and aerated with Ar for 1 minute, then sequentially add THF (0.36 ml, 0.36 mmol) containing 1 M 2-methylpropan-2-ol, 4-methylbenzenesulfonic acid (S)- 2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl ester (0.055 g, 0.18 mmol). After 2 hours, diluted with CH 2 Cl 2 and the reaction was over silica gel (containing the CH 80% EtOAc 2 Cl 2) to afford (S) -1- (5- (2- (2,2- dimethyl -1,3-dioxolan-4-yl)ethylthio)-4-(quinolin-6-yloxy)pyridin-2-yl)-3-methylurea (0.042 g, 0.084 M, 69% yield).

步驟B：將(S)-1-(5-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.042 g，0.0924 mmol)溶解於1 mL MeOH中，接著向其中添加H2O(0.0832 ml，4.62 mmol)及HCl(0.0693 ml，0.277 mmol)，且在室溫下攪拌經週末。濃縮反應物且溶解於1 mL MeOH中，且向其中添加NH4OH(0.0264 ml，0.370 mmol)並再次濃縮反應物至乾燥。將固體懸浮於4：1 CH2Cl2：MeOH 中，且過濾並用Et2O洗滌，得到(S)-1-(5-(3,4-二羥基丁硫基)-4-(喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.016 g，0.0367 mmol，39.7%產率)。質譜(apci)m/z=415.0(M+H)。 Step B : (S)-1-(5-(2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethylthio)-4-(quinoline) -6-yloxy)pyridin-2-yl)-3-methylurea (0.042 g, 0.0924 mmol) was dissolved in 1 mL MeOH, then H 2 O (0.0832 ml, 4.62 mmol) and HCl ( 0.0693 ml, 0.277 mmol) and stirred at room temperature over the weekend. The reaction was concentrated and dissolved in 1 mL MeOH, and added to the NH 4 OH (0.0264 ml, 0.370 mmol) and the reaction was again concentrated to dryness. The solid was suspended in 4:1 CH 2 Cl 2 : MeOH and filtered and washed with Et 2 O to afford (S)-1-(5-(3,4-dihydroxybutylthio)-4-(quinoline) -6-yloxy)pyridin-2-yl)-3-methylurea (0.016 g, 0.0367 mmol, 39.7% yield). Mass spectrum (apci) m/z = 415.0 (M+H).

遵循實例128中之程序，製備以下化合物： Following the procedure in Example 128, the following compounds were prepared:

實例130Example 130

1-甲基-3-(5-(2-側氧基-1,2-二氫吡啶-3-基)-4-(喹啉-5-基氧基)吡啶-2-基)脲 1-methyl-3-(5-(2-o-oxy-1,2-dihydropyridin-3-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)urea

將1-(2'-甲氧基-4-(喹啉-5-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.045 g，0.112 mmol)溶解於1 ml MeCN中，且向其中添加TMS-Cl(0.0356 ml，0.280 mmol)及NaI(0.168 g，1.12 mmol)，且將此物質維持於90℃下隔夜。冷卻反應物，且用濃NH4OH稀釋並攪拌1分鐘，隨後將其傾倒至EtOAc與飽和NaHCO3之兩相混合物中。分離各相且經MgSO4乾燥，過濾並濃縮。將殘餘物溶解於含極少量MeOH之CH2Cl2中。向此物質中添加Et2O，且經由真空過濾收集固體並用Et2O洗滌，得到1-甲基-3-(5-(2-側氧基-1,2-二氫吡啶-3-基)-4-(喹啉-5-基氧基)吡 啶-2-基)脲(0.023 g，0.0594 mmol，53.0%產率)。質譜(apci)m/z=388.0(M+H)。 Dissolve 1-(2'-methoxy-4-(quinolin-5-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea (0.045 g, 0.112 mmol) To 1 ml of MeCN, TMS-Cl (0.0356 ml, 0.280 mmol) and NaI (0.168 g, 1.12 mmol) were added and the material was maintained at 90 ° C overnight. The reaction was cooled, and stirred for 1 minute and diluted with concentrated NH 4 OH, and then poured into a biphasic mixture of 3 EtOAc and saturated NaHCO of. The phases were separated and dried over MgSO 4, filtered and concentrated. The residue was dissolved in MeOH containing a very small amount of CH 2 Cl 2 in. Et 2 O was added to this material, and the solid was collected by vacuum filtration and washed with Et 2 O to give 1-methyl-3-(5-(2- </RTI> 4-(Quinolin-5-yloxy)pyridin-2-yl)urea (0.023 g, 0.0594 mmol, 53.0% yield). Mass spectrum (apci) m/z = 388.0 (M+H).

實例131Example 131

1-乙基-3-(5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基)脲 1-ethyl-3-(5-(3-methoxypropylthio)-4-(quinolin-5-yloxy)pyridin-2-yl)urea

步驟A：在室溫下，於100 mL DMF中組合60% NaH(4.085 g，102.1 mmol)及喹啉-5-醇(14.12 g，97.27 mmol)且攪拌30分鐘，隨後在室溫下緩慢添加2-氯-4-硝基吡啶(15.42 g，97.27 mmol)。在室溫下攪拌反應物隔夜。將反應物傾倒至水(300 mL)中且用EtOAc(3×300 mL)萃取。接著用1 N NaOH(100 mL)、水(2×100 mL)、鹽水(100 mL)洗滌經合併之有機物，經MgSO4乾燥，過濾且濃縮。將所得橙色粗物質懸浮於CH2Cl2(約30 mL)中，且對此漿液進行音波處理5分鐘，隨後添加約300 mL己烷，且在渦旋下對所得懸浮液進行音波處理5分鐘。過濾淺粉紅色固體並乾燥，且濃縮濾液並分離第二批，得到5-(2-氯吡啶-4-基氧基)喹啉(23.88 g，93.03 mmol，95.64%產率)。 Step A : Combine 60% NaH (4.085 g, 102.1 mmol) and quinoline-5-ol (14.12 g, 97.27 mmol) in 100 mL DMF at room temperature and stir for 30 minutes, then slowly add at room temperature 2-Chloro-4-nitropyridine (15.42 g, 97.27 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water (300 mL) andEtOAcEtOAc Followed by 1 N NaOH (100 mL), ,, and dried water (2 × 100 mL) brine (100 mL) The combined organics were washed with MgSO 4, filtered and concentrated. The resulting orange crude material was suspended in CH 2 Cl 2 (ca. 30 mL), and the slurry was sonicated for 5 minutes, then about 300 mL of hexane was added, and the resulting suspension was sonicated for 5 minutes under vortexing. . The light pink solid was filtered and dried, and the filtrate was concentrated and the second crop was evaporated to give 5-(2-chloropyridin-4-yloxy)quinoline (23.88 g, 93.03 mmol, 95.64% yield).

步驟B：在150 mL 4：1甲苯：水(在添加之前用N2充氣20分鐘)中組合5-(2-氯吡啶-4-基氧基)喹啉(23.8 g，92.7 mmol)、胺基甲酸第三丁酯(16.3 g，139 mmol)、K3PO4(59.0 g，278 mmol)、Pd2(dba)3(4.25 g，4.64 mmol)及XantPHOS(2.68 g，4.64 mmol)，且在室溫下攪拌此混合物並用N2充氣20分鐘，隨後密封反應物且加熱至100℃隔夜。將反應物添加至含有500 mL EtOAc之分液漏斗中，且移除水相。用500 mL CH2Cl2 w/10% MeOH稀釋有機物且攪拌20分鐘，隨後經矽藻土襯墊過濾。濃縮濾液，得到34.5 g粗4-(喹啉-5-基氧基)吡啶-2-基胺基甲 酸第三丁酯，其未經進一步純化即繼續使用。 Step B : Combine 5-(2-chloropyridin-4-yloxy)quinoline (23.8 g, 92.7 mmol), amine in 150 mL of 4:1 toluene: water (20 min with N 2 before addition) Tert-butyl carboxylic acid (16.3 g, 139 mmol), K 3 PO 4 (59.0 g, 278 mmol), Pd 2 (dba) 3 (4.25 g, 4.64 mmol) and XantPHOS (2.68 g, 4.64 mmol), the mixture was stirred at room temperature and treated with N inflator 220 minutes the reaction was then sealed and heated to 100 deg.] C overnight. The reaction was added to a sep. funnel containing 500 mL EtOAc and aqueous was removed. 10% MeOH and diluted with 500 mL CH 2 Cl 2 w / organics were stirred for 20 minutes and then filtered through a kieselguhr pad. The filtrate was concentrated to give 34.5 g of crude tris-(4-(phenyl)-5-yloxy)pyridin-2-ylaminocarbacarboxylate, which was used without further purification.

步驟C：將4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(31.3 g，92.78 mmol)懸浮於200 mL CH2Cl2中且冷卻至0℃，隨後緩慢添加TFA(71.48 ml，927.8 mmol)。2小時後，再添加25 mL TFA。5.5小時後，濃縮反應物且不時添加甲苯以幫助移除TFA。將100 mL 1 M NaOH添加至殘餘物中，且攪拌此物質，同時經由吸液管添加50 w% NaOH溶液直至pH值為約9。添加CH2Cl2(600 mL)且攪拌10分鐘。過濾固體，得到2.25 g產物。用CH2Cl2(×2)洗滌濾液，經MgSO4乾燥，過濾且濃縮。用CH2Cl2(300 mL)濕磨殘餘物且過濾，得到11.2 g化合物。在矽膠上(含1% MeOH之EtOAc w/0.75% NH4OH)純化剩餘濾液，得到產量合併之4-(喹啉-5-基氧基)吡啶-2-胺(17.9 g，65%產率)。 Step C: 4- (quinolin-5-yloxy) pyridin-2-yl tert-butyl ester carbamic acid (31.3 g, 92.78 mmol) was suspended in 200 mL CH 2 Cl 2 and cooled to 0 ℃, TFA (71.48 ml, 927.8 mmol) was then added slowly. After 2 hours, add another 25 mL of TFA. After 5.5 hours, the reaction was concentrated and toluene was added from time to time to help remove the TFA. 100 mL of 1 M NaOH was added to the residue and the material was stirred while a 50 w% NaOH solution was added via a pipette until the pH was about 9. CH 2 Cl 2 (600 mL) was added and stirred for 10 minutes. The solid was filtered to give 2.25 g of product. , Dried over MgSO 4 with 2 Cl 2 (× 2) and the filtrate was washed with CH, filtered and concentrated. With CH 2 Cl 2 (300 mL) and the residue was triturated and filtered to give 11.2 g compound. On silica gel (1% EtOAc w MeOH containing it / 0.75% NH 4 OH) remaining filtrate was purified to give the combined yield of 4- (quinolin-5-yloxy) pyridin-2-amine (17.9 g, 65% yield rate).

步驟D：在220 mL 3：1第三丁醇(165 mL)：二噁烷(55 mL)中組合4-(喹啉-5-基氧基)吡啶-2-胺(17.88 g，60.29 mmol)及Boc2O(32.89 g，150.7 mmol)，且此配備有冷凝器並加熱至65℃。3小時後，冷卻反應物且濃縮至一半體積。用飽和NaHCO3(300 mL)稀釋所得漿液且用EtOAc(3×250 mL)萃取，經MgSO4乾燥，過濾並濃縮。使殘餘物吸附於150 g二氧化矽上且在矽膠上(含30% EtOAc之CH2Cl2)純化，得到4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(15 g，67.9%產率)。 Step D : Combine 4-(quinolin-5-yloxy)pyridin-2-amine (17.88 g, 60.29 mmol) in 220 mL of 3:1 EtOAc (EtOAc) And Boc 2 O (32.89 g, 150.7 mmol), and this was equipped with a condenser and heated to 65 °C. After 3 hours, the reaction was cooled and concentrated to half volume. , Dried over MgSO 4 saturated NaHCO 3 (300 mL) The resulting slurry was diluted and extracted with EtOAc (3 × 250 mL), filtered and concentrated. The residue was adsorbed onto 150 g and silicon dioxide on silica gel (containing the CH 30% EtOAc 2 Cl 2) to give 4- (quinolin-5-yloxy) pyridin-2-yl-carboxylic acid group of Tributyl ester (15 g, 67.9% yield).

步驟E：將4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(8.8 g，26 mmol)懸浮於100 mL DMF中且冷卻至0℃，隨後以一整份添加NBS(4.6 g，26 mmol)，且在室溫下攪拌反應物2天。將反應物分配於水(300 mL)與EtOAc(200 mL)之間，且攪拌30分鐘，隨後過濾固體，得到5-溴-4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(4.4 g，11 mmol，41%產率)。 Step E : 3-(Quinolin-5-yloxy)pyridin-2-ylaminocarbamic acid tert-butyl ester (8.8 g, 26 mmol) was suspended in 100 mL DMF and cooled to 0 ° C then NBS (4.6 g, 26 mmol) was added in portions and the mixture was stirred at room temperature for 2 days. The reaction was partitioned between EtOAc (EtOAc) (EtOAc) Tert-butyl carbazate (4.4 g, 11 mmol, 41% yield).

步驟F：在75 mL二噁烷中組合5-溴-4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(9.03 g，21.69 mmol)、DIEA(11.34 ml，65.08 mmol)、Pd2dba3(0.9932 g，1.085 mmol)及Xantphos(1.255 g，2.169 mmol)，且將此物質用N2充氣20分鐘，隨後添加3-巰基丙酸甲酯(3.526 ml，32.54 mmol)，且將反應物再充氣10分鐘，隨後將其密封且加熱至95℃隔夜。冷卻反應物至室溫，經矽藻土過濾且濃縮。在矽膠上(含10%至25% EtOAc之CH2Cl2)純化殘餘物，得到3-(6-(第三丁氧基羰基胺基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯(7.7 g，70%產率)。 Step F : Combine 3-bromo-4-(quinolin-5-yloxy)pyridin-2-ylcarbamic acid tert-butyl ester (9.03 g, 21.69 mmol), DIEA (11.34) in 75 mL of dioxane. Ml, 65.08 mmol), Pd 2 dba 3 (0.9932 g, 1.085 mmol) and Xantphos (1.255 g, 2.169 mmol), and this material was inflated with N 2 for 20 min, then methyl 3-mercaptopropionate (3.526 ml) , 32.54 mmol), and the reaction was re-inflated for 10 minutes, then sealed and heated to 95 ° C overnight. The reaction was cooled to rt, filtered over EtOAc (EtOAc)EtOAc. On silica gel (containing CH 10% to 25% EtOAc of 2 Cl 2) The residue was purified to give 3- (6- (tertiary butoxycarbonyl) -4- (quinolin-5-yloxy) Methyl pyridin-3-ylthio)propanoate (7.7 g, 70% yield).

步驟G：將3-(6-(第三丁氧基羰基胺基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯(3.0 g，6.6 mmol)溶解於THF(40 mL)中，且使N2鼓泡通過，持續5分鐘。添加含1 M 2-甲基丙-2-醇鉀之THF(20 ml，20 mmol)，且劇烈攪拌反應物30秒。添加1-溴-3-甲氧基丙烷(0.93 ml，7.9 mmol)，且在室溫下攪拌反應物5分鐘。用NH4Cl水溶液淬滅反應物，用EtOAc萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含75%至100% EtOAc之己烷)純化殘餘物，得到呈淺黃色固體狀之5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(2.5 g，5.7 mmol，86%產率)。 Step G : Methyl 3-(6-(t-butoxycarbonylamino)-4-(quinolin-5-yloxy)pyridin-3-ylthio)propanoate (3.0 g, 6.6 mmol ) was dissolved in THF (40 mL), and that the N 2 was bubbled through for 5 minutes. THF (20 ml, 20 mmol) containing 1 M 2-methylpropan-2-propoxide was added and the mixture was stirred vigorously for 30 s. 1-Bromo-3-methoxypropane (0.93 ml, 7.9 mmol) was added, and the mixture was stirred at room temperature for 5 min. With aqueous 4 Cl NH quenched reaction was extracted with EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc:EtOAc Pyridyl-2-ylaminocarbamic acid tert-butyl ester (2.5 g, 5.7 mmol, 86% yield).

步驟H：將5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基胺基甲酸第三丁酯(2.5 g，5.66 mmol)溶解於CH2Cl2(30 mL)及MeOH(5 mL)中，接著添加含4 N HCl之二噁烷(10 mL)，且在室溫下攪拌反應物2小時。再添加酸(10 mL)，且在室溫下攪拌反應物隔夜。濃縮反應物且分配於EtOAc與NaHCO3水溶液之間。過濾所得固體且乾燥，得到呈白色固體狀之5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-胺(1.15 g，3.37 mmol，59.5%產率)。 Step H : Dissolving the third butyl 5-(3-methoxypropylthio)-4-(quinolin-5-yloxy)pyridin-2-ylcarbamate (2.5 g, 5.66 mmol) CH 2 Cl 2 (30 mL) and MeOH (5 mL) in dioxane followed by the addition of 4 N HCl (10 mL), and stirred at room temperature for 2 hours. Additional acid (10 mL) was added and the mixture was stirred at room temperature overnight. The reaction was concentrated and partitioned between EtOAc and aqueous NaHCO 3. The resulting solid was filtered and dried to purified crystals crystals crystalssssssssssssssssssssssssssssssss %Yield).

步驟I：在0℃下，於1 mL CH2Cl2中組合5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-胺(0.025 g，0.073 mmol)、吡啶(0.018 ml，0.22 mmol)及氯甲酸4-硝基苯酯(0.032 g，0.16 mmol)，升溫至室溫且 攪拌隔夜。添加含2 M乙胺(0.73 ml，1.5 mmol)之THF，且在室溫下攪拌3小時。濃縮反應物，且添加K2CO3(0.030 g，0.22 mmol)與2 mL EtOH，且在室溫下攪拌此物質經週末。用CH2Cl2稀釋反應物，過濾。濃縮濾液且在矽膠上(含75%至90% EtOAc之CH2Cl2)純化，得到粗物質，經由逆相層析(含20%至70% ACN之水)純化該粗物質，得到1-乙基-3-(5-(3-甲氧基丙硫基)-4-(喹啉-5-基氧基)吡啶-2-基)脲(0.009 g，0.022 mmol，30%產率)。質譜(apci)m/z=413.1(M+H)。 Step I : 5-(3-Methoxypropylthio)-4-(quinolin-5-yloxy)pyridin-2-amine (0.025 g) in 1 mL CH 2 Cl 2 at 0 ° C , 0.073 mmol), pyridine (0.018 ml, 0.22 mmol) and 4-nitrophenyl chloroformate (0.032 g, 0.16 mmol), warmed to room temperature and stirred overnight. 2 M Ethylamine (0.73 ml, 1.5 mmol) in THF was added and stirred at room temperature for 3 hr. The reaction was concentrated, and was added K 2 CO 3 (0.030 g, 0.22 mmol) and 2 mL EtOH, and the material was stirred at room temperature for the weekend. It was diluted with CH 2 Cl 2 The reaction was filtered. The filtrate was concentrated on silica gel (including 2 Cl 2 75% to the 90% CH EtOAc) to give the crude material by reverse phase chromatography (20% water to 70% ACN) to give the crude material to give 1- Ethyl-3-(5-(3-methoxypropylthio)-4-(quinolin-5-yloxy)pyridin-2-yl)urea (0.009 g, 0.022 mmol, 30% yield) . Mass spectrum (apci) m/z = 413.1 (M+H).

遵循實例131中之程序，製備以下化合物： Following the procedure in Example 131, the following compounds were prepared:

實例136Example 136

1-(4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)-5-(1-甲 基-1-H-吡唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-(5,7-Difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy)-5-(1-methyl -1- H -pyrazol-5-yl)pyridin-2-yl)-3-methylurea

步驟A：在2 mL DMF中組合NaH(於油中之60%分散液)(0.0716 g，1.79 mmol)及5,7-二氟-6-羥基-4-甲基喹啉-2(1H)-酮(0.378 g，1.79 mmol)且用N2充氣30分鐘，隨後添加2-氯-4-硝基吡啶(0.284 g，1.79 mmol)，且在室溫下繼續反應。4小時後，將EtOAc(1 mL)及水(5 mL)添加至反應物中且劇烈攪拌30分鐘，隨後將其傾倒至分液漏斗中之水(50 mL)及EtOAc(50 mL)中。經由真空過濾收集所形成之固體且用EtOAc(5 mL)洗滌。發現固體(109 mg)為所要化合物。收集有機層。用EtOAc(50 mL)萃取水層，且經MgSO4乾燥經合併之有機物，過濾且濃縮。用含5% MeOH之CH2Cl2濕磨殘餘物，且經由真空過濾收集固體並與以上所得之固體合併，得到6-(2-氯吡啶-4-基氧基)-5,7-二氟-4-甲基喹啉-2(1H)-酮(0.157 g，0.487 mmol，27.2%產率)。(apci)(M+H)m/z=323.0。 Step A : Combine NaH (60% dispersion in oil) (0.0716 g, 1.79 mmol) and 5,7-difluoro-6-hydroxy-4-methylquinoline-2 (1H) in 2 mL DMF - one (0.378 g, 1.79 mmol) and inflated with N 2 for 30 minutes followed by addition of 2-chloro-4-nitropyridine (0.284 g, 1.79 mmol), and the reaction was continued at room temperature. After 4 hours, EtOAc (1 mL) and EtOAc (EtOAc) (EtOAc) The solid which formed was collected by vacuum filtration and washed with EtOAc (5 mL). The solid (109 mg) was found to be the desired compound. Collect organic layers. With EtOAc (50 mL) and the aqueous layer was extracted and dried over MgSO 4 The organics were combined, filtered and concentrated. The residue was triturated with 2 Cl 2 was of 5% MeOH in CH, and the solid was collected via vacuum filtration and combined with the solid obtained from the above to give 6- (2-chloro-4-yloxy) -5,7- Fluoro-4-methylquinoline-2(1H)-one (0.157 g, 0.487 mmol, 27.2% yield). (apci) (M+H) m/z = 323.0.

步驟B：在室溫下，於1 mL DMF中組合NaH(於油中之60%分散液)(0.0389 g，0.973 mmol)及6-(2-氯吡啶-4-基氧基)-5,7-二氟-4-甲基喹啉-2(1H)-酮(0.157 g，0.487 mmol)且用N2充氣35分鐘，隨後添加硫酸二甲酯(0.0598 ml，0.632 mmol)。1小時後，反應完成且用CH2Cl2(5 mL)稀釋，接著直接加載於二氧化矽上且在矽膠上用含20% EtOAc之CH2Cl2溶離來純化，得到6-(2-氯吡啶-4-基氧基)-5,7-二氟-1,4-二甲基喹啉-2(1H)-酮(0.100 g，0.297 mmol，61.0%產率)。(apci)(M+H) m/z=337.0。 Step B : NaH (60% dispersion in oil) (0.0389 g, 0.973 mmol) and 6-(2-chloropyridin-4-yloxy)-5 were combined in 1 mL of DMF at room temperature. 6,7-difluoro-4-methyl-quinolin -2 (1H) - one (0.157 g, 0.487 mmol) and inflated with N 2 for 35 min followed by addition of dimethyl sulfate (0.0598 ml, 0.632 mmol). After 1 hour, the reaction was complete and diluted with CH 2 Cl 2 (5 mL) , then loaded directly onto silicon dioxide and containing the CH 20% EtOAc in 2 Cl 2 on silica eluting purified to give 6- (2- Chloropyridin-4-yloxy)-5,7-difluoro-1,4-dimethylquinolin-2(1H)-one (0.100 g, 0.297 mmol, 61.0% yield). (apci) (M+H) m/z = 337.0.

步驟C：在1 mL二甲氧基乙烷中組合1-甲基脲(0.0330 g，0.445 mmol)、細粉狀無水磷酸鉀(0.110 g，0.520 mmol)、參(二亞苄基丙酮)二鈀(0)(0.0272 g，0.0297 mmol)及1,1'-聯萘-2-基二第三丁基膦(0.0237 g，0.0594 mmol)，且將此物質用N2充氣15分鐘，隨後將其加熱至60℃，維持45分鐘。冷卻反應物至室溫，且添加6-(2-氯吡啶-4-基氧基)-5,7-二氟-1,4-二甲基喹啉-2(1H)-酮(0.100 g，0.297 mmol)。將反應物充氣5分鐘，隨後將其密封且加熱至90℃。48小時後，用含10% MeOH之CH2Cl2(75 mL)稀釋反應物且攪拌30分鐘，隨後經由真空過濾將其過濾。在減壓下濃縮濾液且在矽膠上用含2% MeOH之EtOAc溶離來純化，得到1-(4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.026 g，0.0660 mmol，22.2%產率)。(apci)(M+H)m/z=375.1。 Step C : Combining 1-methylurea (0.0330 g, 0.445 mmol), finely powdered anhydrous potassium phosphate (0.110 g, 0.520 mmol), ginseng (dibenzylideneacetone) in 1 mL of dimethoxyethane palladium (0) (0.0272 g, 0.0297 mmol) and 1,1'-naphthalen-2-yl-di-tert-butylphosphine (0.0237 g, 0.0594 mmol), of this material and inflated with N 2 for 15 minutes, followed by It was heated to 60 ° C for 45 minutes. The reaction was cooled to room temperature and 6-(2-chloropyridin-4-yloxy)-5,7-difluoro-1,4-dimethylquinolin-2(1H)-one (0.100 g) , 0.297 mmol). The reaction was aerated for 5 minutes, then sealed and heated to 90 °C. After 48 hours, 10% MeOH of CH 2 Cl 2 (75 mL) and the reaction was diluted with containing stirred for 30 minutes, then filtered via vacuum filtration. The filtrate was concentrated under reduced pressure and purified eluting with EtOAc EtOAc EtOAc , 2-dihydroquinolin-6-yloxy)pyridin-2-yl)-3-methylurea (0.026 g, 0.0660 mmol, 22.2% yield). (apci) (M+H) m/z = 375.1.

步驟D：在室溫下，於1 mL DMF中組合1-(4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.054 g，0.14 mmol)及NBS(0.026 g，0.14 mmol)且攪拌隔夜。添加水(10 mL)，且劇烈攪拌反應物。經由真空過濾收集所得固體，得到1-(5-溴-4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.045 g，0.099 mmol，69%產率)。(apci)(M+H)m/z=453.0,455.0。 Step D : Combining 1-(4-(5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinoline) in 1 mL of DMF at room temperature 6-Aminooxypyridin-2-yl)-3-methylurea (0.054 g, 0.14 mmol) and NBS (0.026 g, 0.14 mmol). Water (10 mL) was added and the reaction was stirred vigorously. The obtained solid was collected by vacuum filtration to give 1-(5-bromo-4-(5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6- Benzyloxy)pyridin-2-yl)-3-methylurea (0.045 g, 0.099 mmol, 69% yield). (apci) (M+H) m/z = 453.0, 455.0.

步驟E：在1 mL二噁烷中組合1-(5-溴-4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.0225 g，0.0496 mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(0.0258 g，0.124 mmol)及K2CO3水溶液(0.0993 ml，0.199 mmol)，且將此物質用氮氣充氣2分鐘，隨後添加Pd(PPh3)4(0.00574 g，0.00496 mmol)，且將反應物再充氣1分鐘，隨後將其密封且加熱至100℃。6 小時後，用CH2Cl2稀釋反應物，且直接加載於矽膠上並用含1% MeOH之EtOAc w/1% NH4OH溶離，得到1-(4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.006 g，0.0128 mmol，25.8%產率)。(apci)(M+H)m/z=455.1。 Step E : Combination of 1-(5-bromo-4-(5,7-difluoro-1,4-dimethyl-2-oxo-1,2-dihydroquinoline) in 1 mL of dioxane -6-yloxy)pyridin-2-yl)-3-methylurea (0.0225 g, 0.0496 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3 2-diboron 2-yl)-1H-pyrazole (0.0258 g, 0.124 mmol) and aqueous K 2 CO 3 (0.0993 ml, 0.199 mmol), and this material was inflated with nitrogen for 2 min, then Pd(PPh 3 ) 4 ( 0.00574 g, 0.00496 mmol), and the reaction was re-inflated for 1 minute, then sealed and heated to 100 °C. After 6 hours, diluted with CH 2 Cl 2 reaction, and loaded directly on silica and eluted with EtOAc w 1% MeOH of / 1% NH 4 OH eluting to give 1- (4- (5,7-difluoro-1 ,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy)-5-(1-methyl-1H-pyrazole-5-yl)pyridine-2- Benzyl-3-methylurea (0.006 g, 0.0128 mmol, 25.8% yield). (apci) (M+H) m/z = 455.1.

實例137Example 137

1-(5-溴-4-(5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲 1-(5-Bromo-4-(5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy)pyridine- 2-yl)-3-methylurea

步驟A：在室溫下，於攪拌下，在2 mL DMF中組合5,7-二氟-6-羥基-3,4-二甲基喹啉-2(1H)-酮(0.171 g，0.759 mmol)及NaH(於油中之60%分散液)(0.0304 g，0.759 mmol)，且將此物質用N2充氣45分鐘，隨後添加含2,5-二溴-4-硝基吡啶(0.214 g，0.759 mmol)之1 mL DMF。繼續反應隔夜。次日早晨，添加NaH(於油中之60%分散液)(0.0607 g，1.52 mmol)於1 mL DMF中之懸浮液，且在室溫下於氮氣充氣下攪拌此物質45分鐘，隨後添加硫酸二甲酯(0.108 ml，1.14 mmol)。3小時後，用水(20 mL)稀釋反應物且劇烈攪拌。向反應物中添加EtOAc(50 mL)及水(30 mL)，且分離所得兩相溶液並用EtOAc(3×50 mL)萃取水相。合併有機部分，用鹽水(50 mL)洗滌，經MgSO4乾燥，過濾且濃縮。在矽膠上用含3% EtOAc之CH2Cl2溶離來純化殘餘物，得到6-(2,5-二溴吡啶-4-基氧基)-5,7-二氟-1,3,4-三甲基喹啉-2(1H)-酮(0.177 g，0.373 mmol，49.2%產率)。 Step A : Combine 5,7-difluoro-6-hydroxy-3,4-dimethylquinolin-2(1H)-one (0.171 g, 0.759) in 2 mL DMF with stirring at room temperature. mmol) and NaH (60% dispersion in oil of) (0.0304 g, 0.759 mmol) , and N 2 of this material was inflated 45 minutes, followed by addition of 2,5-dibromo-4-nitropyridine-containing (0.214 g, 0.759 mmol) of 1 mL DMF. Continue to react overnight. The next morning, a suspension of NaH (60% dispersion in oil) (0.0607 g, 1.52 mmol) in 1 mL of DMF was added and the material was stirred at room temperature under a nitrogen atmosphere for 45 minutes, then sulfuric acid was added. Dimethyl ester (0.108 ml, 1.14 mmol). After 3 hours, the reaction was diluted with water (20 mL) and stirred vigorously. EtOAc (50 mL) and water (30 mL) were evaporated. The organic portions were combined, dried over MgSO 4 and washed with brine (50 mL), filtered and concentrated. CH on silica gel with 3% EtOAc containing 2 Cl 2 eluting the residue was purified to give 6- (2,5-dibromo-4-yloxy) -5,7-difluoro-3,4 Trimethylquinoline-2(1H)-one (0.177 g, 0.373 mmol, 49.2% yield).

步驟B：在1 mL二甲氧基乙烷中組合1-甲基脲(0.0415 g，0.560 mmol)、無水細粉狀K3PO4(0.139 g，0.653 mmol)、Pd2(dba)3(0.0171 g，0.0187 mmol)及1,1'-聯萘-2-基二第三丁基膦(0.0298 g，0.0747 mmol)，且將此物質用N2充氣10分鐘，隨後在N2下將其加熱至50℃，維持1小時。冷卻反應物至室溫，且添加6-(2,5-二溴吡啶-4-基氧基)-5,7-二氟-1,3,4-三甲基喹啉-2(1H)-酮(0.177 g，0.373 mmol)。將反應物用N2充氣5分鐘，隨後將其密封且加熱至50℃。次日早晨，加熱升至60℃。48小時後，用CH2Cl2(5 mL)稀釋反應物，直接加載於矽膠上且用含75% EtOAc之CH2Cl2 w/1% NH4OH溶離，得到1-(4-(5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲與1-(5-溴-4-(5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲之混合物。 Step B : Combine 1-methylurea (0.0415 g, 0.560 mmol), anhydrous fine powder K 3 PO 4 (0.139 g, 0.653 mmol), Pd 2 (dba) 3 in 1 mL of dimethoxyethane ( 0.0171 g, 0.017 mmol) and 1,1'-binaphthyl-2-ylditributylphosphine (0.0298 g, 0.0747 mmol), and this material was inflated with N 2 for 10 minutes, then it was taken under N 2 Heat to 50 ° C for 1 hour. The reaction was cooled to room temperature and 6-(2,5-dibromopyridin-4-yloxy)-5,7-difluoro-1,3,4-trimethylquinoline-2 (1H) was added. - Ketone (0.177 g, 0.373 mmol). The reaction was inflated with N 2 for 5 min, then sealed and heated to 50 ℃. The next morning, the heat rose to 60 °C. After 48 hours, the CH 2 Cl 2 (5 mL) The reaction was diluted and loaded directly on silica containing 75% EtOAc in of CH 2 Cl 2 w / 1% NH 4 OH eluting to give 1- (4- (5 ,7-difluoro-1,3,4-trimethyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pyridin-2-yl)-3-methylurea 1-(5-Bromo-4-(5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy)pyridine- Mixture of 2-yl)-3-methylurea.

步驟C：在室溫下，於1 mL DMF中組合1-(4-(5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲與1-(5-溴-4-(5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲之混合物及NBS(0.0257 g，0.144 mmol)隔夜。次日，添加4 mg NBS。3.5小時後，添加水(10 mL)及EtOAc(10 mL)，且經由真空過濾收集所得固體並在真空烘箱中乾燥，得到1-(5-溴-4-(5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.023 g，0.0492 mmol，13.7%產率-經兩個步驟)。(apci)(M+H)m/z=467.0,469.0。 Step C : Combining 1-(4-(5,7-difluoro-1,3,4-trimethyl-2-oxo-1,2-dihydroquine) in 1 mL of DMF at room temperature Phenyl-6-yloxy)pyridin-2-yl)-3-methylurea with 1-(5-bromo-4-(5,7-difluoro-1,3,4-trimethyl-2- A mixture of pendant oxy-1,2-dihydroquinolin-6-yloxy)pyridin-2-yl)-3-methylurea and NBS (0.0257 g, 0.144 mmol) overnight. The next day, 4 mg NBS was added. After 3.5 hours, water (10 mL) and EtOAc (10 mL) was evaporated and evaporated and evaporated. ,3,4-trimethyl-2-oxooxy-1,2-dihydroquinolin-6-yloxy)pyridin-2-yl)-3-methylurea (0.023 g, 0.0492 mmol, 13.7 % yield - in two steps). (apci) (M+H) m/z = 467.0, 469.0.

以下化合物可均以相同方式使用適當官能化之喹諾酮酚類(quinolone phenol)來製備： The following compounds can all be prepared in the same manner using appropriately functionalized quinolone phenols:

實例140Example 140

1-(6-氯-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(6-chloro-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea

步驟A：將喹啉-5-醇(398 mg，2.74 mmol)溶解於DMF(15 mL)中且在冰浴中冷卻。添加60% NaH(110 mg，2.74 mmol)，且攪拌反應物10分鐘。添加2,4,6-三氯吡啶(500 mg，2.74 mmol)，且在室溫下攪拌反應物隔夜。將反應物傾倒至200 mL水中，攪拌20分鐘且過濾。用EtOAc萃取濾液且與固體合併，且在矽膠上(含30% EtOAc之己烷)純化，得到呈白色固體狀之5-(2,6-二氯吡啶-4-基氧基)喹啉(580 mg，1.99 mmol，72.7%產率)(產物與非所要異構體之7：1混合物)。 Step A : Quinoline-5-ol (398 mg, 2.74 mmol) was dissolved in DMF (15 mL). 60% NaH (110 mg, 2.74 mmol) was added and the reaction was stirred 10 min. 2,4,6-Trichloropyridine (500 mg, 2.74 mmol) was added and the reaction was stirred at rt overnight. The reaction was poured into 200 mL water, stirred for 20 min and filtered. The filtrate was extracted with EtOAc and EtOAc (EtOAc m. 580 mg, 1.99 mmol, 72.7% yield) (7:1 mixture of product and desired isomer).

步驟B：遵循實例1步驟B中之程序，5-(2,6-二氯吡啶-4-基氧基) 喹啉(560 mg，1.92 mmol)得到呈白色固體狀之1-(6-氯-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(96 mg，0.292 mmol，15.2%產率)。質譜(apci)m/z=329.0(M+H)。 Step B : Following the procedure in Example 1 Step B, 5-(2,6-dichloropyridin-4-yloxy)quinoline (560 mg, 1.92 mmol) 4-(Quinoline-5-yloxy)pyridin-2-yl)-3-methylurea (96 mg, 0.292 mmol, 15.2% yield). Mass spectrum (apci) m/z = 329.0 (M+H).

遵循實例140中之程序且使用2-溴-4,6-二氟吡啶，合成以下化合物： The following compounds were synthesized following the procedure in Example 140 using 2-bromo-4,6-difluoropyridine:

實例142Example 142

1-(5-溴-6-氯-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-6-chloro-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea

將1-(6-氯-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(75 mg，0.2281 mmol)溶解於DMF(2 mL)中，且添加Br2(11.69 μl，0.2281 mmol)並在室溫下攪拌隔夜。再添加溴(11.69 μl，0.2281 mmol)。1小時後，再添加Br2(11.69 μl，0.2281 mmol)，且將反應物傾倒至水中並劇烈攪拌。添加NaHCO3及NaHSO3以淬滅HBr及Br2。攪拌20分鐘後，過濾反應物且在真空烘箱中乾燥，得到呈紅色固體狀之1-(5-溴-6-氯-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(68 mg，0.1668 mmol，73.12%產率)。質譜(apci)m/z=407.0,409.0(M+H)。 1-(6-Chloro-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea (75 mg, 0.2281 mmol) was dissolved in DMF (2 mL) Br 2 (11.69 μl, 0.2281 mmol) was stirred at room temperature overnight. Additional bromine (11.69 μl, 0.2281 mmol) was added. After 1 hour, additional Br 2 (11.69 μl, 0.2281 mmol) was added and the mixture was poured into water and stirred vigorously. NaHCO 3 and NaHSO 3 were added to quench HBr and Br 2 . After stirring for 20 minutes, the reaction was filtered and dried in vacuo to give 1-(5-bromo-6-chloro-4-(quinolin-5-yloxy)pyridin-2-yl) as a red solid. -3-methylurea (68 mg, 0.1668 mmol, 73.12% yield). Mass spectrum (apci) m/z = 407.0, 409.0 (M+H).

遵循實例142中之程序，合成以下化合物： Following the procedure in Example 142, the following compounds were synthesized:

實例144Example 144

1-(5-(1-(2-羥基乙基)-1H-吡唑-4-基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea

步驟A：在二噁烷(2.0 mL)中組合1-(5-溴-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(50 mg，0.13 mmol)、1-(2-(第三丁基二甲基矽烷氧基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(71 mg，0.20 mmol)及2 M K2CO3(201 μl，0.40 mmol)。將N2鼓泡通入此混合物中，持續5分鐘，繼而添加Pd(PPh3)4(15 mg，0.013 mmol)。將N2鼓泡通入混合物中，再持續1分鐘，隨後將其密封且加熱至100℃隔夜。用10 mL CH2Cl2稀釋反應混合物，且直接加載於二氧化矽管柱上並用15-40%丙酮/CH2Cl2之梯度溶離，獲得1-(5-(1-(2-(第三丁基二甲基矽烷氧基)乙基)-1H-吡唑-4-基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(70 mg，0.067 mmol，50%純，50%產率)。質譜(apci)m/z=519.2(M+H)。 Step A : Combination of 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea (50 mg, 0.13 mmol) in dioxane (2.0 mL) , 1-(2-(Tertiary butyl dimethyl decyloxy) ethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)-1H-pyrazole (71 mg, 0.20 mmol) and 2 MK 2 CO 3 (201 μl, 0.40 mmol). N 2 was bubbled through the mixture for 5 minutes, followed by the addition of Pd(PPh 3 ) 4 (15 mg, 0.013 mmol). N 2 was bubbled through the mixture for an additional 1 minute, then sealed and heated to 100 ° C overnight. The reaction mixture was diluted with 10 mL of CH 2 Cl 2 and directly loaded onto a ruthenium dioxide column and eluted with a gradient of 15-40% acetone/CH 2 Cl 2 to give 1-(5-(1-(2-() Tributyldimethylsilyloxy)ethyl)-1H-pyrazol-4-yl)-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea (70 Mg, 0.067 mmol, 50% pure, 50% yield). Mass spectrum (apci) m/z = 519.2 (M+H).

步驟B：將1-(5-(1-(2-(第三丁基二甲基矽烷氧基)乙基)-1H-吡唑-4-基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(70 mg，0.067 mmol)溶解於0.5 mL MeOH中，添加12 N HCl(11 μl，0.13 mmol)，且在室溫下攪拌隔夜。用1 mL飽和NaHCO3處理混合物，繼而用3 mL CH2Cl2萃取。將有機層加載於二氧化矽管柱上，且首先用75：23：2 CH2Cl2：丙酮：Et3N溶離，接著用44：44：10：2 CH2Cl2：丙酮：MeOH：Et3N溶離，獲得呈褐色固體狀之1-(5-(1-(2-羥基乙基)-1H-吡唑-4-基)-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(8 mg，0.020 mmol，29%產率)。質譜(apci)m/z=405.1(M+H)。 Step B : 1-(5-(1-(2-(Tertiary dimethyl dimethyl decyloxy)ethyl)-1H-pyrazol-4-yl)-4-(quinolin-5-yl) The oxy)pyridin-2-yl)-3-methylurea (70 mg, 0.067 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The mixture was treated with 1 mL 3 saturated NaHCO, and then 3 mL CH 2 Cl 2 and extracted with. The organic layer was loaded onto a ruthenium dioxide column and first dissolved with 75:23:2 CH 2 Cl 2 :acetone:Et 3 N followed by 44:44:10:2 CH 2 Cl 2 :acetone:MeOH: Dissolve in Et 3 N to give 1-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4-(quinolin-5-yloxy)pyridine as a brown solid. 2-yl)-3-methylurea (8 mg, 0.020 mmol, 29% yield). Mass spectrum (apci) m/z = 405.1 (M+H).

實例145Example 145

1-(4-(2,6-二氟苯氧基)-5-(1-(2-羥基乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-Difluorophenoxy)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-3-methyl Urea

步驟A：在1 mL二噁烷中組合1-(2-(第三丁基二甲基矽烷氧基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(0.148 g，0.419 mmol)、1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.100 g，0.279 mmol)、2 M K2CO3(0.419 ml，0.838 mmol)及Pd(PPh3)4(0.0323 g，0.0279 mmol)，且將此物質用N2充氣10分鐘，隨後將其密封且加熱至100℃隔夜。此後，用CH2Cl2稀釋反應物，接著直接加載於二氧化矽上且用含15%丙酮之CH2Cl2進行層析。合併所要溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(5-(1-(2-(第三丁基二甲基矽烷氧基)乙基)-1H-吡唑-4-基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 (0.073 g，0.130 mmol，46.7%產率)。 Step A : Combining 1-(2-(t-butyldimethylsilyloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3 in 1 mL of dioxane 2-diboron -2-yl)-1H-pyrazole (0.148 g, 0.419 mmol), 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.100 g, 0.279 mmol), 2 MK 2 CO 3 (0.419 ml, 0.838 mmol) and Pd(PPh 3 ) 4 (0.0323 g, 0.0279 mmol), and this material was inflated with N 2 for 10 minutes, then sealed And heated to 100 ° C overnight. Thereafter, the reaction was diluted with CH 2 Cl 2 , then directly applied to ruthenium dioxide and chromatographed with CH 2 Cl 2 containing 15% acetone. The desired fractions are combined, concentrated in vacuo and dried under high vacuum to give 1-(5-(1-(2-(t-butyldimethyl-decyloxy)ethyl)-1H-pyrazole- 4-yl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.073 g, 0.130 mmol, 46.7% yield).

步驟B：在1 mL MeOH中組合1-(5-(1-(2-(第三丁基二甲基矽烷氧基)乙基)-1H-吡唑-4-基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.073 g，0.14 mmol)及12 M HCl(0.024 ml，0.29 mmol)且攪拌隔夜。此後反應完成，且向其中添加固體NaHCO3(100 mg)。攪拌此物質隔夜，隨後添加20 mL CH2Cl2，且過濾反應物。在真空中濃縮沖洗液，接著用含30%丙酮之CH2Cl2(含0.5% NH4OH)進行層析。合併含產物之溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-(2,6-二氟苯氧基)-5-(1-(2-羥基乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(0.027 g，0.068 mmol，47%產率)。質譜(apci)m/z=390.1(M+H)。 Step B : Combination of 1-(5-(1-(2-(t-butyldimethyl)alkyl)ethyl)-1H-pyrazol-4-yl)-4-(2) in 1 mL MeOH ,6-Difluorophenoxy)pyridin-2-yl)-3-methylurea (0.073 g, 0.14 mmol) and 12 M HCl (0.024 ml, 0.29 mmol). Thereafter the reaction was completed, and solid NaHCO 3 (100 mg) was added thereto. This material was stirred overnight, followed by addition of 20 mL CH 2 Cl 2, and the reaction was filtered. Rinse solution was concentrated in vacuo, followed by 30% acetone CH 2 Cl 2 (containing 0.5% NH 4 OH) containing chromatography. The product-containing fractions are combined, concentrated in vacuo and dried under high vacuum to give 1-(4-(2,6-difluorophenoxy)-5-(1-(2-hydroxyethyl)- 1H-Pyrazole-4-yl)pyridin-2-yl)-3-methylurea (0.027 g, 0.068 mmol, 47% yield). Mass spectrum (apci) m/z = 390.1 (M+H).

實例146Example 146

1-(4-(5-氯-2-氟苯氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-(5-chloro-2-fluorophenoxy)-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea

步驟A：在1 mL二噁烷中組合1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(0.067 g，0.32 mmol)、1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(0.040 g，0.16 mmol)及2 M K2CO3(0.32 ml，0.65 mmol)，且將此物質用N2充氣3分鐘，隨後添加Pd(PPh3)4(0.019 g，0.016 mmol)。將反應物再充氣2分鐘，隨後將其密封且加熱至50℃，維持2小時。此後觀測到化合物，且加熱反應物至65℃，且3小時後清楚觀測到較快轉化。繼續反應隔夜。用CH2Cl2稀釋反應物且用含20%丙酮之CH2Cl2進行層析。合併含產物之溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-氟-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲 (0.020 g，0.076 mmol，47%產率)。 Step A : Combining 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in 1 mL of dioxane -2-yl)-1H-pyrazole (0.067 g, 0.32 mmol), 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (0.040 g, 0.16 mmol) and 2 MK 2 CO 3 (0.32 ml, 0.65 mmol), and this material was then evaporated with N 2 for 3 min, then Pd(PPh 3 ) 4 (0.019 g, 0.016 mmol). The reaction was re-inflated for 2 minutes, then sealed and heated to 50 °C for 2 hours. Compounds were subsequently observed and the reaction was heated to 65 °C and a faster conversion was clearly observed after 3 hours. Continue to react overnight. Diluted with CH 2 Cl and reaction with CH 20% acetone containing 2 Cl 2 chromatography. The product-containing fractions are combined, concentrated in vacuo and dried under high vacuum to give 1-(4-fluoro-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl) 3-methylurea (0.020 g, 0.076 mmol, 47% yield).

步驟B：在1 mL DMA中組合5-氯-2-氟苯酚(0.013 ml，0.11 mmol)、1-(4-氟-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.020 g，0.080 mmol)及Cs2CO3(0.052 g，0.16 mmol)，且將其加熱至80℃隔夜。加熱升至90℃且維持隔夜。次日早晨，用5 mL水稀釋反應物且用EtOAc(3×50 mL)萃取。合併有機物，經MgSO4乾燥，過濾，且在真空中移除。用含10%丙酮之CH2Cl2(含0.5% NH4OH)對粗物質進行層析。合併所要溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-(5-氯-2-氟苯氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.005 g，0.013 mmol，16%產率)。質譜(apci)m/z=376.1,378.0(M+H)。 Step B : Combination of 5-chloro-2-fluorophenol (0.013 ml, 0.11 mmol), 1-(4-fluoro-5-(1-methyl-1H-pyrazol-5-yl)pyridine in 1 mL of DMA 2-yl) -3-methyl-urea (0.020 g, 0.080 mmol) and Cs 2 CO 3 (0.052 g, 0.16 mmol), and heated to 80 deg.] C overnight. The heat was raised to 90 ° C and maintained overnight. The next morning, the reaction was diluted with EtOAc (3x 50 mL). The organics were combined, dried over MgSO 4, filtered, and removed in vacuo. 10% acetone CH 2 Cl 2 (containing 0.5% NH 4 OH) of the crude material was chromatographed containing. The desired fractions are combined, concentrated in vacuo and dried under high vacuum to give 1-(4-(5-chloro-2-fluorophenoxy)-5-(1-methyl-1H-pyrazole-5 -yl)pyridin-2-yl)-3-methylurea (0.005 g, 0.013 mmol, 16% yield). Mass spectrum (apci) m/z = 376.1, 378.0 (M+H).

實例147Example 147

1-(4-(5-氯-2-氟苯氧基)-5-((3-甲氧基丙基)硫基)吡啶-2-基)-3-甲基脲 1-(4-(5-chloro-2-fluorophenoxy)-5-((3-methoxypropyl)thio)pyridin-2-yl)-3-methylurea

步驟A：在2 mL二噁烷中組合1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(0.033 g，0.13 mmol)及N-乙基-N-異丙基丙-2-胺(d 0.742)(0.046 ml，0.27 mmol)，且將此物質用N2充氣2分鐘，隨後添加Pd2(dba)3(0.012 g，0.013 mmol)及XantPHOS(0.015 g，0.027 mmol)，且用N2充氣5分鐘，隨後添加4-巰基-2-甲基丁-2-醇(0.024 g，0.20 mmol)，且將反應物用N2充氣1分鐘，隨後密封反應物且加熱至50℃，維持2小時。觀測到極少反應。加熱反應物至65℃且清楚觀測到較快轉化。在65℃下繼續反應隔夜，且次日早晨，用CH2Cl2稀釋反應物，直接加載於二氧化矽上且用含20%丙酮之CH2Cl2溶離。合併所要溶離份，在真空中濃 縮，且在高真空下乾燥，得到1-(4-氟-5-(3-羥基-3-甲基丁硫基)吡啶-2-基)-3-甲基脲(0.019 g，0.063 mmol，47%產率)。 Step A : Combining 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (0.033 g, 0.13 mmol) and N-ethyl-N-isopropyl in 2 mL of dioxane Propyl-2-amine (d 0.742) (0.046 ml, 0.27 mmol), and this material was then inflated with N 2 for 2 min, then Pd 2 (dba) 3 (0.012 g, 0.013 mmol) and XantPHOS (0.015 g, 0.027 mmol), and aerated with N 2 for 5 min, then 4-mercapto-2-methylbutan-2-ol (0.024 g, 0.20 mmol) was added and the reaction was then inflated with N 2 for 1 min. And heated to 50 ° C for 2 hours. Very little reaction was observed. The reaction was heated to 65 ° C and a clear conversion was clearly observed. The reaction was continued overnight at 65 ℃, and the next morning, with CH 2 Cl 2 The reaction was diluted and loaded directly onto silicon dioxide containing CH 20% acetone 2 Cl 2 fractions. The desired fractions are combined, concentrated in vacuo and dried under high vacuum to give 1-(4-fluoro-5-(3-hydroxy-3-methylbutylthio)pyridin-2-yl)-3-yl Base urea (0.019 g, 0.063 mmol, 47% yield).

步驟B：在1 mL DMA中組合5-氯-2-氟苯酚(0.011 ml，0.099 mmol)、1-(4-氟-5-(3-羥基-3-甲基丁硫基)吡啶-2-基)-3-甲基脲(0.019 g，0.066 mmol)及Cs2CO3(0.043 g，0.13 mmol)，且將其密封並加熱至80℃。次日早晨，加熱稍升至90℃且維持隔夜。次日早晨，用5 mL水稀釋反應物且用EtOAc(3×50 mL)萃取。合併有機物，經MgSO4乾燥，過濾，且在真空中移除。藉由用含10%丙酮之CH2Cl2(含0.5% NH4OH)進行層析來純化所得粗物質。合併所要溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-(5-氯-2-氟苯氧基)-5-(3-羥基-3-甲基丁硫基)吡啶-2-基)-3-甲基脲(0.009 g，0.020 mmol，30%產率)。質譜(apci)m/z=414.0,416.0(M+H)。 Step B : Combination of 5-chloro-2-fluorophenol (0.011 ml, 0.099 mmol), 1-(4-fluoro-5-(3-hydroxy-3-methylbutylthio)pyridine-2 in 1 mL of DMA 3-yl-3-carbazide (0.019 g, 0.066 mmol) and Cs 2 CO 3 (0.043 g, 0.13 mmol), and sealed and heated to 80 °C. The next morning, the heat was slightly raised to 90 ° C and maintained overnight. The next morning, the reaction was diluted with EtOAc (3x 50 mL). The organics were combined, dried over MgSO 4, filtered, and removed in vacuo. By 10% acetone containing chromatographed CH 2 Cl 2 (containing 0.5% NH 4 OH) resulting crude material was purified. The desired fractions are combined, concentrated in vacuo and dried under high vacuum to give 1-(4-(5-chloro-2-fluorophenoxy)-5-(3-hydroxy-3-methylbutylthio) Pyridin-2-yl)-3-methylurea (0.009 g, 0.020 mmol, 30% yield). Mass spectrum (apci) m/z = 414.0, 416.0 (M+H).

實例148Example 148

1-(4-((5-氯-4-氰基吡啶-3-基)氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-((5-Chloro-4-cyanopyridin-3-yl)oxy)-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3 -methylurea

在0.5 mL DMA中組合1-(4-羥基-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.040 g，0.16 mmol)、3,5-二氯異菸鹼腈(0.042 g，0.24 mmol)及Cs2CO3(0.058 g，0.18 mmol)，且將反應物用N2充氣1分鐘，密封，且加熱至90℃經週末。用水(5 mL)稀釋反應物，接著用EtOAc(3×75 mL)萃取。合併有機物，經MgSO4乾燥，過濾，且在真空中移除。藉由用含10%丙酮之CH2Cl2(含0.5% NH4OH)進行層析來純化所 得粗物質。合併含產物之溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-(5-氯-4-氰基吡啶-3-基氧基)-5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.007 g，0.017 mmol，10%產率)。質譜(apci)m/z=384.1,386.0(M+H)。 1-(4-Hydroxy-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea (0.040 g, 0.16 mmol) was combined in 0.5 mL DMA. 3,5-Dichloroisonicotinonitrile (0.042 g, 0.24 mmol) and Cs 2 CO 3 (0.058 g, 0.18 mmol), and the reaction was inflated with N 2 for 1 min, sealed and heated to 90 ° C over the weekend. . The reaction was diluted with water (5 mL) The organics were combined, dried over MgSO 4, filtered, and removed in vacuo. By 10% acetone containing chromatographed CH 2 Cl 2 (containing 0.5% NH 4 OH) resulting crude material was purified. The product-containing fractions are combined, concentrated in vacuo and dried in vacuo to give 1-(4-(5-chloro-4-cyanopyridin-3-yloxy)-5-(1-methyl -1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea (0.007 g, 0.017 mmol, 10% yield). Mass spectrum (apci) m/z = 384.1, 386.0 (M+H).

遵循實例148中之程序，製備以下化合物： Following the procedure in Example 148, the following compounds were prepared:

實例151Example 151

4-((6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基)亞磺醯基)哌啶-1-甲酸第三丁酯 4-((6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-yl)sulfinyl)piperidine-1-carboxylic acid tert-butyl ester

在室溫下，向4-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)哌啶-1-甲酸第三丁酯(100 mg，0.196 mmol)於1：1丙酮：MeOH(4 mL)中之溶液與NaHCO3(16.5 mg，0.196 mmol)中添加第一當量之過 硫酸氫鉀(Oxone)(121 mg，0.196 mmol)。攪拌混合物2小時。濾出鹽且添加10 mL CH2Cl2。用3 mL水洗滌。經Na2SO4乾燥有機物且濃縮，獲得4-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基亞磺醯基)哌啶-1-甲酸第三丁酯(68 mg，0.125 mmol，64.0%產率)。質譜(apci)m/z=526.2(M+H)。 To the tert-butyl 4-(6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-ylthio)piperidine-1-carboxylate at room temperature (100 mg, 0.196 mmol) in 1: 1 acetone: solution (4 mL) in MeOH and the NaHCO 3 (16.5 mg, 0.196 mmol ) was added in a first equivalent of potassium monopersulfate (oxone) (121 mg, 0.196 mmol ). The mixture was stirred for 2 hours. Salt was filtered off and was added 10 mL CH 2 Cl 2. Wash with 3 mL of water. The organics were dried over Na 2 SO 4 and concentrated to give 4-(6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-ylsulfinyl)piperidine- 1-butylic acid tert-butyl ester (68 mg, 0.125 mmol, 64.0% yield). Mass spectrum (apci) m/z = 526.2 (M+H).

遵循實例151中之程序，製備以下化合物： Following the procedure in Example 151, the following compounds were prepared:

實例153Example 153

4-((6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基)磺醯基)哌啶-1-甲酸第三丁酯 4-((6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-yl)sulfonyl)piperidine-1-carboxylic acid tert-butyl ester

在室溫下，向4-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)哌啶-1-甲酸第三丁酯(100 mg，0.196 mmol)於1：1丙酮：MeOH(4 mL)中之溶液與NaHCO3(16.5 mg，0.196 mmol)中添加過硫酸氫鉀(242 mg，0.392 mmol)。攪拌混合物18小時。濾出鹽且添加15 mL CH2Cl2。用4 mL水洗滌，經Na2SO4乾燥有機物。CH2Cl2溶液在室溫下飽和3小時且形成晶體。收集晶體，發現其為4-(6-(3-甲基脲基)-4- (喹啉-5-基氧基)吡啶-3-基磺醯基)哌啶-1-甲酸第三丁酯(22 mg，0.0394 mmol，20.1%產率)。質譜(apci)m/z=542.2(M+H)。 To the tert-butyl 4-(6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-ylthio)piperidine-1-carboxylate at room temperature (100 mg, 0.196 mmol) in 1: solution of NaHCO 3 (16.5 mg, 0.196 mmol ) was added oxone (242 mg, 0.392 mmol) MeOH (4 mL): 1 acetone. The mixture was stirred for 18 hours. Salt was filtered off and was added 15 mL CH 2 Cl 2. Washed with 4 mL of water, dried organics were dried over Na 2 SO 4. The CH 2 Cl 2 solution was saturated at room temperature for 3 hours and crystals were formed. The crystal was collected and found to be 4-(6-(3-methylureido)-4-(quinolin-5-yloxy)pyridin-3-ylsulfonyl)piperidine-1-carboxylic acid tert-butyl Ester (22 mg, 0.0394 mmol, 20.1% yield). Mass spectrum (apci) m/z = 542.2 (M+H).

遵循實例153中之程序，製備以下化合物： Following the procedure in Example 153, the following compounds were prepared:

實例155Example 155

1-甲基-3-(4-(喹啉-5-基氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲 1-methyl-3-(4-(quinolin-5-yloxy)-2'-(trifluoromethyl)-[3,4'-bipyridyl]-6-yl)urea

在2 mL DMA中組合喹啉-5-醇(0.026 g，0.18 mmol)、1-(4-氟-2'-(三氟甲基)-3,4'-聯吡啶-6-基)-3-甲基脲(0.04 g，0.13 mmol)及K2CO3(0.035 g，0.25 mmol)。將此混合物密封且加熱至90℃隔夜。添加4 mL水且攪拌10分鐘。濾出沈澱物，發現其為1-甲基-3-(4-(喹啉-5-基氧基)-2'-(三氟甲基)-3,4'-聯吡啶-6-基)脲(35 mg，0.079 mmol，62%產率)。質譜(apci)m/z=440.1(M+H)。 Quinoline-5-ol (0.026 g, 0.18 mmol), 1-(4-fluoro-2'-(trifluoromethyl)-3,4'-bipyridin-6-yl)- in 2 mL DMA methyl-urea (0.04 g, 0.13 mmol) and K 2 CO 3 (0.035 g, 0.25 mmol). The mixture was sealed and heated to 90 ° C overnight. Add 4 mL of water and stir for 10 minutes. The precipitate was filtered off and found to be 1-methyl-3-(4-(quinolin-5-yloxy)-2'-(trifluoromethyl)-3,4'-bipyridin-6-yl. Urea (35 mg, 0.079 mmol, 62% yield). Mass spectrum (apci) m/z = 440.1 (M+H).

遵循實例155中之程序，製備以下化合物： Following the procedure in Example 155, the following compounds were prepared:

實例158Example 158

1-(5-(環己-1-烯-1-基)-3-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-(cyclohex-1-en-1-yl)-3-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

向1-(5-溴-3-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.1 g，0.279 mmol)及環己烯-1-基酸(0.070 g，0.56 mmol)於DMF(2.79 ml)中之經攪拌溶液中依序添加Pd(PPh3)4(0.032 g，0.028 mmol)、K2CO3(0.116 g，0.84 mmol)。加熱反應物至100℃且攪拌16小時。添加水以淬滅反應物，且用EtOAc萃取混合物，繼而用CH2Cl2萃取。在真空中濃縮經 合併之有機物。在矽膠上用含0-50% EtOAc之己烷溶離來純化粗產物，得到1-(5-(環己-1-烯-1-基)-3-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.058 g，0.163 mmol，58%產率)。質譜(ESI)m/z=360.0(M+H)。 To 1-(5-bromo-3-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.1 g, 0.279 mmol) and cyclohexen-1-yl Pd(PPh 3 ) 4 (0.032 g, 0.028 mmol), K 2 CO 3 (0.116 g, 0.84 mmol) was added sequentially to a stirred solution of acid (0.070 g, 0.56 mmol) in DMF (2.79 ml). The reaction was heated to 100 ° C and stirred for 16 hours. Water was added to quench the reaction, and the mixture was extracted with EtOAc, then extracted with CH 2 Cl. The combined organics were concentrated in vacuo. The crude product was purified by dissolving from EtOAc (EtOAc) eluting EtOAc (EtOAc) Pyridin-2-yl)-3-methylurea (0.058 g, 0.163 mmol, 58% yield). Mass Spectrum (ESI) m/z = 360.0 (M+H).

遵循實例158中之程序，製備以下化合物： Following the procedure in Example 158, the following compounds were prepared:

實例170Example 170

1-(5-環庚基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-cycloheptyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

向1-(5-(環庚-1-烯-1-基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.013 g，0.035 mmol)於EtOH(0.35 ml)中之溶液中添加Pd/C(0.037 g，0.035 mmol)。在H2氛圍下攪拌所得混合物24小時。經矽膠栓塞過濾混合物且在真空中濃縮，得到1-(5-環庚基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.0102 g，0.027 mmol，78%產率)。質譜(ESI)m/z=376.1(M+H)。 To 1-(5-(cyclohept-1-en-1-yl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.013 g, 0.035 mmol Pd/C (0.037 g, 0.035 mmol) was added to a solution of EtOH (0.35 ml). The resulting mixture was stirred under a H 2 atmosphere for 24 hours. The mixture was filtered through hydrazine gel and concentrated in vacuo to give 1-(5-cycloheptyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.0102 g, 0.027 mmol, 78% yield). Mass Spectrum (ESI) m/z = 376.1 (M+H).

遵循實例170中之程序，製備以下化合物： Following the procedure in Example 170, the following compounds were prepared:

實例174Example 174

1-(4-(2,6-二氟苯氧基)-5-(嗎啉基甲基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(morpholinylmethyl)pyridin-2-yl)-3-methylurea

向二環己基(2',4',6'-三異丙基-[1,1'-聯苯]-2-基)膦(0.027 g，0.056 mmol)、Pd(OAc)2(6.27 mg，0.028 mmol)、1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.1 g，0.28 mmol)及甲基嗎啉三氟硼酸鉀(0.064 g，0.31 mmol)於THF/水(10/1，3 ml)中之經攪拌溶液中添加Cs2CO3(0.273 g，0.84 mmol)。加熱反應混合物至100℃，維持3天。冷卻反應物至室溫，且添加水以淬滅反應物。用EtOAc萃取混合物，繼而用CH2Cl2萃取。在真空中濃縮經合併之有機物。在矽膠上用含0-100% MeOH之CH2Cl2溶離來純化粗物質，得到所要化合物，使其自乙醚中進一步再結晶，得到1-(4-(2,6-二氟苯氧基)-5-(嗎啉基甲基)吡啶-2-基)-3-甲基脲(0.0042 g，0.011 mmol，4%產率)。質譜(ESI)m/z=379.0(M+H)。 Dicyclohexyl (2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.027 g, 0.056 mmol), Pd(OAc) 2 (6.27 mg , 0.028 mmol), 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.1 g, 0.28 mmol) and methylmorpholine III Cs 2 CO 3 (0.273 g, 0.84 mmol) was added to a stirred solution of EtOAc / EtOAc (EtOAc). The reaction mixture was heated to 100 ° C for 3 days. The reaction was cooled to room temperature and water was added to quench the reaction. The mixture was extracted with EtOAc, and then 2 Cl and extracted with CH 2. The combined organics were concentrated in vacuo. CH on silica gel with 0-100% MeOH containing 2 Cl 2 fractions of the crude material was purified to give the desired compound, it is further recrystallized from diethyl ether to give 1- (4- (2,6-difluorophenoxy 5-(Morolinylmethyl)pyridin-2-yl)-3-methylurea (0.0042 g, 0.011 mmol, 4% yield). Mass Spectrum (ESI) m/z = 379.0 (M+H).

實例175Example 175

1-(4-(2,6-二氟苯氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：向燒瓶中添加LiCl(159 mg，3.74 mmol)，且在155℃下於高真空下乾燥燒瓶30分鐘。接著添加Zn(269 mg，4.12 mmol)，且在155℃於高真空下再次乾燥燒瓶20分鐘。使燒瓶冷卻降至室溫，且在N2下添加無水THF(5 mL)，繼而添加1,2-二溴乙烷(0.016 mL，0.187 mmol)。用加熱槍將燒瓶短暫加熱至65℃且冷卻降溫，接著添加氯三甲基矽烷(4.75 μl，0.037 mmol)。短暫攪拌後，添加5滴1 M碘於THF中之溶液。再次短暫攪拌反應物，且添加含4-(溴甲基)四氫-2H-哌喃(670 mg，3.74 mmol)之1 mL THF。加熱反應物至50℃隔夜，得到溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(0.624 M，6 mL)。使鋅少許沈降，接著試劑直接用於下一步驟。 Step A : LiCl (159 mg, 3.74 mmol) was added to the flask and the flask was dried at 155 ° C under high vacuum for 30 min. Then Zn (269 mg, 4.12 mmol) was added and the flask was again dried under high vacuum at 155 °C for 20 min. The flask was cooled down to room temperature, and anhydrous THF (5 mL) under N 2, was added followed by 1,2-dibromoethane (0.016 mL, 0.187 mmol). The flask was briefly heated to 65 ° C with a heat gun and cooled to cool, followed by the addition of chlorotrimethyl decane (4.75 μl, 0.037 mmol). After brief stirring, 5 drops of 1 M iodine in THF were added. The reaction was stirred briefly again and 1 mL THF containing 4-(bromomethyl)tetrahydro-2H-pyran (670 mg, 3.74 mmol). The reaction was heated to 50 &lt;0&gt;C overnight to give ((tetrahydro-2H-pyran-4-yl)methyl)zinc(II) (0.624 M, 6 mL). The zinc was allowed to settle a little and the reagent was used directly in the next step.

步驟B：向含1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(80 mg，0.223 mmol)之燒瓶中添加二乙醯氧基鈀(5.02 mg，0.022 mmol)、S-Phos(18,34 mg，0.045 mmol)且用N2淨化。依序添加經脫氣之THF(2 mL)、溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(1.790 mL，1.117 mmol)。加熱反應物至回流，維持7小時。添加飽和NH4Cl，且用EtOAc萃取混合物。乾燥EtOAc層並濃縮，且藉由矽膠層析(首先用0-50% EtOAc/己烷、接著用0-7% MeOH/CH2Cl2梯度分離)純化，得到56 mg(66%)1-(4-(2,6-二氟苯氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=378.2(M+H)。1H NMR(400 MHz,CDCl3)δ ppm 8.93(br.s,1 H)7.91(br.s.,1 H)7.80(s,1 H)7.13-7.19(m,1 H)6.90-7.06(m,2 H)5.84(br.s.,1 H)3.89(dd,J=11.15,3.52 Hz,2 H)3.29(t,J=11.15 Hz,2 H)2.75(d,J=4.69 Hz,3 H)2.58(d,J=7.24 Hz,2 H)1.86(ddd,J=11.35,7.53,3.81 Hz,1 H)1.53(d,J=13.11 Hz,2 H)1.31(qd,J=12.32,4.70 Hz,2 H)。 Step B : Adding diethyl 2 to a flask containing 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (80 mg, 0.223 mmol) acyl group palladium (5.02 mg, 0.022 mmol), S-Phos (18,34 mg, 0.045 mmol) and purged with N 2. Degassed THF (2 mL), brominated ((tetrahydro-2H-piperidin-4-yl)methyl)zinc(II) (1.790 mL, 1.117 mmol) was added sequentially. The reaction was heated to reflux for 7 hours. Saturated NH 4 Cl, and the mixture was extracted with EtOAc. EtOAc layer was dried and concentrated, and chromatographed by silica gel (first with 0-50% EtOAc / hexane followed by 0-7% MeOH / CH 2 Cl 2 gradient elution) to afford 56 mg (66%) 1- (4-(2,6-Difluorophenoxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 378.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.93 (br.s, 1 H) 7.91 (br.s., 1 H) 7.80 (s, 1 H) 7.13-7.19 (m, 1 H) 6.90-7.06 (m, 2 H) 5.84 (br.s., 1 H) 3.89 (dd, J = 11.15, 3.52 Hz, 2 H) 3.29 (t, J = 11.15 Hz, 2 H) 2.75 (d, J = 4.69 Hz , 3 H) 2.58 (d, J = 7.24 Hz, 2 H) 1.86 (ddd, J = 11.35, 7.53, 3.81 Hz, 1 H) 1.53 (d, J = 13.11 Hz, 2 H) 1.31 (qd, J = 12.32, 4.70 Hz, 2 H).

遵循實例175中之程序，製備以下化合物： Following the procedure in Example 175, the following compounds were prepared:

實例178Example 178

4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)butyric acid

向含4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸乙酯(21 mg，0.053 mmol)之燒瓶中添加MeOH(0.5 mL)、THF(0.500 mL)、1 N LiOH(0.267 mL，0.534 mmol)。在室溫下攪拌反應物隔夜。接著將其用水稀釋且用1 N HCl中和。產生沈澱物。添加EtOAc，然而，沈澱物部分溶解於EtOAc中。因此，過濾溶液混合物。在高真空下乾燥沈澱物。乾燥EtOAc層且濃縮，獲得白色固體。合併沈澱物與固體，得到總共19 mg 4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸(0.052 mmol，97%)。質譜(ESI)m/z=366.2(M+H)。1H NMR(400 MHz,DMSO-d 6)δ ppm 12.05(br.s.,1 H)9.03(s,1 H)8.00(s,1 H)7.65(br.s.,1 H)7.30-7.53(m,3 H)6.80(s,1 H)2.59-2.72(m,5 H)2.27(t,J=7.43 Hz,2 H)1.85(五重峰，J=7.48 Hz,2 H)。 Add to a flask containing ethyl 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)butanoate (21 mg, 0.053 mmol) MeOH (0.5 mL), THF (0.500 mL), 1 N LiOH (0.267 mL, 0.534 mmol). The reaction was stirred at room temperature overnight. It was then diluted with water and neutralized with 1 N HCl. A precipitate is produced. EtOAc was added, however, the precipitate was partially dissolved in EtOAc. Therefore, the solution mixture is filtered. The precipitate was dried under high vacuum. The EtOAc layer was dried and concentrated to give a white solid. The precipitate and solid were combined to give a total of 19 mg of 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)butanoic acid (0.052 mmol, 97 %). Mass Spectrum (ESI) m/z = 366.2 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 12.05 (br.s., 1 H) 9. s (s, 1 H) 8.00 (s, 1 H) 7.65 (br.s., 1 H) 7.30- 7.53 (m, 3 H) 6.80 (s, 1 H) 2.59 - 2.72 (m, 5 H) 2.27 (t, J = 7.43 Hz, 2 H) 1.85 (five-peak, J = 7.48 Hz, 2 H).

實例179Example 179

1-(4-(2,6-二氟苯氧基)-5-(吡啶-2-基甲基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(pyridin-2-ylmethyl)pyridin-2-yl)-3-methylurea

將1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(144 mg，0.355 mmol)、2-(溴甲基)吡啶氫溴酸鹽(135 mg，0.533 mmol)、Pd(PPh3)4(41 mg，0.036 mmol)及2.0 M K2CO3水溶液(0.50 mL，1.0 mmol)於1.7 mL 1,2-二甲氧基乙烷中之經N2脫氣混合物在100℃下攪拌4小時，且冷卻混合物至室溫，經矽藻土襯墊過濾並用EtOAc充分洗滌矽藻土。濃縮濾液且藉由逆相HPLC純化殘餘物，得到8.7 mg 1-(4-(2,6-二氟苯氧基)-5-(吡啶-2-基甲基)吡啶-2-基)-3-甲基脲。質譜ESI(正模式)m/z=371.0(M+H)。1H NMR(400 MHz,CDCl3)δ 8.73(d,J=4.0 Hz,1H),8.00(s,1H),7.93(m,1H),7.50(d,J=8.0 Hz,1H),7.46(d,J=8.0 HZ,1H),7.45(d,J=8.0 Hz,1H),7.37(m,1H),7.13(m 3H),4.41(s,2H),2.84(d,J=4.0 Hz,3H)。 1-(4-(2,6-Difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridin-2-yl)-3-methylurea (144 mg, 0.355 mmol), 2-(bromomethyl)pyridine hydrobromide (135 mg, 0.533 mmol), Pd (PPh 3 ) 4 (41 mg, 0.036 mmol) and a 2.0 MK 2 CO 3 aqueous solution (0.50 mL, 1.0 mmol) in 1.7 mL of 1-dimethoxyethane in a N 2 degassed mixture stirred at 100 ° C for 4 hours The mixture was cooled to room temperature, filtered through a pad of Celite, and washed thoroughly with EtOAc. The filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 8.7 mg of 1-(4-(2,6-difluorophenoxy)-5-(pyridin-2-ylmethyl)pyridin-2-yl)- 3-methylurea. Mass spectrum ESI (positive mode) m/z = 371.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.73 (d, J = 4.0 Hz, 1H), 8.00 (s, 1H), 7.93 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 HZ, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (m, 1H), 7.13 (m 3H), 4.41 (s, 2H), 2.84 (d, J = 4.0) Hz, 3H).

實例180Example 180

1-(4-(2,6-二氟苯氧基)-5-(4-(甲基磺醯基)苯基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-3-methylurea

向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.140 mmol)、(4-(甲基磺醯基)苯基)酸(0.042 g，0.209 mmol)及K2CO3(0.838 ml，0.419 mmol)於1,4-二噁烷(0.140 ml，0.014 mmol)中之經N2脫氣混合物中添加Pd(PPh3)4(0.016 g，0.014 mmol)。將密封管中之所得混合物在100℃下攪拌隔夜。冷卻混合物至室溫且直接進行逆相HPLC純化，得到49.1 mg 1-(4-(2,6-二氟苯氧基)-5-(4-(甲基磺醯基)苯基)-吡啶-2-基)-3-甲基脲。質譜ESI(正模式)m/z=434.0(M+H)。1H NMR(400 MHz,CDCl3)δ 8.11(d,J=4.0 Hz,1H),8.09(d,J=4.0 Hz,1H),8.04(s,1H),7.82(d,J=8.0 Hz,1H),7.55(br s,1H),7.38(m 1H),7.18(dd,J=8.0,8.0 Hz,2H),3.14(s,3H),2.85(d,J=4.0 Hz,3H)。 To 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.050 g, 0.140 mmol), (4-(methylsulfonyl) Phenyl) Adding Pd(PPh 3 ) to the N 2 degassed mixture of acid (0.042 g, 0.209 mmol) and K 2 CO 3 (0.838 ml, 0.419 mmol) in 1,4-dioxane (0.140 ml, 0.014 mmol) 4 (0.016 g, 0.014 mmol). The resulting mixture in the sealed tube was stirred overnight at 100 °C. The mixture was cooled to room temperature and directly subjected to reverse phase HPLC purification to give 49.1 mg of 1-(4-(2,6-difluorophenoxy)-5-(4-(methylsulfonyl)phenyl)-pyridine. -2-yl)-3-methylurea. Mass spectrum ESI (positive mode) m/z = 434.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 4.0 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 8.04 (s, 1H), 7.82 (d, J = 8.0 Hz , 1H), 7.55 (br s, 1H), 7.38 (m 1H), 7.18 (dd, J = 8.0, 8.0 Hz, 2H), 3.14 (s, 3H), 2.85 (d, J = 4.0 Hz, 3H) .

遵循實例180中之程序，製備以下化合物： Following the procedure in Example 180, the following compounds were prepared:

實例194Example 194

1-(4-(2,6-二氟苯氧基)-5-(1-苯基乙基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(1-phenylethyl)pyridin-2-yl)-3-methylurea

在室溫下，於H2氣球下，將1-(4-(2,6-二氟苯氧基)-5-(1-苯基乙烯基)吡啶-2-基)-3-甲基脲(22.0 mg，0.058 mmol)及Pd/C(10重量%(以乾物計)，6.14 mg，5.77 μmol)於MeOH(2.0 ml，49.4 mmol)中之混合物攪拌5小時。經矽藻土襯墊過濾混合物。濃縮濾液且藉由HPLC純化殘餘物，得到9.9 mg 1-(4-(2,6-二氟苯氧基)-5-(1-苯基乙基)吡啶-2-基)-3-甲基脲。質譜ESI(正模式)m/z=384.0(M+H)。1H NMR(400 MHz,CDCl3)δ 7.65(s,1H),7.10-7.19(m,3H),7.28-7.40(m,6H),4.63(m,1H),3.07(m,1H),2.84(br s,1H),2.82(d,J=4.0 Hz,3H),1.73(d,J=4.0 Hz,3H)。 1-(4-(2,6-Difluorophenoxy)-5-(1-phenylvinyl)pyridin-2-yl)-3-methyl at room temperature under H 2 balloon A mixture of urea (22.0 mg, 0.058 mmol) and Pd/C (10% by weight (dry), 6.14 mg, 5.77 μmol) in MeOH (2.0 ml, 49.4 mmol) was stirred for 5 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated and the residue was purified by HPLC to yield s. Base urea. Mass spectrum ESI (positive mode) m/z = 384.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.10-7.19 (m, 3H), 7.28-7.40 (m, 6H), 4.63 (m, 1H), 3.07 (m, 1H), 2.84 (br s, 1H), 2.82 (d, J = 4.0 Hz, 3H), 1.73 (d, J = 4.0 Hz, 3H).

實例195Example 195

(Z)-1-(4-(2,6-二氟苯氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)-3-甲基脲 (Z)-1-(4-(2,6-difluorophenoxy)-5-(2-ethoxyvinyl)pyridin-2-yl)-3-methylurea

向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.111 g，0.310 mmol)及(Z)-1-乙氧基-2-(三丁基錫烷基)乙烯(0.132 mL，0.372 mmol)於甲苯(3 mL)中之經攪拌溶液中添加Pd(PPh3)4(0.072 g，0.062 mmol)。加熱反應物至110℃且繼續攪拌16小時。濃縮混合物且在矽膠上用含0-50% EtOAc之己烷溶離來純化，得到(Z)-1-(4-(2,6-二氟苯氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)-3-甲基脲(0.091 g，0.26 mmol， 84%產率)。質譜(ESI)m/z=350.0(M+H)。1H NMR(500 MHz,CDCl3)δ 8.87(s,1H),7.19-7.27(m,2H),7.06(t,J=7.95 Hz,2H),6.36(d,J=7.09 Hz,1H),5.61(d,J=7.09 Hz,1H),4.05(d,J=7.09 Hz,2H),2.87(d,J=4.65 Hz,3H),1.41(t,J=7.09 Hz,3H)。 To 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.111 g, 0.310 mmol) and (Z)-1-ethoxy Pd(PPh 3 ) 4 (0.072 g, 0.062 mmol) was added to a stirred solution of -2-(tributylstannyl)ethylene (0.132 mL, 0.372 mmol) in toluene (3 mL). The reaction was heated to 110 ° C and stirring was continued for 16 hours. The mixture was concentrated and purified on silica gel eluting with 0-50% EtOAc in hexane to afford (Z)-1-(4-(2,6-difluorophenoxy)-5- (2-ethoxy) Vinyl)pyridin-2-yl)-3-methylurea (0.091 g, 0.26 mmol, 84% yield). Mass Spectrum (ESI) m/z =353. 1 H NMR (500 MHz, CDCl 3 ) δ 8.87 (s, 1H), 7.19-7.27 (m, 2H), 7.06 (t, J = 7.95 Hz, 2H), 6.36 (d, J = 7.09 Hz, 1H) , 5.61 (d, J = 7.09 Hz, 1H), 4.05 (d, J = 7.09 Hz, 2H), 2.87 (d, J = 4.65 Hz, 3H), 1.41 (t, J = 7.09 Hz, 3H).

遵循實例195中之程序，製備以下化合物： Following the procedure in Example 195, the following compounds were prepared:

實例197Example 197

1-(4-(2,6-二氟苯氧基)-5-(2-羥基乙基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(2-hydroxyethyl)pyridin-2-yl)-3-methylurea

步驟A：將(Z)-1-(4-(2,6-二氟苯氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)-3-甲基脲(0.045 g，0.13 mmol)及4 N HCl水溶液(0.129 ml，0.515 mmol)於THF(0.6 mL)中之混合物加熱至回流，維持1.5小時。冷卻混合物至室溫且傾倒至飽和NaHCO3水溶液(20 mL)中。將有機物萃取至CH2Cl2(2×20 mL)中，收集，經MgSO4乾燥且在真空下濃縮，得到1-(4-(2,6-二氟苯氧基)-5-(2-側氧基乙基)吡啶-2-基)-3-甲基脲(0.033 g，0.10 mmol，80%產率)。 Step A : (Z)-1-(4-(2,6-Difluorophenoxy)-5-(2-ethoxyvinyl)pyridin-2-yl)-3-methylurea (0.045 The mixture was stirred with EtOAc (EtOAc m. The mixture was cooled to room temperature and poured into saturated aqueous NaHCO 3 (20 mL) of. The organics were extracted into CH 2 Cl 2 (2 × 20 mL), collected, dried over MgSO 4 and concentrated in vacuo to give 1- (4- (2,6-difluorophenyl) -5- (2 -Phenoxyethyl)pyridin-2-yl)-3-methylurea (0.033 g, 0.10 mmol, 80% yield).

步驟B：向1-(4-(2,6-二氟苯氧基)-5-(2-側氧基乙基)吡啶-2-基)-3-甲基脲(0.033 g，0.10 mmol)於MeOH(1 mL)中之溶液中添加硼氫化鈉(0.0039 g，0.10 mmol)。在室溫下攪拌反應物1.5小時。再添加NaBH4 (0.0039 g，0.10 mmol)，且攪拌反應物2小時。濃縮混合物，且將粗產物分配於EtOAc與0.1 N NaOH(水溶液)之間。收集有機層，經MgSO4乾燥且在真空中濃縮。在矽膠上用含0-10% MeOH之CH2Cl2溶離來純化粗產物，得到1-(4-(2,6-二氟苯氧基)-5-(2-羥基乙基)吡啶-2-基)-3-甲基脲(0.013 g，0.040 mmol，39%產率)。質譜(ESI)m/z=324.0(M+H)。1H NMR(500 MHz,CDCl3)δ 7.95-8.05(m,1H),7.22-7.26(m,1H),7.01-7.15(m,3H),3.95(s,2H),3.00(s,2H),2.88(d,J=4.65 Hz,3H)。 Step B : To 1-(4-(2,6-difluorophenoxy)-5-(2-o-oxyethyl)pyridin-2-yl)-3-methylurea (0.033 g, 0.10 mmol Sodium borohydride (0.0039 g, 0.10 mmol) was added to a solution in MeOH (1 mL). The reaction was stirred at room temperature for 1.5 hours. Add NaBH 4 (0.0039 g, 0.10 mmol ), and the reaction was stirred for 2 hours. The mixture was concentrated, and the crude product was partitioned between EtOAc and 0.1 N NaOH (aq). The organic layer was taken, dried over MgSO 4 On silica gel with 0-10% MeOH containing of CH 2 Cl 2 eluting crude product was purified to give 1- (4- (2,6-difluorophenyl) -5- (2-hydroxyethyl) pyridine - 2-yl)-3-methylurea (0.013 g, 0.040 mmol, 39% yield). Mass Spectrum (ESI) m/z = 324.0 (M+H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.95-8.05 (m, 1H), 7.22-7.26 (m, 1H), 7.01-7.15 (m, 3H), 3.95 (s, 2H), 3.00 (s, 2H) ), 2.88 (d, J = 4.65 Hz, 3H).

實例198Example 198

1-(4-(2,6-二氟苯氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-3,3'-bipyridin-6-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(129 mg，0.36 mmol)、3-吡啶基酸(92 mg，0.75 mmol)、三環己基膦(23 mg，0.083 mmol)及Pd2(dba)3(36 mg，0.04 mmol)添加至小瓶中，接著脫氣且用Ar回填。由注射器向小瓶中添加1,4-二噁烷(3 mL)及1.3 M K3PO4水溶液(0.72 ml，0.94 mmol)。加熱所得反應物至90℃。19小時後，冷卻反應物至室溫，接著在減壓下濃縮。經0.45 μm GHP Acrodisc過濾殘餘物，接著加載於矽膠上(含0-65%預混合89：9：1 CH2Cl2：MeOH：NH4OH之CH2Cl2)，得到膜狀物，用異丙醇濕磨該膜狀物。用Et2O洗滌固體，得到呈白色固體狀之1-(4-(2,6-二氟苯氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(0.0138 g，0.039 mmol，10.75%產率)。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 8.84(1H,d,J=1.6 Hz),8.73(1H,br.s.),8.58-8.65(1H,m),8.14(1H,s),8.00(1H,dt,J=8.0,1.9 Hz),7.43(1H,dd,J=8.0,4.9 Hz),7.28(1H,tt,J=8.5,6.0 Hz),7.04-7.15(2H,m),6.22(1H,br.s.),2.81(3H,d,J=4.7 Hz)。質譜(正模式)m/e：357.1(M+H)+。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (129 mg, 0.36 mmol), 3-pyridyl Acid (92 mg, 0.75 mmol), tricyclohexylphosphine (23 mg, 0.083 mmol) and Pd 2 (dba) 3 (36 mg, 0.04 mmol) were added to the vial, followed by degassing and backfilling with Ar. To the vial was added 1,4-dioxane (3 mL) and 1.3 MK 3 PO 4 aqueous solution (0.72 ml, 0.94 mmol) from a syringe. The resulting reaction was heated to 90 °C. After 19 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. The residue was filtered through 0.45 μm of GHP Acrodisc, then loaded onto silica gel (0-65% premixed 89:9:1 CH 2 Cl 2 : MeOH: NH 4 OH in CH 2 Cl 2 ) to give a membrane. The film was wet-milled with isopropyl alcohol. The solid was washed with Et 2 O, to give a white solid of 1- (4- (2,6-difluorophenoxy) - [3,3'-bipyridine] -6-yl) -3-methylurea (0.0138 g, 0.039 mmol, 10.75% yield). 1 H NMR (400 MHz, methylene chloride-d 2 ) δ ppm 8.84 (1H, d, J = 1.6 Hz), 8.73 (1H, br.s.), 8.58-8.65 (1H, m), 8.14 (1H) , s), 8.00 (1H, dt, J = 8.0, 1.9 Hz), 7.43 (1H, dd, J = 8.0, 4.9 Hz), 7.28 (1H, tt, J = 8.5, 6.0 Hz), 7.04-7.15 ( 2H, m), 6.22 (1H, br.s.), 2.81 (3H, d, J = 4.7 Hz). Mass spectrum (positive mode) m/e: 357.1 (M+H) + .

遵循實例198中之程序，製備以下化合物： Following the procedure in Example 198, the following compounds were prepared:

實例241Example 241

1-(5-(3-氰基-4-甲氧基苯基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-(3-Cyano-4-methoxyphenyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(149 mg，0.42 mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苄腈(220 mg，0.85 mmol)、三環己基膦(26 mg，0.091 mmol)及Pd2(dba)3(40 mg，0.044 mmol)添加至小瓶中，接著脫氣且用Ar回填。由注射器向小瓶中添加二噁烷(2 mL)及1.3 M磷酸三鉀水溶液(0.8 ml，1.04 mmol)。加熱所得反應物至90℃。18小時後，冷卻反應物至室溫，接著在減壓下濃縮。經0.45 μm GHP Acrodisc過濾殘餘物，接著加載於矽膠上(含0-50% EtOAc之CH2Cl2)，得到固體，用MeOH處理該固體，接著在非真空下於旋轉蒸發器(rotovap)上加熱至50℃。20分鐘後，趁熱過濾異質溶液，得到呈白色固體狀之1-(5-(3-氰基-4-甲氧基苯基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.0494 g，0.120 mmol，29.0%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.23(1H,s),8.24(1H,s),7.87-7.96(2H,m),7.33-7.54(5H,m),7.04(1H,s),3.96(3H,s),2.65(3H,d,J=4.4 Hz)。質譜(正模式)m/e：411.1(M+H)+。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (149 mg, 0.42 mmol), 2-methoxy-5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)benzonitrile (220 mg, 0.85 mmol), tricyclohexylphosphine (26 mg, 0.091 mmol) and Pd 2 (dba) 3 (40 mg, 0.044 mmol) were added to the vial, then degassed and used Ar backfill. Dioxane (2 mL) and 1.3 M tripotassium phosphate solution (0.8 ml, 1.04 mmol) were added from a syringe to a vial. The resulting reaction was heated to 90 °C. After 18 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. Was 0.45 μm GHP Acrodisc residue was filtered, then loaded (with the CH 0-50% EtOAc 2 Cl 2) on silica gel to give a solid, the solid was treated with MeOH, followed by non-under vacuum at a rotary evaporator (Rotovap) Heat to 50 °C. After 20 minutes, the heterogeneous solution was filtered to give 1-(5-(3-cyano-4-methoxyphenyl)-4-(2,6-difluorophenoxy)pyridine as a white solid. 2-yl)-3-methylurea (0.0494 g, 0.120 mmol, 29.0% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.23 (1H, s), 8.24 (1H, s), 7.87-7.96 (2H, m), 7.33-7.54 (5H, m), 7.04 (1H, s), 3.96 (3H, s), 2.65 (3H, d, J = 4.4 Hz). Mass spectrum (positive mode) m/e: 411.1 (M+H) + .

遵循實例241中之程序，製備以下化合物： Following the procedure in Example 241, the following compounds were prepared:

實例246Example 246

1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-Difluorophenoxy)-5-(1,1-dioxainyltetrahydro-2H-thiopiperazin-4-yl)pyridin-2-yl)-3 -methylurea

步驟A：將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(122 mg，0.34 mmol)、2-(3,6-二氫-2H-硫代哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼(160 mg，0.71 mmol)、Pd(PPh3)4(47 mg，0.04 mmol)及K2CO3(150 mg，1.08 mmol)添加至小瓶中，接著脫氣且用Ar回填。由注射器向小瓶中添加無水DMF(2 mL)。加熱所得反應物至100℃。19小時後，冷卻反應物至室溫，接著用水稀釋。用CH2Cl2萃取三次後，彙集有機物，接著經無水MgSO4乾燥。過濾並濃縮後，將矽膠添加至黑色殘餘物中，接著加載於矽膠管柱上(含0-55%預混合89：9：1 CH2Cl2：MeOH：NH4OH之CH2Cl2)，得到黑色膜狀物，藉由溶解113 mg於8 mL含0.1% TFA之MeCN中，使用逆相HPLC(含25-90% MeCN(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要化合物之溶離份，接著在減壓下濃縮。將殘餘物溶解於CH2Cl2中，接著用飽和NaHCO3水溶液洗滌兩次且用鹽水洗滌一次。經無水 MgSO4乾燥，過濾並濃縮後，將殘餘物鑑別為1-(4-(2,6-二氟苯氧基)-5-(3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲。質譜(正模式)m/e：378.1(M+H)+。 Step A : 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (122 mg, 0.34 mmol), 2- (3,6) -dihydro-2H-thiopiperazin-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron (160 mg, 0.71 mmol), Pd(PPh 3 ) 4 (47 mg, 0.04 mmol) and K 2 CO 3 (150 mg, 1.08 mmol) were added to the vial, then degassed and backfilled with Ar. Anhydrous DMF (2 mL) was added to the vial from a syringe. The resulting reaction was heated to 100 °C. After 19 hours, the reaction was cooled to room temperature and then diluted with water. After extracting three times with CH 2 Cl 2 , the organics were combined and dried over anhydrous MgSO 4 . After filtration and concentration, the tannin was added to the black residue and then loaded onto a cartridge column (containing 0-55% premixed 89:9:1 CH 2 Cl 2 :MeOH:NH 4 OH in CH 2 Cl 2 ) , a black film was obtained by dissolving 113 mg in 8 mL of MeCN containing 0.1% TFA using reverse phase HPLC (containing 25-90% MeCN (premixed with 0.1% TFA) in water (containing 0.1% TFA) The membrane was further purified. The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2, followed by once with brine and washed twice with saturated NaHCO 3 solution. Dried over anhydrous MgSO 4, filtered and concentrated, the residue was identified as 1- (4- (2,6-difluorophenyl) -5- (3,6-dihydro -2H- thioxo-pyran - 4-yl)pyridin-2-yl)-3-methylurea. Mass spectrum (positive mode) m/e: 378.1 (M+H) + .

步驟B：向含有1-(4-(2,6-二氟苯氧基)-5-(3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(90 mg，0.24 mmol)之小瓶中添加MeOH(2 mL)及水(0.5 mL)。在冰浴中冷卻混合物，接著在約15分鐘後，分數份添加過硫酸氫鉀(306 mg，0.5 mmol)。使反應物升溫至23℃。1.5小時後，濾出過硫酸氫鉀且用MeOH及CH2Cl2沖洗。在減壓下濃縮濾液，接著在矽膠上(含0-100% 89：9：1 CH2Cl2：MeOH：NH4OH預混合溶液之CH2Cl2)純化，得到呈棕色膜狀之1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基-3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(0.0131 g，0.032 mmol，13.49%產率)。質譜(正模式)m/e：410.0(M+H)+。 Step B : To a solution containing 1-(4-(2,6-difluorophenoxy)-5-(3,6-dihydro-2H-thiopiperidin-4-yl)pyridin-2-yl)- A vial of 3-methylurea (90 mg, 0.24 mmol) was added MeOH (2 mL) and water (0.5 mL). The mixture was cooled in an ice bath, and then after about 15 minutes, potassium hydrogen persulfate (306 mg, 0.5 mmol) was added in portions. The reaction was allowed to warm to 23 °C. After 1.5 hours, filtered oxone 2 Cl 2 and rinsed with MeOH and CH. The filtrate was concentrated under reduced pressure, and then on silica gel (containing 0-100% 89: 9: 1 CH 2 Cl 2: MeOH: NH 4 OH CH premixed solution of 2 Cl 2) to give a film of a brown -(4-(2,6-difluorophenoxy)-5-(1,1-dioxyindol-3,6-dihydro-2H-thiopiperazin-4-yl)pyridine-2- 3-methylurea (0.0131 g, 0.032 mmol, 13.49% yield). Mass spectrum (positive mode) m/e: 410.0 (M+H) + .

步驟C：向含有1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基-3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(13 mg，0.032 mmol)於EtOH(2 mL)及EtOAc(2 mL)中之燒瓶中添加Pd/C(10%，38 mg，0.035 mmol)。將燒瓶抽真空，且用N2回填並在23℃下攪拌。約5分鐘後，用H2置換氮氣。17小時後，經矽藻土栓塞過濾反應混合物且在真空中濃縮，得到無色殘餘物，藉由溶解於3 mL DMF中，使用逆相HPLC(含10-90% MeCN(預混有0.1% TFA)之水(含0.1% TFA))純化該殘餘物。合併含有所要產物之溶離份接著在減壓下濃縮。將殘餘物溶解於CH2Cl2中，接著用飽和NaHCO3水溶液洗滌兩次且用鹽水洗滌一次。經無水MgSO4乾燥，過濾並濃縮後，將白色固體鑑別為1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(0.0015 g，3.65 μmol，11.39%產率)。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 7.90(1H,br.s.),7,31-7.42(1H,m),7.15(2H,t,J=8.2 Hz),6.74(1H,br.s.)，3.12-3.31(5H,m),2.78(3H,d, J=4.6 Hz),2.33-2.50(4H,m)。質譜(正模式)m/e：412.1(M+H)+。 Step C : To a solution containing 1-(4-(2,6-difluorophenoxy)-5-(1,1-dioxyindol-3,6-dihydro-2H-thiopipene-4- Pd/C (10%, 38 mg, 0.035 mmol) was added to a flask of pyridine-2-yl)-3-methylurea (13 mg, 0.032 mmol) in EtOAc (2 mL) ). The flask was evacuated and backfilled with N 2 and stirred at 23 ℃. After about 5 minutes, the nitrogen was replaced with H 2 . After 17 hours, the reaction mixture was filtered with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2, followed by once with brine and washed twice with saturated NaHCO 3 solution. Dried over anhydrous MgSO 4, filtered and concentrated, the white solid identified as 1- (4- (2,6-difluorophenyl) -5- (1,1-dioxo-tetrahydro -2H- sulfur ionic group Depipepan-4-yl)pyridin-2-yl)-3-methylurea (0.0015 g, 3.65 μmol, 11.39% yield). 1 H NMR (500 MHz, dichloromethane-d 2 ) δ ppm 7.90 (1H, br. s.), 7, 31-7.42 (1H, m), 7.15 (2H, t, J = 8.2 Hz), 6.74 (1H, br.s.), 3.12-3.31 (5H, m), 2.78 (3H, d, J = 4.6 Hz), 2.33-2.50 (4H, m). Mass spectrum (positive mode) m/e: 412.1 (M+H) + .

實例247Example 247

1-(4'-(2,6-二氟苯氧基)-2,3'-聯吡啶-6'-基)-3-甲基脲 1-(4'-(2,6-difluorophenoxy)-2,3'-bipyridyl-6'-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(130 mg，0.36 mmol)、2-(三丁基錫烷基)吡啶(0.21 ml，0.56 mmol)及Pd(PPh3)4(42 mg，0.037 mmol)於無水甲苯(2 mL)中之混合物用N2脫氣。加熱混合物至100℃。23小時後，冷卻反應物至室溫，接著在減壓下濃縮。經0.45 μm GHP Acrodisc過濾黑色固體，接著加載於矽膠上(含0-55%預混合89：9：1 CH2Cl2：MeOH：NH4OH之CH2Cl2)，得到膜狀物，用2-丙醇濕磨該膜狀物，得到呈白色固體狀之1-(4'-(2,6-二氟苯氧基)-[2,3'-聯吡啶]-6'-基)-3-甲基脲(0.0129 g，0.036 mmol，9.97%產率)。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 8.85(1H,br.s.),8.69-8.79(1H,m),8.66(1H,s),7.96(1H,d,J=7.8 Hz),7.76(1H,td,J=7.8,1.9 Hz),7.22-7.35(2H,m),7.03-7.17(2H,m),6.18(1H,br.s.),2.80(3H,d,J=4.7 Hz)。質譜(正模式)m/e：357.1(M+H)+。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (130 mg, 0.36 mmol), 2-(tributylstannyl)pyridine (0.21 ml, 0.56 mmol) and Pd (PPh 3) 4 (42 mg, 0.037 mmol) in anhydrous toluene (2 mL) of the mixture was degassed with N 2. The mixture was heated to 100 °C. After 23 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. The black solid was filtered through 0.45 μm of GHP Acrodisc, then loaded onto silica gel (containing 0-55% premixed 89:9:1 CH 2 Cl 2 : MeOH: NH 4 OH in CH 2 Cl 2 ) to give a membrane. The film was wet-milled with 2-propanol to give 1-(4'-(2,6-difluorophenoxy)-[2,3'-bipyridyl]-6'-yl) as a white solid. -3-methylurea (0.0129 g, 0.036 mmol, 9.97% yield). 1 H NMR (400 MHz, methylene chloride-d 2 ) δ δ 8.85 (1H, br. s.), 8.69-8.79 (1H, m), 8.66 (1H, s), 7.96 (1H, d, J = 7.8 Hz), 7.76 (1H, td, J = 7.8, 1.9 Hz), 7.22-7.35 (2H, m), 7.03-7.17 (2H, m), 6.18 (1H, br.s.), 2.80 (3H, d, J = 4.7 Hz). Mass spectrum (positive mode) m/e: 357.1 (M+H) + .

遵循實例247中之程序，製備以下化合物： Following the procedure in Example 247, the following compounds were prepared:

實例250Example 250

1-(5-(環己基甲基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-(cyclohexylmethyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

向燒瓶中饋入1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(202 mg，0.56 mmol)、乙酸鈀(II)(42 mg，0.063 mmol)及2-二環己基膦基-2',6'-二甲氧基-1'1'-聯苯(50 mg 0.12 mmol)。將燒瓶脫氣且用Ar回填。在Ar下，由注射器向燒瓶中添加無水THF(4 mL)，接著逐滴添加含0.5 M溴化(環己基甲基)鋅(II)之THF(6 mL，3.00 mmol)。加熱所得反應物至70℃。17.5小時後，冷卻反應物至室溫，接著用EtOAc稀釋。用飽和NH4Cl水溶液將有機物洗滌一次且用鹽水洗滌一次後，經無水Na2SO4乾燥有機層。過濾並濃縮後，將殘餘物加載於矽膠上(含0-40%預混合89：9：1 CH2Cl2：MeOH：NH4OH之CH2Cl2)，得到黃色油狀物，藉由溶解163 mg於10 mL含0.1% TFA之MeCN中，使用逆相HPLC(含25-90% MeCN(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該油狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於CH2Cl2中，接著用飽和NaHCO3水溶液洗滌兩次且用鹽 水洗滌一次。經無水MgSO4乾燥，過濾並濃縮後，將白色固體鑑別為1-(5-(環己基甲基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.0199 g，0.053 mmol，9.39%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 8.99(1H,s),7.95(1H,s),7.66(1H,br.s.),7.32-7.50(3H,m),6.76(1H,s),2.63(3H,d,J=4.6 Hz),2.53(2H,d,J=6.6 Hz),1.50-1.72(6H,m),1.09-1.28(3H,m),0.89-1.04(2H,m)。質譜(正模式)m/e：376.1(M+H)+。 The flask was fed with 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (202 mg, 0.56 mmol), palladium (II) acetate. (42 mg, 0.063 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1'1'-biphenyl (50 mg 0.12 mmol). The flask was degassed and backfilled with Ar. Under argon, anhydrous THF (4 mL) was added from a syringe, followed by dropwise addition of 0.5 M bromo(cyclohexylmethyl)zinc(II) THF (6 mL, 3.00 mmol). The resulting reaction was heated to 70 °C. After 17.5 hours, the reaction was cooled to rt then diluted EtOAc. Saturated with aqueous NH 4 Cl organics were washed once with brine and once, the organic layer was dried over anhydrous Na 2 SO 4. After filtration and concentration, the residue was loaded on silica (0-40% pre-mix 89: 9: 1 CH 2 Cl 2: MeOH: NH 4 OH of CH 2 Cl 2), to give a yellow oil, by 163 mg was dissolved in 10 mL of MeCN containing 0.1% TFA, and the oil was further purified using reverse phase HPLC (25-90% MeCN (premixed with 0.1% TFA) in water (containing 0.1% TFA)). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2, followed by once with brine and washed twice with saturated NaHCO 3 solution. Dried over anhydrous MgSO 4, filtered and concentrated, the white solid identified as 1- (5- (cyclohexylmethyl) -4- (2,6-difluorophenoxy) pyridin-2-yl) -3- Methyl urea (0.0199 g, 0.053 mmol, 9.39% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.99 (1H, s), 7.95 (1H, s), 7.66 (1H, br.s.), 7.32-7.50 (3H, m), 6.76 (1H) , s), 2.63 (3H, d, J = 4.6 Hz), 2.53 (2H, d, J = 6.6 Hz), 1.50-1.72 (6H, m), 1.09-1.28 (3H, m), 0.89-1.04 ( 2H, m). Mass spectrum (positive mode) m/e: 376.1 (M+H) + .

實例251Example 251

1-(4-(2,6-二氟苯氧基)-5-((1-羥基環戊基)乙炔基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-((1-hydroxycyclopentyl)ethynyl)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(154 mg，0.43 mmol)、1-乙炔基環戊醇(0.15 mL，1.31 mmol)、碘化銅(I)(17 mg，0.091 mmol)及PdCl2(PPh3)2(32 mg，0.045 mmol)添加至小瓶中，接著脫氣且用Ar回填。由注射器向小瓶中依序添加無水DMF(3 mL)、NEt3(0.5 mL，3.59 mmol)。加熱反應物至100℃。24小時後，冷卻反應物至室溫，接著用水稀釋。用CH2Cl2萃取三次後，彙集有機物，接著經無水MgSO4乾燥。過濾並濃縮後，將殘餘物加載於矽膠上(含0-50%預混合89：9：1 CH2Cl2：MeOH：NH4OH之CH2Cl2)，得到黃色膜狀物，用EtOAc濕磨該膜狀物，得到呈褐色固體狀之1-(4-(2,6-二氟苯氧基)-5-((1-羥基環戊基)乙炔基)吡啶-2-基)-3-甲基脲(0.0901 g，0.233 mmol，53.9%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.26(1H,s),8.21(1H,s),7.44-7.51(1H,m),7.36-7.44(2H,m),7.28-7.36(1H,m),7.00(1H,s),5.35(1H,s),2.62(3H,d,J=4.6 Hz),1.79-1.95(4H, m),1.59-1.79(4H,m)。質譜(正模式)m/e：388.1(M+H)+。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (154 mg, 0.43 mmol), 1-ethynylcyclopentanol (0.15) mL, 1.31 mmol), copper (I) iodide (17 mg, 0.091 mmol) and PdCl 2 (PPh 3 ) 2 (32 mg, 0.045 mmol) were added to the vial, followed by degassing and backfilling with Ar. Anhydrous DMF (3 mL), NEt 3 (0.5 mL, 3.59 mmol) was added sequentially from a syringe to a vial. The reaction was heated to 100 °C. After 24 hours, the reaction was cooled to room temperature and then diluted with water. After extracting three times with CH 2 Cl 2 , the organics were combined and dried over anhydrous MgSO 4 . After filtration and concentration, the residue was loaded on silica (0-50% pre-mix 89: 9: 1 CH 2 Cl 2: MeOH: NH 4 OH of CH 2 Cl 2), to give a yellow film with EtOAc The film was wet-milled to give 1-(4-(2,6-difluorophenoxy)-5-((1-hydroxycyclopentyl)ethynyl)pyridin-2-yl) as a brown solid. 3-methylurea (0.0901 g, 0.233 mmol, 53.9% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.26 (1H, s), 8.21 (1H, s), 7.44-7.51 (1H, m), 7.36-7.44 (2H, m), 7.28-7.36 (1H , m), 7.00 (1H, s), 5.35 (1H, s), 2.62 (3H, d, J = 4.6 Hz), 1.79-1.95 (4H, m), 1.59-1.79 (4H, m). Mass spectrum (positive mode) m/e: 388.1 (M+H) + .

實例252Example 252

1-(4-((5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基)氧基)吡啶-2-基)-3-甲基脲 1-(4-((5,7-Difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl)oxy)pyridin-2-yl) -3-methylurea

步驟A：在2 mL DMF中組合NaH(於油中之60%分散液)(0.0716 g，1.79 mmol)及5,7-二氟-6-羥基-4-甲基喹啉-2(1H)-酮(0.378 g，1.79 mmol)，且將此物質用N2充氣30分鐘，隨後添加2-氯-4-硝基吡啶(0.284 g，1.79 mmol)，且在室溫下繼續反應。4小時後反應完成，且向反應物中添加1 mL EtOAc及5 mL水。劇烈攪拌此物質30分鐘，隨後將其傾倒至分液漏斗中之50 mL水及50 mL EtOAc中。劇烈震盪此物質，且過濾所得乳液，且收集固體並用EtOAc洗滌。固體含有產物且加以保留。收集有機層，再用50 mL EtOAc洗滌水層，且經MgSO4乾燥經合併之有機物，過濾，且在真空中移除。將粗物質溶解於CH2Cl2中以準備用於在觀測到固體時進行層析。少量MeOH(0.5 mL)不溶解固體，且因此對懸浮液進行音波處理1分鐘，且經由真空過濾收集固體。將此等固體與以上所得之固體合併，得到6-(2-氯吡啶-4-基氧基)-5,7-二氟-4-甲基喹啉-2(1H)-酮(0.157 g，0.487 mmol，27.2%產率)。 Step A : Combine NaH (60% dispersion in oil) (0.0716 g, 1.79 mmol) and 5,7-difluoro-6-hydroxy-4-methylquinoline-2 (1H) in 2 mL DMF - one (0.378 g, 1.79 mmol), and this material inflated with N 2 for 30 minutes followed by addition of 2-chloro-4-nitropyridine (0.284 g, 1.79 mmol), and the reaction was continued at room temperature. After 4 hours the reaction was complete and 1 mL EtOAc and 5 mL water was added to the mixture. This material was stirred vigorously for 30 minutes, then poured into 50 mL water and 50 mL EtOAc in a sep. funnel. The material was shaken vigorously, and the obtained mixture was filtered, and the solid was collected and washed with EtOAc. The solid contains the product and is retained. The organic layer was collected, and then the aqueous layer was washed with 50 mL EtOAc, and the combined dried over MgSO 4 The organics were filtered and removed in vacuo. The crude material was dissolved in CH 2 Cl 2 to prepare for the solid is observed during chromatography. A small amount of MeOH (0.5 mL) did not dissolve solids, and thus the suspension was sonicated for 1 minute and the solid was collected by vacuum filtration. These solids were combined with the solid obtained above to give 6-(2-chloropyridin-4-yloxy)-5,7-difluoro-4-methylquinolin-2(1H)-one (0.157 g , 0.487 mmol, 27.2% yield).

步驟B：在1 mL DMF中組合NaH(於油中之60%分散液)(0.0389 g，0.973 mmol)及6-(2-氯吡啶-4-基氧基)-5,7-二氟-4-甲基喹啉-2(1H)- 酮(0.157 g，0.487 mmol)，且在N2充氣下攪拌此物質35分鐘，隨後添加硫酸二甲酯(0.0598 ml，0.632 mmol)，且在室溫下攪拌此物質。1小時後，反應完成且用CH2Cl2(5 mL)稀釋，接著直接加載於二氧化矽上且用含20% EtOAc之CH2Cl2溶離。合併所要溶離份，在真空中濃縮，且在高真空下乾燥，得到6-(2-氯吡啶-4-基氧基)-5,7-二氟-1,4-二甲基喹啉-2(1H)-酮(0.100 g，0.297 mmol，61.0%產率)。 Step B : Combine NaH (60% dispersion in oil) (0.0389 g, 0.973 mmol) and 6-(2-chloropyridin-4-yloxy)-5,7-difluoro- in 1 mL DMF. 4-methylquinoline-2(1H)-one (0.157 g, 0.487 mmol), and the mixture was stirred under N 2 ag. for 35 min, then dimethyl sulfate (0.0598 ml, 0.632 mmol) was added and Stir the material under warm conditions. After 1 hour, the reaction was complete and diluted with CH 2 Cl 2 (5 mL) , then loaded directly onto silicon dioxide and containing the CH 20% EtOAc 2 Cl 2 fractions. The desired fractions are combined, concentrated in vacuo and dried under high vacuum to give 6-(2-chloropyridin-4-yloxy)-5,7-difluoro-1,4-dimethylquinoline- 2(1H)-one (0.100 g, 0.297 mmol, 61.0% yield).

步驟D：在1 mL MeOCH2CH2OMe中組合1-甲基脲(0.0330 g，0.445 mmol)及細粉狀無水K3PO4(0.110 g，0.520 mmol)，且將此物質用N2充氣5分鐘，隨後添加Pd2(dba)3(0.0136 g，0.0148 mmol)及1,1'-聯萘-2-基二第三丁基膦(0.0237 g，0.0594 mmol)。接著將此混合物用N2充氣10分鐘，隨後將其加熱至60℃，維持45分鐘。冷卻反應物至室溫，且添加6-(2-氯吡啶-4-基氧基)-5,7-二氟-1,4-二甲基喹啉-2(1H)-酮(0.100 g，0.297 mmol)。將反應物用N2充氣5分鐘，隨後將其密封且加熱至90℃。繼續反應經週末，且此後，用75 mL含10% MeOH之CH2Cl2稀釋反應物且攪拌30分鐘，隨後將其過濾。棄去固體，且在真空中濃縮沖洗液，接著在矽膠上(含0-2% MeOH之EtOAc)純化。合併含產物之溶離份，在真空中濃縮，且在高真空下乾燥，得到1-(4-(5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基氧基)吡啶-2-基)-3-甲基脲(0.026 g，0.0660 mmol，22.2%產率)。(apci)(M+H)m/z=375.1。 Step D : Combine 1-methylurea (0.0330 g, 0.445 mmol) and finely powdered anhydrous K 3 PO 4 (0.110 g, 0.520 mmol) in 1 mL of MeOCH 2 CH 2 OMe and inflate the material with N 2 5 minutes followed by the addition of Pd 2 (dba) 3 (0.0136 g, 0.0148 mmol) and 1,1'-binaphthalen-2-yldibutylphosphine (0.0237 g, 0.0594 mmol). This mixture was then aerated with N 2 for 10 minutes and then heated to 60 ° C for 45 minutes. The reaction was cooled to room temperature and 6-(2-chloropyridin-4-yloxy)-5,7-difluoro-1,4-dimethylquinolin-2(1H)-one (0.100 g) , 0.297 mmol). The reaction was inflated with N 2 for 5 min, then sealed and heated to 90 ℃. The reaction was continued over the weekend, and thereafter, with 75 mL of CH 10% MeOH containing Cl 2 The reaction was diluted with 2 and stirred for 30 minutes, then filtered. The solid was discarded and the rinse was concentrated in vacuo then purified on EtOAc (EtOAc EtOAc) The product-containing fractions were combined, concentrated in vacuo and dried under high vacuum to afford 1-(4-(5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2 -Dihydroquinolin-6-yloxy)pyridin-2-yl)-3-methylurea (0.026 g, 0.0660 mmol, 22.2% yield). (apci) (M+H) m/z = 375.1.

實例253Example 253

4-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸 4-(5-((1-ethyl-1 H -pyrazol-5-yl)oxy)-6-(3-methylureido)pyridin-3-yl)butyric acid

將4-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸乙酯(10 mg，0.027 mmol)溶解於0.5 mL 1：1 MeOH：THF混合物中。添加LiOH(2 M溶液)(133 μl，0.266 mmol)，且攪拌隔夜直至完成。用1 M HCl溶液將混合物酸化至pH值為約5，且濃縮至乾燥並置於高真空下，得到4-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸鹽酸鹽(9.2 mg，0.026 mmol，99%產率)。1H NMR(400 MHz,CDCl 3 )δ ppm 7.78(1H,d,J=1.8 Hz),7.40(1H,d,J=2.0 Hz),7.04(1H,br.s),5.66(1H,d,J=2.0 Hz),4.05(2H,q,J=7.2 Hz),2.94(3H,s),2.54(2H,t,J=7.6 Hz),2.26(2H,t,J=7.2 Hz),1.82(2H，五重峰，J=7.4 Hz),1.39(3H,t,J=7.3 Hz)。質譜(ESI)m/z=348,1(M+H)。 Ethyl 4-(5-((1-ethyl-1 H -pyrazol-5-yl)oxy)-6-(3-methylureido)pyridin-3-yl)butanoate (10 mg , 0.027 mmol) was dissolved in 0.5 mL of a 1:1 MeOH:THF mixture. LiOH (2 M solution) (133 μl, 0.266 mmol) was added and stirred overnight until completion. The mixture was acidified to a pH of about 5 with 1 M HCl solution and concentrated to dryness and placed under high vacuum to give 4-(5-((1-ethyl-1H-pyrazol-5-yl)oxy) -6-(3-Methylureido)pyridin-3-yl)butanoic acid hydrochloride (9.2 mg, 0.026 mmol, 99% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.78 (1H, d, J = 1.8 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.04 (1H, br.s), 5.66 (1H, d , J = 2.0 Hz), 4.05 (2H, q, J = 7.2 Hz), 2.94 (3H, s), 2.54 (2H, t, J = 7.6 Hz), 2.26 (2H, t, J = 7.2 Hz), 1.82 (2H, quintuple, J = 7.4 Hz), 1.39 (3H, t, J = 7.3 Hz). Mass Spectrum (ESI) m/z = 348, 1 (M+H).

實例254Example 254

1-(5-環丙基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-cyclopropyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.109 g，0.304 mmol)及環丙基酸(0.052 g，0.61 mmol)於二噁烷(2 mL)中之經攪拌溶液中依序添加Pd2(dba)3(0.028 g，0.030 mmol)、三環己基膦(0.017 g，0.061 mmol)及1.3 M磷酸鉀水溶液(0.585 mL，0.761 mmol)。加熱反應物至90℃且繼續攪拌16小時。濃縮混合物且在矽膠上用含0-50% EtOAc之己烷溶離來純化，得到1-(5-環丙基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.045 g，0.14 mmol，46%產率)。質譜(ESI)m/z=320.0(M+H)。1H NMR(400 MHz,CDCl3)δ 7.60(s,1H),7.32-7.43(m,1H),7.08-7.26(m,3H),2.81(d,J=3.3 Hz,3H),2.01-2.21 (m,1H),1.02-1.19(m,2H),0.68-0.82(m,2H)。 To 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.109 g, 0.304 mmol) and cyclopropyl Add Pd 2 (dba) 3 (0.028 g, 0.030 mmol), tricyclohexylphosphine (0.017 g, 0.061 mmol) to the stirred solution of the acid (0.052 g, 0.61 mmol) in dioxane (2 mL) And a 1.3 M aqueous potassium phosphate solution (0.585 mL, 0.761 mmol). The reaction was heated to 90 ° C and stirring was continued for 16 hours. The mixture was concentrated and purified on silica gel eluting with EtOAc (EtOAc) 3-methylurea (0.045 g, 0.14 mmol, 46% yield). Mass Spectrum (ESI) m/z = 320.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.32-7.43 (m, 1H), 7.08-7.26 (m, 3H), 2.81 (d, J = 3.3 Hz, 3H), 2.01 2.21 (m, 1H), 1.02-1.19 (m, 2H), 0.68-0.82 (m, 2H).

實例255Example 255

1-乙基-3-(5-(吡啶-2-基硫基)-3-(1,3,4-三甲基-1H-吡唑-5-基氧基)吡啶-2-基)脲 1-ethyl-3-(5-(pyridin-2-ylthio)-3-(1,3,4-trimethyl-1H-pyrazol-5-yloxy)pyridin-2-yl) Urea

將5-(吡啶-2-基硫基)-3-(1,3,4-三甲基-1H-吡唑-5-基氧基)吡啶-2-胺(100 mg，0.305 mmol)溶解於THF(1 mL)中，且添加異氰酸酯基乙烷(484 μl，6.11 mmol)並在小瓶中加熱反應物至60℃，維持4小時。在防爆屏障後加熱反應物至70℃隔夜。冷卻反應物至室溫且用CH2Cl2(5 mL)稀釋。添加2 g PS-三胺樹脂(PS-trisamineresin)，且在室溫下攪拌反應物2小時。過濾反應物，用CH2Cl2/MeOH循環(×2)洗滌，濃縮且藉由C18逆相(含20%至95% ACN之水)純化，得到呈白色固體狀之1-乙基-3-(5-(吡啶-2-基硫基)-3-(1,3,4-三甲基-1H-吡唑-5-基氧基)吡啶-2-基)脲(80.3 mg，0.202 mmol，66.0%產率)。質譜(apci)m/z=399.1(M+H)。1H NMR(CDCl3)δ 9.20(t,J=4.5 Hz,1H),8.33(m,1H),8.11(s,1H),7.55-7.46(m,2H),7.06-6.98(m,3H),3.57(s,3H),3.47(m,2H),2.15(s,3H),1.73(s,3H),1.28(t,J=7.0 Hz,3H)。 Dissolve 5-(pyridin-2-ylthio)-3-(1,3,4-trimethyl-1H-pyrazol-5-yloxy)pyridin-2-amine (100 mg, 0.305 mmol) In THF (1 mL), isocyanate ethane (484 μl, 6.11 mmol) was added and the mixture was heated to 60 ° C in a vial for 4 h. The reaction was heated to 70 ° C overnight after the explosion-proof barrier. The reaction was cooled to rt and diluted with CH 2 Cl 2 (5 mL) . 2 g of PS-trisamine resin was added, and the reaction was stirred at room temperature for 2 hours. The reaction was filtered with CH 2 Cl 2 / MeOH cycle (× 2), dried and concentrated by C 18 reverse phase (containing 20-95% of water-ACN) to give a white solid of 1-ethyl - 3-(5-(pyridin-2-ylthio)-3-(1,3,4-trimethyl-1H-pyrazol-5-yloxy)pyridin-2-yl)urea (80.3 mg, 0.202 mmol, 66.0% yield). Mass spectrum (apci) m/z = 399.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.20 (t, J = 4.5 Hz, 1H), 8.33 (m, 1H), 8.11 (s, 1H), 7.55-7.46 (m, 2H), 7.06-6.98 (m, 3H) ), 3.57 (s, 3H), 3.47 (m, 2H), 2.15 (s, 3H), 1.73 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H).

遵循實例255中之程序，亦合成以下化合物： Following the procedure in Example 255, the following compounds were also synthesized:

實例266Example 266

1-(2,3-二羥基丙基)-3-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)脲 1-(2,3-dihydroxypropyl)-3-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)urea

將1-烯丙基-3-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)脲(70 mg，0.172 mmol)溶解於4：1 THF：水(2 mL)中，且添加NMO(26.2 mg，0.223 mmol)及含2.5%氧化鋨(VIII)(21.5 μl，0.00172 mmol)之tBuOH，且在室溫下攪拌反應物隔夜。再添加OsO4(100 μL)，且在室溫下攪拌反應物4小時。添加飽和NaHSO3水溶液(0.5 mL)，且攪拌反應物10分鐘。添加固體NaHCO3以中和反應物， 經矽藻土過濾且濃縮。在矽膠上(含10% MeOH之EtOAc)純化殘餘物，得到呈透明玻璃狀之1-(2,3-二羥基丙基)-3-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)脲(42.9 mg，0.0972 mmol，56.6%產率)。質譜(apci)m/z=442.1(M+H)。1H NMR(CDCl3)δ 9.65(t,J=5.9 Hz,1H),8.46(m,1H),8.32(m,1H),8.12(s,1H),7.68(s,1H),7.50(tt,J=7.8,1.8 Hz,1H),7.29(d,J=8.2 Hz,1H),7.19(dd,J=8.0,4.5 Hz,1H),7.05-6.98(m,3H),3,89(m,1H),3.67(m,2H),3.59(t,J=5.7 Hz,2H),3.20(d,J=4.5 Hz,1H),3.08(t,J=5.3 Hz,1H),2.80(q,J=7.6 Hz,2H),1.26(t,J=7.6 Hz,3H)。 1-Allyl-3-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)urea (70 mg, 0.172 mmol Dissolved in 4:1 THF: water (2 mL), and added NMO (26.2 mg, 0.223 mmol) and tBuOH containing 2.5% yttrium oxide (VIII) (21.5 μl, 0.00172 mmol) and stirred at room temperature The reaction was overnight. Additional OsO 4 (100 μL) was added and the reaction was stirred at room temperature for 4 h. Saturated aqueous NaHSO 3 (0.5 mL), and the reaction was stirred for 10 min. Solid NaHCO 3 was added to neutralize the reaction was filtered through diatomaceous earth and concentrated. The residue was purified on EtOAc (EtOAc EtOAcEtOAc) 5-(p-pyridin-2-ylthio)pyridin-2-yl)urea (42.9 mg, 0.0972 mmol, 56.6% yield). Mass spectrum (apci) m/z = 442.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.65 (t, J = 5.9 Hz, 1H), 8.46 (m, 1H), 8.32 (m, 1H), 8.12 (s, 1H), 7.68 (s, 1H), 7.50 ( Tt, J = 7.8, 1.8 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 8.0, 4.5 Hz, 1H), 7.05-6.98 (m, 3H), 3, 89 (m, 1H), 3.67 (m, 2H), 3.59 (t, J = 5.7 Hz, 2H), 3.20 (d, J = 4.5 Hz, 1H), 3.08 (t, J = 5.3 Hz, 1H), 2.80 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

實例267Example 267

1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)-3-((4-甲基-1H-咪唑-2-基)甲基)脲 1-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-((4-methyl-1H-imidazole- 2-yl)methyl)urea

步驟A：將3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-胺(300 mg，0.925 mmol)溶解於CH2Cl2(5 mL)中，且添加吡啶(224 μl，2.77 mmol)。逐份添加氯甲酸4-硝基苯酯(373 mg，1.85 mmol)，且在室溫下攪拌反應物1小時，得到胺基甲酸單硝基苯酯與胺基甲酸雙硝基苯酯之混合物，其以等分試樣形式用於下一反應中。 Step A : Dissolving 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (300 mg, 0.925 mmol) in CH 2 Cl 2 ( In 5 mL), pyridine (224 μl, 2.77 mmol) was added. 4-Nitrophenyl chloroformate (373 mg, 1.85 mmol) was added portionwise, and the reaction was stirred at room temperature for 1 hour to give a mixture of mononitrophenyl carbazate and bis nitrophenyl benzoate. It was used in the next reaction in the form of an aliquot.

步驟B：將1 mL來自先前步驟之等分試樣(0.18 mmol)添加至(4-甲基-1H-咪唑-2-基)甲胺二鹽酸鹽(101 mg，0.550 mmol)及NEt3(153 μl，1.10 mmol)於CH2Cl2(1 mL)中之懸浮液中。在室溫下攪拌反應物隔夜。將反應物分配於水與CH2Cl2之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含0%至10% MeOH之EtOAc)純化殘餘物，得到呈褐色 固體狀之1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)-3-((4-甲基-1H-咪唑-2-基)甲基)脲(46.4 mg，0.101 mmol，54.8%產率)。質譜(apci)m/z=462.1(M+H)。1H NMR(CDCl3)δ 9.93(t,J=5.9 Hz,1H),9.80(bs,1H),8.46(d,J=4.7 Hz,1H),8.30(m,1H),8.07(d,J=1.4 Hz,1H),7.61(s,1H),7.48(td,J=7.8,1.8 Hz,1H),7.28(m,1H),7.18(dd,J=8.2,4.7 Hz,1H),7.05-6.96(m,3H),6.65(s,1H),4.56(d,J=6.1 Hz,2H),2.79(q,J=7.6 Hz,2H),2.23(s,3H),1.26(t,J=7.4 Hz,3H)。 Step B : 1 mL of an aliquot from the previous step (0.18 mmol) was added to (4-methyl-1H-imidazol-2-yl)methanamine dihydrochloride (101 mg, 0.550 mmol) and NEt 3 (153 μl, 1.10 mmol) in a suspension in CH 2 Cl 2 (1 mL). The reaction was stirred at room temperature overnight. The reaction was partitioned between water and CH 2 Cl 2, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc:EtOAc Thiothio)pyridin-2-yl)-3-((4-methyl-1H-imidazol-2-yl)methyl)urea (46.4 mg, 0.101 mmol, 54.8% yield). Mass spectrum (apci) m/z = 462.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.93 (t, J = 5.9 Hz, 1H), 9.80 (bs, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.30 (m, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.61 (s, 1H), 7.48 (td, J = 7.8, 1.8 Hz, 1H), 7.28 (m, 1H), 7.18 (dd, J = 8.2, 4.7 Hz, 1H), 7.05-6.96 (m, 3H), 6.65 (s, 1H), 4.56 (d, J = 6.1 Hz, 2H), 2.79 (q, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.26 (t) , J = 7.4 Hz, 3H).

遵循實例267中之程序，亦合成以下化合物： Following the procedure in Example 267, the following compounds were also synthesized:

實例311Example 311

(S)-1-(5-溴-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 (S)-1-(5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea

(R)-1-(5-溴-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 (R)-1-(5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea

將5-溴-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-胺(250 mg，0.781 mmol)溶解於CH2Cl2(7 mL)中，且添加吡啶(189 μl，2.34 mmol)。添加氯甲酸4-硝基苯酯(315 mg，1.56 mmol)，且在室溫下攪拌反應物1小時。添加含33%甲胺之EtOH(735 mg，7.81 mmol)，且在室溫下攪 拌反應物隔夜。將反應物分配於水與CH2Cl2之間，用1 N NaOH洗滌，經Na2SO4乾燥，過濾且濃縮。將殘餘物溶解於EtOH(10 mL)中，且添加過量K2CO3，且在室溫下攪拌4小時。過濾反應物，濃縮且在矽膠上(含5% MeOH之EtOAc)純化，得到外消旋物質，藉由對掌性層析(管柱：ODH 20 mm×250 mm，流動速率：35 mL/min，含25% EtOH之超臨界CO2)分離該物質，得到兩種分離之異構體。對於兩種對映異構體，質譜(apci)m/z=376.9,378.9(M+H)。1H NMR(CDCl3)δ 8.99(m,1H),8.57(dd,J=4.7,1.8 Hz,1H),7.87(d,J=2.0 Hz,1H),7.56(dd,J=7.8,1.6 Hz,1H),7.34(d,J=2.0 Hz,1H),7.25(s,1H),7.17(dd,J=7.8,5.0 Hz,1H),5.42(t,J=3.9 Hz,1H),3.11(dt,J=17.8,4.5 Hz,1H),3.00-2.90(m,4H),2.20-1.89(m,4H)。 Dissolve 5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-amine (250 mg, 0.781 mmol) in CH 2 Cl 2 (7 mL) And pyridine (189 μl, 2.34 mmol) was added. 4-Nitrophenyl chloroformate (315 mg, 1.56 mmol) was added, and the mixture was stirred at room temperature for 1 hour. EtOH (735 mg, 7.81 mmol) containing 33% methylamine was added and the mixture was stirred at room temperature overnight. The reaction was partitioned between water and CH 2 Cl 2, washed with 1 N NaOH, dried over Na 2 SO 4, filtered and concentrated. The residue was dissolved in EtOH (10 mL), and the addition of excess K 2 CO 3, and stirred at room temperature for 4 hours. The reaction was filtered, concentrated and purified on EtOAc (EtOAc EtOAc) eluting eluting eluting eluting Separate the material with 25% EtOH supercritical CO 2 ) to give two separated isomers. For the two enantiomers, mass spectrum (apci) m/z = 376.9, 378.9 (M+H). 1 H NMR (CDCl 3 ) δ 8.99 (m, 1 H), 8.57 (dd, J = 4.7, 1.8 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.8, 1.6 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.25 (s, 1H), 7.17 (dd, J = 7.8, 5.0 Hz, 1H), 5.42 (t, J = 3.9 Hz, 1H), 3.11 (dt, J = 17.8, 4.5 Hz, 1H), 3.00-2.90 (m, 4H), 2.20 - 1.89 (m, 4H).

實例312Example 312

1-(2-胺基乙基)-3-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)脲 1-(2-Aminoethyl)-3-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)urea

將2-(3-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)脲基)乙基胺基甲酸第三丁酯(50 mg，0.098 mmol)溶解於CH2Cl2/MeOH(1：1，1 mL)中，且添加含4 N HCl之二噁烷(1 mL)，且在室溫下攪拌反應物經週末。將反應物分配於2 M Na2CO3與CH2Cl2之間，用CH2Cl2萃取(×2)。對水層進行鹽析且用含15% MeOH之CH2Cl2萃取。合併有機層，經Na2SO4乾燥，過濾且濃縮。在逆相上(含5%至80% ACN之水)純化殘餘物。將殘餘物溶解於CH2Cl2/MeOH中，且添加含4 N HCl之二噁烷並移除溶劑，得到呈白色固體狀之1-(2-胺基乙基)-3-(3-(2-乙 基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)脲二鹽酸鹽(15.1 mg，0.0312 mmol，31.9%產率)。質譜(apci)m/z=411.0(M+H-2HCl)。1H NMR(d6-DMSO)δ 9.49(s,1H),9.26(t,J=5.7 Hz,1H),8.48(d,J=5.3 Hz,1H),8.37(m,1H),8.28(d,J=2.0 Hz,1H),8.06(bs,3H),7.84(d,J=8.2 Hz,1H),7.73(s,1H),7.68(m,2H),7.20-7.13(m,2H),3.69(m,1H),3.55-3.44(m,3H),3.06(q,J=7.4 Hz,2H),1.30(t,J=7.6 Hz,3H)。 2-(3-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)ureido)ethylaminocarboxylic acid Butyl ester (50 mg, 0.098 mmol) was dissolved in CH 2 Cl 2 /MeOH (1:1, 1 mL). After the weekend. The reaction was partitioned between 2 M Na 2 CO 3 and between CH 2 Cl 2, extracted with CH 2 Cl 2 (× 2). The aqueous layer was salted and 15% MeOH containing extracted with CH 2 Cl sum. The organic layers were combined, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on a reverse phase (water containing 5% to 80% ACN). The residue was dissolved in CH 2 Cl 2 / MeOH, and the adding of containing 4 N HCl in dioxane and the solvent removed to give a white solid of 1- (2-aminoethyl) -3- (3 (2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)urea dihydrochloride (15.1 mg, 0.0312 mmol, 31.9% yield). Mass spectrum (apci) m/z = 411.0 (M+H-2HCl). 1 H NMR (d 6 -DMSO) δ 9.49 (s, 1H), 9.26 (t, J = 5.7 Hz, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.37 (m, 1H), 8.28 ( d, J = 2.0 Hz, 1H), 8.06 (bs, 3H), 7.84 (d, J = 8.2 Hz, 1H), 7.73 (s, 1H), 7.68 (m, 2H), 7.20-7.13 (m, 2H) ), 3.69 (m, 1H), 3.55-3.44 (m, 3H), 3.06 (q, J = 7.4 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H).

實例313Example 313

1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基亞磺醯基)吡啶-2-基)-3-甲基脲 1-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylsulfinyl)pyridin-2-yl)-3-methylurea

將1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基硫基)吡啶-2-基)-3-甲基脲(74 mg，0.19 mmol)溶解於HOAc(2 mL)中，且添加單水合過硼酸鈉(22 mg，0.21 mmol)，且在室溫下攪拌反應物隔夜。將反應物小心添加至NaHCO3水溶液中，同時添加少量NaHSO3以淬滅過量氧化劑。用CH2Cl2(×2)萃取反應物，經Na2SO4乾燥，過濾且濃縮，得到呈白色固體狀之1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基亞磺醯基)吡啶-2-基)-3-甲基脲(75 mg，0.19 mmol，97%產率)。質譜(apci)m/z=398.1(M+H)。1H NMR(CDCl3)δ 9.07(q,J=4.5 Hz,1H),8.46(m,2H),8.27(d,J=1.8 Hz,1H),7.89(d,J=7.8 Hz,1H),7.83(td,J=7.4,1.6 Hz,1H),7.57(s,1H),7.29(m,1H),7.15(m,2H),7.00(d,J=1.9 Hz,1H),2.95(d,J=4.7 Hz,3H),2.60(m,2H),1.10(t,J=7.6 Hz,3H)。 1-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-methylurea (74 mg, 0.19 mmol) Dissolved in HOAc (2 mL) and added sodium perborate monohydrate (22 mg, 0.21 mmol), and the mixture was stirred at room temperature overnight. The reaction was carefully added to an aqueous solution of NaHCO 3, while a small amount of NaHSO 3 was added to quench the excess oxidant. , Dried with CH 2 Cl 2 (× 2) The reaction was extracted over Na 2 SO 4, filtered and concentrated to give a white solid of 1- (3- (2-ethyl-3-yloxy) -5 -(pyridin-2-ylsulfinyl)pyridin-2-yl)-3-methylurea (75 mg, 0.19 mmol, 97% yield). Mass spectrum (apci) m/z = 398.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.07 (q, J = 4.5 Hz, 1H), 8.46 (m, 2H), 8.27 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H) , 7.83 (td, J = 7.4, 1.6 Hz, 1H), 7.57 (s, 1H), 7.29 (m, 1H), 7.15 (m, 2H), 7.00 (d, J = 1.9 Hz, 1H), 2.95 ( d, J = 4.7 Hz, 3H), 2.60 (m, 2H), 1.10 (t, J = 7.6 Hz, 3H).

實例314 1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基磺醯基)吡啶-2-基)-3-甲基脲 Example 314 1-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylsulfonyl)pyridin-2-yl)-3-methylurea

將1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基亞磺醯基)吡啶-2-基)-3-甲基脲(65 mg，0.164 mmol)溶解於HOAc(2 mL)中，且添加3-氯過氧苯甲酸(40.3 mg，0.164 mmol)，且在室溫下攪拌反應物4小時。將反應物小心添加至NaHCO3水溶液中，同時添加少量NaHSO3以淬滅過量氧化劑。用CH2Cl2(×2)萃取，經Na2SO4乾燥，過濾且濃縮。在逆相上(含20%至80% ACN之水)純化殘餘物，得到呈白色固體狀之1-(3-(2-乙基吡啶-3-基氧基)-5-(吡啶-2-基磺醯基)吡啶-2-基)-3-甲基脲(27.2 mg，0.0658 mmol，40.2%產率)。質譜(apci)m/z=414.1(M+H)。1H NMR(CDCl3)δ 9.09(q,J=4.5 Hz,1H),8.60(m,1H),8.56(d,J=2.0 Hz,1H),8.54(dd,J=4.7,1.6 Hz,1H),8.10(d,J=8.0 Hz,1H),7.92(td,J=7.6,1.4 Hz,1H),7.77(s,1H),7.47(dd,J=7.6,4.7 Hz,1H),7.34(d,J=2.0 Hz,1H),7.28(dd,J=8.2,1.6 Hz,1H),7.24(dd,J=8.2,4.5 Hz,1H),3.00(d,J=4.7 Hz,3H),2.72(q,J=7.6 Hz,2H),1.22(t,J=7.6 Hz,3H)。 1-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylsulfinyl)pyridin-2-yl)-3-methylurea (65 mg, 0.164) Methyl acetate was dissolved in HOAc (2 mL) and 3-chloro-peroxybenzoic acid (40.3 mg, 0.164 mmol) The reaction was carefully added to an aqueous solution of NaHCO 3, while a small amount of NaHSO 3 was added to quench the excess oxidant. It was extracted with CH 2 Cl 2 (× 2) , dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc:EtOAc) - sulfamoyl) pyridin-2-yl)-3-methylurea (27.2 mg, 0.0658 mmol, 40.2% yield). Mass spectrum (apci) m/z = 414.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.09 (q, J = 4.5 Hz, 1H), 8.60 (m, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.92 (td, J = 7.6, 1.4 Hz, 1H), 7.77 (s, 1H), 7.47 (dd, J = 7.6, 4.7 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 1.6 Hz, 1H), 7.24 (dd, J = 8.2, 4.5 Hz, 1H), 3.00 (d, J = 4.7 Hz, 3H) ), 2.72 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H).

實例315Example 315

1-(3-(2-乙基吡啶-3-基氧基)-5-(3-甲氧基丙基磺醯基)吡啶-2-基)-3-甲基脲 1-(3-(2-ethylpyridin-3-yloxy)-5-(3-methoxypropylsulfonyl)pyridin-2-yl)-3-methylurea

將1-(3-(2-乙基吡啶-3-基氧基)-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(30 mg，0.0797 mmol)溶解於1：1 CH2Cl2：HOAc(1.5 mL)中，且添加3-氯過氧苯甲酸(43.2 mg，0.175 mmol)，且在室溫下攪拌隔夜。藉由傾倒至含少量NaHSO3之NaHCO3水溶液中來淬滅反應物，且用CH2Cl2(×3)萃取，經Na2SO4乾燥，過濾並濃縮。在矽膠上(含0%至10% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之1-(3-(2-乙基吡啶-3-基氧基)-5-(3-甲氧基丙基磺醯基)吡啶-2-基)-3-甲基脲(17.3 mg，0.0424 mmol，53.1%產率)。質譜(apci)m/z=409.0(M+H)。1H NMR(CDCl3)δ 9.08(q,J=3.9 Hz,1H),8.55(dd,J=4.5,1.8 Hz,1H),8.42(d,J=2.0 Hz,1H),7.81(s,1H),7.31-7.23(m,2H),7.11(d,J=2.0 Hz,1H),3.40(t,J=5.7 Hz,1H),3.27(s,3H),3.13(m,2H),3.03(d,J=4.7 Hz,3H),2.76(q,J=7.4 Hz,2H),1.94(m,2H),1.27(t,J=7.4 Hz,3H)。 1-(3-(2-ethylpyridin-3-yloxy)-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea (30 mg, 0.0797 mmol) Dissolved in 1:1 CH 2 Cl 2 : HOAc (1.5 mL), and added 3-chloroperoxybenzoic acid (43.2 mg, 0.175 mmol), and stirred at room temperature overnight. By pouring a small amount to a solution of NaHSO 3 aqueous NaHCO 3 solution The reaction was quenched and extracted with CH 2 Cl 2 (× 3) , dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc (EtOAc) Propylsulfonyl)pyridin-2-yl)-3-methylurea (17.3 mg, 0.0424 mmol, 53.1% yield). Mass spectrum (apci) m/z = 409.0 (M+H). 1 H NMR (CDCl 3 ) δ 9.08 (q, J = 3.9 Hz, 1H), 8.55 (dd, J = 4.5, 1.8 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.31-7.23 (m, 2H), 7.11 (d, J = 2.0 Hz, 1H), 3.40 (t, J = 5.7 Hz, 1H), 3.27 (s, 3H), 3.13 (m, 2H), 3.03 (d, J = 4.7 Hz, 3H), 2.76 (q, J = 7.4 Hz, 2H), 1.94 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H).

實例316Example 316

1-甲基-3-(5-(2-甲基吡啶-3-基氧基)-3,3'-聯吡啶-6-基)脲 1-methyl-3-(5-(2-methylpyridin-3-yloxy)-3,3'-bipyridin-6-yl)urea

將1-(5-溴-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(50 mg，0.148 mmol)溶解於二甲氧基乙烷(2 mL)中，且且添加吡啶-3-基酸(36.5 mg，0.297 mmol)及2 M Na2CO3(222 μl，0.445 mmol)，且使N2鼓泡通過反應物，持續5分鐘。添加Pd(PPh3)4(17.1 mg，0.0148 mmol)，且在N2下將反應物傾沒於80℃油浴中，維持1小時。冷卻反應物至室溫，分配於水與EtOAc之間，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含15% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之1- 甲基-3-(5-(2-甲基吡啶-3-基氧基)-3,3'-聯吡啶-6-基)脲(31.3 mg，0.0933 mmol，62.9%產率)。質譜(apci)m/z=336.1(M+H)。1H NMR(CDCl3)δ 9.24(q,J=4.5 Hz,1H),8.67(m,1H),8.60(d,J=4.9 Hz,1H),8.45(d,J=4.5 Hz,1H),8.16(s,1H),7.68(m,1H),7.58(s,1H),7.34(dd,J=8.0,4.9 Hz,1H),7.29(d,J=8.2 Hz,1H),7.22(dd,J=8.0,4.7 Hz,1H),6.97(s,1H),3.03(d,J=4.7 Hz,3H),2.51(s,3H)。 Dissolving 1-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (50 mg, 0.148 mmol) in dimethoxyethane (2 mL) with and without pyridin-3-yl Acid (36.5 mg, 0.297 mmol) and 2 M Na 2 CO 3 (222 μl, 0.445 mmol) and N 2 was bubbled through the reaction for 5 min. Was added Pd (PPh 3) 4 (17.1 mg, 0.0148 mmol), under N 2 and the reaction was poured at 80 deg.] C is not an oil bath for 1 hour. The reaction was cooled to rt EtOAc (EtOAc m. The residue was purified on EtOAc (EtOAc:EtOAc) Bipyridin-6-yl)urea (31.3 mg, 0.0933 mmol, 62.9% yield). Mass spectrum (apci) m/z = 336.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.24 (q, J = 4.5 Hz, 1H), 8.67 (m, 1H), 8.60 (d, J = 4.9 Hz, 1H), 8.45 (d, J = 4.5 Hz, 1H) , 8.16 (s, 1H), 7.68 (m, 1H), 7.58 (s, 1H), 7.34 (dd, J = 8.0, 4.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.22 ( Dd, J = 8.0, 4.7 Hz, 1H), 6.97 (s, 1H), 3.03 (d, J = 4.7 Hz, 3H), 2.51 (s, 3H).

遵循實例316中之程序，亦合成以下化合物： Following the procedure in Example 316, the following compounds were also synthesized:

實例337Example 337

3-(5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯 Methyl 3-(5-(2-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate

將1-(5-溴-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(100 mg，0.30 mmol)溶解於二噁烷(3 mL)中，且添加N-乙基-N-異丙基丙- 2-胺(103 μl，0.59 mmol)及Xantphos(8.6 mg，0.015 mmol)，且使N2鼓泡通過反應物，持續10分鐘。添加3-巰基丙酸甲酯(39 μl，0.36 mmol)及Pd2dba3(6.8 mg，0.0074 mmol)，且在N2下將反應物傾沒於95℃油浴中，維持3小時。冷卻反應物至室溫，經矽藻土過濾，濃縮且在矽膠上(含5% MeOH之EtOAc)純化，得到呈淺黃色固體狀之3-(5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(91.6 mg，0.24 mmol，82.1%產率)。質譜(apci)m/z=377.1(M+H)。1H NMR(CDCl3)δ 9.11(q,J=4.1 Hz,1H),8.45(dd,J=4.5,1.8 Hz,1H),7.98(d,J=1.8 Hz,1H),7.50(s,1H),7.25(dd,J=8.2,1.8 Hz,1H),7.22(dd,J=8.2,4.5 Hz,1H),6.87(d,J=2.0 Hz,1H),3.65(s,3H),3.00(d,J=4.7 Hz,3H),2.97(t,J=7.0 Hz,2H),2.53(t,J=7.2 Hz,2H),2.47(s,3H)。 Dissolve 1-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (100 mg, 0.30 mmol) in dioxane (3 mL) And N-ethyl-N-isopropylpropan-2-amine (103 μl, 0.59 mmol) and Xantphos (8.6 mg, 0.015 mmol) were added and N 2 was bubbled through the reaction for 10 min. . Methyl 3-mercaptopropionate (39 μl, 0.36 mmol) and Pd 2 dba 3 (6.8 mg, 0.0074 mmol) were added and the reaction was poured in a 95 ° C oil bath under N 2 for 3 h. The reaction was cooled to EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl oxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (91.6 mg, 0.24 mmol, 82.1% yield). Mass spectrum (apci) m/z = 377.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.11 (q, J = 4.1 Hz, 1H), 8.45 (dd, J = 4.5, 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.50 (s, 1H), 7.25 (dd, J = 8.2, 1.8 Hz, 1H), 7.22 (dd, J = 8.2, 4.5 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 3.65 (s, 3H), 3.00 (d, J = 4.7 Hz, 3H), 2.97 (t, J = 7.0 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.47 (s, 3H).

遵循實例337中之程序，亦合成以下化合物： Following the procedure in Example 337, the following compounds were also synthesized:

實例350Example 350

1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(吡啶-2-基甲硫基)吡啶-2-基)脲 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylmethylthio)pyridin-2-yl)urea

將3-(5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(90 mg，0.239 mmol)溶解於THF(2 mL)中且用N2淨化。添加2-甲基丙-2-醇鉀(1 M，於THF中，837 μl，0.837 mmol)，且在室溫下攪拌30秒。添加2-(溴甲基)吡啶氫溴酸鹽(60.5 mg，0.239 mmol)，且在室溫下於N2下攪拌反應物1.5小時。用NH4Cl水溶液淬滅反應物，用EtOAc萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含10% MeOH之EtOAc)純化殘餘物，得到呈透明玻璃狀之1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(吡啶-2-基甲硫基)吡啶-2-基)脲(59.2 mg，0.155 mmol，64.9%產率)。質譜(apci)m/z=382.1(M+H)。1H NMR(CDCl3)δ 9.08(m,1H),8.43(m,2H),7.90(m,1H),7.57(t,J=7.6 Hz,1H),7.45(s, 1H),7.20-7.10(m,4H),6.69(s,1H),4.03(s,2H),2.98(d,J=4.5 Hz,3H),2.39(s,3H)。 Dissolve methyl 3-(5-(2-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (90 mg, 0.239 mmol) in THF (2 mL) and treated with N 2 purge. Potassium 2-methylpropan-2-ol (1 M in THF, 837 μl, 0.837 mmol) was added and stirred at room temperature for 30 s. 2- (bromomethyl) pyridine hydrobromide (60.5 mg, 0.239 mmol), and the reaction was stirred under N 2 at room temperature for 1.5 hours. With aqueous 4 Cl NH quenched reaction was extracted with EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAcEtOAc) 2-methylmethylthio)pyridin-2-yl)urea (59.2 mg, 0.155 mmol, 64.9% yield). Mass spectrum (apci) m/z = 382.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.08 (m, 1H), 8.43 (m, 2H), 7.90 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.20- 7.10 (m, 4H), 6.69 (s, 1H), 4.03 (s, 2H), 2.98 (d, J = 4.5 Hz, 3H), 2.39 (s, 3H).

遵循實例350中之程序，亦合成以下化合物： Following the procedure in Example 350, the following compounds were also synthesized:

實例387Example 387

(S)-1-(5-(4-甲氧基丁-2-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 (S)-1-(5-(4-Methoxybut-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methyl Urea

(R)-1-(5-(4-甲氧基丁-2-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 (R)-1-(5-(4-methoxybutan-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methyl Urea

將3-(5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(150 mg，0.398 mmol)溶解於THF(4 mL)中，且使N2鼓泡通過，持續5分鐘。添加含1 M 2-甲基丙-2-醇鉀之THF(1195 μl，1.20 mmol)，且在室溫下攪拌反應物30秒。添加甲烷磺酸4-甲氧基丁-2-基酯(109 mg，0.598 mmol)，且在室溫下攪拌反應物4小時。用NH4Cl水溶液淬滅反應物，用EtOAc萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含0%至5% MeOH之EtOAc)純化殘餘物，得到外消旋物質。藉由對掌性層析分離外消旋物質，得到兩種對映異構體(管柱：ADH 20 mm×250 mm，流動速率：65 mL/min，含7% MeOH之超臨界CO2)。對於第一溶離峰，質譜(apci)m/z=377.0(M+H)；且對於第二溶離峰，m/z=377.1(M+H)。1H NMR(CDCl3)δ 9.14(q,J=4.3 Hz,1H),8.43(dd,J=4.1,2.0 Hz,1H),7.98(s,1H),7.23(m,2H),6.87(d,J=1.8 Hz,1H),3.51-3.37(m,2H),3.26(s,3H),3.09(q,J=6.8 Hz,1H),3.00(d,J=4.7 Hz,3H),2.47(s,3H),1.80-1.64(m,2H),1.20(d,J=6.8 Hz,3H)。 Dissolve methyl 3-(5-(2-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (150 mg, 0.398 mmol) in THF (4 mL), and that the N 2 was bubbled through for 5 minutes. THF (1195 μl, 1.20 mmol) containing 1 M 2-methylpropan-2-ol was added and the mixture was stirred at room temperature for 30 s. 4-Methoxybut-2-yl methanesulfonate (109 mg, 0.598 mmol) was added, and the mixture was stirred at room temperature for 4 hr. With aqueous 4 Cl NH quenched reaction was extracted with EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc) The two enantiomers were obtained by separation of the racemic material by palm chromatography (column: ADH 20 mm × 250 mm, flow rate: 65 mL/min, supercritical CO 2 containing 7% MeOH) . For the first elution peak, mass spectrum (apci) m/z = 377.0 (M+H); and for the second elution peak, m/z = 377.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.14 (q, J = 4.3 Hz, 1H), 8.43 (dd, J = 4.1, 2.0 Hz, 1H), 7.78 (s, 1H), 7.23 (m, 2H), 6.87 ( d, J = 1.8 Hz, 1H), 3.51-3.37 (m, 2H), 3.26 (s, 3H), 3.09 (q, J = 6.8 Hz, 1H), 3.00 (d, J = 4.7 Hz, 3H), 2.47 (s, 3H), 1.80 - 1.64 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H).

實例388Example 388

(S)-1-(5-(3-甲氧基丙硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲鹽酸鹽 (S)-1-(5-(3-methoxypropylthio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3 -methylurea hydrochloride

(R)-1-(5-(3-甲氧基丙硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲鹽酸鹽 (R)-1-(5-(3-methoxypropylthio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3 -methylurea hydrochloride

將3-(6-(3-甲基脲基)-5-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯(130 mg，0.312 mmol)溶解於THF(3 mL)中，且使N2鼓泡 通過，持續5分鐘。添加含1 M 2-甲基丙-2-醇鉀之THF(936 μl，0.936 mmol)，且攪拌反應物30秒。添加1-溴-3-甲氧基丙烷(42.8 μl，0.375 mmol)，且在室溫下攪拌反應物1小時。將反應物分配於水與EtOAc之間，用EtOAc(×2)萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含5% MeOH之EtOAc)純化殘餘物，得到約80 mg外消旋物質。藉由對掌性層析分離外消旋物質，得到兩種對映異構體(管柱：ODH 20 mm×250 mm，流動速率：35 mL/min，含25% EtOH之超臨界CO2)。對於兩種對映異構體，質譜(apci)m/z=403.0(M+H)。1H NMR(CDCl3)δ 8.65(d,J=7.4 Hz,1H),8.58(d,J=5.5 Hz,1H),8.02(s,1H),7.83(t,J=6.2 Hz,1H),7.65(s,1H),7.30(m,1H),6.16(s,1H),3.52(t,J=5.9 Hz,2H),3.50-3.39(m,2H),3.35(s,3H),3.32-3.21(m,1H),3.14(t,J=7.2 Hz,2H),2.82(s,3H),2.35-2.21(m,3H),2.05(m,1H),1.94(m,2H)。 Methyl 3-(6-(3-methylureido)-5-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-3-ylthio)propanoate ( 130 mg, 0.312 mmol) was dissolved in THF (3 mL), and that the N 2 was bubbled through for 5 minutes. THF (936 μl, 0.936 mmol) containing 1 M 2-methylpropan-2-ol was added and the mixture was stirred for 30 s. 1-Bromo-3-methoxypropane (42.8 μl, 0.375 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was partitioned between water and EtOAc, (× 2) extracted with EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc) The two enantiomers were obtained by separating the racemic material by palm chromatography (column: ODH 20 mm × 250 mm, flow rate: 35 mL/min, supercritical CO 2 containing 25% EtOH) . For the two enantiomers, the mass spectrum (apci) m/z = 403.0 (M+H). 1 H NMR (CDCl 3 ) δ 8.65 (d, J = 7.4 Hz, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.02 (s, 1H), 7.83 (t, J = 6.2 Hz, 1H) , 7.65 (s, 1H), 7.30 (m, 1H), 6.16 (s, 1H), 3.52 (t, J = 5.9 Hz, 2H), 3.50-3.39 (m, 2H), 3.35 (s, 3H), 3.32-3.21(m,1H), 3.14 (t, J = 7.2 Hz, 2H), 2.82 (s, 3H), 2.35-2.21 (m, 3H), 2.05 (m, 1H), 1.94 (m, 2H) .

實例389Example 389

1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(哌啶-4-基甲硫基)吡啶-2-基)脲二鹽酸鹽 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5-(piperidin-4-ylmethylthio)pyridin-2-yl)urea dihydrochloride

將4-((5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)甲基)哌啶-1-甲酸第三丁酯(65 mg，0.133 mmol)溶解於CH2Cl2(含10% MeOH)(3 mL)中，且添加含4 N HCl之二噁烷(2 mL)，且在室溫下攪拌30分鐘。濃縮反應物且在真空烘箱中乾燥，得到呈白色固體狀之1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(哌啶-4-基甲硫基)吡啶-2-基)脲二鹽 酸鹽(56.9 mg，0.124 mmol，93.0%產率)。質譜(apci)m/z=388.1(M+H-2HCl)。1H NMR(d6-DMSO)δ 9.19(s,1H),8.90(m,2H),8.67(bs,1H),8.47(dd,J=50,1.2 Hz,1H),8.15(d,J=1.8 Hz,1H),7.73-7.63(m,3H),3.70(m,2H),3.38(s,3H),3.48(m,1H),2.78(m,4H),2.70(s,3H),1.67(m,1H),1.35(m,2H)。 4-((5-(2-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)methyl)piperidine-1-carboxylic acid III Butyl ester (65 mg, 0.133 mmol) was dissolved in CH 2 Cl 2 (10% MeOH) (3 mL). . The reaction was concentrated and dried in vacuo to give 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5- (piperidin-4-yl) as a white solid. Thio)pyridin-2-yl)urea dihydrochloride (56.9 mg, 0.124 mmol, 93.0% yield). Mass spectrum (apci) m/z = 388.1 (M+H-2HCl). 1 H NMR (d 6 -DMSO) δ 9.19 (s, 1H), 8.90 (m, 2H), 8.67 (bs, 1H), 8.47 (dd, J = 50, 1.2 Hz, 1H), 8.15 (d, J =1.8 Hz, 1H), 7.73-7.63 (m, 3H), 3.70 (m, 2H), 3.38 (s, 3H), 3.48 (m, 1H), 2.78 (m, 4H), 2.70 (s, 3H) , 1.67 (m, 1H), 1.35 (m, 2H).

遵循實例389中之程序，亦合成以下化合物： Following the procedure in Example 389, the following compounds were also synthesized:

實例394Example 394

1-(5-苄基-3-(2-甲基吡啶-3-基氧基)吡嗪-2-基)-3-甲基脲 1-(5-benzyl-3-(2-methylpyridin-3-yloxy)pyrazin-2-yl)-3-methylurea

將1-(5-溴-3-(2-甲基吡啶-3-基氧基)吡嗪-2-基)-3-甲基脲(100 mg，0.296 mmol)及Cs2CO3(289 mg，0.887 mmol)溶解於DMF(3 mL)及水(0.3 mL)中且用N2淨化。添加0.5 M 9-苄基-9-硼雙環[3.3.1]壬烷(1.7 mL，0.887 mmol)及PdCl2(dppf)．CH2Cl2(24.1 mg，0.0296 mmol)，且加熱反應物至60℃，維持1小時。冷卻反應物至室溫，分配於EtOAc與水之間，用鹽水洗滌，經Na2SO4乾燥，過濾並濃縮，且在矽膠上(含2% MeOH之EtOAc)純化，得到呈白色固體狀之1-(5-苄基-3-(2-甲基吡啶-3-基氧基)吡嗪-2-基)-3-甲基脲(75.8 mg，0.217 mmol，73.4%產率)。質譜(apci)m/z=350.1(M+H)。1H NMR(CDCl3)δ 8.85(q,J=4.1 Hz,1H),8.45(dd,J=4.7,1.4 Hz,1H),7.64(s,1H),7.47(s,1H),7.34(dd,J=8.0,1.2 Hz,1H),7.26-7.17(m,4H),7.10(m,2H),3.80(s,2H),2.97(d,J=4.7 Hz,3H),2.32(s,3H)。 1-(5-Bromo-3-(2-methylpyridin-3-yloxy)pyrazin-2-yl)-3-methylurea (100 mg, 0.296 mmol) and Cs 2 CO 3 (289 mg, 0.887 mmol) dissolved in DMF (3 mL) and water (0.3 mL) and treated with N 2 purge. Add 0.5 M 9-benzyl-9-borobicyclo[3.3.1]decane (1.7 mL, 0.887 mmol) and PdCl 2 (dppf). CH 2 Cl 2 (24.1 mg, 0.0296 mmol), and the reaction was heated to 60 ° C for 1 hour. The reaction was cooled to rt, partitioned between EtOAc and water, washed with brine, dried over Na 2 SO 4, filtered and concentrated, and purified (2% MeOH in of EtOAc) on silica gel to give a white solid of 1-(5-Benzyl-3-(2-methylpyridin-3-yloxy)pyrazin-2-yl)-3-methylurea (75.8 mg, 0.217 mmol, 73.4% yield). Mass spectrum (apci) m/z = 350.1 (M+H). 1 H NMR (CDCl 3 ) δ 8.85 (q, J = 4.1 Hz, 1H), 8.45 (dd, J = 4.7, 1.4 Hz, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.34 ( Dd, J = 8.0, 1.2 Hz, 1H), 7.26-7.17 (m, 4H), 7.10 (m, 2H), 3.80 (s, 2H), 2.97 (d, J = 4.7 Hz, 3H), 2.32 (s) , 3H).

遵循實例394中之程序，亦合成以下化合物： Following the procedure in Example 394, the following compounds were also synthesized:

實例396Example 396

1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-苯乙基吡嗪-2-基)脲 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5-phenethylpyrazin-2-yl)urea

將(E)-1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-苯乙烯基吡嗪-2-基)脲(50 mg，0.138 mmol)溶解於EtOH(4 mL)及EtOAc(1 mL)中，且添加10% Pd/C。增添H2氣球，且在室溫下攪拌反應物隔夜。經矽藻土過濾反應物且濃縮。在矽膠上(100% EtOAc)純化殘餘物，得到呈白色固體狀之1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-苯乙基吡嗪-2-基)脲(31.2 mg，0.0859 mmol，62.1%產率)。質譜(apci)m/z=364.1(M+H)。1H NMR(CDCl3)δ 8.85(q,J=4.3 Hz,1H),8.45(dd,J=4.7,1.4 Hz,1H),7.55(s,1H),7.47(s,1H),7.35(dd,J=8.2,1.4 Hz,1H),7.26-7.14(m,4H),7.02(m,2H),2.99(d,J=4.7 Hz,3H),2.82(m,4H),2.40(s,3H)。 (E)-1-Methyl-3-(3-(2-methylpyridin-3-yloxy)-5-styrypyrazin-2-yl)urea (50 mg, 0.138 mmol) was dissolved In EtOH (4 mL) and EtOAc (1 mL), 10% Pd / C. Adding H 2 balloon, and the reaction was stirred overnight at room temperature. The reaction was filtered through celite and concentrated. The residue was purified on EtOAc (EtOAc (EtOAc) 2-Based urea (31.2 mg, 0.0859 mmol, 62.1% yield). Mass spectrum (apci) m/z = 364.1 (M+H). 1 H NMR (CDCl 3 ) δ 8.85 (q, J = 4.3 Hz, 1H), 8.45 (dd, J = 4.7, 1.4 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.35 ( Dd, J = 8.2, 1.4 Hz, 1H), 7.26-7.14 (m, 4H), 7.02 (m, 2H), 2.99 (d, J = 4.7 Hz, 3H), 2.82 (m, 4H), 2.40 (s) , 3H).

遵循實例396中之程序，亦合成以下化合物： Following the procedure in Example 396, the following compounds were also synthesized:

實例398Example 398

1-(5-(赤-1,2-二羥基-2-苯基乙基)-3-(2-甲基吡啶-3-基氧基)吡嗪-2-基)-3-甲基脲 1-(5-(erythro-1,2-dihydroxy-2-phenylethyl)-3-(2-methylpyridin-3-yloxy)pyrazin-2-yl)-3-methyl Urea

將(E)-1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-苯乙烯基吡嗪-2-基)脲(50 mg，0.138 mmol)溶解於2：1 THF：水(2 mL)中，且添加NMO(17.8 mg，0.152 mmol)及含2.5% OsO4(17.4 μl，0.00138 mmol)之 tBuOH，且在室溫下攪拌反應物隔夜。用NaHSO3水溶液淬滅反應物，分配於鹽水與EtOAc之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含10% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之1-(5-(赤-1,2-二羥基-2-苯基乙基)-3-(2-甲基吡啶-3-基氧基)吡嗪-2-基)-3-甲基脲(27.1 mg，0.0685 mmol，49.5%產率)。質譜(apci)m/z=396.1(M+H)。1H NMR(CDCl3)δ 8.79(m,1H),8.46(t,J=3.1 Hz,1H),7.64(s,1H),7.52(s,1H),7.30-7.24(m,3H),7.21(d,J=2.9 Hz,2H),7.11(m,2H),4.64(m,2H),2.99(d,J=4.7 Hz,3H),2.83(d,J=6.4 Hz,1H),2.82(d,J=2.9 Hz,1H),2.36(s,3H)。 (E)-1-Methyl-3-(3-(2-methylpyridin-3-yloxy)-5-styrypyrazin-2-yl)urea (50 mg, 0.138 mmol) was dissolved N2 (17.8 mg, 0.152 mmol) and tBuOH containing 2.5% OsO 4 (17.4 μl, 0.00138 mmol) were added in 2:1 THF: water (2 mL), and the mixture was stirred at room temperature overnight. With aqueous NaHSO 3 was quenched reaction was partitioned between brine and EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc) Pyridin-3-yloxy)pyrazin-2-yl)-3-methylurea (27.1 mg, 0.0685 mmol, 49.5% yield). Mass spectrum (apci) m/z = 396.1 (M+H). 1 H NMR (CDCl 3 ) δ 8.79 (m, 1H), 8.46 (t, J = 3.1 Hz, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.30-7.24 (m, 3H), 7.21 (d, J = 2.9 Hz, 2H), 7.11 (m, 2H), 4.64 (m, 2H), 2.99 (d, J = 4.7 Hz, 3H), 2.83 (d, J = 6.4 Hz, 1H), 2.82 (d, J = 2.9 Hz, 1H), 2.36 (s, 3H).

實例399Example 399

1-(3-(苄氧基)-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲 1-(3-(Benzyloxy)-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea

步驟A：將1-(3-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(5.6 g，16.7 mmol)溶解於二噁烷(150 mL)中，且添加Xantphos(0.482 g，0.833 mmol)及N-乙基-N-異丙基丙-2-胺(5.80 ml，33.3 mmol)，且使N2鼓泡通過反應物，持續10分鐘。添加3-巰基丙酸甲酯(2.16 ml，20.0 mmol)及Pd2dba3(0.381 g，0.416 mmol)，在80℃下加熱反應物3小時，且冷卻至室溫隔夜。經矽藻土過濾反應物且濃縮。在矽膠上(含80% EtOAc之己烷)純化殘餘物，得到呈橙色油狀之3-(5-(苄氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(6.3 g，16.8 mmol，101%產率)。 Step A : 1-(3-(Benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (5.6 g, 16.7 mmol) was dissolved in dioxane (150 mL) xantphos (0.482 g, 0.833 mmol) and N- ethyl -N- isopropyl-2-amine (5.80 ml, 33.3 mmol), and that the N 2 was bubbled through the reaction for 10 minutes. Methyl 3-mercaptopropionate (2.16 ml, 20.0 mmol) and Pd 2 dba 3 (0.381 g, 0.416 mmol) were added, and the mixture was stirred at 80 ° C for 3 hr and cooled to room temperature overnight. The reaction was filtered through celite and concentrated. The residue was purified on EtOAc (EtOAc EtOAc EtOAc) Methyl propionate (6.3 g, 16.8 mmol, 101% yield).

步驟B：將3-(5-(苄氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯 (6.3 g，17 mmol)溶解於THF(100 mL)中，且使N2鼓泡通過，持續10分鐘。稍緩慢地添加含1 M 2-甲基丙-2-醇鉀之THF(50 ml，50 mmol)，且在室溫下於N2下攪拌30秒。添加1-溴-3-甲氧基丙烷(2.8 g，18 mmol)，且在室溫下攪拌反應物2小時。用NH4Cl水溶液淬滅反應物，用EtOAc萃取，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含1：1 EtOAc之己烷)純化殘餘物，得到呈黃色油狀之1-(3-(苄氧基)-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(5.2 g，14 mmol，86%產率)。質譜(apci)m/z=362.1(M+H)。1H NMR(CDCl3)δ 9.28(m,1H),7.55(m,3H),7.47(s,1H),7.41-7.30(m,4H),5.40(s,2H),3.40(t,J=5.7 Hz,2H),3.32(s,3H),2.91(d,J=4.7 Hz,3H),2.88(t,J=7.2 Hz,2H),1.75(m,2H)。 Step B : Dissolving methyl 3-(5-(benzyloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (6.3 g, 17 mmol) in THF (100 mL And let N 2 bubble through for 10 minutes. THF (50 ml, 50 mmol) containing 1 M 2-methylpropan-2-ol was added slowly, and stirred at room temperature under N 2 for 30 s. 1-Bromo-3-methoxypropane (2.8 g, 18 mmol) was added, and the mixture was stirred at room temperature for 2 hr. With aqueous 4 Cl NH quenched reaction was extracted with EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc EtOAc) 3-methylurea (5.2 g, 14 mmol, 86% yield). Mass spectrum (apci) m/z = 362.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.28 (m, 1H), 7.55 (m, 3H), 7.47 (s, 1H), 7.41-7.30 (m, 4H), 5.40 (s, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.32 (s, 3H), 2.91 (d, J = 4.7 Hz, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.75 (m, 2H).

實例400Instance 400

(R)-3-(5-(3-甲氧基丙硫基)-2-(3-甲基脲基)吡啶-3-基氧基)吡咯啶-1-甲酸第三丁酯 (R)-3-(5-(3-methoxypropylthio)-2-(3-methylureido)pyridin-3-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

步驟A：將1-(3-(苄氧基)-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(700 mg，1.94 mmol)及2-胺基乙硫醇鹽酸鹽(330 mg，2.90 mmol)溶解於6 M HCl(10 mL)中，且加熱至回流，維持1小時。冷卻反應物至室溫且藉由緩慢添加NaHCO3水溶液淬滅。當pH值達到約7時，用EtOAc(×4)萃取反應物，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含5% MeOH之EtOAc)純化殘餘物，得到呈透明無色油狀之1-(3-羥基-5- (3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(250 mg，0.921 mmol，47.6%產率)。 Step A : 1-(3-(Benzyloxy)-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea (700 mg, 1.94 mmol) and 2-amine Ethyl ethanethiol hydrochloride (330 mg, 2.90 mmol) was dissolved in 6 M HCl (10 mL) and warm to reflux for 1 hour. The reaction was cooled to room temperature and was added by slowly quenched with aqueous NaHCO 3. When the pH of about 7 with EtOAc (× 4) The reaction was extracted, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc EtOAc) Methyl urea (250 mg, 0.921 mmol, 47.6% yield).

步驟B：將1-(3-羥基-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(100 mg，0.369 mmol)溶解於甲苯(3 mL)中，且添加PPh3(96.7 mg，0.369 mmol)及(S)-3-羥基吡咯啶-1-甲酸第三丁酯(69.0 mg，0.369 mmol)，且在室溫下於N2下攪拌。添加逐滴DIAD(73.1 μL，0.369 mmol)，且在室溫下攪拌反應物1小時。濃縮反應物且在矽膠上(含80%至100% EtOAc之己烷)純化，得到粗物質。將殘餘物溶解於EtOH中，且添加過量K2CO3並在75℃下攪拌隔夜。冷卻反應物，過濾，濃縮且經由逆相(C18，含10%至90% ACN之水)純化，得到呈琥珀色玻璃狀之(R)-3-(5-(3-甲氧基丙硫基)-2-(3-甲基脲基)吡啶-3-基氧基)吡咯啶-1-甲酸第三丁酯(58.3 mg，0.132 mmol，35.9%產率)。質譜(apci)m/z=441.2(M+H)。1H NMR(CDCl3)δ 9.16(m,1H),7.83(s,1H),7.24(m,1H),7.06(m,1H),4.92(m,1H),3.69(dd,J=12.7,4.3 Hz,1H),3.66-3.49(m,3H),3.46(t,J=6.1 Hz,2H),3.32(s,3H),2.96(d,J=4.7 Hz,3H),2.90(t,J=7.2 Hz,2H),2.19(m,2H),1.84(m,2H),1.49(s,9H)。 Step B : Dissolving 1-(3-hydroxy-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea (100 mg, 0.369 mmol) in toluene (3 mL) And PPh 3 (96.7 mg, 0.369 mmol) and (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (69.0 mg, 0.369 mmol) were added, and stirred at room temperature under N 2 . A drop of DIAD (73.1 μL, 0.369 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated and purified on EtOAc (EtOAc:EtOAc The residue was dissolved in EtOH and excess K 2 CO 3 was added and stirred at 75 ° C overnight. The reaction was cooled, filtered, concentrated and purified via reverse phase (C 18, containing 10-90% of water, ACN), to give amber glass of (R) -3- (5- (3- methoxypropoxy T-butyl thio)-2-(3-methylureido)pyridin-3-yloxy)pyrrolidine-1-carboxylate (58.3 mg, 0.132 mmol, 35.9% yield). Mass spectrum (apci) m/z = 441.2 (M+H). 1 H NMR (CDCl 3 ) δ 9.16 (m, 1H), 7.83 (s, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 4.92 (m, 1H), 3.69 (dd, J =12.7) , 4.3 Hz, 1H), 3.66-3.49 (m, 3H), 3.46 (t, J = 6.1 Hz, 2H), 3.32 (s, 3H), 2.96 (d, J = 4.7 Hz, 3H), 2.90 (t , J = 7.2 Hz, 2H), 2.19 (m, 2H), 1.84 (m, 2H), 1.49 (s, 9H).

遵循實例400中之程序，亦合成以下化合物： Following the procedure in Example 400, the following compounds were also synthesized:

實例411Example 411

1-(5-(1-乙醯基哌啶-4-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(1-Ethylpiperidin-4-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

將1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(哌啶-4-基硫基)吡啶-2-基)脲(50 mg，0.0881 mmol)懸浮於CH2Cl2(1 mL)中，且添加NEt3(61.4 μL，0.441 mmol)並在室溫下攪拌。添加Ac2O(8.33 μL，0.0881 mmol)，且在室溫下攪拌20分鐘。將反應物分配於NaHCO3水溶液與CH2Cl2之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含5%至10% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之1-(5-(1-乙醯基哌啶-4-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(39.2 mg，0.0943 mmol，107%產率)。質譜(apci)m/z=416.0(M+H)。1H NMR(CDCl3)δ 9.20(q,J=4.3 Hz,1H),8.42(dd,J=4.1,1.8 Hz,1H),8.01(d,J=1.8 Hz,1H),7.31-7.23(m,3H),6.88(d,J=1.8 Hz,1H),4.32(m,1H),3.76(m,1H),3.12(m,1H),3.05-2.97(m,4H),2.83(m,1H),2.48(s,3H),2.07(s,3H),1.88(m,2H),1.44(m,2H)。 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5-(piperidin-4-ylthio)pyridin-2-yl)urea (50 mg, 0.0881 mmol) It was suspended in CH 2 Cl 2 (1 mL), and NEt 3 (61.4 μL, 0.441 mmol) was added and stirred at room temperature. Ac 2 O (8.33 μL, 0.0881 mmol) was added and stirred at room temperature for 20 min. The reaction was partitioned between aqueous NaHCO 3 and CH 2 Cl 2, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc) Methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (39.2 mg, 0.0943 mmol, 107% yield). Mass spectrum (apci) m/z = 416.0 (M+H). 1 H NMR (CDCl 3 ) δ 9.20 (q, J = 4.3 Hz, 1H), 8.42 (dd, J = 4.1, 1.8 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.31-7.23 ( m,3H), 6.88 (d, J = 1.8 Hz, 1H), 4.32 (m, 1H), 3.76 (m, 1H), 3.12 (m, 1H), 3.05-2.97 (m, 4H), 2.83 (m) , 1H), 2.48 (s, 3H), 2.07 (s, 3H), 1.88 (m, 2H), 1.44 (m, 2H).

遵循實例411中之程序，亦合成以下化合物： Following the procedure in Example 411, the following compounds were also synthesized:

實例419Example 419

1-(5-(1-(5-氯嘧啶-2-基)哌啶-4-基硫基)-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(1-(5-chloropyrimidin-2-yl)piperidin-4-ylthio)-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)- 3-methylurea

將1-(3-(2-乙基吡啶-3-基氧基)-5-(哌啶-4-基硫基)吡啶-2-基)-3-甲基脲二鹽酸鹽(50 mg，0.109 mmol)懸浮於小瓶中之CH2Cl2(1 mL)中，且依序添加NEt3(75.7 μl，0.543 mmol)、2,5-二氯嘧啶(16.2 mg，0.109 mmol)並密封。加熱反應物至40℃，維持3天。冷卻反應物至室溫，濃縮且在矽膠上(含80%至100% EtOAc之己烷)純化，得到呈白色固體狀之1-(5-(1-(5-氯嘧啶-2-基)哌啶-4-基硫基)-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(24.6 mg，0.0492 mmol，45.3%產率)。質譜(apci)m/z=500.0(M+H)。1H NMR(CDCl3)δ 9.13(q,J=4.3 Hz,1H),8.50(t,J=3.3 Hz,1H),8.20(m,2H),8.01(d,J=2.0 Hz,1H),7.51(s,1H),7.22(d,J=3.1 Hz,2H),6.87(d,J=1.8 Hz,1.H),4.51(m,2H),3.10-2.97(m,6H),2.79(q,J=7.6 Hz,2H),1.90(m,2H),1.48(m,2H),1.27(t,J=7.6 Hz,3H)。 1-(3-(2-ethylpyridin-3-yloxy)-5-(piperidin-4-ylthio)pyridin-2-yl)-3-methylurea dihydrochloride (50 Mg, 0.109 mmol) was suspended in CH 2 Cl 2 (1 mL) in a vial, and NEt 3 (75.7 μl, 0.543 mmol), 2,5-dichloropyrimidine (16.2 mg, 0.109 mmol) was added and sealed. . The reaction was heated to 40 ° C for 3 days. The reaction was cooled to room temperature, EtOAc (EtOAc:EtOAc:EtOAc Piperidin-4-ylthio)-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (24.6 mg, 0.0492 mmol, 45.3% yield). Mass spectrum (apci) m/z = 500.0 (M + H). 1 H NMR (CDCl 3 ) δ 9.13 (q, J = 4.3 Hz, 1H), 8.50 (t, J = 3.3 Hz, 1H), 8.20 (m, 2H), 8.01 (d, J = 2.0 Hz, 1H) , 7.51 (s, 1H), 7.22 (d, J = 3.1 Hz, 2H), 6.87 (d, J = 1.8 Hz, 1.H), 4.51 (m, 2H), 3.10-2.97 (m, 6H), 2.79 (q, J = 7.6 Hz, 2H), 1.90 (m, 2H), 1.48 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H).

實例420Example 420

1-(5-(1-(5-氯吡嗪-2-基)哌啶-4-基硫基)-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(1-(5-Chloropyrazine-2-yl)piperidin-4-ylthio)-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl) -3-methylurea

將1-(3-(2-乙基吡啶-3-基氧基)-5-(哌啶-4-基硫基)吡啶-2-基)-3-甲基脲二鹽酸鹽(0.100 g，0.217 mmol)、2,5-二氯吡嗪(0.0324 g，0.217 mmol)及NEt3(0.151 ml，1.09 mmol)溶解於DMF(2 mL)中，且加熱至70℃隔夜。濃縮反應物且在矽膠上(含2%至5% MeOH之EtOAc)純化，得到呈黃色固體狀之1-(5-(1-(5-氯吡嗪-2-基)哌啶-4-基硫基)-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.020 g，0.0400 mmol，18.4%產率)。質譜(apci)m/z=500.0(M+H)。1H NMR(CDCl3)δ 9.08(m,1H),8.51(t,J=2.9 Hz,1H),8.04(d,J=1.4 Hz,2H),7.83(d,J=1.4 Hz,1H),7.47(bs,1H),7.31(m,2H),6.91(m,1H),4.12(dt,J=13.9,4.1 Hz,2H),3.10-3.01(m,3H),3.00(d,J=4.7 Hz,3H),2.89(m,2H),1.95(m,2H),1.60-1.50(m,2H),1.32(t,J=7.6 Hz,3H)。 1-(3-(2-ethylpyridin-3-yloxy)-5-(piperidin-4-ylthio)pyridin-2-yl)-3-methylurea dihydrochloride (0.100 g, 0.217 mmol), 2,5-dichloropyrazine (0.0324 g, 0.217 mmol) and NEt 3 (0.151 ml, 1.09 mmol) were dissolved in DMF (2 mL) and warmed to 70 ° C overnight. The reaction was concentrated and purified on EtOAc (EtOAc:EtOAc) Benzylthio)-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (0.020 g, 0.0400 mmol, 18.4% yield). Mass spectrum (apci) m/z = 500.0 (M + H). 1 H NMR (CDCl 3 ) δ 9.08 (m, 1H), 8.51 (t, J = 2.9 Hz, 1H), 8.04 (d, J = 1.4 Hz, 2H), 7.83 (d, J = 1.4 Hz, 1H) , 7.47 (bs, 1H), 7.31 (m, 2H), 6.91 (m, 1H), 4.12 (dt, J = 13.9, 4.1 Hz, 2H), 3.10-3.01 (m, 3H), 3.00 (d, J = 4.7 Hz, 3H), 2.89 (m, 2H), 1.95 (m, 2H), 1.60-1.50 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H).

實例421Example 421

(S)-1-甲基-3-(5-(1-(嘧啶-2-基)哌啶-4-基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲 (S)-1-methyl-3-(5-(1-(pyrimidin-2-yl)piperidin-4-ylthio)-3-(5,6,7,8-tetrahydroquinoline- 5-yloxy)pyridin-2-yl)urea

步驟A：將(S)-3-(6-(3-甲基脲基)-5-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯(0.200 g，0.480 mmol)溶解於THF(5 mL)中。使N2鼓泡通過，持續5分鐘，接著添加含1 M 2-甲基丙-2-醇鉀之THF(1.44 ml，1.44 mmol)且攪拌30秒。添加4-碘哌啶-1-甲酸第三丁酯(0.149 g，0.480 mmol)，且在室溫下攪拌反應物隔夜。用飽和NH4Cl淬滅反應物且用EtOAc及CH2Cl2萃取。經Na2SO4乾燥經合併之有機層，過濾且濃縮。在矽膠上(含0%至5% MeOH之EtOAc，繼之以 含5% MeOH之CH2Cl2)純化殘餘物，得到(S)-4-(6-(3-甲基脲基)-5-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-3-基硫基)哌啶-1-甲酸第三丁酯(30 mg，12.2%產率)。 Step A : (S)-3-(6-(3-methylureido)-5-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-3-ylsulfide Methyl propionate (0.200 g, 0.480 mmol) was dissolved in THF (5 mL). N 2 was bubbled through for 5 minutes, then THF (1. 4 mL, 1.44 mmol) containing 1 M of 2-methylpropan-2-ol was added and stirred for 30 s. Tetrabutyl 4-iodopiperidine-1-carboxylate (0.149 g, 0.480 mmol) was added, and the mixture was stirred at room temperature overnight. With saturated NH 4 Cl The reaction was quenched and extracted with EtOAc and CH 2 Cl. Dried over Na 2 SO 4 the combined organic layers were, filtered and concentrated. On silica gel (0% to 5% MeOH EtOAc in it, followed by the 5% MeOH in CH 2 Cl 2) The residue was purified to give (S) -4- (6- (3- methyl-ureido) - 3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-3-ylthio)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 12.2% yield).

步驟B：將(S)-4-(6-(3-甲基脲基)-5-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-3-基硫基)哌啶-1-甲酸第三丁酯(0.030 g，0.058 mmol)溶解於CH2Cl2(5 mL)及數滴MeOH中。添加含4 N HCl之二噁烷(0.15 ml，0.58 mmol)，且在室溫下攪拌隔夜。濃縮反應物且以粗物質形式用於下一步驟中。 Step B : (S)-4-(6-(3-methylureido)-5-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-3-ylsulfide yl) piperidine-1-carboxylic acid tert-butyl ester (0.030 g, 0.058 mmol) was dissolved in CH 2 Cl 2 (5 mL) and a few drops of MeOH. Dioxane (0.15 ml, 0.58 mmol) containing 4 N HCl was added and stirred at room temperature overnight. The reaction was concentrated and used as a crude material in the next step.

步驟C：將(S)-1-甲基-3-(5-(哌啶-4-基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲二鹽酸鹽(0.028 g，0.058 mmol)、2-氯嘧啶(0.0066 g，0.058 mmol)及N-乙基-N-異丙基丙-2-胺(0.050 ml，0.29 mmol)溶解於DMF(1 mL)中，且加熱至100℃，維持8小時。冷卻反應物且濃縮，使用製備型TLC以含5% MeOH之EtOAc純化，得到呈黃色固體狀之(S)-1-甲基-3-(5-(1-(嘧啶-2-基)哌啶-4-基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)脲(0.010 g，0.020 mmol，35%產率)。質譜(apci)m/z=492.0(M+H)。1H NMR(CDCl3)δ 9.17(q,J=4.7 Hz,1H),8.57(dd,J=4.7,1.6 Hz,1H),8.29(d,J=4.9 Hz,2H),7.92(d,J=1.8 Hz,1H),7.60(dd,J=7.8,1.2 Hz,1H),7.32(s,2H),7.18(dd,J=7.8,4.7,1H),6.48(t,J=4.9 Hz,1H),5.45(m,1H),4.65(dt,13.5,3.9 Hz,2H),3.20-3.06(m,4H),3.01-2.92(m,4H),2.19-1.87(m,6H),1.59(m,2H)。 Step C : (S)-1-Methyl-3-(5-(piperidin-4-ylthio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy Pyridin-2-yl)urea dihydrochloride (0.028 g, 0.058 mmol), 2-chloropyrimidine (0.0066 g, 0.058 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.050 ml) , 0.29 mmol) was dissolved in DMF (1 mL) and heated to 100 ° C for 8 h. The reaction was cooled and concentrated with EtOAc EtOAc EtOAc EtOAc Pyridin-4-ylthio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)urea (0.010 g, 0.020 mmol, 35% yield) . Mass spectrum (apci) m/z = 492.0 (M+H). 1 H NMR (CDCl 3 ) δ 9.17 (q, J = 4.7 Hz, 1H), 8.57 (dd, J = 4.7, 1.6 Hz, 1H), 8.29 (d, J = 4.9 Hz, 2H), 7.92 (d, J = 1.8 Hz, 1H), 7.60 (dd, J = 7.8, 1.2 Hz, 1H), 7.32 (s, 2H), 7.18 (dd, J = 7.8, 4.7, 1H), 6.48 (t, J = 4.9 Hz) , 1H), 5.45 (m, 1H), 4.65 (dt, 13.5, 3.9 Hz, 2H), 3.20-3.06 (m, 4H), 3.01-2.92 (m, 4H), 2.19-1.87 (m, 6H), 1.59 (m, 2H).

實例422Example 422

1-(5-(1-異丙基哌啶-4-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲二鹽酸鹽 1-(5-(1-Isopropylpiperidin-4-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea dihalide Acid salt

將1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(哌啶-4-基硫基)吡啶-2-基)脲雙(2,2,2-三氟乙酸鹽)(100 mg，0.166 mmol)懸浮於DCE(2 mL)中，且添加N-乙基-N-異丙基丙-2-胺(57.9 μl，0.332 mmol)及丙-2-酮(122 μl，1.66 mmol)並攪拌10分鐘。添加Na(OAc)3BH(88.1 mg，0.416 mmol)，且在室溫下攪拌反應物經週末。將反應物分配於NaHCO3水溶液與CH2Cl2之間，經Na2SO4乾燥，過濾且濃縮。在形成鹽酸鹽之後，在矽膠上(含10% MeOH之EtOAc(含NH3))純化殘餘物，得到呈白色固體狀之1-(5-(1-異丙基哌啶-4-基硫基)-3-(2-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲二鹽酸鹽(40.2 mg，0.0823 mmol，49.5%產率)。質譜(apci)m/z=416.1(M+H-2HCl)。1H NMR(d6-DMSO)δ 10.55(m,1H),9.29(s,1H),8.96(m,1H),8.46(d,J=5.3 Hz,1H),8.21(d,J=2.0 Hz,1H),7.87(d,J=8.4 Hz,1H),7.76-7.65(m,3H),3.69(m,1H),3.48(m,1H),3.38(m,1H),3.29(m,2H),3.25-3.05(m,2H),2.93(m,2H),2.73(s,3H),2.02-1.85(m,4H),1.22(d,J=6.6 Hz,6H)。 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5-(piperidin-4-ylthio)pyridin-2-yl)urea bis (2,2, 2-Trifluoroacetate) (100 mg, 0.166 mmol) was suspended in DCE (2 mL) and N-ethyl-N-isopropylpropan-2-amine (57.9 μl, 0.332 mmol) 2-ketone (122 μl, 1.66 mmol) and stirred for 10 minutes. Was added Na (OAc) 3 BH (88.1 mg, 0.416 mmol), and the reaction was stirred over the weekend at room temperature. The reaction was partitioned between aqueous NaHCO 3 and CH 2 Cl 2, dried over Na 2 SO 4, filtered and concentrated. After the formation of the hydrochloride, on silica gel (10% MeOH in of EtOAc (containing NH 3)) The residue was purified to give a white solid of l- (5- (1-isopropyl-piperidin-4-yl Thio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea dihydrochloride (40.2 mg, 0.0823 mmol, 49.5% yield). Mass spectrum (apci) m/z = 416.1 (M+H-2HCl). 1 H NMR (d 6 -DMSO) δ 10.55 (m, 1H), 9.29 (s, 1H), 8.96 (m, 1H), 8.46 (d, J = 5.3 Hz, 1H), 8.21. (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.76-7.65 (m, 3H), 3.69 (m, 1H), 3.48 (m, 1H), 3.38 (m, 1H), 3.29 (m) , 2H), 3.25-3.05 (m, 2H), 2.93 (m, 2H), 2.73 (s, 3H), 2.02-1.85 (m, 4H), 1.22 (d, J = 6.6 Hz, 6H).

實例423Example 423

3-(5-(2-乙基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸 3-(5-(2-ethylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoic acid

將3-(5-(2-乙基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(100 mg，0.256 mmol)溶解於THF(1.5 mL)中，添加1 N NaOH (256 μL，0.256 mmol)，且在室溫下攪拌反應物隔夜。將反應物傾倒至水中且用EtOAc萃取。將水層酸化至pH 4且用含10% MeOH之CH2Cl2萃取，得到油狀物。經由逆相(C18，含10%至90% ACN之水)純化該油狀物，乾燥後得到呈褐色固體狀之3-(5-(2-乙基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸(50.1 mg，0.133 mmol，52.0%產率)。質譜(apci)m/z=377.0(M+H)。1H NMR(d6-DMSO)δ 8.90(q,J=4.1 Hz,1H),8.70(s,1H),8.34(dd,J=4.5,1.2 Hz,1H),8.01(d,J=1.6 Hz,1H),7.30(dd,J=8.1,1.2 Hz,1H),7.25(dd,J=8.0,4.5 Hz,1H),7.13(d,J=1.6 Hz,1H),2.95(t,J=7.0 Hz,2H),2.82(t,J=7.4 Hz,2H),2.78(d,J=4.7 Hz,3H),2.33(m,2H),1.20(t,J=7.4 Hz,3H)。 Dissolve methyl 3-(5-(2-ethylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (100 mg, 0.256 mmol) 1 N NaOH (256 μL, 0.256 mmol) was added in THF (1.5 mL) and the mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with EtOAc. The aqueous layer was acidified to pH 4 and extracted with 2 Cl 2 containing the CH 10% MeOH, to give an oil. This oil was purified by reverse phase ( C18 , EtOAc (EtOAc) EtOAc) 6-(3-Methylureido)pyridin-3-ylthio)propanoic acid (50.1 mg, 0.133 mmol, 52.0% yield). Mass spectrum (apci) m/z = 377.0 (M+H). 1 H NMR (d 6 -DMSO) δ 8.90 (q, J = 4.1 Hz, 1H), 8.70 (s, 1H), 8.34 (dd, J = 4.5, 1.2 Hz, 1H), 8.01 (d, J = 1.6) Hz, 1H), 7.30 (dd, J = 8.1, 1.2 Hz, 1H), 7.25 (dd, J = 8.0, 4.5 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 2.95 (t, J =7.0 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H), 2.33 (m, 2H), 1.20 (t, J = 7.4 Hz, 3H).

實例424Example 424

1-(5-((S)-3,4-二羥基丁硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-((S)-3,4-dihydroxybutylthio)-3-((S)-5,6,7,8-tetrahydroquinolin-5-yloxy)pyridine-2 -yl)-3-methylurea

步驟A：將(S)-3-(6-(3-甲基脲基)-5-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯(0.200 g，0.480 mmol)溶解於THF(4 mL)中。使N2鼓泡通過，持續5分鐘。添加含1 M 2-甲基丙-2-醇鉀之THF(1.44 ml，1.44 mmol)，且在室溫下攪拌反應物30秒。添加4-甲基苯磺酸(S)-2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙酯(0.188 g，0.624 mmol)，且在室溫下攪拌反應物2小時。用NH4Cl水溶液淬滅反應物且濃縮。在矽膠上(含0%至7% MeOH之EtOAc)純化殘餘物，得到1-(5-(2-((S)-2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)-3-((S)-5,6,7,8-四氫 喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.136 g，0.297 mmol，61.8%產率)。 Step A : (S)-3-(6-(3-methylureido)-5-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-3-ylsulfide Methyl propionate (0.200 g, 0.480 mmol) was dissolved in THF (4 mL). N 2 was bubbled through for 5 minutes. THF (1.44 ml, 1.44 mmol) containing 1 M 2-methylpropan-2-propoxide was added and the mixture was stirred at room temperature for 30 s. Add (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate (0.188 g, 0.624 mmol), and The reaction was stirred at room temperature for 2 hours. With aqueous NH 4 Cl The reaction was quenched and concentrated. The residue was purified on EtOAc (EtOAc EtOAc:EtOAc) 4-yl)ethylthio)-3-((S)-5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea (0.136 g, 0.297 mmol, 61.8% yield).

步驟B：將1-(5-(2-((S)-2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.136 g，0.297 mmol)溶解於MeOH(4 mL)中，且添加含4 HCl之二噁烷(0.222 ml，0.890 mmol)及H2O(0.267 g，14.8 mmol)，且在室溫下攪拌反應物2小時。濃縮反應物且在矽膠上(100% EtOAc，繼之以含5%氨化MeOH之CH2Cl2)純化，得到1-(5-((S)-3,4-二羥基丁硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.088 g，0.210 mmol，70.9%產率)。質譜(apci)m/z=419.2(M+H)。1H NMR(CDCl3)δ 9.19(q,J=4.7 Hz,1H),8.54(dd,J=4.7,1.6 Hz,1H),7.85(d,J=2.0,1H),7.59(dd,J=7.6,1.4 Hz,1H),7.31(m,2H),7.17(dd,J=7.8,4.9 Hz,1H),5.45(m,1H),3.87(m,1H),3.64(dd,J=11.1,3.3 Hz,1H),3.45(dd,J=10.9,7.2 Hz,1H),3.15-3.01(m,2H),2.99-2.88(m,5H),2.17-2.00(m,3H),1.90(m,1H),1.82-1.66(m,2H)。 Step B : 1-(5-(2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylthio)-3-((S) -5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea (0.136 g, 0.297 mmol) was dissolved in MeOH (4 mL) 4 HCl in dioxane (0.222 ml, 0.890 mmol) and H 2 O (0.267 g, 14.8 mmol). And the reaction was concentrated on silica gel (100% EtOAc, 2 Cl 2 followed by 5% MeOH amides of CH) to give 1- (5 - ((S) -3,4- dihydroxy butyl group) -3-((S)-5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl)-3-methylurea (0.088 g, 0.210 mmol, 70.9% yield ). Mass spectrum (apci) m/z = 419.2 (M+H). 1 H NMR (CDCl 3 ) δ 9.19 (q, J = 4.7 Hz, 1H), 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 7.85 (d, J = 2.0, 1H), 7.59 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (m, 2H), 7.17 (dd, J = 7.8, 4.9 Hz, 1H), 5.45 (m, 1H), 3.87 (m, 1H), 3.64 (dd, J = 11.1, 3.3 Hz, 1H), 3.45 (dd, J = 10.9, 7.2 Hz, 1H), 3.15-3.01 (m, 2H), 2.99-2.88 (m, 5H), 2.17-2.00 (m, 3H), 1.90 (m, 1H), 1.82-1.66 (m, 2H).

遵循實例424中之程序，亦合成以下化合物： Following the procedure in Example 424, the following compounds were also synthesized:

實例427Example 427

1-(5-(順-3,4-二羥基環戊基硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(cis-3,4-dihydroxycyclopentylthio)-3-((S)-5,6,7,8-tetrahydroquinolin-5-yloxy)pyridine-2 -yl)-3-methylurea

將(S)-1-(5-(環戊-3-烯基硫基)-3-(5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(0.100 g，0.252 mmol)溶解於THF(3 ml)中。依序添加NMO(0.0768 g，0.328 mmol)、含2.5重量% OsO4(0.0316 ml，0.00252 mmol)之t-BuOH。在室溫下攪拌反應物隔夜。將反應物分配於其中含少量NaHSO3之NaHCO3水溶液與EtOAc之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含10%至20% MeOH之EtOAc)純化殘餘物，得到粗物質，再次經由逆相(C18，含10%至90% ACN之水)純化該粗物質，得到呈白色固體狀之1-(5-(順-3,4-二羥基環戊基硫基)-3-((S)-5,6,7,8-四氫喹啉-5-基氧基)吡啶-2-基)-3-甲基脲(8.9 mg，0.021 mmol)。質譜(apci)m/z=431.2(M+H)。1H NMR(d6-DMSO)δ 8.90(q,J=4.5 Hz,1H),8.48(dd,J=4.7,1.6 Hz,1H),7.82(dd,J=3.3,1.6 Hz,1H),7.75-7.68(m,2H),7.57(d,J=7.4 Hz,1H),7.25(dd,J=7.8,4.7 Hz,1H),5.78(m,1H),4.51(m,2H),3.94(m,1H),3.79(m,1H),3.31(s,2H),3.00-2.78(m,3H),2.75(d,J=4.7 Hz,3H),2.19(m,1H),1.84(m,1H),1.69(m,1H),1.60(m,1H)。 (S)-1-(5-(cyclopent-3-enylthio)-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-yl) 3-Methylurea (0.100 g, 0.252 mmol) was dissolved in THF (3 mL). NMO (0.0768 g, 0.328 mmol), containing 2.5% by weight of OsO 4 (0.0316 ml, 0.00252 mmol) of t-BuOH were added sequentially. The reaction was stirred at room temperature overnight. The reaction was partitioned between which contain small amounts of NaHCO 3 aq NaHSO 3 and EtOAc, dried over Na 2 SO 4, filtered and concentrated. On silica gel (10% to 20% MeOH of EtOAc) to the residue to give the crude material via reverse phase (C 18, containing 10 to 90% aqueous ACN of) to give the crude material again to give a white solid 1-(5-(cis-3,4-dihydroxycyclopentylthio)-3-((S)-5,6,7,8-tetrahydroquinolin-5-yloxy)pyridine- 2-yl)-3-methylurea (8.9 mg, 0.021 mmol). Mass spectrum (apci) m/z = 431.2 (M+H). 1 H NMR (d 6 -DMSO) δ 8.90 (q, J = 4.5 Hz, 1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H), 7.82 (dd, J = 3.3, 1.6 Hz, 1H), 7.75-7.68 (m, 2H), 7.57 (d, J = 7.4 Hz, 1H), 7.25 (dd, J = 7.8, 4.7 Hz, 1H), 5.78 (m, 1H), 4.51 (m, 2H), 3.94 (m, 1H), 3.79 (m, 1H), 3.31 (s, 2H), 3.00-2.78 (m, 3H), 2.75 (d, J = 4.7 Hz, 3H), 2.19 (m, 1H), 1.84 ( m, 1H), 1.69 (m, 1H), 1.60 (m, 1H).

遵循實例425中之程序，亦合成以下化合物： Following the procedure in Example 425, the following compounds were also synthesized:

實例429Example 429

1-(3-(2-乙基吡啶-3-基氧基)-5-(反-4-羥基環己基硫基)吡啶-2-基)-3-甲基脲 1-(3-(2-ethylpyridin-3-yloxy)-5-(trans-4-hydroxycyclohexylthio)pyridin-2-yl)-3-methylurea

步驟A：將1-(3-(2-乙基吡啶-3-基氧基)-5-(順-4-羥基環己基硫基)吡啶-2-基)-3-甲基脲(140 mg，0.348 mmol)溶解於THF(3 mL)中，且添加4-硝基苯甲酸(93.0 mg，0.557 mmol)及PPh3(146 mg，0.557 mmol)並在室溫下攪拌。逐滴添加DIAD(110 μl，0.557 mmol)，且在室溫下攪拌反應物3小時。將反應物分配於水與EtOAc之間，經Na2SO4乾燥，過濾且濃縮。在矽膠上純化殘餘物，得到P(O)Ph3與4-硝基苯甲酸反-4-(5-(2-乙基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)環己酯之混合物(192 mg，0.348 mmol，100%產率)。 Step A : 1-(3-(2-ethylpyridin-3-yloxy)-5-(cis-4-hydroxycyclohexylthio)pyridin-2-yl)-3-methylurea (140 mg, 0.348 mmol) was dissolved in THF (3 mL), and 4-nitrobenzoic acid (93.0 mg, 0.557 mmol) and PPh 3 (146 mg, 0.557 mmol ) and stirred at rt. DIAD (110 μl, 0.557 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. The reaction was partitioned between water and EtOAc, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on silica gel to give P(O)Ph 3 and 4-nitrobenzoic acid trans-4-(5-(2-ethylpyridin-3-yloxy)-6-(3-methylurea) Mixture of pyridine-3-ylthio)cyclohexyl ester (192 mg, 0.348 mmol, 100% yield).

步驟B：將粗4-硝基苯甲酸反-4-(5-(2-乙基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)環己酯(192 mg，0.348 mmol)溶解於THF(3 mL)中，且添加1 M NaOH(696 μl，0.696 mmol)，且在室溫下攪拌反應物隔夜。將反應物分配於NH4Cl與EtOAc之間，經Na2SO4乾燥，過濾且濃縮。經由逆相層析(C18，含10%至90% ACN之水)純化殘餘物，得到呈透明玻璃狀之1-(3-(2-乙基吡啶-3-基氧基)-5-(反-4-羥基環己基硫基)吡啶-2-基)-3-甲基脲(36.8 mg，0.0914 mmol，26.3%產率)。質譜(apci)m/z=403.0(M+H)。1H NMR(CDCl3)δ 9.14(m,1H),8.49(m,1H),7.90(m,1H),7.53(m,1H),7.21(m,2H),6.85(m,1H),3.60(m,1H),3.00(d,J=4.7 Hz,3H),2.83-2.70(m,3H),1.95(m,3H),1.80-1.55(m,3H),1.36-1.20(m,6H)。 Step B : Crude 4-nitrobenzoic acid trans-4-(5-(2-ethylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio) Cyclohexyl ester (192 mg, 0.348 mmol) was dissolved in THF (3 mL) and 1M EtOAc (EtOAc, EtOAc. The reaction was partitioned between NH 4 Cl and EtOAc, dried over Na 2 SO 4, filtered and concentrated. Via reverse phase chromatography (C 18, containing 10-90% of water ACN) to give the residue, to give a clear glass of 1- (3- (2-ethyl-3-yloxy) -5- (trans-4-hydroxycyclohexylthio)pyridin-2-yl)-3-methylurea (36.8 mg, 0.0914 mmol, 26.3% yield). Mass spectrum (apci) m/z = 403.0 (M+H). 1 H NMR (CDCl 3 ) δ 9.14 (m, 1H), 8.49 (m, 1H), 7.90 (m, 1H), 7.53 (m, 1H), 7.21 (m, 2H), 6.85 (m, 1H), 3.60 (m, 1H), 3.00 (d, J = 4.7 Hz, 3H), 2.83-2.70 (m, 3H), 1.95 (m, 3H), 1.80-1.55 (m, 3H), 1.36-1.20 (m, 6H).

實例430Example 430

1-(3-(2-氰基-6-(三氟甲基)苯氧基)-5-((3-甲氧基丙基)硫基)吡啶-2-基)-3-甲基脲 1-(3-(2-Cyano-6-(trifluoromethyl)phenoxy)-5-((3-methoxypropyl)thio)pyridin-2-yl)-3-methyl Urea

步驟A：將1-(3-(苄氧基)-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(700 mg，1.94 mmol)及2-胺基乙硫醇鹽酸鹽(330 mg，2.90 mmol)溶解於6 M HCl(10 mL)中，且加熱至回流，維持1小時。冷卻反應物至室溫且藉由緩慢添加NaHCO3水溶液淬滅。當pH值達到約7時，用EtOAc(×4)萃取反應物，經Na2SO4乾燥，過濾且濃縮。在矽膠上(含5% MeOH之EtOAc)純化殘餘物，得到呈透明無色油狀之1-(3-羥基-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(250 mg，0.921 mmol，47.6%產率)。 Step A : 1-(3-(Benzyloxy)-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea (700 mg, 1.94 mmol) and 2-amine Ethyl ethanethiol hydrochloride (330 mg, 2.90 mmol) was dissolved in 6 M HCl (10 mL) and warm to reflux for 1 hour. The reaction was cooled to room temperature and was added by slowly quenched with aqueous NaHCO 3. When the pH of about 7 with EtOAc (× 4) The reaction was extracted, dried over Na 2 SO 4, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc EtOAc) Methyl urea (250 mg, 0.921 mmol, 47.6% yield).

步驟B：將1-(3-羥基-5-(3-甲氧基丙硫基)吡啶-2-基)-3-甲基脲(100 mg，0.369 mmol)溶解於DMF(3 mL)中，且添加NaH(14.7 mg，0.369 mmol)並在室溫下攪拌10分鐘。添加2-氟-3-(三氟甲基)苄腈(58.1 μl，0.405 mmol)，且在室溫下攪拌反應物7小時。用飽和NH4Cl(5 mL)淬滅反應物，且用20 mL CH2Cl2萃取並在真空中濃縮，且置於高真空下隔夜以移除DMF。使用純EtOAc至10% MeOH/EtOAc之梯度純化，分離出呈褐色固體狀之1-(3-(2-氰基-6-(三氟甲基)苯氧基)-5-((3-甲氧基丙基)硫基)吡啶-2-基)-3-甲基脲(5.5 mg，0.0125 mmol，3.4%產率)。質譜(apci)m/z=441.1(M+H)。1H NMR(CDCl3)δ 8.93(br s,1H),8.05(d,J=7.8 Hz,1H),8.01(d,J=8.0 Hz,1H),7.73(m,1H),7.69(d, J=2.4 Hz,1H),7.37(d,J=2.3 Hz,1H),4.34(br s,1H),3.44(m,2H),3.30(s,3H),2.95(t,J=7.0 Hz,2H),2.91(d,J=4.7 Hz,2H),1.86(m,2H)。 Step B : Dissolving 1-(3-hydroxy-5-(3-methoxypropylthio)pyridin-2-yl)-3-methylurea (100 mg, 0.369 mmol) in DMF (3 mL) And NaH (14.7 mg, 0.369 mmol) was added and stirred at room temperature for 10 min. 2-Fluoro-3-(trifluoromethyl)benzonitrile (58.1 μl, 0.405 mmol) was added, and the mixture was stirred at room temperature for 7 hr. With saturated NH 4 Cl (5 mL) The reaction was quenched, and washed with 20 mL CH 2 Cl 2 was extracted and concentrated in vacuo overnight and placed under high vacuum to remove DMF. Purified by a gradient of EtOAc to EtOAc (EtOAc:EtOAc) Methoxypropyl)thio)pyridin-2-yl)-3-methylurea (5.5 mg, 0.0125 mmol, 3.4% yield). Mass spectrum (apci) m/z = 441.1 (M+H). 1 H NMR (CDCl 3 ) δ 8.93 (br s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.1 (d, J = 8.0 Hz, 1H), 7.73 (m, 1H), 7.69 (d) , J = 2.4 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 4.34 (br s, 1H), 3.44 (m, 2H), 3.30 (s, 3H), 2.95 (t, J = 7.0) Hz, 2H), 2.91 (d, J = 4.7 Hz, 2H), 1.86 (m, 2H).

實例431Example 431

1-(3-((4-氯-1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)硫基)吡啶-2-基)-3-甲基脲 1-(3-((4-Chloro-1-ethyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-piperidin-4-yl)thio)pyridine- 2-yl)-3-methylurea

將1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)硫基)吡啶-2-基)-3-甲基脲(0.0216 g，0.0572 mmol)溶解於THF中，且添加N-氯代丁二醯亞胺(0.037 g，0.275 mmol)並在50℃下攪拌2小時。濃縮反應物且經由矽膠層析(己烷/丙酮)純化粗混合物，得到呈白色固體狀之1-(3-((4-氯-1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)硫基)吡啶-2-基)-3-甲基脲(0.023 g，96%)。質譜(apci)m/z=412.1,414.1(M+H)。1H NMR(CDCl3)δ 9.12(q,J=4.5 Hz,1H),8.05(d,J=1.8 Hz,1H),7.65(s,1H),7.50(s,1H),7.02(d,J=1.8 Hz,1H),4.05(q,J=7.4 Hz,2H),3.95(dt,J=11.5,3.5 Hz,2H),3.37(td,J=11.3,2.3 Hz,2H),3.07-2.98(m,4H),1.80(m,2H),1.59(m,2H),1.39(t,J=7.2 Hz,3H)。 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-pyran-4-yl)thio)pyridin-2-yl -3 Methylurea (0.0216 g, 0.0572 mmol) was dissolved in THF, and N-chlorosuccinimide (0.037 g, 0.275 mmol) was added and stirred at 50 ° C for 2 hours. The reaction was concentrated and the crude mixture was purified eluting elut elut elut elut elut elut 5-(4-tetrahydro-2H-piperazin-4-yl)thio)pyridin-2-yl)-3-methylurea (0.023 g, 96%). Mass spectrum (apci) m/z = 412.1, 414.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.12 (q, J = 4.5 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 7.02 (d, J = 1.8 Hz, 1H), 4.05 (q, J = 7.4 Hz, 2H), 3.95 (dt, J = 11.5, 3.5 Hz, 2H), 3.37 (td, J = 11.3, 2.3 Hz, 2H), 3.07- 2.98 (m, 4H), 1.80 (m, 2H), 1.59 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H).

實例432Example 432

1-(5-((3-甲氧基丙基)硫基)-3-((1,3,5-三甲基-1H-吡唑-4-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((3-methoxypropyl)thio)-3-((1,3,5-trimethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl -3-methylurea

步驟A：將5-溴-2-氯-3-氟吡啶(2.00 g，9.50 mmol)溶解於30 mLDMSO中。添加1,3,5-三甲基-1H-吡唑-4-醇(1.20 g，9.50 mmol)及Cs2CO3(3.10 g，9.50 mmol)，且在室溫下攪拌反應物3天。添加水(300 mL)，產生白色沈澱物，藉由過濾收集該沈澱物，用水洗滌且在高真空下乾燥，得到呈白色固體狀之5-溴-2-氯-3-(1,3,5-三甲基-1H-吡唑-4-基氧基)吡啶(2.16 g，72%)。 Step A : 5-Bromo-2-chloro-3-fluoropyridine (2.00 g, 9.50 mmol) was dissolved in 30 mL DMSO. 1,3,5-Trimethyl-1H-pyrazol-4-ol (1.20 g, 9.50 mmol) and Cs 2 CO 3 (3.10 g, 9.50 mmol) were added, and the mixture was stirred at room temperature for 3 days. Add water (300 mL) to give a white solid, which crystals crystals crystals crystals crystals 5-Trimethyl-1H-pyrazol-4-yloxy)pyridine (2.16 g, 72%).

步驟B：將5-溴-2-氯-3-(1,3,5-三甲基-1H-吡唑-4-基氧基)吡啶(0.500 g，1.58 mmol)、DIEA(0.550 ml，3.16 mmol)及Xantphos(0.0914 g，0.158 mmol)溶解於二噁烷中，且用N2脫氣5分鐘。添加Pd2(dba)3(0.0723 g，0.0790 mmol)，使N2鼓泡通過，再持續5分鐘，且添加3-甲氧基丙烷-1-硫醇(0.210 ml，1.58 mmol)，且加熱反應物至50℃，維持6小時。將反應物分配於EtOAc與水之間，且依序用水、鹽水洗滌有機層，且經Na2SO4乾燥，接著濃縮至棕色油狀物。經由矽膠層析(己烷/丙酮)純化粗混合物，得到呈透明油狀之2-氯-5-(3-甲氧基丙硫基)-3-(1,3,5-三甲基-1H-吡唑-4-基氧基)吡啶(0.444 g，82%)。 Step B : 5-Bromo-2-chloro-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridine (0.500 g, 1.58 mmol), DIEA (0.550 ml, 3.16 mmol) and Xantphos (0.0914 g, 0.158 mmol) was dissolved in dioxane, and degassed for 5 minutes with N 2. Pd 2 (dba) 3 (0.0723 g, 0.0790 mmol) was added, N 2 was bubbled through for a further 5 min, and 3-methoxypropane-1-thiol (0.210 ml, 1.58 mmol) was added and heated The reaction was brought to 50 ° C for 6 hours. The reaction was partitioned between EtOAc and water, and washed sequentially with water, the organic layer was washed with brine, and dried over Na 2 SO 4, then concentrated to a brown oil. The crude mixture was purified via EtOAc (hexane/EtOAc) to afford 2-chloro-5-(3-methoxypropylthio)-3-(1,3,5-trimethyl- 1H-Pyrazole-4-yloxy)pyridine (0.444 g, 82%).

步驟C：將1-甲基脲(23.9 mg，0.322 mmol)、5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑(16.3 mg，0.0322 mmol)及K3PO4(51.3 mg，0.242 mmol)以漿液形式溶解於DME中。使N2鼓泡通過，持續5分鐘。添加Pd2(dba)3(7.38 mg，0.00806 mmol)，使N2鼓泡通過，持續5分鐘，且在室溫下攪拌溶液1小時。將2-氯-5-(3-甲氧基丙硫基)-3-(1,3,5-三甲基-1H-吡唑-4-基氧基)吡啶(55.1 mg，0.161 mmol)於DME中之溶液用N2脫氣5分鐘，添加至反應物中，且加熱至120℃，維持48 小時。將反應物分配於EtOAc與水之間，且依序用水、鹽水洗滌有機層，且經Na2SO4乾燥，接著濃縮至棕色油狀物。經由逆相C18層析(水/MeCN)純化粗混合物，得到呈透明油狀之1-(5-((3-甲氧基丙基)硫基)-3-((1,3,5-三甲基-1H-吡唑-4-基)氧基)吡啶-2-基)-3-甲基脲(0.0069 g，11%)。質譜(apci)m/z=380.2(M+H)。1H NMR(CDCl3)δ 9.14(q,J=4.5 Hz,1H),7.86(d,J=1.6 Hz,1H),7.55(s,1H),6.87(d,J=1.7 Hz,1H),3.75(s,3H),3.41(t,J=5.9 Hz,2H),3.29(s,3H),3.00(d,J=4.5 Hz,3H),2.82(t,J=7.2 Hz,2H),2.08(s,3H),2.02(s,3H),1.78(m,2H)。 Step C : 1-methylurea (23.9 mg, 0.322 mmol), 5-(di-t-butylphosphino)-1',3',5'-triphenyl-1'H-1,4' Bipyridine (16.3 mg, 0.0322 mmol) and K 3 PO 4 (51.3 mg, 0.242 mmol) were dissolved in DME as a slurry. N 2 was bubbled through for 5 minutes. Pd 2 (dba) 3 (7.38 mg, 0.00806 mmol) was added, and N 2 was bubbled through for 5 minutes, and the solution was stirred at room temperature for 1 hour. 2-Chloro-5-(3-methoxypropylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridine (55.1 mg, 0.161 mmol) in the solution in DME was degassed with N 2 for 5 min, was added to the reaction, and heated to 120 deg.] C, for 48 hours. The reaction was partitioned between EtOAc and water, and washed sequentially with water, the organic layer was washed with brine, and dried over Na 2 SO 4, then concentrated to a brown oil. The crude mixture was purified via reverse phase C18 chromatography (water /MeCN) to afford 1-(5-((3-methoxypropyl)thio)-3-((1,3,5) as a clear oil. -Trimethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-3-methylurea (0.0069 g, 11%). Mass spectrum (apci) m/z = 380.2 (M+H). 1 H NMR (CDCl 3 ) δ 9.14 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 6.87 (d, J = 1.7 Hz, 1H) , 3.75 (s, 3H), 3.41 (t, J = 5.9 Hz, 2H), 3.29 (s, 3H), 3.00 (d, J = 4.5 Hz, 3H), 2.82 (t, J = 7.2 Hz, 2H) , 2.08 (s, 3H), 2.02 (s, 3H), 1.78 (m, 2H).

遵循實例432中之程序，亦合成以下化合物： Following the procedure in Example 432, the following compounds were also synthesized:

遵循實例432步驟C中之程序，使用5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑或1,1'-聯萘-2-基二第三丁基膦作為配位體，亦合成以下化合物： Example 432 following the procedure of Step C, using 5- (two t-butyl phosphino) -1 ', 3', 5'-triphenyl -1 'H -1,4'- or bipyrazolyl 1, 1'-Binaphthyl-2-yldi-tert-butylphosphine as a ligand, the following compounds were also synthesized:

實例447Example 447

1-(5-溴-3-((1-甲基-1H-吲唑-5-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-3-((1-methyl-1H-indazol-5-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：將5-溴-3-氟吡啶-2-胺(0.200 g，1.05 mmol)溶解於CH2Cl2中，且依序添加吡啶(0.254 ml，3.14 mmol)、氯甲酸4-硝基苯酯(0.443 g，2.20 mmol)。在室溫下攪拌反應物1小時。添加含甲胺(0.52 ml，4.18 mmol)之EtOH且攪拌2小時。添加水，分離各層，且經Na2SO4乾燥有機物，過濾並濃縮。經由矽膠層析(己烷/丙酮)純化粗混合物，得到呈褐色固體狀之1-(5-溴-3-氟吡啶-2-基)-3-甲基脲(0.135 g，52%)。 Step A : Dissolve 5-bromo-3-fluoropyridin-2-amine (0.200 g, 1.05 mmol) in CH 2 Cl 2 and add pyridine (0.254 ml, 3.14 mmol). Phenyl ester (0.443 g, 2.20 mmol). The reaction was stirred at room temperature for 1 hour. Methylamine (0.52 ml, 4.18 mmol) in EtOH was added and stirred for 2 h. Water was added, the layers were separated, and dried over Na 2 SO 4 organics were filtered and concentrated. The crude mixture was purified by EtOAc EtOAc (EtOAc:EtOAc)

步驟B：將1-(5-溴-3-氟吡啶-2-基)-3-甲基脲(0.010 g，0.040 mmol)、1-甲基-1H-吲唑-5-醇(0.0066 g，0.044 mmol)、K2CO3(0.011 g，0.081 mmol)溶解於NMP中，且加熱至80℃，維持16小時。將反應物分配於EtOAc與水之間，且依序用水、鹽水洗滌有機層，且經Na2SO4乾燥，接著濃縮至棕色油狀物。經由矽膠層析(己烷/丙酮)純化粗混合物，得到呈透明油狀之1-(5-溴-3-((1-甲基-1H-吲唑-5-基)氧基)吡啶-2-基)-3-甲基脲(0.010 g，67%)。質譜(apci)m/z=376.0,378.0(M+H)。 Step B : 1-(5-Bromo-3-fluoropyridin-2-yl)-3-methylurea (0.010 g, 0.040 mmol), 1-methyl-1H-indazole-5-ol (0.0066 g) , 0.044 mmol), K 2 CO 3 (0.011 g, 0.081 mmol) was dissolved in NMP and heated to 80 ° C for 16 h. The reaction was partitioned between EtOAc and water, and washed sequentially with water, the organic layer was washed with brine, and dried over Na 2 SO 4, then concentrated to a brown oil. The crude mixture was purified via EtOAc (hexane/EtOAc) to afford 1-(5-bromo-3-((1-methyl-1H-indazol-5-yl)oxy)pyridine as a clear oil. 2-yl)-3-methylurea (0.010 g, 67%). Mass spectrum (apci) m/z = 376.0, 378.0 (M+H).

實例448Example 448

1-(5-((3-羥基-3-甲基丁基)硫基)-3-((1-甲基-1H-吲唑-5-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((3-Hydroxy-3-methylbutyl)thio)-3-((1-methyl-1H-indazol-5-yl)oxy)pyridin-2-yl)- 3-methylurea

將1-(5-溴-3-(1-甲基-1H-吲唑-5-基氧基)吡啶-2-基)-3-甲基脲(0.0085 g，0.023 mmol)、4-巰基-2-甲基丁-2-醇(0.0030 g，0.025 mmol)、DIEA(0.0079 ml，0.045 mmol)及Xantphos(0.0013 g，0.0023 mmol)溶解於二噁烷中，且使N2鼓泡通過，持續5分鐘。添加Pd2dba3(0.0010 g，0.0011 mmol)，使N2鼓泡通過，持續5分鐘，且加熱反應物至80℃，維持1小時。將反應物分配於EtOAc與水之間，且依序用水、鹽水洗滌有機層，且經Na2SO4乾燥，接著濃縮至棕色油狀物。經由矽膠層析(己烷/丙酮)純化粗混合物，得到呈透明油狀之1-(5-((3-羥基-3-甲基丁基)硫基)-3-((1-甲基-1H-吲唑-5-基)氧基)吡啶-2-基)-3-甲基脲(0.0076 g，81%)。質譜(apci)m/z=416.1(M+H)。 1-(5-Bromo-3-(1-methyl-1H-indazol-5-yloxy)pyridin-2-yl)-3-methylurea (0.0085 g, 0.023 mmol), 4-decyl -2-methylbutan-2-ol (0.0030 g, 0.025 mmol), DIEA (0.0079 ml, 0.045 mmol) and Xantphos (0.0013 g, 0.0023 mmol) were dissolved in dioxane and N 2 was bubbled through. Lasts 5 minutes. Pd 2 dba 3 (0.0010 g, 0.0011 mmol) was added, and N 2 was bubbled through for 5 minutes, and the reaction was heated to 80 ° C for 1 hour. The reaction was partitioned between EtOAc and water, and washed sequentially with water, the organic layer was washed with brine, and dried over Na 2 SO 4, then concentrated to a brown oil. The crude mixture was purified via EtOAc (hexane/EtOAc) to afford 1-(5-((3-hydroxy-3-methylbutyl)thio)-3-((methyl) -1H-indazol-5-yl)oxy)pyridin-2-yl)-3-methylurea (0.0076 g, 81%). Mass spectrum (apci) m/z = 416.1 (M+H).

實例449Example 449

1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)脲 1-methyl-3-(3-((2-methylpyridin-3-yl)oxy)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridin-2-yl Urea

步驟A：向燒瓶中添加LiCl(159 mg，3.74 mmol)，且在155℃下於高真空下乾燥燒瓶30分鐘。接著添加鋅(269 mg，4.12 mmol)，且在155℃下於高真空下再次乾燥燒瓶20分鐘。使燒瓶冷卻至室溫，且在N2下添加無水THF(5 mL)，繼而添加1,2-二溴乙烷(0.016 mL，0.187 mmol)。用加熱槍將燒瓶短暫加熱至65℃，冷卻，接著添加氯三甲基矽烷(4.75 μl，0.037 mmol)。短暫攪拌後，添加5滴1 M I2於THF中之溶液。短暫攪拌反應物，且添加含4-(溴甲基)四氫-2H-哌喃(670 mg，3.74 mmol)之1 mL THF。加熱反應物至50℃隔夜，得到溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(0.624 M，6 mL)。鋅沈降後，該試劑直接用於下一步驟。 Step A : LiCl (159 mg, 3.74 mmol) was added to the flask and the flask was dried at 155 ° C under high vacuum for 30 min. Zinc (269 mg, 4.12 mmol) was then added and the flask was again dried under high vacuum at 155 °C for 20 minutes. The flask was cooled to rt, and anhydrous THF (5 mL) under N 2, was added followed by 1,2-dibromoethane (0.016 mL, 0.187 mmol). The flask was briefly heated to 65 ° C with a heat gun, cooled, and then chlorotrimethylnonane (4.75 μl, 0.037 mmol) was added. After brief stirring, 5 drops of 1 MI 2 solution in THF were added. The reaction was stirred briefly and 1 mL THF containing 4-(bromomethyl)tetrahydro-2H-pyran (670 mg, 3.74 mmol). The reaction was heated to 50 &lt;0&gt;C overnight to give ((tetrahydro-2H-pyran-4-yl)methyl)zinc(II) (0.624 M, 6 mL). After the zinc settled, the reagent was used directly in the next step.

步驟B：向含1-(5-溴-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(85 mg，0.252 mmol)之燒瓶中添加二乙醯氧基鈀(5.66 mg，0.025 mmol)、S-Phos(20.70 mg，0.050 mmol)，且將反應燒瓶置於高真空泵上10分鐘，接著用N2填充。依序添加經脫氣之THF(2 mL)、在先前步驟中當場產生之溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(1.616 mL，1.008 mmol)。加熱反應物至回流，維持7小時。添加飽和NH4Cl，且用EtOAc萃取混合物。乾燥EtOAc層並濃縮，且使用矽膠層析(0-7% MeOH/CH2Cl2梯度分離)純化。藉由逆相HPLC進一步純化含有產物之溶離份，得到1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)脲(47 mg，0.132 mmol，52.3%)。質譜(ESI)m/z=357.2(M+H)。1H NMR(400 MHz,CDCl3)δ ppm 9.16(d,J=4.11 Hz,1 H)8.34(t,J=3.03 Hz,1 H)7.61-7.76(m,1 H)7.32(s,1 H)7.12(d,J=3.13 Hz,2 H)6.55(d,J=1.57 Hz,1 H)3.85(dd,J=11.25,3.42 Hz,2 H)3.10-3.31(m,2 H)2.92(d,J=4.89 Hz,3 H)2.41(s,3 H)2.33(d,J=7.04 Hz,2 H)1.47-1.53(m,1 H)1.41(d,J=13.11 Hz,2 H)1.13-1.27(m,2 H)。 Step B : To a flask containing 1-(5-bromo-3-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (85 mg, 0.252 mmol) two acetyl group added palladium (5.66 mg, 0.025 mmol), S-Phos (20.70 mg, 0.050 mmol), and the reaction flask was placed on a high vacuum pump for 10 minutes, and then filled with 2 N. Add degassed THF (2 mL), brominated ((tetrahydro-2H-piperidin-4-yl)methyl)zinc(II) (1.616 mL, 1.008 mmol) on the spot in the previous step. . The reaction was heated to reflux for 7 hours. Saturated NH 4 Cl, and the mixture was extracted with EtOAc. EtOAc layer was dried and concentrated and purified using silica gel chromatography (0-7% MeOH / CH 2 Cl 2 gradient separation). The product-containing fraction was further purified by reverse phase HPLC to give 1-methyl-3-(3-((2-methylpyridin-3-yl)oxy)-5-((tetrahydro-2H-piperidin) Butan-4-yl)methyl)pyridin-2-yl)urea (47 mg, 0.132 mmol, 52.3%). Mass Spectrum (ESI) m/z = 357.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.16 (d, J = 4.11 Hz, 1 H) 8.34 (t, J = 3.03 Hz, 1 H) 7.61 - 7.76 (m, 1 H) 7.32 (s, 1 H) 7.12 (d, J = 3.13 Hz, 2 H) 6.55 (d, J = 1.57 Hz, 1 H) 3.85 (dd, J = 11.25, 3.42 Hz, 2 H) 3.10-3.31 (m, 2 H) 2.92 (d, J = 4.89 Hz, 3 H) 2.41 (s, 3 H) 2.33 (d, J = 7.04 Hz, 2 H) 1.47-1.53 (m, 1 H) 1.41 (d, J = 13.11 Hz, 2 H ) 1.13-1.27 (m, 2 H).

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449, the following compounds were prepared:

實例466Example 466

(S)-1-(5-(4,5-二羥基戊基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (S)-1-(5-(4,5-dihydroxypentyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

向含(S)-1-(5-(3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(18.9 mg，0.046 mmol)之燒瓶中添加EtOH(1.4 mL)及0.14 mL 1 N HCl。加熱反應物至70℃，維持2小時。添加水，繼而添加少許飽和NaHCO3溶液以將反應物中和至約pH 7。接著用EtOAc萃取反應物。乾燥EtOAc層且濃縮。用Et2O沖洗粗產物，且過濾並乾燥，得到(S)-1-(5-(4,5-二羥基戊基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(15 mg，0.040 mmol，88%)。質譜(ESI)m/z=375.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.36(dd,J=4.69,1.37 Hz,1 H)7.91(d,J=1.37 Hz,1 H)7.41(dd,J=8.22,1.17 Hz,1 H)7.34(dd,J=8.31,4.79 Hz,1 H)6.96(d,J=1.76 Hz,1 H) 3.52-3.61(m,1 H)3.38-3.46(m,2 H)2.94(s,3 H)2.89(q,J=7.63 Hz,2 H)2.47-2.65(m,2 H)1.66-1.78(m,1 H)1.45-1.64(m,2 H)1.36(ddd,J=13.35,9.05,4.21 Hz,1 H)1.29(t,J=7.53 Hz,3 H)。 To (S)-1-(5-(3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl)-3-((2-ethyl) To a flask of pyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (18.9 mg, 0.046 mmol) was added EtOH (1.4 mL) and 0.14 mL of 1 N HCl. The reaction was heated to 70 ° C for 2 hours. Water was added, followed by saturated NaHCO 3 solution was added a little to the reaction was neutralized to about pH 7. The reaction was then extracted with EtOAc. The EtOAc layer was dried and concentrated. The crude product was washed with Et 2 O and filtered and dried to give (S)-1-(5-(4,5-dihydroxypentyl)-3-((2-ethylpyridin-3-yl)oxy Pyridin-2-yl)-3-methylurea (15 mg, 0.040 mmol, 88%). Mass Spectrum (ESI) m/z = 375.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.36 (dd, J = 4.69, 1.37 Hz, 1 H) 7.91 (d, J = 1.37 Hz, 1 H) 7.41 (dd, J = 8.22, 1.17 Hz, 1 H ) 7.34 (dd, J = 8.31, 4.79 Hz, 1 H) 6.96 (d, J = 1.76 Hz, 1 H) 3.52-3.61 (m, 1 H) 3.38-3.46 (m, 2 H) 2.94 (s, 3) H) 2.89 (q, J = 7.63 Hz, 2 H) 2.47-2.65 (m, 2 H) 1.66-1.78 (m, 1 H) 1.45-1.64 (m, 2 H) 1.36 (ddd, J = 13.35, 9.05 , 4.21 Hz, 1 H) 1.29 (t, J = 7.53 Hz, 3 H).

實例467Example 467

1-(3-((2-乙基吡啶-3-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(4-hydroxy-4-methylpentyl)pyridin-2-yl)-3-methylurea

用甲苯使含4-(5-((2-乙基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸乙酯(12 mg，0.031 mmol)之燒瓶共沸。接著添加無水Et2O(1 mL)。在冰浴中冷卻燒瓶。接著逐滴添加1.6 M甲基鋰之Et2O溶液(0.097 mL，0.155 mmol)，且形成白色混濁混合物。使燒瓶升至室溫，接著添加THF(1.000 mL)。攪拌反應物1小時且用飽和NH4Cl溶液淬滅。用EtOAc萃取反應物，乾燥且濃縮。藉由逆相HPLC以10-40%梯度純化粗物質，得到1-(3-((2-乙基吡啶-3-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲(3.2 mg，0.0086 mmol，28%)。質譜(ESI)m/z=373.2(M+H)。1H NMR(400 MHz,CDCl3)δ ppm 9.19(d,J=4.50 Hz,1 H)8.38(t,J=3.03 Hz,1 H)7.69(d,J=1.76 Hz,1 H)7.32(s,1 H)7.10(d,J=2.93 Hz,2 H)6.60(d,J=1.76 Hz,1 H)2.92(d,J=4.69 Hz,3 H)2.69-2.80(m,2 H)2.40(t,J=7.53 Hz,2 H)1.45-1.55(m,2 H)1.32-1.39(m,2 H)1.21(t,J=7.63 Hz,4 H)1.10(s,6 H)。 Ethyl 4-(5-((2-ethylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)butanoate (12 mg, 0.031) The flask of mmol) was azeotroped. Anhydrous Et 2 O (1 mL) was then added. The flask was cooled in an ice bath. Then 1.6 M methyllithium in Et 2 O (0.097 mL, 0.155 mmol) was added dropwise and a white turbid mixture was formed. The flask was allowed to warm to room temperature then THF (1.000 mL) was added. The reaction was stirred for 4 Cl solution for 1 h and quenched with saturated NH. The reaction was extracted with EtOAc, dried and concentrated. The crude material was purified by reverse phase HPLC eluting with 10-40% to give 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(4-hydroxy-4-methylpentyl) Pyridin-2-yl)-3-methylurea (3.2 mg, 0.0086 mmol, 28%). Mass Spectrum (ESI) m/z = 373.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.19 (d, J = 4.50 Hz, 1 H) 8.38 (t, J = 3.03 Hz, 1 H) 7.69 (d, J = 1.76 Hz, 1 H) 7.32 ( s, 1 H) 7.10 (d, J = 2.93 Hz, 2 H) 6.60 (d, J = 1.76 Hz, 1 H) 2.92 (d, J = 4.69 Hz, 3 H) 2.69-2.80 (m, 2 H) 2.40 (t, J = 7.53 Hz, 2 H) 1.45-1.55 (m, 2 H) 1.32-1.39 (m, 2 H) 1.21 (t, J = 7.63 Hz, 4 H) 1.10 (s, 6 H).

遵循實例467中之程序，製備以下化合物： Following the procedure in Example 467, the following compounds were prepared:

實例471Example 471

1-(5-(3,6-二氫-2H-哌喃-4-基)-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(3,6-Dihydro-2H-piperidin-4-yl)-3-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-A Base urea

向1-(5-溴-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(65 mg，0.193 mmol)於2.6 mL經脫氣DMF中之經攪拌溶液中添加Pd(PPh3)4(22.28 mg，0.019 mmol)、K2CO3(80 mg，0.578 mmol)、2-(3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼(81 mg，0.386 mmol)。在100℃下繼續攪拌隔夜。添加水以淬滅反應物，且用EtOAc 萃取混合物。乾燥有機層且在真空中濃縮。在矽膠上純化粗產物，得到37.5 mg 1-(5-(3,6-二氫-2H-哌喃-4-基)-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(57%)。質譜(ESI)m/z=341.2(M+H)。1H NMR(400 MHz,CDCl3)δ 9.25(d,J=4.30 Hz,1 H)8.43(dd,J=4.11,2.15 Hz,1 H)7.96(d,J=1.96 Hz,1 H)7.46(br.s.,1 H)7.15-7.26(m,2 H)6.85(d,J=1.96 Hz,1 H)5.87-6.00(m,1 H)4.26(q,J=2.87 Hz,2 H)3.89(t,J=5.48 Hz,2 H)3.01(d,J=4.69 Hz,3 H)2.51(s,3 H)2.31-2.43(m,2 H)。 Degassed to 2.6 mL of 1-(5-bromo-3-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (65 mg, 0.193 mmol) Pd(PPh 3 ) 4 (22.28 mg, 0.019 mmol), K 2 CO 3 (80 mg, 0.578 mmol), 2-(3,6-dihydro-2H-pyran-4) were added to the stirred solution in DMF. -yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron (81 mg, 0.386 mmol). Stirring was continued overnight at 100 °C. Water was added to quench the reaction and the mixture was extracted with EtOAc. The organic layer was dried and concentrated in vacuo. The crude product was purified on silica gel to give 37.5 mg of 1-(5-(3,6-dihydro-2H-pyran-4-yl)-3-((2-methylpyridin-3-yl)oxy) Pyridin-2-yl)-3-methylurea (57%). Mass Spectrum (ESI) m/z = 341.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.25 (d, J = 4.30 Hz, 1 H) 8.43 (dd, J = 4.11, 2.15 Hz, 1 H) 7.96 (d, J = 1.96 Hz, 1 H) 7.46 (br.s., 1 H) 7.15-7.26 (m, 2 H) 6.85 (d, J = 1.96 Hz, 1 H) 5.87-6.00 (m, 1 H) 4.26 (q, J = 2.87 Hz, 2 H 3.89 (t, J = 5.48 Hz, 2 H) 3.01 (d, J = 4.69 Hz, 3 H) 2.51 (s, 3 H) 2.31-2.43 (m, 2 H).

遵循實例471中之程序，製備以下化合物： Following the procedure in Example 471, the following compounds were prepared:

實例474Example 474

1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-(四氫-2H-哌喃-4-基)吡啶-2-基)脲 1-methyl-3-(3-((2-methylpyridin-3-yl)oxy)-5-(tetrahydro-2H-piperidin-4-yl)pyridin-2-yl)urea

向1-(5-(3,6-二氫-2H-哌喃-4-基)-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(29 mg，0.085 mmol)於EtOH(0.852 mL，0.085 mmol)、EtOAc(0.852 mL，0.085 mmol)中之溶液中添加Pd/C(18.13 mg，0.017 mmol)。首先用H2淨化混合物，接著在H2氣球下攪拌24小時。經矽藻土襯墊過濾反應物且濃縮，得到22 mg 1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-(四氫-2H-哌喃-4-基)吡啶-2-基)脲(75%)。質譜(ESI)m/z=343.2(M+H)。1H NMR(400 MHz,CDCl3)δ 9.24(br.s.,1 H)8.35-8.51(m,1 H)7.81(d,J=1.76 Hz,1 H)7.41(br.s.,1 H)7.14-7.24(m,2 H)6.69(d,J=1.76 Hz,1 H)3.98-4.09(m,2 H)3.46(td,J=11.15,3.33 Hz,2 H)2.89-3.10(m,3 H)2.56-2.72(m,1 H)2.49(s,3 H)1.57-1.74(m,4 H)。 To 1-(5-(3,6-dihydro-2H-piperidin-4-yl)-3-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- To a solution of methylurea (29 mg, 0.085 mmol) in EtOAc (EtOAc: EtOAc (EtOAc) Mixture was purified first with H 2, then stirred under H 2 balloon for 24 h. The reaction was filtered through a pad of celite and concentrated to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& Methyl-4-yl)pyridin-2-yl)urea (75%). Mass Spectrum (ESI) m/z = 343.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (br.s., 1 H) 8.35-8.51 (m, 1 H) 7.81 (d, J = 1.76 Hz, 1 H) 7.41 (br.s., 1 H) 7.14 - 7.24 (m, 2 H) 6.69 (d, J = 1.76 Hz, 1 H) 3.98 - 4.09 (m, 2 H) 3.46 (td, J = 11.15, 3.33 Hz, 2 H) 2.89-3.10 ( m, 3 H) 2.56-2.72 (m, 1 H) 2.49 (s, 3 H) 1.57-1.74 (m, 4 H).

遵循實例474中之程序，亦合成以下化合物： Following the procedure in Example 474, the following compounds were also synthesized:

實例476Example 476

1-(3-((2-乙基吡啶-3-基)氧基)-5-(苯基乙炔基)吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(phenylethynyl)pyridin-2-yl)-3-methylurea

在黑暗中，用N2淨化裝有1-(5-溴-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.150 g，0.427 mmol)、PdCl2(PPh3)3(0.030 g， 0.043 mmol)、Et3N(0.048 ml，0.342 mmol)、苯基乙炔(0.094 ml，0.854 mmol)及CuI(1.447 μl，0.043 mmol)之燒瓶。添加經脫氣之THF(2.136 ml)。在黑暗中加熱反應物至回流隔夜，接著冷卻至室溫。用EtOAc稀釋反應物，用鹽水洗滌，經MgSO4乾燥，過濾且在真空中濃縮，得到粗物質。藉由矽膠層析，用0%至10% MeOH/CH2Cl2溶離來純化粗物質，得到呈白色固體狀之1-(3-((2-乙基吡啶-3-基)氧基)-5-(苯基乙炔基)吡啶-2-基)-3-甲基脲(0.130 g，0.349 mmol，82%產率)。質譜(ESI)m/z=373.0(M+H)。1H NMR(400 MHz,CDCl3)δ ppm 8.51(1H,dd,J=4.5,2.0 Hz),8.10(1H,d,J=2.0 Hz),7.48(1H,dd,J=6.7,3.0 Hz),7.20-7.36(6H,m),6.89(1H,d,J=2.0 Hz),3.03(3H,d,J=4.7 Hz),2.83(2H,d,J=7.4 Hz),1.31(3H,t,J=7.4 Hz)。 Purified with N 2 in the dark with 1-(5-bromo-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.150 g, 0.427 mmol), PdCl 2 (PPh 3 ) 3 (0.030 g, 0.043 mmol), Et 3 N (0.048 ml, 0.342 mmol), phenylacetylene (0.094 ml, 0.854 mmol) and CuI (1.447 μl, 0.043 mmol) Flask. Degassed THF (2.136 ml) was added. The reaction was heated in the dark to reflux overnight then cooled to rt. The reaction was diluted with EtOAc, washed with brine, dried over MgSO 4, filtered and concentrated in vacuo to give crude material. By silica gel chromatography with 0% to 10% MeOH / CH 2 Cl 2 eluting the crude material was purified, to give a white solid of 1- (3 - ((2-ethyl-3-yl) oxy) 5-(-Phenylethynyl)pyridin-2-yl)-3-methylurea (0.130 g, 0.349 mmol, 82% yield). Mass Spectrum (ESI) m/z = 373.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.51 (1H, dd, J = 4.5, 2.0 Hz), 8.10 (1H, d, J = 2.0 Hz), 7.48 (1H, dd, J = 6.7, 3.0 Hz ), 7.20-7.36 (6H, m), 6.89 (1H, d, J = 2.0 Hz), 3.03 (3H, d, J = 4.7 Hz), 2.83 (2H, d, J = 7.4 Hz), 1.31 (3H) , t, J = 7.4 Hz).

遵循實例476中之程序，亦合成以下化合物： Following the procedure in Example 476, the following compounds were also synthesized:

實例479Example 479

(Z)-1-(3-((2-乙基吡啶-3-基)氧基)-5-苯乙烯基吡啶-2-基)-3-甲基脲 (Z)-1-(3-((2-ethylpyridin-3-yl)oxy)-5-styrylpyridin-2-yl)-3-methylurea

步驟A：在25℃下，向1-(3-((2-乙基吡啶-3-基)氧基)-5-(苯基乙炔基)吡啶-2-基)-3-甲基脲(0.013 g，0.035 mmol)於EtOH(0.70 ml)及EtOAc(0.7 ml)中之溶液中添加林德拉催化劑(Lindlar catalyst)(2.3 mg)。在25℃下於H2氛圍下攪拌反應物隔夜，得到E及Z烯烴之混合物(混合物A)。 Step A : to 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(phenylethynyl)pyridin-2-yl)-3-methylurea at 25 °C (0.013 g, 0.035 mmol) In a solution of EtOH (0.70 ml) and EtOAc (0.7 ml). The reaction was stirred overnight at 25 ° C under H 2 to give a mixture of E and Z olefins (mixture A).

步驟B：在室溫下，向1-(3-((2-乙基吡啶-3-基)氧基)-5-(苯基乙炔基)吡啶-2-基)-3-甲基脲(0.022 g，0.059 mmol)於甲苯(0.537 ml)及H2O(0.054 ml)中之溶液中添加Pd(dppf)Cl2(0.724 mg，0.886 μmol)、1,1'-雙(二苯基膦基)二茂鐵(1.637 mg，2.95 μmol)、三乙基矽烷(0.017 ml，0.118 mmol)及五水合硫酸銅(2.212 mg，8.86 μmol)。加熱反應物至回流隔夜。濃縮反應物，得到E及Z烯烴之混合物(混合物B)。合併混合物A與B且使用製備型HPLC純化，得到呈白色固體狀之(Z)-1-(3-((2-乙基吡啶-3-基)氧基)-5-苯乙烯基吡啶-2-基)-3-甲基脲(0.0013 g，3.47 μmol)。質譜(ESI)m/z=375.0(M+H)。1H NMR(400 MHz，甲醇-d 4)δ ppm 8.29(1H,dd,J=4.3,2.0 Hz),7.89(1H,s),7.02-7.27(7H,m),6.68(1H,d,J=9.0 Hz),6.61(1H,s),6.48(2H,1H,d,J=9.0 Hz),2.92(3H,s),2.67(2H,q,J=7.5 Hz),1.15(3H,t,J=7.5 Hz)。 Step B : To 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(phenylethynyl)pyridin-2-yl)-3-methylurea at room temperature (0.022 g, 0.059 mmol) Pd(dppf)Cl 2 (0.724 mg, 0.886 μmol), 1,1'-bis(diphenyl) in a solution of toluene (0.537 ml) and H 2 O (0.054 ml) Phosphyl)ferrocene (1.637 mg, 2.95 μmol), triethyldecane (0.017 ml, 0.118 mmol) and copper sulfate pentahydrate (2.212 mg, 8.86 μmol). The reaction was heated to reflux overnight. The reactants were concentrated to give a mixture of E and Z olefins (mixture B). The mixture was combined with a preparative HPLC to give (Z)-1-(3-((2-ethylpyridin-3-yl)oxy)-5-styrylpyridine as a white solid. 2-yl)-3-methylurea (0.0013 g, 3.47 μmol). Mass Spectrum (ESI) m/z = 375.0 (M+H). 1 H NMR (400 MHz, methanol - d 4 ) δ ppm 8.29 (1H, dd, J = 4.3, 2.0 Hz), 7.89 (1H, s), 7.02-7.27 (7H, m), 6.68 (1H, d, J = 9.0 Hz), 6.61 (1H, s), 6.48 (2H, 1H, d, J = 9.0 Hz), 2.92 (3H, s), 2.67 (2H, q, J = 7.5 Hz), 1.15 (3H, t, J = 7.5 Hz).

實例480Example 480

1-(3-((2-乙基吡啶-3-基)氧基)-5-苯乙基吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-phenethylpyridin-2-yl)-3-methylurea

在25℃下，向1-(3-((2-乙基吡啶-3-基)氧基)-5-(苯基乙炔基)吡啶-2-基)-3-甲基脲(0.020 g，0.054 mmol)於MeOH(0.537 ml)及EtOAc(0.537 ml)中之溶液中添加Pd/C(8.57 mg，8.06 μmol)。在25℃下於1 atm H2氛圍下攪拌反應物隔夜。經矽藻土襯墊過濾混合物，且用EtOAc洗滌。濃縮濾液，得到1-(3-((2-乙基吡啶-3-基)氧基)-5-苯乙基吡啶-2-基)-3-甲基脲(0.017 g，0.045 mmol，84%產率)。質譜(ESI)m/z=377.0(M+H)。1H NMR(400 MHz，甲醇-d 4)δ ppm 8.29(1H,dd,J=4.3,2.0 Hz),7.83(1H,s),7.02-7.50(7H,m),6.65(1H,s),2.92(3H,s),2.85-2.95(6H,m),2.67(2H,q,J=7.5 Hz),1.15(3H,t,J=7.5 Hz)。 To 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(phenylethynyl)pyridin-2-yl)-3-methylurea (0.020 g) at 25 °C Pd/C (8.57 mg, 8.06 μmol) was added to a solution of MeOH (0.537 ml The reaction was stirred overnight at 25 ° C under 1 atm H 2 atmosphere. The mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated to give 1-(3-((2-ethylpyridin-3-yl)oxy)-5-phenethylpyridin-2-yl)-3-methylurea (0.017 g, 0.045 mmol, 84 %Yield). Mass Spectrum (ESI) m/z = 377.0 (M+H). 1 H NMR (400 MHz, methanol - d 4 ) δ ppm 8.29 (1H, dd, J = 4.3, 2.0 Hz), 7.83 (1H, s), 7.02-7.50 (7H, m), 6.65 (1H, s) , 2.92 (3H, s), 2.85-2.95 (6H, m), 2.67 (2H, q, J = 7.5 Hz), 1.15 (3H, t, J = 7.5 Hz).

遵循實例480中之程序，亦合成以下化合物： Following the procedure in Example 480, the following compounds were also synthesized:

實例483Example 483

1-(5-環己烯基-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-cyclohexenyl-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

向1-(5-溴-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.10 g，0.285 mmol)及環己烯-1-基酸(0.072 g，0.569 mmol)於二噁烷(2 mL)中之經攪拌溶液中添加Pd2(dba)3(0.026 g，0.028 mmol)，繼而添 加三環己基膦(0.016 g，0.057 mmol)、1.3 M磷酸鉀水溶液(0.548 ml， 0.712 mmol)。加熱反應物至90℃且繼續攪拌16小時。濃縮混合物且在矽膠上用含0-2.5% MeOH之CH2Cl2溶離來純化，得到1-(5-環己烯基-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.080 g，0.227 mmol，80%產率)。質譜(ESI)m/z=353.0(M+H)。1H NMR(400 MHz,CDCl3)δ 9.31(br.s.,1H),8.47(t,J=3.03 Hz,1H),7.96(d,J=1.96 Hz,1H),7.42(s,1H),7.20(d,J=3.13 Hz,2H),6.87(d,J=1.96 Hz,1H),5.94(s,1H),3.03(d,J=4.70 Hz,3H),2.86(q,J=7.50 Hz,2H),2.23-2.32(m,2H),2.12-2.22(m,2H),1.71-1.83(m,2H),1.62-1.69(m,2H),1.32(t,J=7.63 Hz,3H)。 To 1-(5-bromo-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.10 g, 0.285 mmol) and cyclohexene-1 -base Add Pd 2 (dba) 3 (0.026 g, 0.028 mmol) to a stirred solution of the acid (0.072 g, 0.569 mmol) in dioxane (2 mL), followed by tricyclohexylphosphine (0.016 g, 0.057 mmol) , 1.3 M aqueous potassium phosphate solution (0.548 ml, 0.712 mmol). The reaction was heated to 90 ° C and stirring was continued for 16 hours. The mixture was concentrated on silica gel and containing CH 0-2.5% MeOH 2 Cl 2 solution of purified away to give 1- (5-hexenyl-3- (2-ethyl-pyridin-3-yloxy) pyridine - 2-yl)-3-methylurea (0.080 g, 0.227 mmol, 80% yield). Mass Spectrum (ESI) m/z = 353.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (br.s., 1H), 8.47 (t, J = 3.03 Hz, 1H), 7.96 (d, J = 1.96 Hz, 1H), 7.42 (s, 1H) ), 7.20 (d, J = 3.13 Hz, 2H), 6.87 (d, J = 1.96 Hz, 1H), 5.94 (s, 1H), 3.03 (d, J = 4.70 Hz, 3H), 2.86 (q, J) =7.50 Hz, 2H), 2.23 - 2.32 (m, 2H), 2.12 - 2.22 (m, 2H), 1.71-1.83 (m, 2H), 1.62-1.69 (m, 2H), 1.32 (t, J = 7.63) Hz, 3H).

遵循實例483中之程序，亦合成以下化合物： Following the procedure in Example 483, the following compounds were also synthesized:

實例486Example 486

1-(5-環己基-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-cyclohexyl-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

向1-(5-(環己-1-烯-1-基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.055 g，0.156 mmol)於MeOH(0.35 ml)中之溶液中添加5% Pd(0.008 g，0.003 mmol)。在H2氛圍下攪拌所得混合物24小時。經針筒過濾器過濾混合物且在真空中濃縮，得到1-(5-環己基-3-(2-乙基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.048 g，0.135 mmol，87%產率)。質譜(ESI)m/z=355.0(M+H)。1H NMR(400 MHz,CDCl3)δ 8.48(dd,J=1.96,4.30 Hz,1H),7.81(d,J=1.56 Hz,1H),7.14-7.25(m,2H),6.72(d,J=1.57 Hz,1H),3.02(d,J=4.70 Hz,3H),2.85(q,J=7.63 Hz,2H),2.41(t,J=11.74 Hz,1H),1.66-1.92(m,5H),1.21-1.39(m,8H)。 To 1-(5-(cyclohex-1-en-1-yl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.055 g, 0.156 mmol) 5% Pd (0.008 g, 0.003 mmol). The resulting mixture was stirred under a H 2 atmosphere for 24 hours. The mixture was filtered through a syringe filter and concentrated in vacuo to give 1-(5-cyclohexyl-3-(2-ethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea 0.048 g, 0.135 mmol, 87% yield). Mass Spectrum (ESI) m/z = 355.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (dd, J =1.96, 4.30 Hz, 1H), 7.81 (d, J = 1.56 Hz, 1H), 7.14-7.25 (m, 2H), 6.72 (d, J = 1.57 Hz, 1H), 3.02 (d, J = 4.70 Hz, 3H), 2.85 (q, J = 7.63 Hz, 2H), 2.41 (t, J = 11.74 Hz, 1H), 1.66-1.92 (m, 5H), 1.21-1.39 (m, 8H).

遵循實例486中之程序，亦合成以下化合物： Following the procedure in Example 486, the following compounds were also synthesized:

實例488Example 488

N,N-二甲基-4-(5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基)-5,6-二氫吡啶-1(2H)-甲醯胺 N,N-Dimethyl-4-(5-(2-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-yl)-5,6-dihydrogen Pyridine-1(2 H )-formamide

步驟A：向5-((2-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)-5',6'-二氫- [3,4'-聯吡啶]-1'(2'H)-甲酸第三丁酯(0.105 g，0.239 mmol)於CH2Cl2(2 mL)中之溶液中添加TFA(0.184 mL，2.39 mmol)。在室溫下攪拌反應物16小時，接著在真空下濃縮，得到1-甲基-3-(5-((2-甲基吡啶-3-基)氧基)-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)脲2,2,2-三氟乙酸鹽(0.081 g，0.18 mmol，75%產率)。 Step A : to 5-((2-methylpyridin-3-yl)oxy)-6-(3-methylureido)-5',6'-dihydro-[3,4'-bipyridine ] -1 '(2'H) - acid tert-butyl ester (0.105 g, 0.239 mmol) in CH 2 Cl 2 (2 mL) was added in the TFA (0.184 mL, 2.39 mmol) . The reaction was stirred at room temperature for 16 h then concentrated in vacuo to give 1-methyl-3-(5-((2-methylpyridin-3-yl)oxy)-1',2',3 ',6'-Tetrahydro-[3,4'-bipyridyl]-6-yl)urea 2,2,2-trifluoroacetate (0.081 g, 0.18 mmol, 75% yield).

步驟B：將1-甲基-3-(5-((2-甲基吡啶-3-基)氧基)-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)脲2,2,2-三氟乙酸鹽(0.040 g，0.12 mmol)、(二甲基胺基)羰基氯(0.014 ml，0.15 mmol)及DIEA(0.70 ml，4.0 mmol)於CH2Cl2(1 mL)與DMF(0.5 mL)溶液之混合物中組合。在室溫下攪拌反應物2小時且在真空下濃縮。在矽膠上用含0-10% MeOH之CH2Cl2溶離來純化粗產物，得到N,N-二甲基-4-(5-(2-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基)-5,6-二氫吡啶-1(2H)-甲醯胺(0.025 g，0.061 mmol，52%產率)。質譜(ESI)m/z=411.1(M+H)。1H NMR(500 MHz,CDCl3)δ 9.23(br.s.,1H),8.44(s,1H),7.96(s,1H),7.45(br.s.,1H),7.23(s,2H),6.77-6.93(m,1H),5.87(br.s.,1H),3.88(d,J=2.93 Hz,2H),3.42(t,J=5.62 Hz,2H),3.01(d,J=4.65 Hz,3H),2.85(s,6H),2.52(s,3H),2.40-2.48(m,2H)。 Step B : 1-methyl-3-(5-((2-methylpyridin-3-yl)oxy)-1',2',3',6'-tetrahydro-[3,4' -bipyridyl]-6-yl)urea 2,2,2-trifluoroacetate (0.040 g, 0.12 mmol), (dimethylamino)carbonyl chloride (0.014 ml, 0.15 mmol) and DIEA (0.70 ml, 4.0 mmol) was combined in a mixture of CH 2 Cl 2 (1 mL) and DMF (0.5 mL). The reaction was stirred at rt for 2 h and concentrated in vacuo. CH on silica gel with 0-10% MeOH containing 2 Cl 2 fractions of the crude product was purified to give the N, N- dimethyl-4- (5- (2-methyl-pyridin-3-yloxy) -6 -(3-Methylureido)pyridin-3-yl)-5,6-dihydropyridine-1( 2H )-carboxamide (0.025 g, 0.061 mmol, 52% yield). Mass Spectrum (ESI) m/z = 411.1 (M+H). 1 H NMR (500 MHz, CDCl 3 ) δ 9.23 (br.s., 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.45 (br.s., 1H), 7.23 (s, 2H) ), 6.77-6.93 (m, 1H), 5.87 (br.s., 1H), 3.88 (d, J = 2.93 Hz, 2H), 3.42 (t, J = 5.62 Hz, 2H), 3.01 (d, J = 4.65 Hz, 3H), 2.85 (s, 6H), 2.52 (s, 3H), 2.40-2.48 (m, 2H).

遵循實例488中之程序，亦合成以下化合物： Following the procedure in Example 488, the following compounds were also synthesized:

實例493Example 493

1-甲基-3-(3-(2-甲基吡啶-3-基氧基)-5-(哌啶-4-基甲基)吡啶-2-基)脲2,2,2-三氟乙酸鹽 1-methyl-3-(3-(2-methylpyridin-3-yloxy)-5-(piperidin-4-ylmethyl)pyridin-2-yl)urea 2,2,2-three Fluoroacetate

步驟A：在Ar下，向50 mL圓底燒瓶中饋入1-n-boc-4-亞甲基-哌啶(1.785 mL，9.05 mmol)。在0℃下添加0.5 M 9-BBN於THF中之溶液(18.45 mL，9.23 mmol)，接著在室溫下攪拌反應物2小時。將所得溶液添加至1-(5-溴-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.61 g，1.809 mmol)、PdCl2(dppf)(0.044 g，0.054 mmol)、三苯胂(0.045 mL，0.181 mmol)、Cs2CO3(0.725 g，2.225 mmol)、DMF(4 mL)及水(0.36 mL)之混合物中。在60℃下加熱混合物且攪拌16小時。冷卻至室溫且傾倒至水中後，用10% NaOH(水溶液)將pH值調整至11，且用EtOAc(2×50 mL)萃取混合物。經MgSO4乾燥經合併之有機萃取物，過濾且在真空中濃縮。在矽膠上用含0-2.5% MeOH之CH2Cl2溶離來純化粗物質，得到4-((5-((2-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)甲基)哌啶-1-甲酸第三丁酯(0.055 g，0.12 mmol，6.7%產率)。質譜(ESI)m/z=456.1(M+H)。 Step A : To a 50 mL round bottom flask was charged 1- n- boc-4-methylene-piperidine (1.785 mL, 9.05 mmol) under ar. A solution of 0.5 M 9-BBN in THF (18.45 mL, 9.23 mmol) was then. The resulting solution was added to 1-(5-bromo-3-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.61 g, 1.809 mmol), PdCl A mixture of 2 (dppf) (0.044 g, 0.054 mmol), triphenylsulfonium (0.045 mL, 0.181 mmol), Cs 2 CO 3 (0.725 g, 2.225 mmol), DMF (4 mL) and water (0.36 mL). The mixture was heated at 60 ° C and stirred for 16 hours. After cooling to room temperature and poured into water, neutralized with 10% NaOH (aq) to adjust the pH to 11, and the mixture was extracted with EtOAc (2 × 50 mL). Dried over MgSO 4 the organic extracts were combined, filtered and concentrated in vacuo. CH on silica gel with 0-2.5% MeOH containing 2 Cl 2 fractions of the crude material was purified to give 4 - ((5 - ((2-methyl-pyridin-3-yl) oxy) -6- (3- Tert-butyl ester of pyridyl-3-yl)methyl)piperidine-1-carboxylate (0.055 g, 0.12 mmol, 6.7% yield). Mass Spectrum (ESI) m/z = 456.1 (M+H).

步驟B：向4-((5-((2-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)甲基)哌啶-1-甲酸第三丁酯(0.055 g，0.12 mmol)於CH2Cl2(1 mL)中之溶液中添加TFA(0.1 mL，1.298 mmol)。在室溫下攪拌反應物16小時，接著在真空下濃縮，得到1-甲基-3-(3-((2-甲基吡啶-3-基氧基)-5-(哌啶-4-基甲基)吡啶-2-基)脲2,2,2-三氟乙酸鹽(0.034 g，0.072 mmol，60%產率)。質譜(ESI)m/z=356.0(M+H)。1H NMR(500 MHz,MeOH- d4)δ 8.44(dd,J=1.22,5.38 Hz,1H),7.98(d,J=1.71 Hz,1H),7.69-7.79(m,1H),7.61(dd,J=5.26,8.44 Hz,1H),7.34(d,J=1.71 Hz,1H),3.37(d,J=13.20 Hz,2H),2.85-2.99(m,5H),2.68(s,3H),2.59(d,J=6.60 Hz,2H),1.78-1.91(m,3H),1.33-1.48(m,2H)。 Step B : To 4-((5-((2-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)methyl)piperidine-1- was added TFA 2 Cl 2 (1 mL) solution of the acid tert-butyl ester (0.055 g, 0.12 mmol) in CH (0.1 mL, 1.298 mmol) . The reaction was stirred at room temperature for 16 h then concentrated in vacuo to give 1-methyl-3-(3-((2-methylpyridin-3-yloxy)-5- (piperidin-4- ylmethyl) pyridin-2-yl) urea 2,2,2-trifluoroacetate (0.034 g, 0.072 mmol, 60 % yield). mass Spectrum (ESI) m / z = 356.0 (m + H). 1 H NMR (500 MHz, MeO H- d 4 ) δ 8.44 (dd, J = 1.22, 5.38 Hz, 1H), 7.98 (d, J = 1.71 Hz, 1H), 7.69-7.79 (m, 1H), 7.61 ( Dd, J = 5.26, 8.44 Hz, 1H), 7.34 (d, J = 1.71 Hz, 1H), 3.37 (d, J = 13.20 Hz, 2H), 2.85-2.99 (m, 5H), 2.68 (s, 3H) ), 2.59 (d, J = 6.60 Hz, 2H), 1.78-1.91 (m, 3H), 1.33-1.48 (m, 2H).

實例494Example 494

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(5-甲氧基戊基)吡啶-2-基)-3-甲基脲 1-(3-((1-ethyl-1 H -pyrazol-5-yl)oxy)-5-(5-methoxypentyl)pyridin-2-yl)-3-methylurea

將1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(5-甲氧基戊-1-炔-1-基)吡啶-2-基)-3-甲基脲(35 mg，0.098 mmol)溶解於EtOAc(0.5 ml)中。向溶液中添加氧化鉑(IV)(2.80 mg，0.012 mmol)。用H2吹洗反應燒瓶，接著在H2氣球下攪拌24小時。經矽藻土襯墊過濾漿液且用EtOAc洗滌。濃縮濾液，得到1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(5-甲氧基戊基)吡啶-2-基)-3-甲基脲(33 mg，0.091 mmol，93%產率)。1H NMR(400 MHz,CDCl 3 )δ ppm 9.21(1H,br.q,J=4.3,4.3,4.3 Hz),7.78(1H,d,J=1.8 Hz),7.44(1H,d,J=2.2 Hz),7.28(1H,br.s),7.00(1H,d,J=2.0 Hz),5.67(1H,d,J=2.0 Hz),4.05(2H,q,J=7.3 Hz),3.34(2H,t,J=6.5 Hz),3.31(3H,s),2.98(3H,d,J=4.7 Hz),2.50(2H,t,J=7.6 Hz),1.48-1.64(4H,m),1.42(3H,t,J=7.2 Hz),1.30-1.39(2H,m)。質譜(ESI)m/z=362.0(M+H)。 1-(3-((1-Ethyl-1 H -pyrazol-5-yl)oxy)-5-(5-methoxypent-1-yn-1-yl)pyridin-2-yl -3 Methylurea (35 mg, 0.098 mmol) was dissolved in EtOAc (0.5 mL). Platinum (IV) oxide (2.80 mg, 0.012 mmol) was added to the solution. The reaction was purged with H 2 flask, followed by stirring under H 2 balloon for 24 h. The slurry was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated to give 1-(3-((1-ethyl-1 H -pyrazol-5-yl)oxy)-5-(5-methoxypentyl)pyridin-2-yl)-3- Methyl urea (33 mg, 0.091 mmol, 93% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm 9.21 (1H, br.q, J = 4.3, 4.3, 4.3 Hz), 7.78 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.28 (1H, br.s), 7.00 (1H, d, J = 2.0 Hz), 5.67 (1H, d, J = 2.0 Hz), 4.05 (2H, q, J = 7.3 Hz), 3.34 ( 2H, t, J = 6.5 Hz), 3.31 (3H, s), 2.98 (3H, d, J = 4.7 Hz), 2.50 (2H, t, J = 7.6 Hz), 1.48-1.64 (4H, m), 1.42 (3H, t, J = 7.2 Hz), 1.30-1.39 (2H, m). Mass Spectrum (ESI) m/z = 362.0 (M+H).

遵循實例494中之程序，亦合成以下化合物： Following the procedure in Example 494, the following compounds were also synthesized:

實例496Example 496

1-甲基-3-(5'-(2-甲基吡啶-3-基氧基)-2,3'-聯吡啶-6'-基)脲 1-methyl-3-(5'-(2-methylpyridin-3-yloxy)-2,3'-bipyridyl-6'-yl)urea

向1-(5-溴-3-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.108 g，0.320 mmol)及2-(三丁基錫烷基)吡啶(0.13 mL，0.406 mmol)於甲苯(3 mL)中之經攪拌溶液中添加Pd(PPh3)4(0.074 g，0.064 mmol)。加熱反應物至110℃且攪拌2小時。濃縮反應物且在矽膠上用含0-5% MeOH之CH2Cl2溶離來純化，得到1-甲基-3-(5'-((2-甲基吡啶-3-基)氧基)-[2,3'-聯吡啶]-6'-基)脲(0.068 g，0.203 mmol，63.3%產率)。質譜(ESI)m/z=336.0(M+H)。1H NMR(400 MHz,CDCl3)δ 9.33(d,J=4.30 Hz,1H),8.56-8.63(m,1H),8.52(d,J=1.96 Hz,1H),8.44(dd,J=1.37,4.70 Hz,1H),7.73(dt,J=1.76,7.73 Hz,1H),7.55-7.65(m,3H),7.18-7.25(m,2H),3.04(d,J=4.70 Hz,3H),2.53(s,3H)。 To 1-(5-bromo-3-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.108 g, 0.320 mmol) and 2-(tributyltin) Pd(PPh 3 ) 4 (0.074 g, 0.064 mmol) was added to a stirred solution of aq. pyridine (0.13 mL, 0.406 mmol) in toluene (3 mL). The reaction was heated to 110 ° C and stirred for 2 hours. The reaction was concentrated 2 Cl 2 and purified on silica gel eluting with 0-5% MeOH containing of CH, to give 1-methyl-3- (5 '- ((2-methyl-pyridin-3-yl) oxy) -[2,3'-bipyridyl]-6'-yl)urea (0.068 g, 0.203 mmol, 63.3% yield). Mass Spectrum (ESI) m/z = 336.0 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.33 (d, J = 4.30 Hz, 1H), 8.56-8.63 (m, 1H), 8.52 (d, J = 1.96 Hz, 1H), 8.44 (dd, J = 1.37, 4.70 Hz, 1H), 7.73 (dt, J = 1.76, 7.73 Hz, 1H), 7.55-7.65 (m, 3H), 7.18-7.25 (m, 2H), 3.04 (d, J = 4.70 Hz, 3H ), 2.53 (s, 3H).

實例497Example 497

4-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸 4-(5-((1-ethyl-1 H -pyrazol-5-yl)oxy)-6-(3-methylureido)pyridin-3-yl)butyric acid

將4-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸乙酯(10 mg，0.027 mmol)溶解於0.5 mL 1：1 MeOH：THF混合物中。添加LiOH(2 M溶液)(133 μl，0.266 mmol)，且攪拌隔夜直至完成。用1 M HCl溶液將混合物酸化至pH值為約5，且濃縮至乾燥並置於高真空下，得到4-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸鹽酸鹽(9.2 mg，0.026 mmol，99%產率)。1H NMR(400 MHz,CDCl 3 )δ ppm 7.78(1H,d,J=1.8 Hz),7.40(1H,d,J=2.0 Hz),7.04(1H,br.s),5.66(1H,d,J=2.0 Hz),4.05(2H,q,J=7.2 Hz),2.94(3H,s),2.54(2H,t,J=7.6 Hz),2.26(2H,t,J=7.2 Hz),1.82(2H，五重峰，J=7.4 Hz), 1.39(3H,t,J=7.3 Hz)。質譜(ESI)m/z=348.1(M+H)。 Ethyl 4-(5-((1-ethyl-1 H -pyrazol-5-yl)oxy)-6-(3-methylureido)pyridin-3-yl)butanoate (10 mg , 0.027 mmol) was dissolved in 0.5 mL of a 1:1 MeOH:THF mixture. LiOH (2 M solution) (133 μl, 0.266 mmol) was added and stirred overnight until completion. The mixture was acidified to a pH of about 5 with 1 M HCl solution and concentrated to dryness and placed under high vacuum to give 4-(5-((1-ethyl-1H-pyrazol-5-yl)oxy) -6-(3-Methylureido)pyridin-3-yl)butanoic acid hydrochloride (9.2 mg, 0.026 mmol, 99% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.78 (1H, d, J = 1.8 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.04 (1H, br.s), 5.66 (1H, d , J = 2.0 Hz), 4.05 (2H, q, J = 7.2 Hz), 2.94 (3H, s), 2.54 (2H, t, J = 7.6 Hz), 2.26 (2H, t, J = 7.2 Hz), 1.82 (2H, quintuple, J = 7.4 Hz), 1.39 (3H, t, J = 7.3 Hz). Mass Spectrum (ESI) m/z = 348.1 (M+H).

實例498Example 498

(1-(5-(2-羥基乙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (1-(5-(2-hydroxyethyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

遵循實例197中之程序製備化合物。質譜(ESI)m/z=302.9(M+H)。 Compounds were prepared following the procedure in Example 197. Mass Spectrum (ESI) m/z = 302.9 (M+H).

實例499Example 499

1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

向500 mL圓底燒瓶中添加含3-羥基-5-甲基吡啶(7.23 g，64.3 mmol)、氟化銫(14.64 g，96 mmol)及1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(15.94 g，64.3 mmol)之AcCN(320 ml)。在80℃下於回流下加熱反應物16小時。冷卻反應物至室溫，濃縮且用水稀釋。過濾白色沈澱物，收集且在減壓下乾燥，得到呈白色固體狀之1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(20.4 g，60.5 mmol，94%產率)。質譜(ESI)m/z=336.9,339.0(M+H)。1H NMR(400 MHz,CDCl3)δ 8.39(s,1H),8.30(s,1H),8.24(s,1H),8.07(s,1H),6.08(s,1H),2.83(d,J=4.7 Hz,3H),2.41(s,3H)。 Add 3-hydroxy-5-methylpyridine (7.23 g, 64.3 mmol), cesium fluoride (14.64 g, 96 mmol) and 1-(5-bromo-4-fluoropyridine-2) to a 500 mL round bottom flask. -Methyl 3-carbazide (15.94 g, 64.3 mmol) of AcCN (320 ml). The reaction was heated at 80 ° C under reflux for 16 hours. The reaction was cooled to room temperature, concentrated and diluted with water. The white precipitate was filtered, dried and evaporated to dry crystals crystals crystals crystals 3-methylurea (20.4 g, 60.5 mmol, 94% yield). Mass Spectrum (ESI) m/z =353. 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 6.08 (s, 1H), 2.83 (d, J = 4.7 Hz, 3H), 2.41 (s, 3H).

實例500Example 500

1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶-2-基)脲 1-methyl-3-(3-((2-methylpyridin-3-yl)oxy)-5-phenoxypyridin-2-yl)urea

步驟A：向裝有5-溴-3-((2-甲基吡啶-3-基)氧基)-2-氰基吡啶(1200 mg，4.14 mmol)之燒瓶中添加無水磷酸鉀(1756 mg，8.27 mmol)、2-二第三丁基膦基-2,4,6-三異丙基-1,1-聯苯(263 mg，0.620 mmol)、苯酚(506 mg，5.38 mmol)、乙酸鈀(ii)(93 mg，0.414 mmol)。在高真空下用氮氣吹洗燒瓶。添加經脫氣之甲苯。加熱反應物至120℃隔夜，維持22小時。經矽藻土過濾反應物且濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至50% EtOAc之己烷梯度溶離進行層析來純化，得到680 mg 3-((2-甲基吡啶-3-基)氧基)-5-苯氧基-2-氰基吡啶。質譜(ESI)m/z=304.1(M+H)。 Step A : Add anhydrous potassium phosphate (1756 mg) to a flask containing 5-bromo-3-((2-methylpyridin-3-yl)oxy)-2-cyanopyridine (1200 mg, 4.14 mmol). , 8.27 mmol), 2-di-t-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl (263 mg, 0.620 mmol), phenol (506 mg, 5.38 mmol), acetic acid Palladium (ii) (93 mg, 0.414 mmol). The flask was purged with nitrogen under high vacuum. Degassed toluene was added. The reaction was heated to 120 ° C overnight and maintained for 22 hours. The reaction was filtered through celite and concentrated. The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium column containing 0% to 50% EtOAc in EtOAc EtOAc (EtOAc) eluting -Methylpyridin-3-yl)oxy)-5-phenoxy-2-cyanopyridine. Mass Spectrum (ESI) m/z = 304.1 (M+H).

步驟B：類似於製備15步驟B所述來製備。 Step B : Prepared analogously to the preparation of Step 15 Step B.

步驟C：製備3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶-2-胺向含3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶醯胺(610 mg，1.898 mmol)之燒瓶中添加MeOH(9 mL)，且使燒瓶冷卻降至0℃。依序添加NBS(439 mg，2.468 mmol)、0.6 mL水，且冷卻反應物1分鐘。接著逐滴添加1 mL含KOH(1 mL，9.74 mmol)之水，接著使反應物升至室溫且攪拌隔夜。反應未完成。因此將其加熱至65℃隔夜。在早晨添加含100 mg KOH之0.4 mL H2O，且繼續加熱隔夜。用15 mL水稀釋反應物，添加1 N HCl以將反應物調節至弱鹼性。再添加水且產生沈澱物。MS顯示沈澱物為產物，在70℃下於高真空下乾燥該產物，得到410 mg 3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶-2-胺。質譜 (ESI)m/z=322.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 8.36(dd,J=4.69,1.37 Hz,1 H)7.75(s,1 H)7.29-7.34(m,2 H)7.21-7.25(m,1 H)7.14-7.19(m,1 H)7.04-7.10(m,1 H)6.88-6.95(m,2 H)6.67(d,J=2.35 Hz,1 H)4.73(br.s.,2 H)2.55(s,3 H)。 Step C : Preparation of 3-((2-methylpyridin-3-yl)oxy)-5-phenoxypyridin-2-amine to 3-((2-methylpyridin-3-yl)oxy To a flask of 5-phenoxypyridinamide (610 mg, 1.988 mmol) was added MeOH (9 mL) and the flask was cooled to 0 °C. NBS (439 mg, 2.468 mmol), 0.6 mL water was added sequentially and the reaction was cooled 1 min. 1 mL of KOH (1 mL, 9.74 mmol) in water was then added dropwise, then the mixture was warmed to room temperature and stirred overnight. The reaction was not completed. It was therefore heated to 65 ° C overnight. 0.4 mL H 2 O containing 100 mg KOH was added in the morning and heating was continued overnight. The reaction was diluted with 15 mL water and 1 N HCl was added to adjust the mixture to weakly basic. Additional water is added and a precipitate is produced. MS showed the precipitate as a product which was dried under high vacuum at 70 ° C to give 410 mg of 3-((2-methylpyridin-3-yl)oxy)-5-phenoxypyridin-2-amine. . Mass Spectrum (ESI) m/z = 322.2 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 8.36 (dd, J = 4.69, 1.37 Hz, 1 H) 7.75 (s, 1 H) 7.29-7.34 (m, 2 H) 7.21 - 7.25 (m, 1 H) 7.14-7.19 (m, 1 H) 7.04-7.10 (m, 1 H) 6.88-6.95 (m, 2 H) 6.67 (d, J = 2.35 Hz, 1 H) 4.73 (br.s., 2 H ) 2.55 (s, 3 H).

步驟D 1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶-2-基)脲 Step D 1-methyl-3-(3-((2-methylpyridin-3-yl)oxy)-5-phenoxypyridin-2-yl)urea

用甲苯使含3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶-2-胺(74.7 mg，0.255 mmol)之燒瓶共沸且在高真空下乾燥。將CH2Cl2(2.5 mL)添加至反應物中，繼而添加吡啶(0.062 mL，0.764 mmol)。接著添加氯甲酸4-硝基苯酯(92 mg，0.458 mmol)。45分鐘後，再添加少量氯甲酸硝基苯酯及15毫升吡啶。再攪拌15分鐘。接著添加甲胺(0.509 mL，1.019 mmol)及三乙胺(0.106 mL，0.764 mmol)。用黃色聚乙烯蓋將燒瓶封蓋以防止甲胺逸出，且攪拌反應物隔夜。添加水且用EtOAc萃取反應物。用NaHCO3洗滌EtOAc層兩次且用鹽水洗滌一次。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至50%)直接純化粗物質，得到受硝基苯酚污染之產物。因此，藉由經Redi-Sep預裝填矽膠管柱，以含0%至50% EtOAc之己烷梯度、接著以2-8% MeOH/DCM梯度溶離進行層析再純化該產物，得到9 mg 1-甲基-3-(3-((2-甲基吡啶-3-基)氧基)-5-苯氧基吡啶-2-基)脲。質譜(ESI)m/z=351.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.32(dd,J=4.89,1.37 Hz,1 H)7.82(d,J=2.35 Hz,1 H)7.49(dd,J=8.31,1.27 Hz,1 H)7.28-7.40(m,3 H)7.07-7.20(m,1 H)6.92-7.03(m,2 H)6.78(d,J=2.35 Hz,1 H)2.94(s,3 H)2.50(s,3 H)。 The flask containing 3-((2-methylpyridin-3-yl)oxy)-5-phenoxypyridin-2-amine (74.7 mg, 0.255 mmol) was azeotroped with toluene and dried under high vacuum. CH 2 Cl 2 (2.5 mL) was added to the reaction then pyridine (0.062 mL, 0.764 mmol). Then 4-nitrophenyl chloroformate (92 mg, 0.458 mmol) was added. After 45 minutes, a small amount of nitrophenyl chloroformate and 15 ml of pyridine were added. Stir for another 15 minutes. Methylamine (0.509 mL, 1.019 mmol) and triethylamine (0.106 mL, 0.764 mmol) were then added. The flask was capped with a yellow polyethylene cap to prevent methylamine from escaping and the reaction was stirred overnight. Water was added and the reaction was extracted with EtOAc. Washed once with brine and NaHCO 3 layer was washed twice with EtOAc. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10-50%) crude material was purified directly, to give the product contaminated by nitro phenol. Thus, the product was repurified by chromatography on a Redi-Sep prefilled cartridge column with a gradient of 0% to 50% EtOAc in hexanes followed by a gradient of 2-8% MeOH/DCM to give 9 mg. 1-Methyl-3-(3-((2-methylpyridin-3-yl)oxy)-5-phenoxypyridin-2-yl)urea. Mass Spectrum (ESI) m/z = 351.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.32 (dd, J = 4.89, 1.37 Hz, 1 H) 7.82 (d, J = 2.35 Hz, 1 H) 7.49 (dd, J = 8.31, 1.27 Hz, 1 H ) 7.28-7.40 (m, 3 H) 7.07-7.20 (m, 1 H) 6.92-7.03 (m, 2 H) 6.78 (d, J = 2.35 Hz, 1 H) 2.94 (s, 3 H) 2.50 (s) , 3 H).

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449 , the following compounds were prepared:

遵循實例535中之程序，製備以下化合物： Following the procedure in Example 535 , the following compounds were prepared:

遵循實例477中之程序，製備以下化合物： Following the procedure in Example 477 , the following compounds were prepared:

遵循實例481中之程序，製備以下化合物： Following the procedure in Example 481 , the following compounds were prepared:

遵循實例1127中之程序，製備以下化合物： Following the procedure in Example 1127 , the following compounds were prepared:

實例525Example 525

4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丁醯胺 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)-N-methylbutyramine

向含4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)丁酸(21 mg，0.057 mmol)之燒瓶中添加EDC(22.04 mg，0.115 mmol)、水合1-羥基苯并三唑(0.017 mL，0.115 mmol)。接著依序添加DMF(1.2 mL)、甲胺溶液(0.057 mL，0.115 mmol)、尼希氏鹼(hunig's base)(0.035 mL，0.198 mmol)。用黃色聚乙烯蓋密封反應物且攪拌隔夜。將水添加至反應物中，繼而用EtOAc萃取。乾燥有機層且濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至8% MeOH之二氯甲烷梯度溶離進行層析來純化，得到11 mg 4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丁醯胺，藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至50%)再純化，得到7.8 mg4-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丁醯胺。質譜(ESI)m/z=379.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 7.91(s,1 H)7.22-7.31(m,1 H)7.09(s,2 H)6.24-6.28(m,1 H)6.26(s,1 H)2.71(s,3 H)2.63-2.69(m,2 H)2.61(s,3 H)2.12-2.20(m,2 H)1.85-1.94(m,2 H)。 Add EDC to a flask containing 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)butanoic acid (21 mg, 0.057 mmol). 22.04 mg, 0.115 mmol), hydrated 1-hydroxybenzotriazole (0.017 mL, 0.115 mmol). Then DMF (1.2 mL), methylamine solution (0.057 mL, 0.115 mmol), and hunig's base (0.035 mL, 0.198 mmol) were added sequentially. The reaction was sealed with a yellow polyethylene lid and stirred overnight. Water was added to the reaction which was then extracted with EtOAc. The organic layer was dried and concentrated. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prepacked cartridge column with a gradient of 0% to 8% MeOH in dichloromethane to give 11 mg 4-(4). -(2,6-Difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)-N-methylbutyramine, by reverse phase preparative HPLC, using 0.1% Further purification of CH 3 CN/H 2 O (gradient 10% to 50%) of TFA afforded 7.8 mg of 4-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridine 3-yl)-N-methylbutyramine. Mass Spectrum (ESI) m/z = 379.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 7.91 (s, 1 H) 7.22-7.31 (m, 1 H) 7.09 (s, 2 H) 6.24-6.28 (m, 1 H) 6.26 (s, 1 H) 2.71 (s, 3 H) 2.63 - 2.69 (m, 2 H) 2.61 (s, 3 H) 2.12 - 2.20 (m, 2 H) 1.85-1.94 (m, 2 H).

遵循實例525中之程序，製備以下化合物： Following the procedure in Example 525 , the following compounds were prepared:

遵循實例175中之程序，製備以下化合物： Following the procedure in Example 175 , the following compounds were prepared:

遵循實例195中之程序，製備以下化合物： Following the procedure in Example 195 , the following compounds were prepared:

實例535Example 535

1-(4-(2,6-二氟苯氧基)-5-(2,3-二羥基丙基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(2,3-dihydroxypropyl)pyridin-2-yl)-3-methylurea

向含1-(5-烯丙基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(25 mg，0.078 mmol)之燒瓶中添加THF(2 mL)、水(2.000 mL)。接著依序添加含四氧化鋨(0.098 mL，7.83 μmol)之t-BuOH(2.5重量%溶液)、NMO(18.34 mg，0.157 mmol)。攪拌反應物約3天。用偏亞硫酸氫鈉溶液淬滅反應物且用EtOAc萃取。乾燥EtOAc層且濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至10% MeOH之二氯甲烷梯度溶離進行層析來純化，得到18 mg呈白色固體狀之1-(4-(2,6-二氟苯氧基)-5-(2,3-二羥基丙基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=354.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.06(s,1 H)7.31-7.43(m,1 H)7.15-7.26(m,2 H)6.38(s,1 H)3.95-4.05 (m,1 H)3.56-3.63(m,1 H)3.48-3.56(m,1 H)3.03(dd,J=13.89,5.09 Hz,1 H)2.82(s,3 H)2.72(dd,J=13.99,7.92 Hz,1 H)。 Add THF (2) to a flask containing 1-(5-allyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (25 mg, 0.078 mmol) mL), water (2.000 mL). Next, t-BuOH (2.5 wt% solution) and NMO (18.34 mg, 0.157 mmol) containing osmium tetroxide (0.098 mL, 7.83 μmol) were added in that order. The reaction was stirred for about 3 days. The reaction was quenched with sodium bisulfite solution and extracted with EtOAc. The EtOAc layer was dried and concentrated. The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium column packed with 0% to 10% MeOH. 1-(4-(2,6-Difluorophenoxy)-5-(2,3-dihydroxypropyl)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 354.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.06 (s, 1 H) 7.31 - 7.43 (m, 1 H) 7.15-7.26 (m, 2 H) 6.38 (s, 1 H) 3.95-4.05 (m, 1 H) 3.56-3.63 (m, 1 H) 3.48-3.56 (m, 1 H) 3.03 (dd, J = 13.89, 5.09 Hz, 1 H) 2.82 (s, 3 H) 2.72 (dd, J = 13.99, 7.92) Hz, 1 H).

遵循實例535中之程序，製備以下化合物： Following the procedure in Example 535 , the following compounds were prepared:

實例537Example 537

(S)-1-(5-(3-(1,3-二氧雜環戊烷-4-基)丙基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 (S)-1-(5-(3-(1,3-dioxol-4-yl)propyl)-4-(2,6-difluorophenoxy)pyridin-2-yl -3-methylurea

用甲苯使含(S)-1-(4-(2,6-二氟苯氧基)-5-(4,5-二羥基戊基)吡啶-2-基)-3-甲基脲(14 mg，0.037 mmol)之燒瓶共沸且用氮氣吹洗。添加1.5 mL二甲氧基甲烷以溶解起始物質。使反應物在冰浴中冷卻降溫。接著添加2,6-二甲基吡啶(9.83 mg，0.092 mmol，2.5當量)，繼而逐滴添加三氟甲烷磺酸三甲基矽烷酯(10.027 mL，0.151 mmol，4.1當量)。使反應物升至室溫且攪拌1.5小時，接著用飽和NaHCO3淬滅。用乙酸乙酯稀釋反應物，用1 N硫酸氫鈉及鹽水洗滌有機層，乾燥(MgSO4)，且在真空中蒸發。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至70%)純化粗物質，得到2.7 mg(S)-1-(5-(3-(1,3-二氧雜環戊烷-4-基)丙基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基 脲。質譜(ESI)m/z=394.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.04(s,1 H)7.32-7.45(m,1 H)7.22(s,2 H)6.32-6.43(m,1 H)4.98(s,1 H)4.84(s,1 H)3.93-4.11(m,2 H)3.40-3.48(m,1 H)2.75-2.89(m,5 H)1.60-1.94(m,4 H)。 (S)-1-(4-(2,6-difluorophenoxy)-5-(4,5-dihydroxypentyl)pyridin-2-yl)-3-methylurea was added with toluene ( The 14 mg, 0.037 mmol) flask was azeotroped and purged with nitrogen. 1.5 mL of dimethoxymethane was added to dissolve the starting material. The reaction was allowed to cool in an ice bath to cool. Then 2,6-lutidine (9.83 mg, 0.092 mmol, 2.5 eq.) was added followed by trimethylmethane trifluoromethanesulfonate (10.027 mL, 0.151 mmol, 4.1 eq.). The reaction was warmed to room temperature and stirred for 1.5 hours and then quenched with 3 saturated NaHCO. The reaction was diluted with ethyl acetate, the organic layer was washed with 1 N sodium bisulfate and brine, dried (MgSO 4), and evaporated in vacuo. By reverse phase preparative HPLC, using 0.1% TFA in sum CH 3 CN / H 2 O (gradient 10-70%) crude material was purified to give 2.7 mg (S) -1- (5- (3- (1 , 3-dioxolan-4-yl)propyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 394.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.04 (s, 1 H) 7.32 - 7.45 (m, 1 H) 7.22 (s, 2 H) 6.32-6.43 (m, 1 H) 4.98 (s, 1 H) 4.84 (s, 1 H) 3.93-4.11 (m, 2 H) 3.40-3.48 (m, 1 H) 2.75-2.89 (m, 5 H) 1.60-1.94 (m, 4 H).

實例538Example 538

1-(4-((5-乙基吡啶-3-基)氧基)-5-(3-側氧基環戊-1-烯-1-基)吡啶-2-基)-3-甲基脲 1-(4-((5-ethylpyridin-3-yl)oxy)-5-(3-o-oxocyclopent-1-en-1-yl)pyridin-2-yl)-3-yl Base urea

向含1-(5-溴-4-((5-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(80 mg，0.228 mmol)之燒瓶中添加氟化鉀(0.021 mL，0.911 mmol)、乙酸鈀(ii)(5.11 mg，0.023 mmol)且用氮氣淨化。依序添加經脫氣之DMF(1.5 mL)、2-環戊烯-1-酮(0.076 mL，0.911 mmol)。加熱反應物隔夜。添加水，繼而用EtOAc萃取。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O純化粗物質，得到10 mg 1-(4-((5-乙基吡啶-3-基)氧基)-5-(3-側氧基環戊-1-烯-1-基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=353.2(M+H)。1H NMR(500 MHz,MeOH)δ ppm 8.61(s,1 H)8.44(d,J=1.22 Hz,1 H)8.33(d,J=2.45 Hz,1 H)7.64(s,1 H)6.85(s,1 H)6.59(s,1 H)3.26(dd,J=4.77,2.81 Hz,2 H)2.85(s,3 H)2.80(q,J=7.58 Hz,2 H)2.57(dt,J=4.95,2.29 Hz,2 H)1.33(t,J=7.46 Hz,3 H)。 Adding fluorine to a flask containing 1-(5-bromo-4-((5-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (80 mg, 0.228 mmol) Potassium (0.021 mL, 0.911 mmol), palladium acetate (ii) (5.11 mg, 0.023 mmol) and purified with nitrogen. Degassed DMF (1.5 mL) and 2-cyclopenten-1-one (0.076 mL, 0.911 mmol) were added sequentially. The reaction was heated overnight. Water was added, followed by extraction with EtOAc. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O crude material was purified to give 10 mg 1- (4 - (( 5- ethyl-pyridin-3-yl) oxy) -5 -(3-Sideoxycyclopent-1-en-1-yl)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 353.2 (M+H). 1 H NMR (500 MHz, MeOH) δ ppm 8.61 (s, 1 H) 8.44 (d, J = 1.22 Hz, 1 H) 8.33 (d, J = 2.45 Hz, 1 H) 7.64 (s, 1 H) 6.85 (s, 1 H) 6.59 (s, 1 H) 3.26 (dd, J = 4.77, 2.81 Hz, 2 H) 2.85 (s, 3 H) 2.80 (q, J = 7.58 Hz, 2 H) 2.57 (dt, J = 4.95, 2.29 Hz, 2 H) 1.33 (t, J = 7.46 Hz, 3 H).

遵循實例477中之程序，製備以下化合物： Following the procedure in Example 477 , the following compounds were prepared:

遵循實例481中之程序，製備以下化合物： Following the procedure in Example 481 , the following compounds were prepared:

遵循實例198中之程序，製備以下化合物： Following the procedure in Example 198 , the following compounds were prepared:

實例555Example 555

1-(3-((2-乙基吡啶-3-基)氧基)-5-乙烯基吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-vinylpyridin-2-yl)-3-methylurea

藉由遵循實例195中之程序製備化合物。質譜(ESI)m/z=299.2(M+H)。 Compounds were prepared by following the procedure in Example 195. Mass Spectrum (ESI) m/z = 299.2 (M+H).

實例556Example 556

1-(5-(亞環戊基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(Cyclopentylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

在室溫下，向1-(3-((2-乙基吡啶-3-基)氧基)-5-乙烯基吡啶-2-基)-3-甲基脲(61.0 mg，0.204 mmol)及亞甲基環戊烷(0.215 mL，2.045 mmol)於DCM(4.0 mL)中之溶液中添加第2代荷維達-格拉布催化劑(hoveyda-grubbs catalyst 2nd generation)(12.81 mg，0.020 mmol)。將所得反應混合物脫氣三次，且在55℃下於氮氣下攪拌隔夜。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)直接純化反應混合物，得到標題化合物1-(5-(亞環戊基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=353.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.38(4H,br.s.),8.62(1H,dd,J=4.3,2.3 Hz),8.03(1H,s),7.48-7.76(2H,m),7.23(1H,d,J=1.6 Hz),6.16-6.24(1H,m),3.24(2H,q,J=7.6 Hz),2.99(3H,d,J=4.3 Hz),2.50(2H,t,J=7.1 Hz),2.38(2H,t,J=7.0 Hz),1.81(2H，五重峰，J=6.9 Hz),1.59-1.73(2H,m),1.43(3H,t,J=7.6 Hz)。 To 1-(3-((2-ethylpyridin-3-yl)oxy)-5-vinylpyridin-2-yl)-3-methylurea (61.0 mg, 0.204 mmol) at rt And a solution of methylene-cyclohexanes (0.215 mL, 2.045 mmol) in DCM (4.0 mL . The resulting reaction mixture was degassed three times and stirred at <RTI ID=0.0> By reverse phase preparative HPLC, using 0.1% TFA-containing directly purified of CH 3 CN / H 2 O (gradient 10% to 90%) the reaction mixture, to give the title compound 1- (5- (alkylene cyclopentylmethyl) -3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 353.2 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.38 (4H, br. s.), 8.62 (1H, dd, J = 4.3, 2.3 Hz), 8.03 (1H, s), 7.48-7.76 (2H, m), 7.23 (1H, d, J = 1.6 Hz), 6.16-6.24 (1H, m), 3.24 (2H, q, J = 7.6 Hz), 2.99 (3H, d, J = 4.3 Hz), 2.50 ( 2H, t, J = 7.1 Hz), 2.38 (2H, t, J = 7.0 Hz), 1.81 (2H, quintuple, J = 6.9 Hz), 1.59-1.73 (2H, m), 1.43 (3H, t , J = 7.6 Hz).

實例557Example 557

(E)-1-(3-((2-乙基吡啶-3-基)氧基)-5-(3-羥基-2-甲基丙-1-烯-1-基)吡啶-2-基)-3-甲基脲 ( E )-1-(3-((2-ethylpyridin-3-yl)oxy)-5-(3-hydroxy-2-methylprop-1-en-1-yl)pyridine-2- 3-methylurea

藉由遵循實例556中之程序製備化合物。質譜(ESI)m/z=343.2(M+H)。 Compounds were prepared by following the procedure in Example 556. Mass Spectrum (ESI) m/z = 343.2 (M+H).

實例558Example 558

1-(5-(環戊基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(cyclopentylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

藉由遵循實例481中之程序製備化合物。質譜(ESI)m/z=355.3(M+H)。 Compounds were prepared by following the procedure in Example 481. Mass Spectrum (ESI) m/z = 355.3 (M+H).

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449, the following compounds were prepared:

實例562Example 562

1-(5-(溴(1-甲氧基環戊基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(Bromo(1-methoxycyclopentyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

在0℃下，向1-(5-(亞環戊基甲基)-3-((2-乙基吡啶-3-基)氧基)吡 啶-2-基)-3-甲基脲(15.0 mg，0.043 mmol)於MeOH(4.0 mL)中之溶液中添加n-溴代丁二醯亞胺(8.33 mg，0.047 mmol)。在0℃下於氮氣下攪拌所得反應混合物2小時，接著在室溫下攪拌16小時。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)直接純化反應混合物，得到標題化合物。質譜(ESI)m/z=464.4(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.54(1H,d,J=2.9 Hz),8.65(2H,d,J=3.7 Hz),8.07(1H,d,J=1.8 Hz),7.44-7.60(2H,m),7.31(1H,d,J=1.6 Hz),4.13(1H,s),3.29(3H,s),3.10-3.23(2H,m),2.94-3.09(3H,m),2.18(1H,d,J=6.7 Hz),1.93-2.10(4H,m),1.69-1.92(3H,m),1.39(3H,t,J=7.6 Hz)。 To 1-(5-(cyclohexylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea at 0 °C 15.0 mg, 0.043 mmol) of MeOH (4.0 mL) was added n-bromobutaneimide (8.33 mg, 0.047 mmol). The resulting reaction mixture was stirred at 0 ° C under nitrogen for 2 hr then stirred at room temperature for 16 hr. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10% to 90%) direct reaction mixture was purified to give the title compound. Mass Spectrum (ESI) m/z = 464.4 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.54 (1H, d, J = 2.9 Hz), 8.65 (2H, d, J = 3.7 Hz), 8.07 (1H, d, J = 1.8 Hz), 7.44 -7.60 (2H, m), 7.31 (1H, d, J = 1.6 Hz), 4.13 (1H, s), 3.29 (3H, s), 3.10-3.23 (2H, m), 2.94-3.09 (3H, m ), 2.18 (1H, d, J = 6.7 Hz), 1.93-2.10 (4H, m), 1.69-1.92 (3H, m), 1.39 (3H, t, J = 7.6 Hz).

實例563Example 563

1-(5-(溴(1-甲氧基環戊基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(Bromo(1-methoxycyclopentyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

藉由遵循實例481中之程序製備化合物。質譜(ESI)m/z=385.2(M+H)。 Compounds were prepared by following the procedure in Example 481. Mass Spectrum (ESI) m/z = 385.2 (M+H).

實例564Example 564

1-(3-((2-乙基吡啶-3-基)氧基)-5-((1-羥基環戊基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-((1-hydroxycyclopentyl)methyl)pyridin-2-yl)-3-methylurea

步驟A：在0℃下，向1-(5-(亞環戊基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(119.0 mg，0.338 mmol)於1,4-二噁烷(4.0 mL)及水(0.2 mL)中之溶液中添加n-溴代丁二醯亞胺(66.1 mg，0.371 mmol)。在0℃下於氮氣下攪拌所得反應混合物18小時。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)直接純化反應混合物，得到化合物1-(5-(溴(1-羥基環戊基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=450.2(M+H)。 Step A : to 1-(5-(cyclohexylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-yl at 0 °C To a solution of the carbazide (119.0 mg, 0.338 mmol) in 1,4-dioxane (4.0 mL) and water (0.2 mL) was added n-bromobutaneimide (66.1 mg, 0.371 mmol). The resulting reaction mixture was stirred at 0 ° C under nitrogen for 18 h. The reaction mixture was directly purified by reverse phase preparative HPLC using CH 3 CN/H 2 O (gradient 10% to 90%) containing 0.1% TFA to give compound 1-(5-(bromo(1-hydroxycyclopentyl)) )methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 450.2 (M+H).

步驟B：向1-(5-(溴(1-羥基環戊基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(51.0 mg，0.113 mmol)於甲醇(10 mL)及乙酸乙酯(5.0 mL)中之溶液中添加10重量%鈀/活性碳(0.018 mL，0.017 mmol)。使反應混合物經歷三次抽真空/氫氣回填循環，且在室溫下於氫氣下攪拌2.5小時。濾除催化劑。移除溶劑，藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)純化反應混合物，得到標題化合物。質譜(ESI)m/z=371.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 8.51(1H,dd,J=5.2,1.3 Hz),7.94(1H,d,J=1.4 Hz),7.64(1H,dd,J=8.4,1.4 Hz),7.55(1H,dd,J=8.4,5.3 Hz),7.41(1H,d,J=1.6 Hz),4.40(2H,d,J=7.4 Hz),3.03(2H,q,J=7.6 Hz),2.75-2.91(3H,m),2.04(1H,d,J=8.0 Hz),1.44-1.73(5H,m),1.36-1.44(2H,m),1.27-1.36(3H,m)。 Step B : To 1-(5-(bromo(1-hydroxycyclopentyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-yl To a solution of the base urea (51.0 mg, 0.113 mmol) in methanol (10 mL) and ethyl acetate (5.0 mL) was added 10 wt% palladium / activated carbon (0.018 mL, 0.017 mmol). The reaction mixture was subjected to three vacuum/hydrogen backfill cycles and stirred at room temperature under hydrogen for 2.5 h. The catalyst was filtered off. The solvent was removed by reversed-phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10% to 90%) the reaction mixture was purified to give the title compound. Mass Spectrum (ESI) m/z = 371.2 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 8.51 (1H, dd, J = 5.2, 1.3 Hz), 7.94 (1H, d, J = 1.4 Hz), 7.64 (1H, dd, J = 8.4, 1.4 Hz), 7.55 (1H, dd, J = 8.4, 5.3 Hz), 7.41 (1H, d, J = 1.6 Hz), 4.40 (2H, d, J = 7.4 Hz), 3.03 (2H, q, J = 7.6) Hz), 2.75-2.91 (3H, m), 2.04 (1H, d, J = 8.0 Hz), 1.44-1.73 (5H, m), 1.36-1.44 (2H, m), 1.27-1.36 (3H, m) .

實例565Example 565

1-(6'-乙氧基-5-(((3S,3aR,6aS)-六氫呋喃并[2,3-b]呋喃-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-ethoxy-5-(((3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl)oxy)-[3,3'-linked Pyridyl]-6-yl)-3-methylurea

步驟A：在0℃下，向60%氫化鈉於礦物油中之分散液(0.035 ml，2.77 mmol)於DMF(7.68 ml)中之懸浮溶液中添加六氫-(3r,3as,6ar)-rel-呋喃并[2,3-b]呋喃-3-醇(0.3 g，2.305 mmol)，且在室溫下攪拌所得反應混合物30分鐘，且亦添加含5-溴-2-氯-3-氟吡啶(0.534 g，2.54 mmol)之DMF(1.0 ml)。在室溫下攪拌反應混合物4小時。用乙酸乙酯(60 ml)稀釋反應混合物且用水及鹽水洗滌，經MgSO4乾燥。移除溶劑，且粗產物5-溴-2-氯-3-(((3S,3aR,6aS)-六氫呋喃并[2,3-b]呋喃-3-基)氧基)吡啶未經進一步純化即用於下一步驟。質譜(ESI)m/z=321.0(M+H)。 Step A : Add hexahydro-(3r, 3as, 6ar) to a suspension of 60% sodium hydride in mineral oil (0.035 ml, 2.77 mmol) in DMF (7.68 ml) at 0 °C. Rel-furo[2,3-b]furan-3-ol (0.3 g, 2.305 mmol), and the resulting reaction mixture was stirred at room temperature for 30 min and added with 5-bromo-2-chloro-3- Fluoride (0.534 g, 2.54 mmol) in DMF (1.0 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with water and brine, dried over MgSO 4. The solvent was removed and the crude product 5-bromo-2-chloro-3-((3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-yl)oxy)pyridine was not Further purification was used in the next step. Mass Spectrum (ESI) m/z = 321.0 (M+H).

步驟B：藉由遵循實例198中之程序製備6-氯-6'-乙氧基-5-(((3S,3aR,6aS)-六氫呋喃并[2,3-b]呋喃-3-基)氧基)-3,3'-聯吡啶。質譜(ESI)m/z=363.1(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 8.49(1H,d,J=2.3 Hz),8.25(1H,d,J=2.0 Hz),7.96(1H,d,J=8.6 Hz),7.37(1H,s),7.00(1H,d,J=8.8 Hz),5.86(1H,d,J=5.1 Hz),4.97-5.09(1H,m),4.44(2H,q,J=7.0 Hz),4.25(1H,dd,J=9.8,6.1 Hz),4.04-4.17(2H,m),4.01(1H,dd,J=9.8,6.3 Hz),3.22(1H,dd,J=7.1,2.2 Hz),2.35(1H,dt,J=13.1,2.7 Hz),1.89-2.07(1H,m),1.50(3H,t,J=7.0 Hz)。 Step B : Preparation of 6-chloro-6'-ethoxy-5-(((3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3- by following the procedure in Example 198. Alkyloxy-3,3'-bipyridyl. Mass Spectrum (ESI) m/z = 363.1 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 8.49 (1H, d, J = 2.3 Hz), 8.25 (1H, d, J = 2.0 Hz), 7.96 (1H, d, J = 8.6 Hz), 7.37 (1H, s), 7.00 (1H, d, J = 8.8 Hz), 5.86 (1H, d, J = 5.1 Hz), 4.97-5.09 (1H, m), 4.44 (2H, q, J = 7.0 Hz) , 4.25 (1H, dd, J = 9.8, 6.1 Hz), 4.04-4.17 (2H, m), 4.01 (1H, dd, J = 9.8, 6.3 Hz), 3.22 (1H, dd, J = 7.1, 2.2 Hz) ), 2.35 (1H, dt, J = 13.1, 2.7 Hz), 1.89-2.07 (1H, m), 1.50 (3H, t, J = 7.0 Hz).

步驟C：將參(二亞苄基丙酮)二鈀(0)(22.21 mg，0.024 mmol)及二第三丁基(2',4',6'-三異丙基-3,6-二甲氧基-[1,1'-聯苯]-2-基)膦(21.38 mg，0.044 mmol)於THF(0.55 ml)及水(1.0 μl，0.055 mmol)中製漿。接著在110℃下加熱此混合物5分鐘，得到具有細沈澱物之黑色反應混合物。將1-甲基脲(65.3 mg，0.882 mmol)、6-氯-6'-乙氧基-5-(((3S,3aR,6aS)-六氫呋喃并[2,3-b]呋喃-3-基)氧基)-3,3'-聯吡啶(80.0 mg，0.221 mmol)及99.9%(以金屬計)碳酸銫(26.5 μl，0.331 mmol)於THF(0.55 ml)中製漿。接著將預活化之催化劑溶液在氮氣下轉移至反應燒瓶中，且在75℃下加熱反應混合物隔夜。LCMS結果指示反應完 成。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)純化棕色反應漿液，得到標題化合物。質譜(ESI)m/z=401.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 8.45(1H,d,J=2.5 Hz),7.93(1H,s),7.86(1H,dd,J=8.8,2.5 Hz),7.36(1H,s),6.98(1H,d,J=8.6 Hz),5.87(1H,d,J=5.1 Hz),5.00(1H,q,J=8.1 Hz),4.44(2H,q,J=7.0 Hz),4.28(1H,dd,J=9.4,7.2 Hz),4.17(1H,t,J=9.1 Hz),3.96-4.11(2H,m),3.23(1H,dt,J=5.1,2.3 Hz),2.99(3H,d,J=3.9 Hz),1.98-2.14(1H,m),1.76-1.97(1H,m),1.49(3H,t,J=7.0 Hz)。 Step C : ginseng (dibenzylideneacetone) dipalladium (0) (22.21 mg, 0.024 mmol) and di-tert-butyl (2',4',6'-triisopropyl-3,6-di Methoxy-[1,1'-biphenyl]-2-yl)phosphine (21.38 mg, 0.044 mmol) was slurried in THF (0.55 ml) and water (1. The mixture was then heated at 110 ° C for 5 minutes to give a black reaction mixture with a fine precipitate. 1-methylurea (65.3 mg, 0.882 mmol), 6-chloro-6'-ethoxy-5-(((3S,3aR,6aS)-hexahydrofuro[2,3-b]furan- 3-Methoxy)-3,3'-bipyridine (80.0 mg, 0.221 mmol) and 99.9% (based on metal) cesium carbonate (26.5 μl, 0.331 mmol) were slurried in THF (0.55 ml). The preactivated catalyst solution was then transferred to the reaction flask under nitrogen and the reaction mixture was heated at 75 ° C overnight. LCMS results indicated the reaction was complete. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10-90%) to give a brown reaction slurry, to give the title compound. Mass Spectrum (ESI) m/z = 401.2 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 8.45 (1H, d, J = 2.5 Hz), 7.93 (1H, s), 7.86 (1H, dd, J = 8.8, 2.5 Hz), 7.36 (1H, s), 6.98 (1H, d, J = 8.6 Hz), 5.87 (1H, d, J = 5.1 Hz), 5.00 (1H, q, J = 8.1 Hz), 4.44 (2H, q, J = 7.0 Hz) , 4.28 (1H, dd, J = 9.4, 7.2 Hz), 4.17 (1H, t, J = 9.1 Hz), 3.96-4.11 (2H, m), 3.23 (1H, dt, J = 5.1, 2.3 Hz), 2.99 (3H, d, J = 3.9 Hz), 1.98-2.14 (1H, m), 1.76-1.97 (1H, m), 1.49 (3H, t, J = 7.0 Hz).

實例566Example 566

1-(5-(亞環戊基甲基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-(cyclopentylmethyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

藉由遵循實例556中之程序製備化合物。質譜(ESI)m/z=360.2(M+H)。 Compounds were prepared by following the procedure in Example 556. Mass Spectrum (ESI) m/z = 360.2 (M+H).

實例567Example 567

1-(5-(環戊基甲基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-(cyclopentylmethyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

藉由遵循實例481中之程序製備化合物。質譜(ESI)m/z=362.2(M+H)。 Compounds were prepared by following the procedure in Example 481 . Mass Spectrum (ESI) m/z = 362.2 (M+H).

實例568Example 568

1-(4-(2,6-二氟苯氧基)-5-((1-甲氧基環戊基)甲基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-((1-methoxycyclopentyl)methyl)pyridin-2-yl)-3-methylurea

藉由遵循實例563中之程序製備化合物。質譜(ESI)m/z=392.2(M+H)。 Compounds were prepared by following the procedure in Example 563 . Mass Spectrum (ESI) m/z = 392.2 (M+H).

實例569Example 569

1-(4-(2,6-二氟苯氧基)-5-((1-羥基環戊基)甲基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-((1-hydroxycyclopentyl)methyl)pyridin-2-yl)-3-methylurea

藉由遵循實例564中之程序製備化合物。質譜(ESI)m/z=378.2(M+H)。 Compounds were prepared by following the procedure in Example 564 . Mass Spectrum (ESI) m/z = 378.2 (M+H).

實例570Example 570

1-(5-(2-溴-1-(2-羥基乙氧基)乙基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-(2-Bromo-1-(2-hydroxyethoxy)ethyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

藉由遵循實例564中之程序製備化合物。質譜(ESI)m/z=447.0(M+H)。 Compounds were prepared by following the procedure in Example 564 . Mass Spectrum (ESI) m/z = 447.0 (M+H).

遵循實例481中之程序，製備以下化合物： Following the procedure in Example 481 , the following compounds were prepared:

遵循實例562中之程序，製備以下化合物： Following the procedure in Example 562 , the following compounds were prepared:

實例580Example 580

1-(4-(烷-5-基氧基)-5-(1-(2,5-二側氧基吡咯啶-1-基)乙基)吡啶-2-基)-3-甲基脲 1-(4-( Alkan-5-yloxy)-5-(1-(2,5-di-oxypyrrolidin-1-yl)ethyl)pyridin-2-yl)-3-methylurea

向藉由遵循實例562中之程序製備之1-(5-(2-溴-1-(2,5-二側氧基吡咯啶-1-基)乙基)-4-(烷-5-基氧基)吡啶-2-基)-3-甲基脲(60 mg，0.119 mmol)於甲醇(5.0 mL)中之溶液中添加20目鋅顆粒(78 mg，1.192 mmol)及氯化銨晶體(31.9 mg，0.596 mmol)(飽和水溶液(0.2 ml))。在40℃下攪拌反應混合物1小時。LCMS指示反應完成。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)純化混合物，得到標題化合物。質譜(ESI)m/z=425.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 8.15(1H,s),7.23(1H,s),7.17(1H,t,J=8.2 Hz),6.82(1H,d,J=7.4 Hz),6.47(1H,dd,J=8.0,0.8 Hz),5.75(1H,d,J=7.0 Hz),4.13-4.27(2H,m),2.81(3H,d,J=4.7 Hz),2.67(4H,s),2.49-2.64(1H,m),2.36-2.49(1H,m),1.98(2H,dd,J=6.4,4.2 Hz),1.78(3H,d,J=7.2 Hz)。 1-(5-(2-Bromo-1-(2,5-di-oxypyrrolidin-1-yl)ethyl)-4- (1) prepared by following the procedure in Example 562 Add a 20 mesh zinc granule (78 mg, 1.192 mmol) to a solution of the alkyl-5-yloxy)pyridin-2-yl)-3-methylurea (60 mg, 0.119 mmol) in methanol (5.0 mL) Ammonium chloride crystals (31.9 mg, 0.596 mmol) (saturated aqueous solution (0.2 ml)). The reaction mixture was stirred at 40 ° C for 1 hour. LCMS indicated the reaction was complete. By reverse phase preparative HPLC, purified using a mixture of 0.1% TFA containing CH 3 CN / H 2 O (gradient 10% to 90%), to give the title compound. Mass Spectrum (ESI) m/z = 425.2 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 8.15 (1H, s), 7.23 (1H, s), 7.17 (1H, t, J = 8.2 Hz), 6.82 (1H, d, J = 7.4 Hz) , 6.47 (1H, dd, J = 8.0, 0.8 Hz), 5.75 (1H, d, J = 7.0 Hz), 4.13-4.27 (2H, m), 2.81 (3H, d, J = 4.7 Hz), 2.67 ( 4H, s), 2.49-2.64 (1H, m), 2.36-2.49 (1H, m), 1.98 (2H, dd, J = 6.4, 4.2 Hz), 1.78 (3H, d, J = 7.2 Hz).

實例581Example 581

1-(4-(烷-5-基氧基)-5-乙烯基吡啶-2-基)-3-甲基脲 1-(4-( Alkan-5-yloxy)-5-vinylpyridin-2-yl)-3-methylurea

藉由遵循實例195中之程序製備化合物。質譜(ESI)m/z=326.2(M+H)。 Compounds were prepared by following the procedure in Example 195 . Mass Spectrum (ESI) m/z = 326.2 (M+H).

實例582Example 582

1-(4-(2,6-二氟苯氧基)-5-(1,4-二噁烷-2-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(1,4-dioxan-2-yl)pyridin-2-yl)-3-methylurea

在80℃下，向1-(5-(2-溴-1-(2-羥基乙氧基)乙基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(100.0 mg，0.224 mmol)於二噁烷(3.00 mL)及 水(3.0 mL)中之溶液中添加a.c.s.試劑氫氧化鈉球粒(40.3 mg，1.008 mmol)。在80℃於氫氣下攪拌所得反應混合物4小時。藉由R-HPLC直接純化反應混合物，得到混合物，藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至90%)純化該混合物，得到標題化合物。質譜(ESI)m/z=366.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 7.91(1H,s),7.35(1H,s),7.13(3H,t,J=8.1 Hz),5.19(1H,t,J=4.2 Hz),3.81-4.05(4H,m),3.14(2H,d,J=4.3 Hz),2.82(3H,d,J=4.7 Hz)。 To 1-(5-(2-bromo-1-(2-hydroxyethoxy)ethyl)-4-(2,6-difluorophenoxy)pyridin-2-yl)- at 80 ° C Add a solution of sodium hydroxide pellets (40.3 mg, 1.008 mmol) to a solution of 3-methylurea (100.0 mg, 0.224 mmol) in dioxane (3.00 mL) and water (3.0 mL). The resulting reaction mixture was stirred at 80 ° C under hydrogen for 4 hr. Directly purified by R-HPLC the reaction mixture to obtain a mixture, by reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10% to 90%) the mixture was purified to give the title compound. Mass Spectrum (ESI) m/z = 366.2 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 7.91 (1H, s), 7.35 (1H, s), 7.13 (3H, t, J = 8.1 Hz), 5.19 (1H, t, J = 4.2 Hz) , 3.81-4.05 (4H, m), 3.14 (2H, d, J = 4.3 Hz), 2.82 (3H, d, J = 4.7 Hz).

遵循實例582中之程序，製備以下化合物： Following the procedure in Example 582 , the following compounds were prepared:

實例586Example 586

1-(5-乙醯基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-Ethyl-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

藉由遵循實例582中之程序製備化合物。質譜(ESI)m/z=322.2(M+H)。 Compounds were prepared by following the procedure in Example 582 . Mass Spectrum (ESI) m/z = 322.2 (M+H).

遵循實例198中之程序，製備以下化合物： Following the procedure in Example 198 , the following compounds were prepared:

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449 , the following compounds were prepared:

藉由基本上遵循實例449步驟B中之程序，使用市售鋅試劑製備以下化合物： The following compounds were prepared using a commercially available zinc reagent by essentially following the procedure in Example 427, Step B:

遵循實例497中之程序，製備以下化合物： Following the procedure in Example 497, the following compounds were prepared:

實例597Example 597

3-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丙醯胺 3-(5-((1-ethyl-1H-pyrazol-5-yl)oxy)-6-(3-methylureido)pyridin-3-yl)-N-methylpropanamide

將3-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)丙酸二鹽酸鹽(33 mg，0.081 mmol)溶解於DMF(0.8 ml)中。向溶液中添加三乙胺(57 μl，0.41 mmol)、2.0 M甲胺於THF中之溶液(200 μl，0.41 mmol)及六氟磷酸溴-參-吡咯啶基鏻(95 mg，0.20 mmol)。攪拌所得溶液1.5小時。接著用水(15 mL)稀釋反應混合物，且用乙酸乙酯(2×35 ml)及二氯甲烷(1×35 mL)萃取混合物。用1 N氯化鋰(1×25 mL)及鹽水(1×25 ml)洗滌經合併之有機層且經硫酸鎂乾燥。接著藉由中壓層析(二氧化矽，0%至10% MeOH：DCM)純化粗產物，得到3-(5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丙醯胺(22 mg，0.062 mmol，76%產率)。質譜(ESI)m/z=347.0(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.16(1H,br.s.),7.83(1H,d,J=1.8 Hz),7.44(1H,d,J=2.0 Hz),7.29(1H,br.s.),7.07(1H,s),5.67(1H,d,J=1.8 Hz),5.44(1H,br.s.),4.05(2H,q,J=7.2 Hz),2.97(3H,d,J=4.7 Hz),2.87(2H,t,J=7.3 Hz),2.77(3H,d,J=4.9 Hz),2.38(2H,t,J=7.4 Hz),1.42(3H,t,J=7.2 Hz)。 3-(5-((1-Ethyl-1H-pyrazol-5-yl)oxy)-6-(3-methylureido)pyridin-3-yl)propionic acid dihydrochloride (33 Mg, 0.081 mmol) was dissolved in DMF (0.8 ml). A solution of triethylamine (57 μl, 0.41 mmol), 2.0 M methylamine in THF (200 μl, 0.41 mmol) and bromo-pyrrolidinyl hexafluoropyridinium (95 mg, 0.20 mmol) was added to the solution. . The resulting solution was stirred for 1.5 hours. The reaction mixture was then diluted with water (15 mL) and EtOAc (EtOAc) The combined organic layers were washed with 1N EtOAc (1×25 mL) and brine. The crude product was then purified by medium pressure chromatography (EtOAc, EtOAc (EtOAc:EtOAc) -6-(3-Methylureido)pyridin-3-yl)-N-methylpropanamide (22 mg, 0.062 mmol, 76% yield). Mass Spectrum (ESI) m/z = 347.0 (M+H). 1H NMR (400 MHz, chloroform- d ) δ ppm 9.16 (1H, br. s.), 7.83 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.29 (1H, Br.s.), 7.07 (1H, s), 5.67 (1H, d, J = 1.8 Hz), 5.44 (1H, br.s.), 4.05 (2H, q, J = 7.2 Hz), 2.97 (3H , d, J = 4.7 Hz), 2.87 (2H, t, J = 7.3 Hz), 2.77 (3H, d, J = 4.9 Hz), 2.38 (2H, t, J = 7.4 Hz), 1.42 (3H, t , J = 7.2 Hz).

藉由基本上遵循實例597中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 597:

實例599Example 599

1-(5-(1,1-二氧離子基異噻唑啶-2-基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(1,1-Dioxalisothiazolidin-2-yl)-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-yl) -3-methylurea

步驟A：將3-氯丙烷磺醯氯(15.0 ml，120 mmol)添加至125 mL二氯甲烷中且冷卻至0℃。逐滴添加濃氫氧化銨溶液(約29% w/w)，且使反應物升溫至室溫並攪拌2.5天。添加水(40 ml)，且分離各層。經硫酸鎂乾燥有機層且濃縮，得到粗中間物3-氯丙烷-1-磺醯胺(含有約50%所要最終產物)。使此物質直接進行後續環化反應。將粗3-氯丙烷-1-磺醯胺(6.9 g，44 mmol)於乙醇(25 ml)中製漿，且添加乙醇鈉(2.1 g，30.9 mmol)，且使混合物回流24小時。濃縮反應混合物，接著將殘餘物分配於二氯甲烷與水(約20 mL)之間。分離各層，且用二 氯甲烷(3×50 ml)萃取水層。合併有機層且經硫酸鎂乾燥，得到粗異噻唑啶1,1-二氧化物。1H NMR(400 MHz，氯仿-d)δ ppm 4.19(1H,br.s.),3.44(2H,q,J=6.7 Hz),3.10(2H,t,J=7.4 Hz),2.40-2.55(2H,m)。質譜(ESI)m/e=122.1(M+H)。 Step A : 3-Chloropropanesulfonium chloride (15.0 ml, 120 mmol) was added to 125 mL dichloromethane and cooled to 0. Concentrated ammonium hydroxide solution (about 29% w/w) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 2.5 days. Water (40 ml) was added and the layers were separated. The organic layer was dried <RTI ID=0.0> This material is directly subjected to a subsequent cyclization reaction. Crude 3-chloropropane-1-sulfonamide (6.9 g, 44 mmol) was slurried in ethanol (25 ml), and sodium ethoxide (2.1 g, 30.9 mmol) was added and the mixture was refluxed for 24 hours. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and water (~ 20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×50 ml). The organic layers were combined and dried over magnesium sulfate to give crude <RTIgt; 1 H NMR (400 MHz, chloroform - d ) δ ppm 4.19 (1H, br. s.), 3.44 (2H, q, J = 6.7 Hz), 3.10 (2H, t, J = 7.4 Hz), 2.40-2.55 (2H, m). Mass Spectrum (ESI) m/e = 1221. (M+H).

步驟B：將4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃(57 mg，0.099 mmol)、異噻唑啶1,1-二氧化物(80 mg，0.66 mmol)、5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶(200 mg，0.66 mmol)、碳酸銫(300 mg，0.93 mmol)、Pd2(dba)3(30 mg，0.033 mmol)及3埃分子篩(約100 mg)於二噁烷(2.0 ml)中製漿，且在100℃下置於Discover型微波反應器(CEM,Matthews,NC)中兩小時。接著用乙酸乙酯及二氯甲烷稀釋漿液，接著過濾移除固體。濃縮濾液，且藉由中壓層析(二氧化矽，0%至100%乙酸乙酯：己烷，接著用0%至10%甲醇：DCM吹洗)純化殘餘物，得到2-(6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基)異噻唑啶1,1-二氧化物(50 mg，0.15 mmol，22%產率)。質譜(ESI)m/z=342.9(M+H)。 Step B : 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (57 mg, 0.099 mmol), isothiazolidine 1,1-dioxide (80 mg , 0.66 mmol), 5-bromo-2-chloro-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridine (200 mg, 0.66 mmol), cesium carbonate (300 mg, 0.93) Methyl), Pd 2 (dba) 3 (30 mg, 0.033 mmol) and 3 angstrom molecular sieves (about 100 mg) were slurried in dioxane (2.0 ml) and placed in a Discover microwave reactor at 100 °C. Two hours in CEM, Matthews, NC). The slurry was then diluted with ethyl acetate and dichloromethane, then filtered to remove solid. The filtrate was concentrated and the residue was purified mpjjjjjjjjjj Chloro-5-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-3-yl)isothiazolidine 1,1-dioxide (50 mg, 0.15 mmol, 22% yield ). Mass Spectrum (ESI) m/z = 342.9 (M+H).

又，藉由基本上遵循步驟B中之程序，製備以下化合物： Again, the following compounds were prepared by essentially following the procedure in Step B:

步驟C：藉由基本上遵循實例432步驟C中之程序，製備以下化合物： Step C: The following compounds were prepared by essentially following the procedure in Example 432, Step C:

實例604Example 604

(+/-)-1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(1-(四氫-2H-哌喃-4-基)乙基)吡啶-2-基)-3-甲基脲 (+/-)-1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(1-(tetrahydro-2H-pyran-4-yl)B Pyridin-2-yl)-3-methylurea

步驟A：將5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶(400 mg，1.3 mmol)溶解於THF(13 ml)中且冷卻至-78℃。接著逐滴添加正丁基鋰(1.6 M，於己烷中)(0.91 ml，1.4 mmol)，且攪拌所得黃色溶液7分鐘。接著逐滴添加四氫-2H-哌喃-4-甲酸(0.21 ml，2.0 mmol)，且經1.5小時之時段使溶液升溫至10℃。接著用飽和氯化銨(20 mL)淬滅反應物，且用乙酸乙酯(3×50 mL)萃取此混合物。用鹽水(1×30 mL)洗滌經合併之有機層且經硫酸鎂乾燥。接著藉由中壓層析(二氧化矽，75%至100%乙酸乙酯：己烷)純化粗產物，得到(6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基)(四氫-2H-哌喃-4-基)甲醇(140 mg，0.42 mmol，32%產率)。質譜(ESI)m/e=338.0(M+H)。 Step A : Dissolve 5-bromo-2-chloro-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridine (400 mg, 1.3 mmol) in THF (13 mL) Cool to -78 °C. Then n-butyllithium (1.6 M in hexanes) (0.91 ml, 1.4 mmol) was added dropwise and the resulting yellow solution was stirred for 7 min. Tetrahydro-2H-pentan-4-carboxylic acid (0.21 ml, 2.0 mmol) was then added dropwise and the solution was warmed to 10 °C over a period of 1.5 h. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with brine (1×30 mL) and dried over magnesium sulfate. The crude product is then purified by medium pressure chromatography (c.c., 75% to 100% ethyl acetate:hexane) to afford (6-chloro-5-((1-ethyl-1H-pyrazole-5-) (Ethyloxy)pyridin-3-yl)(tetrahydro-2H-piperidin-4-yl)methanol (140 mg, 0.42 mmol, 32% yield). Mass Spectrum (ESI) m/e = 338.0 (M+H).

步驟B：將6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基)(四氫-2H-哌喃-4-基)甲醇(140 mg，0.41 mmol)溶解於DCM(3.0 ml)中且冷卻至0℃。接著添加1,1,1-三乙醯氧基-1,1-二氫-1,2-苯并碘氧雜環戊-3(1H)-酮(350 mg，0.83 mmol)，且經1.5小時使反應物升溫至室溫。接著用乙酸乙酯(35 mL)稀釋反應物，且用1 M硫代硫酸鈉溶液(2×20 ml)、飽和碳酸氫鈉溶液(2×20 mL)及鹽水(1×20 mL)洗滌。經硫酸鎂乾燥經合併之有機層，且藉由中壓層析(二氧化矽，0%至100%乙酸乙酯：己烷)純化粗產物，得到6-氯-5-((1-乙基-1H-吡唑-5-基)氧基)吡啶-3-基(四氫-2H-哌喃-4-基)甲酮(74 mg，0.22 mmol，53%產率)。質譜(ESI)m/e=336.0(M+H)。 Step B : 6-Chloro-5-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methanol (tetrahydro-2H-pyran-4-yl)methanol 140 mg, 0.41 mmol) was dissolved in DCM (3.0 mL) and cooled to 0. Next, 1,1,1-triethoxycarbonyl-1,1-dihydro-1,2-benziodooxacyclo-3(1H)-one (350 mg, 0.83 mmol) was added, and 1.5 The reaction was allowed to warm to room temperature over an hour. The reaction was then diluted with EtOAc (3 mL EtOAc) (EtOAc)EtOAc. The combined organic layers were dried over MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Base-1H-pyrazol-5-yl)oxy)pyridin-3-yl(tetrahydro-2H-piperidin-4-yl)methanone (74 mg, 0.22 mmol, 53% yield). Mass Spectrum (ESI) m/e = 336.0 (M+H).

步驟C：上文實例600步驟C中所示之實例603。 Step C : Example 603 shown in Example 600, Step C above.

步驟D：將1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(四氫-2H-哌喃-4-羰基)吡啶-2-基)-3-甲基脲(12 mg，0.032 mmol)及溴化甲基三苯基鏻(23 mg，0.064 mmol)溶解於THF(160 μl)中且冷卻至0℃。逐滴添加第三丁醇鉀(1.0 M，於THF中)(160 μl，0.160 mmol)，且在0℃下攪拌所得橙色混合物1.5小時。用33 μL 5 M HCl淬滅反應物至pH值為約6，接著濃縮至乾燥。藉由逆相製備型HPLC，使用Phenomenex Gemini管柱(10微米，C18，100 Å，150×30 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度2%至90%)純化粗物質，得到呈三氟乙酸鹽形式之1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(1-(四氫-2H-哌喃-4-基)乙烯基)吡啶-2-基)-3-甲基脲(3.0 mg，8.0 μmol，25%產率)。質譜(ESI)m/z=372.2(M+H)。 Step D : 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-(tetrahydro-2H-pyran-4-carbonyl)pyridin-2-yl) 3-Methylurea (12 mg, 0.032 mmol) and methyltriphenylphosphonium bromide (23 mg, 0.064 mmol) were dissolved in THF (160 l) and cooled to 0. Potassium tert-butoxide (1.0 M in THF) (160 μl, 0.160 mmol) was added dropwise and the resulting orange mixture was stirred at 0 ° C for 1.5 h. The reaction was quenched with 33 [mu]L of 5 M HCl to pH ~ 6 and then concentrated to dry. By reverse phase preparative HPLC, using a Phenomenex Gemini column (10 micron, C18,100 Å, 150 × 30 mm , containing 0.1% TFA of CH 3 CN / H 2 O, over 25 minutes gradient 2-90%) The crude material was purified to give 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(1-(tetrahydro-2H-pyran) as a trifluoroacetic acid salt. 4-yl)vinyl)pyridin-2-yl)-3-methylurea (3.0 mg, 8.0 μmol, 25% yield). Mass Spectrum (ESI) m/z = 372.2 (M+H).

步驟E：遵循實例170中之程序，製備標題化合物： Step E : Following the procedure in Example 170, the title compound was prepared:

實例605Example 605

1-(4-(2,6-二氟苯氧基)-5-(3-羥基氧雜環丁烷-3-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(3-hydroxyoxetan-3-yl)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(150 mg，0.42 mmol)於Et2O(4.2 mL)中製漿且冷卻至-78℃。接著逐滴添加正丁基鋰 (1.6 M，於己烷中)(790 μl，1.3 mmol)。在-78℃下攪拌漿液45分鐘，接著自乾冰浴中上提5分鐘，引起微小黃色變化。接著將漿液回置於乾冰浴中，且添加氧雜環丁烷-3-酮(27.0 μl，0.46 mmol)。使漿液緩慢升溫至室溫且攪拌隔夜。用飽和氯化銨溶液(10 mL)淬滅反應物且用乙酸乙酯(3×25 mL)萃取。經硫酸鎂乾燥經合併之有機層且濃縮。藉由中壓層析(二氧化矽，3%至10%甲醇：DCM)純化粗產物，得到1-(4-(2,6-二氟苯氧基)-5-(3-羥基氧雜環丁烷-3-基)吡啶-2-基)-3-甲基脲(9.5 mg，0.027 mmol，6.5%產率)。質譜(ESI)m/z=352.0(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.00(1H,br.s.),8.60(1H,s),8.10(1H,s),7.22-7.33(2H,m),7.05-7.11(2H,m),6.04(1H,s),5.23(2H,d,J=7.2 Hz),4.94(2H,d,J=7.2 Hz),2.80(3H,d,J=4.7 Hz)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (150 mg, 0.42 mmol) in Et 2 O (4.2 mL) The slurry was cooled to -78 °C. Then n-butyllithium (1.6 M in hexanes) (790 μl, 1.3 mmol) was added dropwise. The slurry was stirred at -78 °C for 45 minutes and then lifted from the dry ice bath for 5 minutes, causing a slight yellow change. The slurry was then placed back in a dry ice bath and oxetane-3-one (27.0 μl, 0.46 mmol) was added. The slurry was slowly warmed to room temperature and stirred overnight. The reaction was quenched with EtOAc EtOAc (EtOAc) The combined organic layers were dried with MgSO4 and evaporated. The crude product was purified by medium pressure chromatography (cerium dioxide, 3% to 10% methanol: DCM) to give 1-(4-(2,6-difluorophenoxy)-5-(3-hydroxyoxa) Cyclobutane-3-yl)pyridin-2-yl)-3-methylurea (9.5 mg, 0.027 mmol, 6.5% yield). Mass Spectrum (ESI) m/z = 352.0 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.00 (1H, br. s.), 8.60 (1H, s), 8.10 (1H, s), 7.22-7.33 (2H, m), 7.05-7.11 ( 2H, m), 6.04 (1H, s), 5.23 (2H, d, J = 7.2 Hz), 4.94 (2H, d, J = 7.2 Hz), 2.80 (3H, d, J = 4.7 Hz).

實例606Example 606

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(3-氟-3-甲基丁基)吡啶-2-基)-3-甲基脲 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(3-fluoro-3-methylbutyl)pyridin-2-yl)-3-methyl Urea

將1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(3-羥基-3-甲基丁基)吡啶-2-基)-3-甲基脲(17 mg，0.049 mmol)溶解於DCM(1.0 ml)中。向溶液中添加三氟化雙(2-甲氧基乙基)胺基硫(0.014 ml，0.073 mmol)。攪拌所得淺黃色溶液1.5小時。接著用飽和氯化銨溶液(5 mL)淬滅反應物且用二氯甲烷(2×20 mL)萃取。經硫酸鎂乾燥經合併之有機層。藉由中壓層析(二氧化矽，0%至7.5% MeOH：DCM)純化殘餘物，得到約70%純的所要產物。藉由逆相製備型HPLC，使用Phenomenex Gemini管柱 (10微米，C18，100 Å，150×30 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度10%至90%)純化粗物質，得到所要產物之三氟乙酸鹽。接著經SCX管柱溶離三氟乙酸鹽，得到1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(3-氟-3-甲基丁基)吡啶-2-基)-3-甲基脲(7.0 mg，0.020 mmol，41%產率)。質譜(ESI)m/z=350.0(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.55(1H,br.s.),8.71-10.16(1H,m),7.84(1H,s),7.55(1H,d,J=2.2 Hz),7.27(1H,s),5.67(1H,d,J=2.2 Hz),4.21(2H,q,J=7.2 Hz),2.99(3H,d,J=4.5 Hz),2.58-2.80(2H,m),1.69-1.98(2H,m),1.40-1.50(6H,m),1.38(3H,s)(三氟乙酸鹽)。 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-(3-hydroxy-3-methylbutyl)pyridin-2-yl)-3-yl The base urea (17 mg, 0.049 mmol) was dissolved in DCM (1.0 ml). To the solution was added bis(2-methoxyethyl)aminosulfur trifluoride (0.014 ml, 0.073 mmol). The resulting pale yellow solution was stirred for 1.5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The combined organic layers were dried over MgSO4. The residue was purified by mp EtOAc (EtOAc:EtOAc:EtOAc By reverse phase preparative HPLC, using a Phenomenex Gemini column (10 micron, C18,100 Å, 150 × 30 mm , containing 0.1% TFA of CH 3 CN / H 2 O, gradient over 25 minutes from 10 to 90%) The crude material is purified to give the desired product as the trifluoroacetic acid salt. The trifluoroacetate is then dissolved in an SCX column to give 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(3-fluoro-3-methylbutyl) Pyridin-2-yl)-3-methylurea (7.0 mg, 0.020 mmol, 41% yield). Mass Spectrum (ESI) m/z =353. 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.55 (1H, br. s.), 8.71-10.16 (1H, m), 7.84 (1H, s), 7.55 (1H, d, J = 2.2 Hz) , 7.27 (1H, s), 5.67 (1H, d, J = 2.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 2.99 (3H, d, J = 4.5 Hz), 2.58-2.80 (2H, m), 1.69-1.98 (2H, m), 1.40-1.50 (6H, m), 1.38 (3H, s) (trifluoroacetate).

藉由基本上遵循實例606中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 606:

實例608Example 608

1-(4-(2,6-二氟苯氧基)-5-((3-甲基氧雜環丁烷-3-基)乙炔基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)-3-methylurea

將三水合氟化四丁基銨(130 mg，0.42 mmol)、三甲基((3-甲基氧雜環丁烷-3-基)乙炔基)矽烷(71 mg，0.42 mmol)、碘化銅(I)(8.0 mg，0.042 mmol)、Pd(Ph3P)4(48 mg，0.042 mmol)於四氫呋喃(3.0 ml)中製 漿。接著在氬氣下加熱反應混合物至80℃。用乙酸乙酯(40 mL)稀釋反應混合物。用水(1×10 mL)、1：1水：鹽水溶液(1×10 mL)及鹽水(1×10 mL)洗滌此混合物，接著經硫酸鎂乾燥。對粗產物進行中壓層析(二氧化矽，0%至5%甲醇：二氯甲烷)，得到受初始物質污染之所要產物。藉由逆相製備型HPLC，使用Phenomenex Gemini管柱(10微米，C18，100 Å，150×30 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度10%至90%)純化此物質，得到所要產物之三氟乙酸鹽。接著經SCX管柱，用0至2 M氨之甲醇溶液溶離三氟乙酸鹽，得到1-(4-(2,6-二氟苯氧基)-5-((3-甲基氧雜環丁烷-3-基)乙炔基)吡啶-2-基)-3-甲基脲(22 mg，0.059 mmol，14%產率)。質譜(ESI)m/z=374.0(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.27(1H,br.s.),8.88(1H,br.s.),8.14(1H,s),7.15-7.26(1H,m),6.97-7.14(2H,m),6.15(1H,s),4.93(2H,d,J=5.5 Hz),4.48(2H,s),2.69-2.84(3H,m),1.72(3H,s)。 Tetrabutylammonium fluoride (130 mg, 0.42 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)decane (71 mg, 0.42 mmol), iodide Copper (I) (8.0 mg, 0.042 mmol), Pd(Ph 3 P) 4 (48 mg, 0.042 mmol) was slurried in tetrahydrofuran (3.0 ml). The reaction mixture was then heated to 80 ° C under argon. The reaction mixture was diluted with ethyl acetate (40 mL). The mixture was washed with water (1×10 mL), 1:1 water: brine (1×10 mL) and brine (1×10 mL) and then dried over magnesium sulfate. The crude product was subjected to medium pressure chromatography (cerium oxide, 0% to 5% methanol: dichloromethane) to give the desired product which was contaminated with starting material. By reverse phase preparative HPLC, using a Phenomenex Gemini column (10 micron, C18,100 Å, 150 × 30 mm , containing 0.1% TFA of CH 3 CN / H 2 O, gradient over 25 minutes from 10 to 90%) This material was purified to give the desired product as the trifluoroacetic acid salt. The trifluoroacetate is then dissolved in a solution of 0 to 2 M ammonia in methanol via an SCX column to give 1-(4-(2,6-difluorophenoxy)-5-((3-methyloxyheterocycle). Butan-3-yl)ethynyl)pyridin-2-yl)-3-methylurea (22 mg, 0.059 mmol, 14% yield). Mass Spectrum (ESI) m/z = 374.0 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.27 (1H, br. s.), 8.88 (1H, br.s.), 8.14 (1H, s), 7.15-7.26 (1H, m), 6.97 -7.14 (2H, m), 6.15 (1H, s), 4.93 (2H, d, J = 5.5 Hz), 4.48 (2H, s), 2.69 - 2.84 (3H, m), 1.72 (3H, s).

遵循實例608中之程序，製備以下化合物： Following the procedure in Example 608, the following compounds were prepared:

遵循實例494中之程序，製備以下化合物： Following the procedure in Example 494, the following compounds were prepared:

遵循實例494中之程序，製備以下化合物。經由SCX管柱進行逆相純化及後續中和之後，此化合物為該程序之副產物： Following the procedure in Example 494, the following compounds were prepared. This compound is a by-product of this procedure after reverse phase purification via SCX column and subsequent neutralization:

實例615Example 615

1-(4-(2,6-二氟苯氧基)-5-(2-側氧基吡咯啶-1-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(2-o-oxypyrrolidin-1-yl)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲、吡咯啶-2-酮(120 mg，1.50 mmol)、N,N'-二甲基乙二胺(21 mg，0.24 mmol)、碘化銅(I)(19 mg，0.097 mmol)及碳酸鉀(200 mg，1.5 mmol)於二噁烷(4.0 ml)中製漿，且添加3埃分子篩(約100 mg)。將所得漿液置於Discover型微波反應器(CEM,Matthews,NC)中，且在劇烈攪拌下加熱至120℃，維持3小時。過濾所得藍色漿液，且用乙酸乙酯及二氯甲烷洗滌。濃縮濾液且藉由中壓層析(二氧化矽，0%至7%氨之甲醇溶液：DCM)純化殘餘物，得到受內醯胺起始物質污染之所要產物。藉由逆相製備型HPLC，使用Phenomenex Gemini管柱(10微米，C18，100 Å，150×30 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度10%至95%)純化不純物質，得到所要產物之三氟乙酸鹽。接著藉由經SCX管柱，用0至2 M氨之甲醇溶液溶離該物質使鹽呈游離鹼形式，得到1-(4-(2,6-二氟苯氧基)-5-(2-側氧基吡咯啶-1-基)吡啶-2-基)-3-甲基脲(15 mg，0.041 mmol，8.5%產率)。質譜(ESI)m/z=363.0(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.01(1H,s),8.81-8.97(1H,m),8.10(1H,s),7.17-7.27(1H,m),7.00-7.12(2H,m),6.16(1H,s),3.87(2H,t,J=7.0 Hz),2.76(3H,d,J=4.7 Hz),2.59(2H,t,J=8.0 Hz),2.23(2H，五重峰，J=7.6 Hz)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea, pyrrolidin-2-one (120 mg, 1.50 mmol), N, N'-Dimethylethylenediamine (21 mg, 0.24 mmol), copper (I) iodide (19 mg, 0.097 mmol) and potassium carbonate (200 mg, 1.5 mmol) in dioxane (4.0 ml) Slurry and add 3 angstrom molecular sieves (about 100 mg). The resulting slurry was placed in a Discover type microwave reactor (CEM, Matthews, NC) and heated to 120 ° C with vigorous stirring for 3 hours. The resulting blue syrup was filtered and washed with ethyl acetate and dichloromethane. The filtrate was concentrated and the residue was purified by EtOAc EtOAc (EtOAc) By reverse phase preparative HPLC, using a Phenomenex Gemini column (10 micron, C18,100 Å, 150 × 30 mm , containing 0.1% TFA of CH 3 CN / H 2 O, gradient over 25 minutes from 10 to 95%) The impure material is purified to give the desired product as the trifluoroacetate salt. The salt is then dissolved in a free base using a solution of 0 to 2 M ammonia in methanol over an SCX column to give 1-(4-(2,6-difluorophenoxy)-5-(2- Phenoxypyrrolidin-1-yl)pyridin-2-yl)-3-methylurea (15 mg, 0.041 mmol, 8.5% yield). Mass Spectrum (ESI) m/z = 363.0 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.01 (1H, s), 8.81-8.97 (1H, m), 8.10 (1H, s), 7.17-7.27 (1H, m), 7.00-7.12 (2H , m), 6.16 (1H, s), 3.87 (2H, t, J = 7.0 Hz), 2.76 (3H, d, J = 4.7 Hz), 2.59 (2H, t, J = 8.0 Hz), 2.23 (2H , Wufeng, J = 7.6 Hz).

實例616Example 616

1-(4-(2,6-二氟苯氧基)-5-(4-羥基-3-(羥基甲基)-3-甲基丁基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-Difluorophenoxy)-5-(4-hydroxy-3-(hydroxymethyl)-3-methylbutyl)pyridin-2-yl)-3-methyl Urea

將1-(4-(2,6-二氟苯氧基)-5-(2-(3-甲基氧雜環丁烷-3-基)乙基)吡啶-2-基)-3-甲基脲(17 mg，0.045 mmol)溶解於二噁烷(0.25 mL)中。添加2.0 mL 5%(w/w)硫酸溶液，且在85℃下加熱所得溶液1.5小時。接著冷卻反應物至室溫，且用飽和碳酸氫鈉溶液鹼化。接著用乙酸乙酯(3×25 mL)萃取混合物。經硫酸鎂乾燥經合併之有機層，且藉由中壓層析(二氧化矽，0%至10% MeOH：DCM)純化粗產物，得到1-(4-(2,6-二氟苯氧基)-5-(4-羥基-3-(羥基甲基)-3-甲基丁基)吡啶-2-基)-3-甲基脲(12 mg，0.030 mmol，67%產率)。質譜(ESI)m/z=396.1(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.06(1H,br.s.),8.14(1H,s),7.93(1H,s),7.17-7.26(1H,m),6.92-7.13(2H,m),5.94(1H,s),3.50-3.73(4H,m),2.81(3H,d,J=4.7 Hz),2.65-2.75(2H,m),2.45(1H,br.s.),1.65-1.76(2H,m),1.78(1H,br.s.),0.93(3H,s)。 1-(4-(2,6-Difluorophenoxy)-5-(2-(3-methyloxetan-3-yl)ethyl)pyridin-2-yl)-3- Methylurea (17 mg, 0.045 mmol) was dissolved in dioxane (0.25 mL). 2.0 mL of a 5% (w/w) sulfuric acid solution was added, and the resulting solution was heated at 85 ° C for 1.5 hours. The reaction was then cooled to room temperature and basified with saturated aqueous sodium bicarbonate. The mixture was then extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried <RTI ID=0.0>(M. 5-(4-hydroxy-3-(hydroxymethyl)-3-methylbutyl)pyridin-2-yl)-3-methylurea (12 mg, 0.030 mmol, 67% yield). Mass Spectrum (ESI) m/z = 396.1 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.06 (1H, br. s.), 8.14 (1H, s), 7.93 (1H, s), 7.17-7.26 (1H, m), 6.92-7.13 ( 2H,m), 5.94 (1H, s), 3.50-3.73 (4H, m), 2.81 (3H, d, J = 4.7 Hz), 2.65-2.75 (2H, m), 2.45 (1H, br.s. ), 1.65-1.76 (2H, m), 1.78 (1H, br.s.), 0.93 (3H, s).

實例617Example 617

1-(3-((4-溴-1-乙基-1H-吡唑-5-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲 1-(3-((4-Bromo-1-ethyl-1H-pyrazol-5-yl)oxy)-5-(4-hydroxy-4-methylpentyl)pyridin-2-yl)- 3-methylurea

將1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲(13 mg，0.036 mmol)溶解於二噁烷(140 μl)中，且添加溴(7.4 μl，0.14 mmol)。在室溫下攪拌所得橙色溶液45分鐘。接著用水(10 mL)稀釋反應物。用乙酸乙酯(1×20 mL)及二氯甲烷(1×10 mL)萃取混合物。合併有機層，且用水(1×20 mL)及鹽水(1×10 mL)洗滌，且經硫酸鎂乾燥。藉由中壓層析(二氧化矽，0%至7% MeOH：DCM)純化粗產物，得到1-(3-((4-溴-1-乙基-1H-吡唑-5-基)氧基)-5-(4-羥基-4-甲 基戊基)吡啶-2-基)-3-甲基脲(12 mg，0.027 mmol，76%產率)。質譜(ESI)m/z=440.0(M+H),442.0(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.21(1H,br.q,J=4.3,4.3,4.3 Hz),7.79(1H,d,J=1.6 Hz),7.50(1H,s),7.39(1H,br.s),6.72(1H,d,J=1.8 Hz),4.04(2H,q,J=7.3 Hz),3.00(3H,d,J=4.7 Hz),2.52(2H,t,J=7.4 Hz),1.52-1.73(3H,m),1.34-1.47(5H,m),1.11-1.21(6H,m)。 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-(4-hydroxy-4-methylpentyl)pyridin-2-yl)-3-yl The base urea (13 mg, 0.036 mmol) was dissolved in dioxane (140 μl) and bromine (7.4 μl, 0.14 mmol) was added. The resulting orange solution was stirred at room temperature for 45 minutes. The reaction was then diluted with water (10 mL). The mixture was extracted with ethyl acetate (1×20 mL) and dichloromethane (1×10 mL). The combined organic layers were washed with water (1×20 mL) and brine The crude product was purified by medium pressure chromatography (yield: EtOAc, EtOAc:EtOAc) Oxy)-5-(4-hydroxy-4-methylpentyl)pyridin-2-yl)-3-methylurea (12 mg, 0.027 mmol, 76% yield). Mass Spectrum (ESI) m/z = 44. (M+H) 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.21. (1H, br.q, J = 4.3, 4.3, 4.3 Hz), 7.79 (1H, d, J = 1.6 Hz), 7.50 (1H, s), 7.39 (1H, br.s), 6.72 (1H, d, J = 1.8 Hz), 4.04 (2H, q, J = 7.3 Hz), 3.00 (3H, d, J = 4.7 Hz), 2.52 (2H, t , J = 7.4 Hz), 1.52-1.73 (3H, m), 1.34-1.47 (5H, m), 1.11-1.21 (6H, m).

實例618Example 618

1-(3-((1-乙基-4-甲基-1H-吡唑-5-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲 1-(3-((1-Ethyl-4-methyl-1H-pyrazol-5-yl)oxy)-5-(4-hydroxy-4-methylpentyl)pyridin-2-yl) -3-methylurea

將1-(3-((4-溴-1-乙基-1H-吡唑-5-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲(11 mg，0.025 mmol)溶解於THF(120 μl)中，且添加乙酸鈀(II)(0.280 mg，1.2 μmol)及S-Phos(1.0 mg，2.5 μmol)。向此混合物中添加二甲基鋅(1.0 M，於庚烷中)(220 μl，0.23 mmol)溶液。接著加熱混合物至回流且攪拌4.5小時。接著用飽和氯化銨淬滅反應物。用EtOAc(2×20 mL)萃取此混合物。用鹽水洗滌經合併之層且經硫酸鎂乾燥。藉由逆相製備型HPLC，使用Phenomenex Gemini管柱(10微米，C18，100 Å，150×30 mm，含0.1% TFA之CH3CN/H2O，經20分鐘梯度10%至95%)純化粗物質，得到1-(3-((1-乙基-4-甲基-1H-吡唑-5-基)氧基)-5-(4-羥基-4-甲基戊基)吡啶-2-基)-3-甲基脲(0.6 mg，1.6 μmol，6.4%產率)。質譜(ESI)m/z=376.1(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 9.24(1H,br.q,J=3.9,3.9,3.9 Hz),7.75(1H,d,J=1.8 Hz),7.41(1H,s),7.37(1H,s),6.66(1H,d,J=1.8 Hz),3.95(2H, q,J=7.2 Hz),3.01(2H,d,J=4.7 Hz),2.49(2H,t,J=7.4 Hz),1.78(3H,s),1.39-1.46(3H,m),1.32-1.38(3H,m),1.18(6H,s)。 1-(3-((4-Bromo-1-ethyl-1H-pyrazol-5-yl)oxy)-5-(4-hydroxy-4-methylpentyl)pyridin-2-yl) -3-methylurea (11 mg, 0.025 mmol) was dissolved in THF (120 μl), and palladium(II) acetate (0.280 mg, 1.2 μmol) and S-Phos (1.0 mg, 2.5 μmol) were added. A solution of dimethyl zinc (1.0 M in heptane) (220 μl, 0.23 mmol) was added to this mixture. The mixture was then heated to reflux and stirred for 4.5 hours. The reaction was then quenched with saturated aqueous ammonium chloride. The mixture was extracted with EtOAc (2×20 mL). The combined layers were washed with brine and dried over magnesium sulfate. By reverse phase preparative HPLC, using a Phenomenex Gemini column (10 micron, C18,100 Å, 150 × 30 mm , containing 0.1% TFA of CH 3 CN / H 2 O, 20 min gradient from 10 to 95%) The crude material was purified to give 1-(3-((1-ethyl-4-methyl-1H-pyrazol-5-yl)oxy)-5-(4-hydroxy-4-methylpentyl)pyridine. -2-yl)-3-methylurea (0.6 mg, 1.6 μmol, 6.4% yield). Mass Spectrum (ESI) m/z = 376.1 (M+H). 1 H NMR (400 MHz, chloroform - d ) δ ppm 9.24 (1H, br.q, J = 3.9, 3.9, 3.9 Hz), 7.75 (1H, d, J = 1.8 Hz), 7.41 (1H, s), 7.37 (1H, s), 6.66 (1H, d, J = 1.8 Hz), 3.95 (2H, q, J = 7.2 Hz), 3.01 (2H, d, J = 4.7 Hz), 2.49 (2H, t, J = 7.4 Hz), 1.78 (3H, s), 1.39-1.46 (3H, m), 1.32-1.38 (3H, m), 1.18 (6H, s).

實例619Example 619

1-(4-((5-氟嘧啶-2-基)氧基)-5-(四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲 1-(4-((5-fluoropyrimidin-2-yl)oxy)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylurea

藉由基本上遵循實例870中之程序，但使用醇1-(4-羥基-5-(四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲及2-氯-5-氟嘧啶來製備標題化合物，得到1-(4-((5-氟嘧啶-2-基)氧基)-5-(四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=348.0(M+H)。1HNMR(500 MHz,DMSO-d 6)δ ppm 9.15(1H,s),9.00(1H,s),8.82(2H,s),8.10(1H,s),6.77(1H,s),3.95(2H,d,J=13.4 Hz),3.39-3.49(2H,m),2.65(3H,d,J=4.5 Hz),1.74-1.87(4H,m)。 By essentially following the procedure in Example 870 , but using the alcohol 1-(4-hydroxy-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylurea and 2 -Chloro-5-fluoropyrimidine to give the title compound to give 1-(4-((5-fluoropyrimidin-2-yl)oxy)-5-(tetrahydro-2H-pyran-4-yl)pyridine- 2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 348.0 (M+H). 1 H NMR (500 MHz, DMSO - d 6 ) δ ppm 9.15 (1H, s), 9.00 (1H, s), 8.82 (2H, s), 8.10 (1H, s), 6.77 (1H, s), 3.95 ( 2H, d, J = 13.4 Hz), 3.39-3.49 (2H, m), 2.65 (3H, d, J = 4.5 Hz), 1.74-1.87 (4H, m).

藉由基本上遵循實例619中之程序，但使用相應反應性芳基氟化物及1-(4-羥基-5-(四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲作為起始物質來製備以下化合物： By essentially following the procedure in Example 619 , but using the corresponding reactive aryl fluoride and 1-(4-hydroxy-5-(tetrahydro-2H-piperidin-4-yl)pyridin-2-yl)- 3-methylurea was used as the starting material to prepare the following compounds:

藉由基本上遵循實例1040中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 1040 :

藉由基本上遵循實例198中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 198:

藉由基本上遵循實例170中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 170:

實例635Example 635

1-(5-溴-4-((2,5-二側氧基吡咯啶-1-基)甲基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-((2,5-di-oxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：向硝基甲烷(1.1 ml，20 mmol)於DMF(100 mL)中之溶液中添加氫化鈉(60%分散液)(0.36 g，15 mmol)，且攪拌混合物15分鐘。接著添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.50 g，10.08 mmol)，且在130℃下加熱所得溶液。加熱反應物2.5小時，接著冷卻至室溫。接著用水(125 mL)稀釋混合物且用乙酸乙酯(1×150 mL)萃取。在高真空下濃縮水層，得到經濃縮之殘餘物。將殘餘物溶解於極少量水中，且用10% MeOH：DCM(3×100 mL)萃取。經硫酸鎂乾燥經合併之有機層且濃縮濾液，得到粗的所要產物1-(5-溴-4-(硝基甲基)吡啶-2-基)-3-甲基脲(2.0 g，7.0 mmol，70%產率)。質譜(ESI)m/z=288.9,290.8(M+H)。 Step A : To a solution of nitromethane (1.1 ml, 20 mmol) in EtOAc (EtOAc) Then 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (2.50 g, 10.08 mmol) was added, and the resulting solution was heated at 130 °C. The reaction was heated for 2.5 hours and then cooled to room temperature. The mixture was then diluted with water (125 mL) and ethyl acetate (1×150 mL). The aqueous layer was concentrated under high vacuum to give a concentrated residue. The residue was dissolved in a very small amount of water and extracted with 10% MeOH:EtOAc (EtOAc) The combined organic layers were dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ M, 70% yield). Mass Spectrum (ESI) m/z = 288.9, 290.8 (M+H).

步驟B：將1-(5-溴-4-(硝基甲基)吡啶-2-基)-3-甲基脲(1.5 g，5.3 mmol)於AcOH(27 ml)中製漿，且冷卻漿液至10℃。添加鋅粉(1.7 g，27 mmol)，且經8.5小時之時段使漿液緩慢升溫至室溫。接著再用乙酸(約50 ml)稀釋反應漿液，接著過濾。用乙酸洗滌固體，且在減壓下濃縮經合併之濾液，得到所要粗產物之乙酸鹽。使粗物質吸收於矽膠栓塞上，且藉由用7.5%至10% 2 M氨之甲醇溶液：DCM溶離進行層析來純化，得到1-(4-(胺基甲基)-5-溴吡啶-2-基)-3-甲基脲(320 mg，1.2 mmol，23%產率)。質譜(ESI)m/z=260.9(M+H)。 Step B : 1-(5-Bromo-4-(nitromethyl)pyridin-2-yl)-3-methylurea (1.5 g, 5.3 mmol) was taken in AcOH (27 ml) and cooled The slurry was allowed to reach 10 °C. Zinc powder (1.7 g, 27 mmol) was added and the slurry was slowly warmed to room temperature over a period of 8.5 hours. The reaction slurry was then diluted with acetic acid (about 50 ml), followed by filtration. The solid was washed with acetic acid, and the combined filtrate was concentrated under reduced pressure to give the desired crude product. The crude material was absorbed onto a silicone plug and purified by chromatography with 7.5% to 10% 2 M ammonia in methanol: DCM to give 1-(4-(aminomethyl)-5-bromopyridine. -2-yl)-3-methylurea (320 mg, 1.2 mmol, 23% yield). Mass Spectrum (ESI) m/z = 260.9 (M+H).

步驟C：向玻璃微波反應容器中饋入含1-(4-(胺基甲基)-5-溴吡啶-2-基)-3-甲基脲(250 mg，0.97 mmol)及丁二酸酐(120 mg，1.2 mmol)之DMF(1.3 mL)，且在100℃下置於Discover型微波反應器(CEM,Matthews,NC)中30分鐘。冷卻反應混合物，且添加乙酸酐(0.36 ml，3.9 mmol)。接著再加熱此混合物至100℃，維持30分鐘。接著冷卻反應物，且用水(30 mL)及乙酸乙酯(50 mL)稀釋。分離各層，且用二氯甲烷(1×50 mL)萃取水層。合併有機層，且用飽和碳酸氫鈉(3×25 mL)及水(3×25 mL)萃取混合物，且經硫酸鎂乾燥。使粗物 質吸附於矽膠栓塞上，且藉由用2.5%至6% MeOH：DCM溶離進行層析來純化，得到1-(5-溴-4-((2,5-二側氧基吡咯啶-1-基)甲基)吡啶-2-基)-3-甲基脲(150 mg，0.440 mmol，46%產率)。質譜(ESI)m/z=342.9(M+H)。1H NMR(400 MHz,CDCl3)δ 9.37(1H,s),8.88(1H,br.q,J=1.8,1.8,1.8 Hz),8.20(1H,s),6.54(1H,s),4.70(2H,s),2.93(2H,d,J=4.9 Hz),2.86(3H,br.s.)。 Step C : Feeding a glass microwave reaction vessel with 1-(4-(aminomethyl)-5-bromopyridin-2-yl)-3-methylurea (250 mg, 0.97 mmol) and succinic anhydride (120 mg, 1.2 mmol) in DMF (1.3 mL) and placed in a Discover-type microwave reactor (CEM, Matthews, NC) for 30 min at 100 °C. The reaction mixture was cooled and acetic anhydride (0.36 ml, 3.9 mmol). This mixture was then heated again to 100 ° C for 30 minutes. The reaction was then cooled and diluted with water (30 mL) &EtOAc. The layers were separated and the aqueous extracted with dichloromethane (1×50 mL). The combined organic layers were extracted with EtOAc EtOAc EtOAc (EtOAc) The crude material was adsorbed onto a silica gel plug and purified by chromatography with 2.5% to 6% MeOH:DCM to give 1-(5-bromo-4-((2,5-di- oxypyrrolidine) 1-yl)methyl)pyridin-2-yl)-3-methylurea (150 mg, 0.440 mmol, 46% yield). Mass Spectrum (ESI) m/z = 342.9 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (1H, s), 8.88 (1H, br.q, J = 1.8, 1.8, 1.8 Hz), 8.20 (1H, s), 6.54 (1H, s), 4.70 (2H, s), 2.93 (2H, d, J = 4.9 Hz), 2.86 (3H, br.s.).

藉由基本上遵循實例870中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 870:

實例655Example 655

1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea

將1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(1.40 g，5.6 mmol)及苄醇(0.88 mL，8.5 mmol)溶解於DMF(56 mL)中。將氫化鈉(60%分散液)(340 mg，8.5 mmol)小心添加至溶液中。接著在65℃下攪拌所得深 棕色溶液2.5天。接著冷卻反應物至室溫且傾倒至約300 mL水中。過濾所得漿液且用水洗滌。將濕沈澱物溶解於約550 mL 10% MeOH：DCM混合物中，接著經硫酸鎂乾燥。濃縮濾液，得到粗1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(1.55 g，4.61 mmol，82%產率)。質譜(ESI)m/z=336.2(M+H),338.2(M+H)。1H NMR(DMSO-d6)δ：9.24(s,1H),8.18(s,1H),7.36-7.49(m,5H),5.21(s,2H),2.70(d,J=4.7 Hz,3H)。 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (1.40 g, 5.6 mmol) and benzyl alcohol (0.88 mL, 8.5 mmol) were dissolved in DMF (56 mL). Sodium hydride (60% dispersion) (340 mg, 8.5 mmol) was carefully added to the solution. The resulting dark brown solution was then stirred at 65 ° C for 2.5 days. The reaction was then cooled to room temperature and poured into about 300 mL of water. The resulting slurry was filtered and washed with water. The wet precipitate was dissolved in approximately 550 mL of 10% MeOH: DCM mixture then dried over magnesium sulfate. The filtrate was concentrated to give EtOAc (EtOAc m. Mass Spectrum (ESI) m/z = 336.2 (M+H) 1 H NMR (DMSO-d 6 ) δ: 9.24 (s, 1H), 8.18 (s, 1H), 7.36-7.49 (m, 5H), 5.21. (s, 2H), 2.70 (d, J = 4.7 Hz, 3H).

藉由基本上遵循實例1084中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 1084 :

遵循實例250中之程序，製備以下化合物： Following the procedure in Example 250, the following compounds were prepared:

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

遵循實例253中之程序，製備以下化合物： Following the procedure in Example 253, the following compounds were prepared:

遵循實例72中之程序，製備以下化合物： Following the procedure in Example 72, the following compounds were prepared:

遵循實例195中之程序，製備以下化合物： Following the procedure in Example 195, the following compounds were prepared:

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449, the following compounds were prepared:

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449, the following compounds were prepared:

遵循實例870中之程序，製備以下化合物： Following the procedure in Example 870 , the following compounds were prepared:

遵循實例467中之程序，製備以下化合物： Following the procedure in Example 467, the following compounds were prepared:

遵循實例499中之程序，製備以下化合物： Following the procedure in Example 499, the following compounds were prepared:

遵循實例251中之程序，製備以下化合物： Following the procedure in Example 251, the following compounds were prepared:

實例701Example 701

3-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丙醯胺 3-(4-(2,6-Difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)-N-methylpropanamide

向含3-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)丙酸(0.007 g，0.020 mmol)之燒瓶中添加TBTU(7.68 mg，0.024 mmol)、N-乙基-N-異丙基丙-2-胺(10.44 μL，0.060 mmol)、DMF(0.415 mL)、N-乙基- N-異丙基丙-2-胺(10.44 μL，0.060 mmol)及甲胺(0.050 mL，0.100 mmol)。將燒瓶密封且攪拌2小時，接著濃縮至乾燥。將產物分配於水與EtOAc之間。收集有機層，經MgSO4乾燥，過濾且濃縮。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至50%)純化粗物質，得到呈白色固體狀之3-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-N-甲基丙醯胺(0.0023 g，6.3 μmol，32%產率)。質譜(ESI)m/z=365.1(M+H)。1H NMR(MeOH-d4)δ 8.05(s,1H),7.34-7.48(m,1H),7.13-7.30(m,2H),6.40(s,1H),2.98-3.11(m,2H),2.84(s,3H),2.73(s,3H),2.59(t,J=7.6 Hz,2H)。 Add TBTU to a flask containing 3-(4-(2,6-difluorophenoxy)-6-(3-methylureido)pyridin-3-yl)propanoic acid (0.007 g, 0.020 mmol). 7.68 mg, 0.024 mmol), N-ethyl-N-isopropylpropan-2-amine (10.44 μL, 0.060 mmol), DMF (0.415 mL), N-ethyl-N-isopropylpropan-2- Amine (10.44 μL, 0.060 mmol) and methylamine (0.050 mL, 0.100 mmol). The flask was sealed and stirred for 2 hours then concentrated to dryness. The product was partitioned between water and EtOAc. The organic layer was collected, dried over MgSO 4, filtered and concentrated. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10-50%) to give the crude material as a white solid of 3- (4- (2,6 Fluorophenoxy)-6-(3-methylureido)pyridin-3-yl)-N-methylpropanamide (0.0023 g, 6.3 μmol, 32% yield). Mass Spectrum (ESI) m/z = 365.1 (M+H). 1 H NMR (MeOH-d 4 ) δ 8.05 (s, 1H), 7.34-7.48 (m, 1H), 7.13-7.30 (m, 2H), 6.40 (s, 1H), 2.98-3.11 (m, 2H) , 2.84 (s, 3H), 2.73 (s, 3H), 2.59 (t, J = 7.6 Hz, 2H).

實例702Example 702

1-(5-氰基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲 1-(5-Cyano-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea

向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.140 mmol)於DMF(0.14 mL)中之溶液中添加氰化銅(i)(0.016 g，0.175 mmol)。在150℃下攪拌反應混合物18小時，接著冷卻至室溫。藉由逆相製備型HPLC，使用SB C8管柱(含0.1% TFA之CH3CN/H2O，梯度20%至85%)純化粗物質。合併所要溶離份，濃縮，用飽和NaHCO3水溶液中和，且用EtOAc萃取。乾燥(MgSO4)有機層，過濾且濃縮，得到呈白色固體狀之1-(5-氰基-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.0006 g，2 μmol，1.4%產率)。質譜(ESI)m/z=305.1(M+H)。1H NMR(MeOH-d4)δ 8.44(s,1H),7.35(t,J=8.6 Hz,1H),7.15(t,J=8.3 Hz,2H),6.68(s,1H),2.69(s,3H)。 To a solution of 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.050 g, 0.140 mmol) in DMF (0.14 mL) Copper cyanide (i) (0.016 g, 0.175 mmol) was added. The reaction mixture was stirred at 150 ° C for 18 hours and then cooled to room temperature. By reverse phase preparative HPLC, using SB C8 column (including the CH 0.1% TFA 3 CN / H 2 O, 20-85% gradient) to give crude material. Desired fractions were combined, concentrated, and saturated aqueous NaHCO 3 solution, and extracted with EtOAc. The organic layer was dried (MgSO 4), filtered and concentrated to give a white solid of 1- (5-cyano-4- (2,6-difluorophenoxy) pyridin-2-yl) -3-methyl Urea (0.0006 g, 2 μmol, 1.4% yield). Mass Spectrum (ESI) m/z = 305.1 (M+H). 1 H NMR (MeOH-d 4 ) δ 8.44 (s, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.15 (t, J = 8.3 Hz, 2H), 6.68 (s, 1H), 2.69 ( s, 3H).

實例703Example 703

(E)-1-(5-(2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙烯基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (E)-1-(5-(2-(1,1-dioxalyltetrahydro-2H-thiopiperazin-4-yl)vinyl)-3-((2-ethylpyridine-3) -yl)oxy)pyridin-2-yl)-3-methylurea

首先用氬氣、接著用氮氣淨化裝有含1-(3-((2-乙基吡啶-3-基)氧基)-5-乙烯基吡啶-2-基)-3-甲基脲(0.048 g，0.161 mmol)之DCM(3.22 mL)之燒瓶。添加4-乙烯基四氫-2H-硫代哌喃1,1-二氧化物(0.111 g，0.692 mmol)及第2代荷維達-格拉布催化劑(10.08 mg，0.016 mmol)。將反應混合物脫氣三次，接著在40℃下加熱18小時。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，得到呈灰白色固體狀之(E)-1-(5-(2-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)乙烯基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.014 g，0.033 mmol，20%產率)。質譜(ESI)m/z=431.1(M+H)。1H NMR(MeOH-d4)δ 8.38(dd,J=4.8,1.3 Hz,1H),8.05(d,J=1.7 Hz,1H),7.39-7.47(m,1H),7.35(dd,J=8.3,4.6 Hz,1H),7.18(d,J=1.7 Hz,1H),6.44(d,J=16.1 Hz,1H),6.15(d,J=7.1 Hz,1H),3.13-3.24(m,2H),3.01-3.11(m,2H),2.95(s,3H),2.90(q,J=7.6 Hz,2H),2.45-2.58(m,1H),2.11-2.20(m,2H),1.99-2.09(m,2H),1.28-1.31(m,3H)。 First, purify with 1-(3-((2-ethylpyridin-3-yl)oxy)-5-vinylpyridin-2-yl)-3-methylurea with argon and then with nitrogen ( 0.048 g, 0.161 mmol) of DCM (3.22 mL). 4-vinyltetrahydro-2H-thiopentan 1,1-dioxide (0.111 g, 0.692 mmol) and a second generation of Hovoda-Grubb catalyst (10.08 mg, 0.016 mmol) were added. The reaction mixture was degassed three times and then heated at 40 ° C for 18 hours. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc (EtOAc) (E)-1-(5-(2-(1,1-Dioxalyltetrahydro-2H-thiopiperazin-4-yl)vinyl)-3-((2-ethylpyridine) 3-yl)oxy)pyridin-2-yl)-3-methylurea (0.014 g, 0.033 mmol, 20% yield). Mass Spectrum (ESI) m/z = 431.1 (M+H). 1 H NMR (MeOH-d 4 ) δ 8.38 (dd, J = 4.8, 1.3 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.39-7.47 (m, 1H), 7.35 (dd, J =8.3, 4.6 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 6.44 (d, J = 16.1 Hz, 1H), 6.15 (d, J = 7.1 Hz, 1H), 3.13 - 3.24 (m) , 2H), 3.01-3.11 (m, 2H), 2.95 (s, 3H), 2.90 (q, J = 7.6 Hz, 2H), 2.45-2.58 (m, 1H), 2.11-2.20 (m, 2H), 1.99-2.09 (m, 2H), 1.28-1.31 (m, 3H).

遵循實例703中之程序，製備以下化合物： Following the procedure in Example 703 , the following compounds were prepared:

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449, the following compounds were prepared:

遵循實例467中之程序，製備以下化合物： Following the procedure in Example 467, the following compounds were prepared:

遵循實例250中之程序，製備以下化合物： Following the procedure in Example 250, the following compounds were prepared:

遵循實例253中之程序，製備以下化合物： Following the procedure in Example 253, the following compounds were prepared:

遵循實例701中之程序，製備以下化合物： Following the procedure in Example 701 , the following compounds were prepared:

遵循實例195中之程序，製備以下化合物： Following the procedure in Example 195, the following compounds were prepared:

遵循實例198中之程序，製備以下化合物： Following the procedure in Example 198, the following compounds were prepared:

遵循實例1090中之程序，製備以下化合物： Following the procedure in Example 1090 , the following compounds were prepared:

實例725Example 725

1-(3-((2-乙基吡啶-3-基)氧基)-5-(4-羥基環己基)吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(4-hydroxycyclohexyl)pyridin-2-yl)-3-methylurea

在25℃下，向1-(3-((2-乙基吡啶-3-基)氧基)-5-(4-側氧基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲(0.020 g，0.055 mmol)於MeOH(0.546 mL)中之溶液中添加氧化鉑(iv)(2.5 mg，10 μmol)。在25℃下於氫氣氛圍下攪拌反應混合物18小時。經矽藻土襯墊過濾反應混合物且用MeOH洗滌。濃縮濾液。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之DCM梯度溶離進行層析來純化。藉由逆相製備型HPLC，使用Eclipse管柱(含0.1% TFA之CH3CN/H2O，經25分鐘梯度10%至70%)進一步純化產物，得到所要產物之三氟乙酸鹽。合併所要溶離份，濃縮，用飽和NaHCO3水溶液中和，且用EtOAc萃取。乾燥(MgSO4)有機層且濃縮，得到1-(3-((2-乙基吡啶-3-基)氧基)-5-(4-羥基環己基)吡啶-2-基)-3-甲基脲(0.008 g，0.0216 mmol，39%產率)。質譜(ESI)m/z=371.1(M+H)。 To 1-(3-((2-ethylpyridin-3-yl)oxy)-5-(4-oxocyclohex-1-en-1-yl)pyridine-2- at 25 °C Platinum (iv) (2.5 mg, 10 μmol) was added to a solution of -3-methylurea (0.020 g, 0.055 mmol) in MeOH (0.546 mL). The reaction mixture was stirred under a hydrogen atmosphere at 25 ° C for 18 hours. The reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated. The crude material was taken up on a silica gel plug and purified by chromatography on a Redi-Sep prefilled cartridge column (4 g) eluting with a gradient of 0% to 10% MeOH in DCM. By reverse phase preparative HPLC, using Eclipse column (including the CH 0.1% TFA 3 CN / H 2 O, 10-70% over 25 minutes gradient) to further purify the product, the trifluoroacetate salt of the desired product. Desired fractions were combined, concentrated, and saturated aqueous NaHCO 3 solution, and extracted with EtOAc. Dried (MgSO 4), and the organic layer was concentrated to give 1- (3 - ((2-ethyl-3-yl) oxy) -5- (4-hydroxycyclohexyl) pyridin-2-yl) -3- Methyl urea (0.008 g, 0.0216 mmol, 39% yield). Mass Spectrum (ESI) m/z = 371.1 (M+H).

實例726Example 726

5-溴-N-(2,4-二甲氧基苄基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-胺 5-bromo-N-(2,4-dimethoxybenzyl)-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-amine

向玻璃微波反應容器中饋入2,4-二甲氧基苄胺(0.991 mL，6.60 mmol)及含5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶(0.499 g，1.65 mmol)之NMP(2.75 mL)，且在180℃下置於微波反應器中1小時。冷卻反應物至室溫，用水(10 mL)稀釋且用乙酸乙酯(2×10 mL)萃取。用水、鹽水洗滌經合併之有機層，且經MgSO4乾燥。過濾溶液且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，用含0%至50% EtOAc之己烷溶離進行層析來純化，得到呈灰白色固體狀之5-溴-N-(2,4-二甲氧基苄基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-胺(0.590 g，1.36 mmol，83%產率)。質譜(ESI)m/z=433.0,435.0(M+H)。1H NMR(CDCl3)δ 8.00(d,J=2.2 Hz,1H),7.44(d,J=2.0 Hz,1H),7.28(s,1H),7.09(d,J=2.0 Hz,1H),6.41-6.58(m,2H),5.69(d,J=2.0 Hz,1H),4.63(d,J=5.3 Hz,2H),4.05(d,J=7.2 Hz,2H),3.83(d,J=1.8 Hz,6H),1.42(t,J=7.2 Hz,3H)。 Feeding 2,4-dimethoxybenzylamine (0.991 mL, 6.60 mmol) and 5-bromo-2-chloro-3-((1-ethyl-1H-pyrazole-5) into a glass microwave reaction vessel -Methoxy)pyridine (0.499 g, 1.65 mmol) in NMP (2.75 mL), and placed in a microwave reactor for one hour at 180 °C. The reaction was cooled to room temperature, diluted with H~~~~ Water, washed with brine and dried 4 the combined organic layers over MgSO. The solution was filtered and concentrated in vacuo. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc (EtOAc) eluting with EtOAc (EtOAc) 5-Bromo-N-(2,4-dimethoxybenzyl)-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-amine (0.590 g, 1.36 mmol, 83% yield). Mass Spectrum (ESI) m/z =437. 1 H NMR (CDCl 3 ) δ 8.00 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H) , 6.41-6.58 (m, 2H), 5.69 (d, J = 2.0 Hz, 1H), 4.63 (d, J = 5.3 Hz, 2H), 4.05 (d, J = 7.2 Hz, 2H), 3.83 (d, J = 1.8 Hz, 6H), 1.42 (t, J = 7.2 Hz, 3H).

製備preparation

3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-胺 3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridin-2-amine

在0℃下，向N-(2,4-二甲氧基苄基)-3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-胺(0.359 g，0.793 mmol)於 DCM(8 mL)中之溶液中添加2,2,2-三氟乙酸(1.834 mL，23.80 mmol)。使混合物升溫至室溫且攪拌4小時。濃縮混合物，用DCM稀釋，用飽和NaHCO3水溶液(1 mL)洗滌且經MgSO4乾燥。過濾溶液且在真空中濃縮。藉由經Redi-Sep預裝填矽膠管柱，以含0%至10% MeOH之DCM梯度溶離進行層析來純化粗物質。藉由逆相製備型HPLC，使用SB C8管柱(含0.1% TFA之CH3CN/H2O，經25分鐘梯度10%至60%)進一步純化產物，得到3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-胺(0.140 g，0.463 mmol，58.4%產率)。質譜(ESI)m/z=303.1(M+H)。1H NMR(MeOH-d4)δ 7.63(s,1H),7.37-7.46(m,1H),7.06-7.14(m,1H),5.61-5.70(m,1H),4.14(q,J=7.3 Hz,2H),3.92(dd,J=11.5,3.7 Hz,2H),3.35-3.44(m,2H),2.44(d,J=7.3 Hz,2H),1.68(dt,J=7.5,3.9 Hz,1H),1.55(d,J=12.7 Hz,2H),1.37-1.46(m,3H),1.28(qd,J=12.4,4.4 Hz,2H)。 To N-(2,4-dimethoxybenzyl)-3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-) at 0 °C Add 2,2,2-trifluoroacetic acid (1.834 mL, 23.80 mmol) to a solution of 2H-pyran-4-yl)methyl)pyridin-2-amine (0.359 g, 0.793 mmol ). The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was concentrated, diluted with DCM, washed with saturated aqueous NaHCO 3 (1 mL) and dried over MgSO 4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography on a Redi-Sep prefilled cartridge column eluting with a gradient of 0% to 10% MeOH in DCM. By reverse phase preparative HPLC, using SB C8 column (including the CH 0.1% TFA 3 CN / H 2 O, 10-60% over 25 minutes gradient) to further purify the product, to give 3 - ((1-ethyl -1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridin-2-amine (0.140 g, 0.463 mmol, 58.4% yield) . Mass Spectrum (ESI) m/z = 303.1 (M+H). 1 H NMR (MeOH-d 4 ) δ 7.63 (s, 1H), 7.37-7.46 (m, 1H), 7.06-7.14 (m, 1H), 5.61-5.70 (m, 1H), 4.14 (q, J = 7.3 Hz, 2H), 3.92 (dd, J = 11.5, 3.7 Hz, 2H), 3.35-3.44 (m, 2H), 2.44 (d, J = 7.3 Hz, 2H), 1.68 (dt, J = 7.5, 3.9 Hz, 1H), 1.55 (d, J = 12.7 Hz, 2H), 1.37-1.46 (m, 3H), 1.28 (qd, J = 12.4, 4.4 Hz, 2H).

遵循實例1793中之程序，製備以下化合物： Following the procedure in Example 1793, the following compounds were prepared:

製備preparation

6-溴-1-甲基吲哚啉-2-酮 6-bromo-1-methyl porphyrin-2-one

在100℃下，於N2下，向60%氫化鈉於礦物油中之分散液(0.120 g，3.00 mmol)於甲苯(12 mL)中之懸浮液中逐滴添加6-溴-2-羥吲哚(0.656 g，3.0 mmol)於甲苯(3 mL)中之溶液。在100℃下攪拌所得混合物1小時。此後，一次性添加硫酸二甲酯(0.29 mL，3.06 mmol)，且在100℃下攪拌所得反應混合物18小時。用水稀釋粗混合物，用EtOAc萃取。經MgSO4乾燥經合併之有機萃取物，過濾且在減壓下濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至25% EtOAc之己烷梯度溶離進行層析來純化，得到呈灰白色固體狀之6-溴-1-甲基吲哚啉-2-酮(0.271 g，1.199 mmol，40.0%產率)。質譜(ESI)m/z=225.9(M+H)。1H NMR(400 MHz,CDCl3)δ 7.18(1H,dd,J=7.8,1.6 Hz),7.10(1H,d,J=7.8 Hz),6.97(1H,d,J=1.6 Hz),3.47(2H,s),3.20(3H,s)。 Add 6-bromo-2-hydroxyl to a suspension of 60% sodium hydride in mineral oil (0.120 g, 3.00 mmol) in toluene (12 mL) at 100 ° C under N 2 A solution of hydrazine (0.656 g, 3.0 mmol) in toluene (3 mL). The resulting mixture was stirred at 100 ° C for 1 hour. Thereafter, dimethyl sulfate (0.29 mL, 3.06 mmol) was added in one portion, and the resulting reaction mixture was stirred at 100 ° C for 18 hours. The crude mixture was diluted with water and extracted with EtOAc. Dried over MgSO 4 the organic extracts were combined, filtered and concentrated under reduced pressure. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc (EtOAc) 6-Bromo-1-methylindol-2-one (0.271 g, 1.199 mmol, 40.0% yield). Mass Spectrum (ESI) m/z = 225.9 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 (1H, dd, J = 7.8, 1.6 Hz), 7.10 (1H, d, J = 7.8 Hz), 6.97 (1H, d, J = 1.6 Hz), 3.47 (2H, s), 3.20 (3H, s).

遵循實例197中之程序，製備以下化合物： Following the procedure in Example 197, the following compounds were prepared:

遵循實例195中之程序，製備以下化合物： Following the procedure in Example 195, the following compounds were prepared:

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

遵循實例1307中之程序，製備以下化合物： Following the procedure in Example 1307 , the following compounds were prepared:

遵循實例499中之程序，製備以下化合物： Following the procedure in Example 499 , the following compounds were prepared:

遵循實例870中之程序，製備以下化合物： Following the procedure in Example 870 , the following compounds were prepared:

遵循實例1018中之程序，製備以下化合物： Following the procedure in Example 1018 , the following compounds were prepared:

實例753Example 753

1-(4-(3-氯-2-氟苯氧基)-5-(2-側氧基吲哚啉-5-基)吡啶-2-基)-3-甲基脲 1-(4-(3-chloro-2-fluorophenoxy)-5-(2-o-oxoindol-5-yl)pyridin-2-yl)-3-methylurea

在含有攪拌磁體之10 mL隔膜封蓋管中，將1-(4-(3-氯-2-氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(0.088 g，0.209 mmol)、5-溴羥吲哚(0.066 g，0.313 mmol)及肆(三苯基膦)鈀(0.024 g，0.021 mmol)懸浮於DMF(0.522 ml)中。向此物質中添加NaHCO3(0.053 g，0.626 mmol)及水(0.522 mL)。在150℃下於Discover型微波反應器(CEM,Matthews,NC)中加熱混合物10分鐘。反應完成後，冷卻小瓶至室溫。將粗混合物分配於EtOAc與水之間。經MgSO4乾燥經合併之有機層，過濾且濃縮。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘梯度5%至95%)純化粗產物，得到1-(4-(3-氯-2-氟苯氧基)-5-(2-側氧基吲哚啉-5-基)吡啶-2-基)-3-甲基脲(0.012 g，0.028 mmol，13%產率)。質譜(ESI)m/z=427.0(M+H)。1H NMR(500 MHz,MeOH-d4)δ 8.20(1H,s),7.44-7.55(3H,m),7.27-7.36(2H,m),7.01(1H,d,J=8.1 Hz),6.50(1H,s),3.58-3.63(2H,m),2.84(3H,s)。 1-(4-(3-Chloro-2-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3 in a 10 mL septum cap tube containing a stirring magnet 2-diboron 2-yl)pyridin-2-yl)-3-methylurea (0.088 g, 0.209 mmol), 5-bromohydroxyindole (0.066 g, 0.313 mmol) and hydrazine (triphenylphosphine) palladium (0.024 g) , 0.021 mmol) was suspended in DMF (0.522 ml). To this material was added NaHCO 3 (0.053 g, 0.626 mmol) and water (0.522 mL). The mixture was heated in a Discover type microwave reactor (CEM, Matthews, NC) at 150 °C for 10 minutes. After the reaction was completed, the vial was cooled to room temperature. The crude mixture was partitioned between EtOAc and water. The organic layer was dried over MgSO 4 merger, filtered and concentrated. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient over 25 minutes from 5 to 95%) crude product was purified to give 1- (4- (3-chloro-2-fluoro Phenoxy)-5-(2-oxo oxalin-5-yl)pyridin-2-yl)-3-methylurea (0.012 g, 0.028 mmol, 13% yield). Mass Spectrum (ESI) m/z = 427.0 (M+H). 1 H NMR (500 MHz, MeOH-d 4 ) δ 8.20 (1H, s), 7.44 - 7.55 (3H, m), 7.27-7.36 (2H, m), 7.01 (1H, d, J = 8.1 Hz), 6.50 (1H, s), 3.58-3.63 (2H, m), 2.84 (3H, s).

遵循實例753中之程序，製備以下化合物： Following the procedure in Example 753 , the following compounds were prepared:

遵循製備II中之程序，製備以下化合物： Following the procedure in Preparation II , the following compounds were prepared:

實例761Example 761

1-(4-(2,6-二氟苯氧基)-5-(3-羥基丙-1-烯-2-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(3-hydroxyprop-1-en-2-yl)pyridin-2-yl)-3-methylurea

將1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(0.104 g，0.257 mmol)、2-溴烯丙醇(0.070 mL，0.513 mmol)、(1,1'-雙(二苯基膦基)二茂鐵)二氯鈀(ii)(0.021 g，0.026 mmol)及2 M碳酸鈉水溶液(1.283 mL，2.57 mmol)於DMF(3.0 mL)中組合，且在90℃下於氬氣下加熱18小時。用EtOAc及水稀釋反應混合物。收集有機層，經MgSO4乾燥，過濾且在減壓下濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，得到呈白色粉末狀之1-(4-(2,6-二氟苯氧基)-5-(3-羥基丙-1-烯-2-基)吡啶-2-基)-3-甲基脲(0.034 g，0.10 mmol，40%產率)。質譜(ESI)m/z=336.0(M+H)。1H NMR(500 MHz,MeOH-d4)δ 8.08(1H,s),7.32-7.43(1H,m),7.19(2H,t,J=8.2 Hz),6.42(1H,s),5.58(1H,q,J=1.6 Hz),5.34(1H,d,J=1.7 Hz),4.44(2H,s),2.82(3H,s)。 1-(4-(2,6-Difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridin-2-yl)-3-methylurea (0.104 g, 0.257 mmol), 2-bromoallyl alcohol (0.070 mL, 0.513 mmol), (1,1'-bis(diphenyl) Phosphyl)ferrocene)dichloropalladium(ii) (0.021 g, 0.026 mmol) and 2 M aqueous sodium carbonate (1.283 mL, 2.57 mmol) combined in DMF (3.0 mL) and argon at 90 ° C Heat for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was collected, dried over MgSO 4 The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc EtOAc (EtOAc) 1-(4-(2,6-Difluorophenoxy)-5-(3-hydroxyprop-1-en-2-yl)pyridin-2-yl)-3-methylurea (0.034 g , 0.10 mmol, 40% yield). Mass Spectrum (ESI) m/z = 336.0 (M+H). 1 H NMR (500 MHz, MeOH-d 4 ) δ 8.08 (1H, s), 7.32 - 7.43 (1H, m), 7.19 (2H, t, J = 8.2 Hz), 6.42 (1H, s), 5.58 ( 1H, q, J = 1.6 Hz), 5.34 (1H, d, J = 1.7 Hz), 4.44 (2H, s), 2.82 (3H, s).

實例762Example 762

1-(5-(2-羥基乙基)-4-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(2-hydroxyethyl)-4-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：向100 mL圓底燒瓶中添加含1-(4-氟-5-(2-羥基乙基)吡 啶-2-基)-3-甲基脲(0.50 g，2.3 mmol)、咪唑(0.192 g，2.81 mmol)及TMS-Cl(0.437 g，2.81 mmol)之DMF(13 mL)。在室溫下攪拌反應混合物18小時。將TMS-Cl(0.437 g，2.81 mmol)及咪唑(0.186 ml，2.81 mmol)再添加至反應混合物中且再攪拌18小時。用水稀釋反應物且用EtOAc萃取。收集有機層且經MgSO4乾燥。過濾溶液且在真空中濃縮，得到粗物質。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至50% EtOAc之己烷梯度溶離進行層析來純化，得到呈灰白色固體狀之1-(5-(2-((第三丁基二甲基矽烷基)氧基)乙基)-4-氟吡啶-2-基)-3-甲基脲(0.505 g，1.54 mmol，65.8%產率)。質譜(ESI)m/z=328.1(M+H)。 Step A : To a 100 mL round bottom flask was added 1-(4-fluoro-5-(2-hydroxyethyl)pyridin-2-yl)-3-methylurea (0.50 g, 2.3 mmol), imidazole ( 0.192 g, 2.81 mmol) and TMS-Cl (0.437 g, 2.81 mmol) in DMF (13 mL). The reaction mixture was stirred at room temperature for 18 hours. TMS-Cl (0.437 g, 2.81 mmol) and imidazole (0.186 ml, 2.81 mmol) were then added to the reaction mixture and stirred for additional 18 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was collected and dried over MgSO 4. The solution was filtered and concentrated in vacuo to give a crude material. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc (EtOAc) eluting with EtOAc. 1-(5-(2-((t-butyldimethyl)alkyl)oxy)ethyl)-4-fluoropyridin-2-yl)-3-methylurea (0.505 g, 1.54 mmol , 65.8% yield). Mass Spectrum (ESI) m/z = 328.1 (M+H).

步驟B：向小瓶中添加含1-(5-(2-((第三丁基二甲基矽烷基)氧基)乙基)-4-氟吡啶-2-基)-3-甲基脲(0.050 g，0.15 mmol)、3-羥基-2-甲基吡啶(0.018 g，0.17 mmol)及氟化銫(0.058 g，0.38 mmol)之乙腈(1.5 mL)。在80℃下加熱反應物18小時，接著冷卻至室溫。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之1-(5-(2-羥基乙基)-4-((2-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.020 g，0.066 mmol，43%產率)。質譜(ESI)m/z=303.1(M+H)。1H NMR(500 MHz,MeOH-d4)δ 8.35-8.48(1H,m),8.08(1H,s),7.61(1H,d,J=7.1 Hz),7.43(1H,dd,J=8.1,4.9 Hz),6.23(1H,s),3.85(2H,t,J=6.6 Hz),2.95(2H,t,J=6.6 Hz),2.80(3H,s),2.43(3H,s)。 Step B : Add 1-(5-(2-((t-butyldimethyl)alkyl)oxy)ethyl)-4-fluoropyridin-2-yl)-3-methylurea to the vial (0.050 g, 0.15 mmol), 3-hydroxy-2-methylpyridine (0.018 g, 0.17 mmol) and yttrium fluoride (0.058 g, 0.38 mmol). The reaction was heated at 80 ° C for 18 hours and then cooled to room temperature. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 . 1-(5-(2-hydroxyethyl)-4-((2-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.020 g, white solid) 0.066 mmol, 43% yield). Mass Spectrum (ESI) m/z = 303.1 (M+H). 1 H NMR (500 MHz, MeOH-d 4 ) δ 8.35-8.48 (1H, m), 8.08 (1H, s), 7.61 (1H, d, J = 7.1 Hz), 7.43 (1H, dd, J = 8.1 , 4.9 Hz), 6.23 (1H, s), 3.85 (2H, t, J = 6.6 Hz), 2.95 (2H, t, J = 6.6 Hz), 2.80 (3H, s), 2.43 (3H, s).

遵循實例197中之程序，製備以下化合物： Following the procedure in Example 197, the following compounds were prepared:

遵循實例197中之程序，製備以下化合物： Following the procedure in Example 197, the following compounds were prepared:

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

遵循實例198中之程序，製備以下化合物： Following the procedure in Example 198, the following compounds were prepared:

實例817Example 817

1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-Difluorophenoxy)-5-(1,1-dioxainyltetrahydro-2H-thiopiperazin-4-yl)pyridin-2-yl)-3 -methylurea

步驟A：將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.12 g，0.34 mmol)、2-(3,6-二氫-2H-硫代哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼(0.16 g，0.71 mmol)、肆(三苯基膦)鈀(0)(46 mg，0.04 mmol)及碳酸鉀(0.15 g，1.08 mmol)添加至小瓶中，接著脫氣且用氬氣回填。由注射器向小瓶中添加無水DMF(2 mL)。加熱所得反應物至100℃且用TLC及LC-MS監測。19小時後，冷卻反應物至室溫，接著用水稀釋。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，將矽膠添加至黑色殘餘物中，接著加載於矽 膠管柱上(含0-55%預混合89：9：1二氯甲烷：甲醇：氫氧化銨之二氯甲烷)，得到黑色膜狀物，藉由溶解113 mg於8 mL含0.1% TFA之乙腈中，使用逆相HPLC(含25-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，殘餘物未經進一步純化即使用。質譜(ESI)m/z=378.1(M+H)。 Step A : 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.12 g, 0.34 mmol), 2- (3,6) -dihydro-2H-thiopiperazin-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron (0.16 g, 0.71 mmol), hydrazine (triphenylphosphine) palladium (0) (46 mg, 0.04 mmol) and potassium carbonate (0.15 g, 1.08 mmol) were added to a vial, then degassed and backfilled with argon. Anhydrous DMF (2 mL) was added to the vial from a syringe. The resulting reaction was heated to 100 ° C and was monitored by TLC and LC-MS. After 19 hours, the reaction was cooled to room temperature and then diluted with water. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the tannin was added to the black residue, and then loaded onto a cartridge column (containing 0-55% premixed 89:9:1 dichloromethane: methanol: ammonium hydroxide in dichloromethane). A black membrane was prepared by dissolving 113 mg in 8 mL of acetonitrile containing 0.1% TFA using reverse phase HPLC (25-90% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA)) The membrane was purified. The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous MgSO.sub.4, filtered. Mass Spectrum (ESI) m/z = 378.1 (M+H).

步驟B：向含有1-(4-(2,6-二氟苯氧基)-5-(3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(89.5 mg，0.24 mmol)之小瓶中添加甲醇(2 mL)及水(0.5 mL)。在冰浴中冷卻混合物，接著在約15分鐘後，分數份添加過硫酸氫鉀(306 mg，0.5 mmol)。使反應物升溫至23℃且用TLC及LC-MS監測。1.5小時後，濾出過硫酸氫鉀且用甲醇及二氯甲烷沖洗。在減壓下濃縮濾液，接著在矽膠上(含0-100% 89：9：1二氯甲烷：甲醇：氫氧化銨預混合溶液之二氯甲烷)純化，得到呈棕色膜狀之1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基-3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(13 mg，0.032 mmol，13.49%產率)，其未經進一步純化即使用。質譜(正模式)m/e：410.0(M+H)+。 Step B : To a solution containing 1-(4-(2,6-difluorophenoxy)-5-(3,6-dihydro-2H-thiopiperidin-4-yl)pyridin-2-yl)- Methanol (2 mL) and water (0.5 mL) were added to a vial of 3-methylurea (89.5 mg, 0.24 mmol). The mixture was cooled in an ice bath, and then after about 15 minutes, potassium hydrogen persulfate (306 mg, 0.5 mmol) was added in portions. The reaction was warmed to 23 &lt;0&gt;C and was monitored by TLC and LC-MS. After 1.5 hours, potassium persulfate was filtered off and rinsed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure, and then purified on silica gel (dichloromethane: 0-100%: 89:9:1 dichloromethane:methanol:methanol). 4-(2,6-Difluorophenoxy)-5-(1,1-dioxyindol-3,6-dihydro-2H-thiopiperazin-4-yl)pyridin-2-yl) -3-methylurea (13 mg, 0.032 mmol, 13.49% yield) was used without further purification. Mass spectrum (positive mode) m/e: 410.0 (M+H) + .

步驟C：向含有1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基-3,6-二氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(13 mg，0.032 mmol)於乙醇(2 mL)及乙酸乙酯(2 mL)中之燒瓶中添加10%鈀/活性碳(38 mg，0.035 mmol)。將燒瓶抽真空並用氮氣回填，且在23℃下攪拌。約5分鐘後，用氫氣置換氮氣。用TLC及LC-MS監測反應。17小時後，經矽藻土栓塞過濾反應混合物且在真空中濃縮，得到無色殘餘物，藉由溶解於3 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))純化該殘餘物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉 水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為1-(4-(2,6-二氟苯氧基)-5-(1,1-二氧離子基四氫-2H-硫代哌喃-4-基)吡啶-2-基)-3-甲基脲(2 mg，3.65 μmol，11.39%產率)。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 7.90(1H,br.s.),7.31-7.42(1H,m),7.15(2H,t,J=8.2 Hz),6.74(1H,br.s.),3.12-3.31(5H,m),2.78(3H,d,J=4.6 Hz),2.33-2.50(4H,m)。質譜(ESI)m/z=412.1(M+H) Step C : To a solution containing 1-(4-(2,6-difluorophenoxy)-5-(1,1-dioxyindol-3,6-dihydro-2H-thiopipene-4- Add 10% palladium/activated carbon (38 mg, in a flask of ethanol (2 mL) and ethyl acetate (2 mL) in pyridine-2-yl)-3-methylurea (13 mg, 0.032 mmol) 0.035 mmol). The flask was evacuated and backfilled with nitrogen and stirred at 23 °C. After about 5 minutes, the nitrogen was replaced with hydrogen. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction mixture was filtered with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtration and concentration, the white solid was identified as 1-(4-(2,6-difluorophenoxy)-5-(1,1-dioxy-ionic tetrahydro-2H-sulfur Depipepan-4-yl)pyridin-2-yl)-3-methylurea (2 mg, 3.65 μmol, 11.39% yield). 1 H NMR (500 MHz, dichloromethane-d 2 ) δ ppm 7.90 (1H, br. s.), 7.31-7.42 (1H, m), 7.15 (2H, t, J = 8.2 Hz), 6.74 (1H) , br.s.), 3.12-3.31 (5H , m), 2.78 (3H, d, J = 4.6 Hz), 2.33-2.50 (4H, m). Mass Spectrum (ESI) m/z = 412.1 (M+H)

實例818Example 818

N-(4'-(2,6-二氟苯氧基)-6'-(3-甲基脲基)-[3,3'-聯吡啶]-5-基)甲烷磺醯胺 N-(4'-(2,6-Difluorophenoxy)-6'-(3-methylureido)-[3,3'-bipyridyl]-5-yl)methanesulfonamide

步驟A：在乾燥圓底燒瓶中，將5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-胺(0.10 g，0.47 mmol)溶解於無水二氯甲烷(2 mL)及吡啶(0.12 mL，1.47 mmol)中。向此混合物中逐滴添加甲烷磺醯氯(0.056 mL，0.72 mmol)。在23℃下攪拌反應物且用TLC及LC-MS監測。20小時後，在減壓下濃縮反應物，得到呈黃色油狀之5-(甲基磺醯胺基)吡啶-3-基酸，其未經純化即使用。質譜(正模式)m/e：217.1(M+H)+。 Step A : 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in a dry round bottom flask Benzyl-3-pyridin-3-amine (0.10 g, 0.47 mmol) was dissolved in dichloromethane (2 mL) Methanesulfonium chloride (0.056 mL, 0.72 mmol) was added dropwise to this mixture. The reaction was stirred at 23 ° C and was monitored by TLC and LC-MS. After 20 hours, the reaction was concentrated under reduced pressure to give 5-(methylsulfonamido)pyridin-3-yl as a yellow oil. Acid, which is used without purification. Mass spectrum (positive mode) m/e: 217.1 (M+H) + .

步驟B：將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.10 g，0.29 mmol)、(5-(甲基磺醯胺基)吡啶-3-基)酸(0.14 g，0.65 mmol)、三環己基膦(17 mg，0.059 mmol)及參(二亞苄基丙酮)二鈀(0)(28 mg，0.03 mmol)添加至小瓶中，接著脫氣且用氬氣回填。由注射 器向小瓶中添加1,4-二噁烷(2 mL)及1.3 M磷酸三鉀水溶液(0.56 mL，0.73 mmol)。加熱所得反應物至90℃且用TLC及LC-MS監測。18小時後，冷卻反應物至室溫，接著在減壓下濃縮。經0.45 μm GHP Acrodisc過濾殘餘物，接著加載於矽膠上(含0-100%乙酸乙酯之二氯甲烷，繼之以含30%甲醇之二氯甲烷等濃度沖提)，得到膜狀物，藉由溶解於2.4 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為N-(4'-(2,6-二氟苯氧基)-6'-(3-甲基脲基)-[3,3'-聯吡啶]-5-基)甲烷磺醯胺(16 mg，0.037 mmol，12.73%產率)。1H NMR(400 MHz,DMSO-d6)δ ppm 10.16(1H,s),9.28(1H,s),8.47-8.55(1H,m),8.41(1H,d,J=2.2 Hz),8.29(1H,s),7.81-7.88(1H,m),7.34-7.54(4H,m),7.07(1H,s),3.07(3H,s),2.60-2.69(3H,m)。質譜(ESI)m/z=450.1(M+H)。 Step B : 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.10 g, 0.29 mmol), (5-(methyl) Sulfonylamino)pyridin-3-yl) Acid (0.14 g, 0.65 mmol), tricyclohexylphosphine (17 mg, 0.059 mmol) and bis(dibenzylideneacetone) dipalladium (0) (28 mg, 0.03 mmol) were added to the vial, followed by degassing and Backfill with argon. To the vial was added 1,4-dioxane (2 mL) and a 1.3 M aqueous solution of tri-potassium phosphate (0.56 mL, 0.73 mmol) from a syringe. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After 18 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. The residue was filtered through 0.45 μm of GHP Acrodisc, and then loaded onto silica gel (dichloromethane containing 0-100% ethyl acetate, followed by a concentration of dichloromethane containing 30% methanol) to give a film. The membrane was further purified by dissolving in 2.4 mL of DMF using reverse phase HPLC (10-90% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as N-(4'-(2,6-difluorophenoxy)-6'-(3-methylureido)-[3,3 '-Bipyridyl]-5-yl)methanesulfonamide (16 mg, 0.037 mmol, 12.73% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.16 (1H, s), 9.28 (1H, s), 8.47-8.55 (1H, m), 8.41 (1H, d, J = 2.2 Hz), 8.29 (1H, s), 7.81-7.88 (1H, m), 7.34-7.54 (4H, m), 7.07 (1H, s), 3.07 (3H, s), 2.60-2.69 (3H, m). Mass Spectrum (ESI) m/z = 450.1 (M+H).

實例819Example 819

N-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-基)甲烷磺醯胺 N-(4-(2,6-Difluorophenoxy)-6-(3-methylureido)-[3,4'-bipyridyl]-2'-yl)methanesulfonamide

步驟A：將含有4-溴吡啶-2-胺(0.50 g，2.9 mmol)於無水吡啶(6 mL)中之乾燥小瓶在冰浴中冷卻至0℃。15分鐘後，小心逐滴添加甲烷磺醯氯(0.46 mL，5.95 mmol)。使反應物升溫至23℃且用TLC及LC-MS監測。0.5小時後，用乙酸乙酯稀釋反應物，接著用飽和碳酸氫鈉 水溶液洗滌一次且用鹽水洗滌一次。經無水硫酸鈉乾燥，過濾並濃縮後，用異丙醇處理微黃色固體，接著在非真空下於旋轉蒸發器上加熱至50℃。30分鐘後，趁熱過濾固體，接著用異丙醇洗滌一次，得到呈淡黃色固體狀之N-(4-溴吡啶-2-基)甲烷磺醯胺(347 mg，1.38 mmol，47.4%產率)，其未經進一步純化即使用。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 8.13(1H,d,J=5.7 Hz),7.51(1H,d,J=1.2 Hz),7.18(1H,dd,J=5.7,1.8 Hz),3.16(3H,s)。 Step A : A dry vial containing 4-bromopyridin-2-amine (0.50 g, 2.9 mmol) in dry EtOAc (6 mL) was cooled to EtOAc. After 15 minutes, methanesulfonium chloride (0.46 mL, 5.95 mmol) was carefully added dropwise. The reaction was warmed to 23 &lt;0&gt;C and was monitored by TLC and LC-MS. After 0.5 hours, the reaction was diluted with EtOAc then EtOAc (EtOAc)EtOAc. After drying over anhydrous sodium sulphate, filtered and concentrated, a slightly yellow solid was taken with isopropyl alcohol and then warmed to 50 &lt;0&gt;C on a rotary evaporator under vacuum. After 30 minutes, the solid was filtered with EtOAc (EtOAc) (EtOAc) Rate), which was used without further purification. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ δ 8.13 (1H, d, J = 5.7 Hz), 7.51 (1H, d, J = 1.2 Hz), 7.18 (1H, dd, J = 5.7, 1.8 Hz), 3.16 (3H, s).

步驟B：將N-(4-溴吡啶-2-基)甲烷磺醯胺(347 mg，1.38 mmol)、雙(頻哪醇根基)二硼(429 mg，1.69 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(116 mg，0.14 mmol)及乙酸鉀(432 g，4.4 mmol)於無水1,4-二噁烷(7 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。48小時後，冷卻反應物至室溫，接著經矽藻土過濾。在減壓下移除有機溶劑，且將殘餘物鑑別為(2-(甲基磺醯胺基)吡啶-4-基)酸，其未經純化即使用。質譜(正模式)m/e：217.0(M+H)+。 Step B : N-(4-bromopyridin-2-yl)methanesulfonamide (347 mg, 1.38 mmol), bis(pinadol) diboron (429 mg, 1.69 mmol), [1, 1- a complex of bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (116 mg, 0.14 mmol) and potassium acetate (432 g, 4.4 mmol) in anhydrous 1,4-dioxin The stirred mixture in aq. (7 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 48 hours, the reaction was cooled to room temperature then filtered over EtOAc. The organic solvent was removed under reduced pressure and the residue was identified as (2-(methylsulfonamido)pyridin-4-yl) Acid, which is used without purification. Mass spectrum (positive mode) m/e: 217.0 (M+H) + .

步驟C：將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(137 mg，0.38 mmol)、(2-(甲基磺醯胺基)吡啶-4-基)酸(168 mg，0.78 mmol)、三環己基膦(22 mg，0.08 mmol)及參(二亞苄基丙酮)二鈀(0)(36 mg，0.04 mmol)添加至小瓶中，接著脫氣且用氬氣回填。由注射器向小瓶中添加1,4-二噁烷(2 mL)及1.3 M磷酸三鉀水溶液(0.74 mL，0.96 mmol)。加熱所得反應物至90℃且用TLC及LC-MS監測。18小時後，冷卻反應物至室溫，接著在減壓下濃縮。經0.45 μm GHP Acrodisc過濾殘餘物，接著加載於矽膠上(含0-100%乙酸乙酯之二氯甲烷，繼之以含30%甲醇之二氯甲烷等濃度沖提)，得到棕色膜狀物，藉由溶解於5 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產 物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為N-(4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-基)甲烷磺醯胺(2 mg，5.12 μmol，1.340%產率)。1H NMR(500 MHz,MeOH)δ ppm 8.29(1H,s),8.19(1H,d,J=5.6 Hz),7.39(1H,tt,J=8.6,6.0 Hz),7.12-7.28(4H,m),6.58(1H,s),3.18(3H,s),2.83(3H,s)。質譜(ESI)m/z=450.1(M+H)。 Step C : 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (137 mg, 0.38 mmol), (2-(methyl) Sulfonyl)pyridin-4-yl) Acid (168 mg, 0.78 mmol), tricyclohexylphosphine (22 mg, 0.08 mmol) and bis(dibenzylideneacetone) dipalladium (0) (36 mg, 0.04 mmol) were added to the vial, followed by degassing and Backfill with argon. To the vial was added 1,4-dioxane (2 mL) and a 1.3 M aqueous solution of tri-potassium phosphate (0.74 mL, 0.96 mmol) from a syringe. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After 18 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. The residue was filtered through 0.45 μm of GHP Acrodisc, then loaded onto silica gel (dichloromethane containing 0-100% ethyl acetate, followed by a concentration of dichloromethane containing 30% methanol) to give a brown film. The membrane was further purified by reverse phase HPLC (water containing 10-90% acetonitrile (premixed with 0.1% TFA) (containing 0.1% TFA)) by dissolving in 5 mL DMF. The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as N-(4-(2,6-difluorophenoxy)-6-(3-methylureido)-[3,4'- Bipyridyl]-2'-yl)methanesulfonamide (2 mg, 5.12 μmol, 1.340% yield). 1 H NMR (500 MHz, MeOH) δ ppm 8.29 (1H, s), 8.19 (1H, d, J = 5.6 Hz), 7.39 (1H, tt, J = 8.6, 6.0 Hz), 7.12-7.28 (4H, m), 6.58 (1H, s), 3.18 (3H, s), 2.83 (3H, s). Mass Spectrum (ESI) m/z = 450.1 (M+H).

遵循實例817-819中之程序，製備以下化合物： Following the procedure in Example 817-819, the following compounds were prepared:

製備preparation

步驟A：向5-氯吡啶-2-醇(10 g，77.5 mmol)於DMF(250 mL)中之溶液中依序添加Cs2CO3(38 g，116 mmol)、氯二氟乙酸鈉(14.1 g，93 mmol)，且加熱反應混合物至100℃，維持3小時。冷卻反應混合物至室溫，添加水(300 mL)且用乙醚(500 mL×2)萃取。經硫酸鈉乾燥有機部分，過濾且濃縮，獲得粗物質，藉由使用矽膠(100-200目)及含0-5%乙酸乙酯之己烷進行管柱層析進一步純化該粗物質，得到呈無色油狀之5-氯-2-(二氟甲氧基)吡啶。1H NMR(DMSO-d6,400 MHz)δ 8.361(d,J=2.8Hz,1H),8.07-8.4(m,1H),7.672(t,1H),7.177(d,J=8.8 Hz,1H)。 Step A : Add Cs 2 CO 3 (38 g, 116 mmol), sodium chlorodifluoroacetate (s) to a solution of 5-chloropyridin-2-ol (10 g, 77.5 mmol) in DMF (250 mL). 14.1 g, 93 mmol), and the reaction mixture was heated to 100 ° C for 3 h. The reaction mixture was cooled to room temperature, water (300 mL) was evaporated. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using EtOAc (100-200 mesh) 5-Chloro-2-(difluoromethoxy)pyridine as a colorless oil. 1 H NMR (DMSO-d 6, 400 MHz) δ 8.361 (d, J = 2.8 Hz, 1H), 8.07-8.4 (m, 1H), 7.672 (t, 1H), 7.177 (d, J = 8.8 Hz, 1H).

步驟B：將5-氯-2-(二氟甲氧基)吡啶(0.13 g，0.75 mmol)、雙(頻哪醇根基)二硼(0.21 g，0.83 mmol)、[1,1-雙(二苯基膦基)二茂鐵]氯化鈀(II)與二氯甲烷之複合物(62 mg，0.076 mmol)及乙酸鉀(0.23 g，2.30 mmol)於無水1,4-二噁烷(4 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經矽藻土過濾。在減壓下移除有機溶劑，且將黑色殘餘物鑑別為(6-(二氟甲氧基)吡啶-3-基)酸，其未經純化即使用。 Step B : 5-Chloro-2-(difluoromethoxy)pyridine (0.13 g, 0.75 mmol), bis(pinadol) diboron (0.21 g, 0.83 mmol), [1, 1- a complex of diphenylphosphino)ferrocene]palladium(II) chloride with methylene chloride (62 mg, 0.076 mmol) and potassium acetate (0.23 g, 2.30 mmol) in anhydrous 1,4-dioxane ( The stirred mixture in 4 mL) was purged three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature then filtered over EtOAc. The organic solvent was removed under reduced pressure and the black residue was identified as (6-(difluoromethoxy)pyridin-3-yl) Acid, which is used without purification.

製備preparation

步驟A：向含有1-(5-溴吡啶-2-基)乙酮(240 mg，1.2 mmol)之乾燥圓底燒瓶中添加無水二氯甲烷(2 mL)與無水甲醇(2 mL)之預混合溶液。在0℃下攪拌約15分鐘後，在0℃下小心添加硼氫化鈉(101 mg，2.66 mmol)。添加完成後，使反應物升溫至23℃。1.5小時後，在冰浴中冷卻反應物，接著用水小心淬滅，且用二氯甲烷萃取三次。經無水硫酸鎂乾燥並過濾後，在減壓下移除有機溶劑。將無色殘餘物鑑別為1-(5-溴吡啶-2-基)乙醇(193.4 mg，0.96 mmol，80%產率)，其未經純化即使用。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 8.59(1H,d,J=2.0 Hz),7.83(1H,dd,J=8.4,2.3 Hz),7.24(1H,d,J=8.2 Hz),4.83(1H,q,J=6.5 Hz),3.64(1H,br.s.),1.45(3H,d,J=6.5 Hz)。 Step A : To a dry round bottom flask containing 1-(5-bromopyridin-2-yl)ethanone (240 mg, 1.2 mmol) was added anhydrous dichloromethane (2 mL) and anhydrous methanol (2 mL) mixture. After stirring at 0 °C for about 15 minutes, sodium borohydride (101 mg, 2.66 mmol) was carefully added at 0 °C. After the addition was complete, the reaction was allowed to warm to 23 °C. After 1.5 hours, the reaction was cooled in an ice-br. EtOAc. After drying over anhydrous magnesium sulfate and filtration, the organic solvent was removed under reduced pressure. The colorless residue was identified as 1-(5-bromopyridin-2-yl)ethanol (193.4 mg, 0.96 mmol, 80% yield) which was used without purification. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ δ 8.59 (1H, d, J = 2.0 Hz), 7.83 (1H, dd, J = 8.4, 2.3 Hz), 7.24 (1H, d, J = 8.2 Hz), 4.83 (1H, q, J = 6.5 Hz), 3.64 (1H, br.s.), 1.45 (3H, d, J = 6.5 Hz).

步驟B：將1-(5-溴吡啶-2-基)乙醇(193 mg，0.96 mmol)、雙(頻哪醇根基)二硼(368 mg，1.45 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(238 mg，0.29 mmol)及乙酸鉀(289 mg，2.94 mmol)於無水1,4-二噁烷(4 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。18小時後，冷卻反應物至室溫，接著鑑別為1-(5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)乙醇，其未經純化即使用。質譜(正模式)m/e：168.1(M+H)+。(酸之MS) Step B : 1-(5-Bromopyridin-2-yl)ethanol (193 mg, 0.96 mmol), bis(pinacolyl)diboron (368 mg, 1.45 mmol), [1,1-di(di) a complex of phenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (238 mg, 0.29 mmol) and potassium acetate (289 mg, 2.94 mmol) in anhydrous 1,4-dioxane (4 The stirred mixture in mL) was purged three times with argon and placed under vacuum three times. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 18 hours, the reaction was cooled to room temperature and then identified as 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)pyridin-2-yl)ethanol, which was used without purification. Mass spectrum (positive mode) m/e: 168.1 (M+H) + . ( Acid MS)

製備preparation

步驟A：將2-[(5-溴-2-吡啶基)氧基]-乙醇(306 mg，1.40 mmol)、雙(頻哪醇根基)二硼(536 mg，2.11 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(347 mg，0.42 mmol)及乙酸鉀(492 mg，5.01 mmol)於無水1,4-二噁烷(7 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。18小時後，冷卻反應物至室溫，接著鑑別為2-((5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)氧基)乙醇，其未經純化即使用。質譜(正模式)m/e：266.2(M+H)+。 Step A : 2-[(5-Bromo-2-pyridyl)oxy]-ethanol (306 mg, 1.40 mmol), bis (pinadol) diboron (536 mg, 2.11 mmol), [1, a complex of 1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (347 mg, 0.42 mmol) and potassium acetate (492 mg, 5.01 mmol) in anhydrous 1,4- The stirred mixture in dioxane (7 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 18 hours, the reaction was cooled to room temperature and then identified as 2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)pyridin-2-yl)oxy)ethanol, which was used without purification. Mass spectrum (positive mode) m/e: 266.2 (M+H) + .

製備preparation

步驟A：將含有4-溴吡啶-2-甲酸(405 mg，2.01 mmol)及HATU(1.53 g，4.02 mmol)之乾燥小瓶抽真空且用氬氣回填三次。在氬氣保護下，由注射器各別地依序添加無水DMF(10 mL)、二異丙基乙胺(1.4 mL，8.05 mmol)。在23℃下於氬氣下攪拌混合物。30分鐘後，由注射器逐滴添加2-甲氧基乙胺(0.27 mL，3.11 mmol)。添加完成後，在23℃下攪拌反應物且用TLC及LC-MS監測。17小時後，用水稀釋反應物，接著用二氯甲烷萃取三次。彙集有機物，接著用飽和氯化銨水溶液洗滌三次，用飽和碳酸氫鈉水溶液洗滌三次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，在矽膠上(含0-25%乙酸乙酯之二氯甲烷)純化殘餘物，得到呈黃色油狀之4-溴-N-(2-甲氧基乙基)吡啶醯胺(375.6 mg，1.450 mmol，72.2%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.38(1H,d,J=5.1 Hz),8.33(1H,d,J=2.0 Hz),8.05-8.26(1H,m),7.62(1H,dd,J=5.1,2.0 Hz), 3.58-3.64(2H,m),3.51-3.57(2H,m),3.37(3H,s)。 Step A : A dry vial containing 4-bromopyridine-2-carboxylic acid (405 mg, 2.01 mmol) and HATU (1.53 g, 4.02 mmol. Anhydrous DMF (10 mL) and diisopropylethylamine (1.4 mL, 8.05 mmol) were added sequentially from a syringe under argon. The mixture was stirred under argon at 23 °C. After 30 minutes, 2-methoxyethylamine (0.27 mL, 3.11 mmol) was added dropwise from a syringe. After the addition was complete, the reaction was stirred at <RTI ID=0.0></RTI><RTIgt; After 17 hours, the reaction was diluted with water and then extracted three times with dichloromethane. The organics were combined, washed three times with saturated aqueous ammonium chloride solution, three times with saturated aqueous sodium hydrogen carbonate and brine. After drying over anhydrous magnesium sulfate, EtOAc (EtOAc m.) Ethyl pyridinamine (375.6 mg, 1.450 mmol, 72.2% yield) was used without further purification. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ ppm 8.38 (1H, d, J = 5.1 Hz), 8.33 (1H, d, J = 2.0 Hz), 8.05-8.26 (1H, m), 7.62 (1H, dd, J = 5.1, 2.0 Hz), 3.58-3.64 (2H, m), 3.51-3.57 (2H, m), 3.37 (3H, s).

步驟B：將4-溴-N-(2-甲氧基乙基)吡啶醯胺(376 mg，1.45 mmol)、雙(頻哪醇根基)二硼(554 mg，2.18 mmol)、[1,1-雙(二苯基膦基)二茂鐵]氯化鈀(II)與二氯甲烷之複合物(360 mg，0.44 mmol)及乙酸鉀(500 mg，5.09 mmol)於無水1,4-二噁烷(7 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。18小時後，冷卻反應物至室溫，接著推測性地鑑別為N-(2-甲氧基乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶醯胺，其未經純化即使用。質譜(正模式)m/e：225.1(M+H)+。 Step B : 4-Bromo-N-(2-methoxyethyl)pyridiniumamine (376 mg, 1.45 mmol), bis(pinacolyl)diboron (554 mg, 2.18 mmol), [1, a complex of 1-bis(diphenylphosphino)ferrocene]palladium(II) chloride with methylene chloride (360 mg, 0.44 mmol) and potassium acetate (500 mg, 5.09 mmol) in anhydrous 1,4- The stirred mixture in dioxane (7 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 18 hours, the reaction was cooled to room temperature and then speculatively identified as N-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxon 2-yl)pyridiniumamine, which was used without purification. Mass spectrum (positive mode) m/e: 225.1 (M+H) + .

製備preparation

步驟A：將4-碘-N-甲基吡啶醯胺(112 mg，0.43 mmol)、雙(頻哪醇根基)二硼(167 mg，0.66 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(106 mg，0.13 mmol)及乙酸鉀(129 mg，1.31 mmol)於無水1,4-二噁烷(4 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。18小時後，冷卻反應物至室溫，接著推測性地鑑別為N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶醯胺。質譜(正模式)m/e：181.0(M+H)+。 Step A : 4-iodo-N-methylpyridiniumamine (112 mg, 0.43 mmol), bis(pinacolyl)diboron (167 mg, 0.66 mmol), [1,1-bis(diphenyl) a complex of phosphino)ferrocene]dichloropalladium(II) with methylene chloride (106 mg, 0.13 mmol) and potassium acetate (129 mg, 1.31 mmol) in anhydrous 1,4-dioxane (4 mL) The stirred mixture was purged three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 18 hours, the reaction was cooled to room temperature and then speculatively identified as N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron. 2-yl)pyridiniumamine. Mass spectrum (positive mode) m/e: 181.0 (M+H) + .

製備preparation

步驟A：在冰水浴中冷卻含有2-[(5-溴-2-吡啶基)氧基]-乙醇(320 mg，1.47 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，將60%氫化鈉於礦物油中之分散液(176 mg，4.41 mmol)分數份添加至冷反應溶液中。1小時後，在0℃下由注射器逐滴添加碘甲烷(0.19 mL，3.06 mmol)。碘甲烷添加完成後，使混合物升溫至23℃且用TLC及LC-MS監測。17小時後，加熱反應物至85℃且用TLC及LC-MS監測。5天後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-15%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之5-溴-2-(2-甲氧基乙氧基)吡啶(226 mg，0.97 mmol，66.3%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.17(1H,d,J=2.4 Hz),7.66(1H,dd,J=8.8,2.7 Hz),6.69(1H,d,J=8.8 Hz),4.34-4.43(2H,m),3.65-3.72(2H,m),3.38(3H,s)。 Step A : A dry vial containing 2-[(5-bromo-2-pyridinyl)oxy]-ethanol (320 mg, 1.47 mmol) in anhydrous cyclopentylmethyl ether (10 mL) was cooled in ice water. . After 20 minutes, a 60% dispersion of sodium hydride in mineral oil (176 mg, 4.41 mmol) was added to the cold reaction solution. After 1 hour, methyl iodide (0.19 mL, 3.06 mmol) was added dropwise from a syringe at 0 °C. After the addition of methyl iodide was completed, the mixture was allowed to warm to 23 ° C and was monitored by TLC and LC-MS. After 17 hours, the reaction was heated to 85 ° C and was monitored by TLC and LC-MS. After 5 days, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified eluted eluted elute (226 mg, 0.97 mmol, 66.3% yield) which was used without further purification. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ δ 8.17 (1H, d, J = 2.4 Hz), 7.66 (1H, dd, J = 8.8, 2.7 Hz), 6.69 (1H, d, J = 8.8 Hz), 4.34 - 4.43 (2H, m), 3.65 - 3.72 (2H, m), 3.38 (3H, s).

步驟B：將5-溴-2-(2-甲氧基乙氧基)吡啶(226 mg，0.97 mmol)、雙(頻哪醇根基)二硼(372 mg，1.46 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(241 mg，0.30 mmol)及乙酸鉀(289 mg，2.94 mmol)於無水1,4-二噁烷(5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。18小時後，冷卻反應物至室溫，接著鑑別為2-(2-甲氧基乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶，其未經純化即使用。質譜(正模式)m/e：280.1(M+H)+。 Step B : 5-Bromo-2-(2-methoxyethoxy)pyridine (226 mg, 0.97 mmol), bis(pinacolyl)diboron (372 mg, 1.46 mmol), [1,1 - a complex of bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (241 mg, 0.30 mmol) and potassium acetate (289 mg, 2.94 mmol) in anhydrous 1,4-di The stirred mixture in oxane (5 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 18 hours, the reaction was cooled to room temperature and then identified as 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-diox. boron 2-yl)pyridine, which was used without purification. Mass spectrum (positive mode) m/e: 280.1 (M+H) + .

製備preparation

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(240 mg，6.01 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將3-甲氧基-1-丙醇(0.38 mL，3.97 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.94 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-15%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之5-溴-2-(3-甲氧基丙氧基)吡啶(439 mg，1.78 mmol，92%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.17(1H,d,J=2.4 Hz),7.65(1H,dd,J=8.8,2.4 Hz),6.62-6.68(1H,m),4.32(2H,t,J=6.5 Hz),3.49(2H,t,J=6.2 Hz),3.31(3H,s),1.99(2H，五重峰，J=6.4 Hz)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (240 mg, 6.01 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice-water bath. After 20 minutes, 3-methoxy-1-propanol (0.38 mL, 3.97 mmol) was added dropwise to the cold reaction solution by syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.94 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified mjjjjjjjjj (439 mg, 1.78 mmol, 92% yield) which was used without further purification. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ ppm 8.17 (1H, d, J = 2.4 Hz), 7.65 (1H, dd, J = 8.8, 2.4 Hz), 6.62-6.68 (1H, m) , 4.32 (2H, t, J = 6.5 Hz), 3.49 (2H, t, J = 6.2 Hz), 3.31 (3H, s), 1.99 (2H, quintuple, J = 6.4 Hz).

步驟B：將5-溴-2-(3-甲氧基丙氧基)吡啶(257 mg，1.04 mmol)、雙(頻哪醇根基)二硼(400 mg，1.58 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(257 mg，0.31 mmol)及乙酸鉀(308 mg，3.14 mmol)於無水1,4-二噁烷(5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著鑑別為2-(3-甲氧基丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶，其未經純化即使用。質譜(正模式)m/e：294.1(M+H)+。 Step B : 5-Bromo-2-(3-methoxypropoxy)pyridine (257 mg, 1.04 mmol), bis(pinacolyl)diboron (400 mg, 1.58 mmol), [1,1 - a complex of bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (257 mg, 0.31 mmol) and potassium acetate (308 mg, 3.14 mmol) in anhydrous 1,4-di The stirred mixture in oxane (5 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified as 2-(3-methoxypropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-diox. boron 2-yl)pyridine, which was used without purification. Mass spectrum (positive mode) m/e: 294.1 (M+H) + .

製備preparation

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液 (212 mg，5.30 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將1-甲氧基-2-丙醇(0.35 mL，3.57 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.74 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-10%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之5-溴-2-((1-甲氧基丙-2-基)氧基)吡啶(334 mg，1.36 mmol，78%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.16(1H,d,J=2.4 Hz),7.65(1H,dd,J=8.7,2.6 Hz),6.64(1H,d,J=8.8 Hz),5.28-5.35(1H,m),3.54(1H,dd,J=10.4,6.0 Hz),3.47(1H,dd,J=10.5,4.2 Hz),3.35(3H,s),1.28(3H,d,J=6.4 Hz)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (212 mg, 5.30 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice-water bath. After 20 minutes, 1-methoxy-2-propanol (0.35 mL, 3.57 mmol) was added dropwise to a cold reaction solution by a syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.74 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified mjjjjjjjjjj (Alkyloxy)pyridine (334 mg, 1.36 mmol, 78% yield) was used without further purification. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ ppm 8.16 (1H, d, J = 2.4 Hz), 7.65 (1H, dd, J = 8.7, 2.6 Hz), 6.64 (1H, d, J = 8.8 Hz), 5.28-5.35 (1H, m), 3.54 (1H, dd, J = 10.4, 6.0 Hz), 3.47 (1H, dd, J = 10.5, 4.2 Hz), 3.35 (3H, s), 1.28 ( 3H,d, J =6.4 Hz).

步驟B：將5-溴-2-((1-甲氧基丙-2-基)氧基)吡啶(265 mg，1.08 mmol)、雙(頻哪醇根基)二硼(411 mg，1.62 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(265 mg，0.32 mmol)及乙酸鉀(323 mg，3.29 mmol)於無水1,4-二噁烷(6 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著鑑別為2-((1-甲氧基丙-2-基)氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶，其未經純化即使用。質譜(正模式)m/e：294.1(M+H)+。 Step B : 5-Bromo-2-((1-methoxypropan-2-yl)oxy)pyridine (265 mg, 1.08 mmol), bis (pinadol) diboron (411 mg, 1.62 mmol) , a complex of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (265 mg, 0.32 mmol) and potassium acetate (323 mg, 3.29 mmol) The stirred mixture in anhydrous 1,4-dioxane (6 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to 2-((1-methoxypropan-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaboron 2-yl)pyridine, which was used without purification. Mass spectrum (positive mode) m/e: 294.1 (M+H) + .

製備preparation

步驟A：將含有4-溴吡啶甲酸(401 mg，1.99 mmol)及HATU(1.52 g，3.98 mmol)之乾燥小瓶抽真空且用氬氣回填三次。在氬氣保護下，由注射器各別地依序添加無水DMF(10 mL)、二異丙基乙胺(1.4 ml，8.05 mmol)。在23℃下於氬氣下攪拌混合物。30分鐘後，分數份添加2-(甲基磺醯基)乙胺鹽酸鹽(250 mg，1.57 mmol)。添加完成後，在23℃下攪拌反應物且用TLC及LC-MS監測。17小時後，用水稀釋反應物，接著用乙酸乙酯萃取三次。彙集有機物，接著用飽和碳酸氫鈉水溶液洗滌三次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，在矽膠上(含30-90%乙酸乙酯之己烷)純化殘餘物，得到呈灰白色固體狀之4-溴-N-(2-(甲基磺醯基)乙基)吡啶醯胺(349 mg，1.14 mmol，57.2%產率)，其未經進一步純化即使用。1H NMR(500 MHz,DMSO-d6)δ ppm 9.08(1H,t,J=5.9 Hz),8.55(1H,d,J=5.4 Hz),8.18(1H,d,J=2.0 Hz),7.92(1H,dd,J=5.1,2.0 Hz),3.74(2H,q,J=6.6 Hz),3.40(2H,t,J=6.8 Hz),3.03(3H,s)。 Step A : A dry vial containing 4-bromopicolinic acid (401 mg, 1.99 mmol) and HATU (1.52 g, 3.98 mmol) was vacuumed and backfilled three times with argon. Anhydrous DMF (10 mL) and diisopropylethylamine (1.4 ml, 8.05 mmol) were added sequentially from a syringe under argon. The mixture was stirred under argon at 23 °C. After 30 minutes, 2-(methylsulfonyl)ethylamine hydrochloride (250 mg, 1.57 mmol) was added in portions. After the addition was complete, the reaction was stirred at <RTI ID=0.0></RTI><RTIgt; After 17 hours, the reaction was diluted with water and then extracted three times with ethyl acetate. The organics were combined, washed three times with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, EtOAc (EtOAc m.) Methyl)ethyl)pyridiniumamine (349 mg, 1.14 mmol, 57.2% yield) was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.08 (1H, t, J = 5.9 Hz), 8.55 (1H, d, J = 5.4 Hz), 8.18 (1H, d, J = 2.0 Hz), 7.92 (1H, dd, J = 5.1, 2.0 Hz), 3.74 (2H, q, J = 6.6 Hz), 3.40 (2H, t, J = 6.8 Hz), 3.03 (3H, s).

步驟B：將4-溴-N-(2-(甲基磺醯基)乙基)吡啶醯胺(349 mg，1.14 mmol)、雙(頻哪醇根基)二硼(437 mg，1.72 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(280 mg，0.34 mmol)及乙酸鉀(337 mg，3.43 mmol)於無水1,4-二噁烷(7 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著鑑別為N-(2-(甲基磺醯基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶醯胺，其未經純化即使用。質譜(正模式)m/e：294.1(M+H)+。LC-MS對應於(2-((2-(甲基磺醯基)乙基)胺甲醯基)吡啶-4-基)酸。 Step B : 4-Bromo-N-(2-(methylsulfonyl)ethyl)pyridiniumamine (349 mg, 1.14 mmol), bis(pinacolyl)diboron (437 mg, 1.72 mmol) , a complex of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (280 mg, 0.34 mmol) and potassium acetate (337 mg, 3.43 mmol) in anhydrous The stirred mixture in 1,4-dioxane (7 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified as N-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2 -BO 2-yl)pyridiniumamine, which was used without purification. Mass spectrum (positive mode) m/e: 294.1 (M+H) + . LC-MS corresponds to (2-((2-(methylsulfonyl)ethyl))aminomethyl)pyridin-4-yl) acid.

製備preparation

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(217 mg，5.42 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將(S)-(+)-2-甲氧基丙醇(0.34 mL，3.54 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.74 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-10%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之(S)-5-溴-2-(2-甲氧基丙氧基)吡啶(393 mg，1.60 mmol，92%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.17(1H,d,J=2.7 Hz),7.66(1H,dd,J=8.8,2.7 Hz),6.69(1H,d,J=8.8 Hz),4.17-4.28(2H,m),3.67(1H，五重峰，J=6.2,6.2,6.2,6.2,4.4 Hz),3.37(3H,s),1.20(3H,d,J=6.4 Hz)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (217 mg, 5.42 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice-water bath. After 20 minutes, (S)-(+)-2-methoxypropanol (0.34 mL, 3.54 mmol) was added dropwise to a cold reaction solution by a syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.74 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified mjjjjjjjjjj Oxy)pyridine (393 mg, 1.60 mmol, 92% yield) was used without further purification. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ δ 8.17 (1H, d, J = 2.7 Hz), 7.66 (1H, dd, J = 8.8, 2.7 Hz), 6.69 (1H, d, J = 8.8 Hz), 4.17-4.28 (2H, m), 3.67 (1H, quintuple, J = 6.2, 6.2, 6.2, 6.2, 4.4 Hz), 3.37 (3H, s), 1.20 (3H, d, J = 6.4 Hz).

步驟B：將(S)-5-溴-2-(2-甲氧基丙氧基)吡啶(264 mg，1.07 mmol)、雙(頻哪醇根基)二硼(409 mg，1.61 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(263 mg，0.32 mmol)及乙酸鉀(328 mg，3.34 mmol)於無水1,4-二噁烷(6 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著鑑別為(S)-2-(2-甲氧基丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶，其未經純化即使用。質譜(正模式)m/e：294.1(M+H)+。 Step B : (S)-5-Bromo-2-(2-methoxypropoxy)pyridine (264 mg, 1.07 mmol), bis(pinadol) diboron (409 mg, 1.61 mmol), [1,1-bis(diphenylphosphino)ferrocene] complex of dichloropalladium(II) with methylene chloride (263 mg, 0.32 mmol) and potassium acetate (328 mg, 3.34 mmol) in anhydrous 1 The stirred mixture in 4-dioxane (6 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified as (S)-2-(2-methoxypropoxy)-5-(4,4,5,5-tetramethyl-1,3, 2-diboron 2-yl)pyridine, which was used without purification. Mass spectrum (positive mode) m/e: 294.1 (M+H) + .

製備preparation

步驟A：將含有4-溴吡啶甲酸(204 mg，1.01 mmol)及HATU(778 mg，2.05 mmol)之乾燥小瓶抽真空且用氬氣回填三次。在氬氣保護下，由注射器各別地依序添加無水DMF(5 mL)、二異丙基乙胺(0.53 mL，3.05 mmol)。在0℃下於氬氣下攪拌混合物。30分鐘後，分數份添加N-(2-胺基乙基)甲烷磺醯胺鹽酸鹽(267 mg，1.53 mmol)。添加完成後，在23℃下攪拌反應物且用TLC及LC-MS監測。17小時後，用水稀釋反應物，接著用乙酸乙酯萃取三次。彙集有機物，接著用飽和碳酸氫鈉水溶液洗滌三次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，在矽膠上(含30-90%乙酸乙酯之己烷)純化殘餘物，得到呈黃色膜狀之4-溴-N-(2-(甲基磺醯胺基)乙基)吡啶醯胺(97 mg，0.3 mmol，29.6%產率)，其未經進一步純化即使用。質譜(正模式)m/e：322.0(M+H)+。 Step A : A dry vial containing 4-bromopicolinic acid (204 mg, 1.01 mmol) and HATU (778 mg, 2.05 mmol) was vacuumed and backfilled three times with argon. Anhydrous DMF (5 mL) and diisopropylethylamine (0.53 mL, 3.05 mmol) were added sequentially from a syringe under argon. The mixture was stirred at 0 ° C under argon. After 30 minutes, N-(2-aminoethyl)methanesulfonamide hydrochloride (267 mg, 1.53 mmol) was obtained. After the addition was complete, the reaction was stirred at <RTI ID=0.0></RTI><RTIgt; After 17 hours, the reaction was diluted with water and then extracted three times with ethyl acetate. The organics were combined, washed three times with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, EtOAc mjjjjjj Amidino)ethyl)pyridiniumamine (97 mg, 0.3 mmol, 29.6% yield) was used without further purification. Mass spectrum (positive mode) m/e: 322.0 (M+H) + .

步驟B：將4-溴-N-(2-(甲基磺醯胺基)乙基)吡啶醯胺(97 mg，0.3 mmol)、雙(頻哪醇根基)二硼(115 mg，0.45 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(22 mg，0.06 mmol)、參(二亞苄基丙酮)二鈀(0)(28 mg，0.03 mmol)及乙酸鉀(90 mg，0.92 mmol)於無水DMF(2 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經鑑別含有(2-((2-(甲基磺醯胺基)乙基)胺甲醯基)吡啶-4-基)酸，其未經純化即使用。質譜(正模式)m/e：288.1(M+H)+。 Step B : 4-Bromo-N-(2-(methylsulfonyl)ethyl)pyridiniumamine (97 mg, 0.3 mmol), bis(pinacolyl)diboron (115 mg, 0.45 mmol) , butyl di-1-adamantylphosphine n-BuPAd 2 (22 mg, 0.06 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (28 mg, 0.03 mmol) and potassium acetate (90 mg) The stirred mixture in anhydrous DMF (2 mL) was purified with argon three times and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain (2-((2-(methylsulfonyl)ethyl)amine). Acid, which is used without purification. Mass spectrum (positive mode) m/e: 288.1 (M+H) + .

製備preparation

步驟A：將含有4-溴吡啶甲酸(303 mg，1.5 mmol)及HATU(1.14 g，3.01 mmol)之乾燥小瓶抽真空且用氬氣回填三次。在氬氣保護下，由注射器各別地依序添加無水N,N-二甲基甲醯胺(7 mL)、二異丙基乙胺(0.79 mL，4.54 mmol)。在0℃下於氬氣下攪拌混合物。30分鐘後，逐滴添加4-胺基-2-丁醇(0.22 mL，2.2 mmol)。添加完成後，在23℃下攪拌反應物且用TLC及LC-MS監測。17小時後，用水稀釋反應物，接著用乙酸乙酯萃取三次。彙集有機物，接著用飽和碳酸氫鈉水溶液洗滌三次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，在矽膠上(含30-90%乙酸乙酯之己烷)純化殘餘物，得到呈黃色膜狀之4-溴-N-(3-羥基丁基)吡啶醯胺，其未經進一步純化即使用。質譜(正模式)m/e：272.9(M+H)+。 Step A : A dry vial containing 4-bromopicolinic acid (303 mg, 1.5 mmol) and HATU (1.14 g, 3.01 mmol) was taken to vacuum and backfilled three times with argon. Under an argon atmosphere, anhydrous N,N-dimethylformamide (7 mL) and diisopropylethylamine (0.79 mL, 4.54 mmol) were sequentially added from a syringe. The mixture was stirred at 0 ° C under argon. After 30 minutes, 4-amino-2-butanol (0.22 mL, 2.2 mmol) was added dropwise. After the addition was complete, the reaction was stirred at <RTI ID=0.0></RTI><RTIgt; After 17 hours, the reaction was diluted with water and then extracted three times with ethyl acetate. The organics were combined, washed three times with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, EtOAc mjjjjjj Pyridinamine, which was used without further purification. Mass spectrum (positive mode) m/e: 272.9 (M+H) + .

步驟B：將4-溴-N-(3-羥基丁基)吡啶醯胺(311 mg，1.14 mmol)、雙(頻哪醇根基)二硼(434 mg，1.71 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(82 mg，0.23 mmol)、參(二亞苄基丙酮)二鈀(0)(106 mg，0.12 mmol)及乙酸鉀(341 mg，3.47 mmol)於無水N,N-二甲基乙醯胺(2.5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經鑑別含有(2-((3-羥基丁基)胺甲醯基)吡啶-4-基)酸，其未經純化即使用。質譜(正模式)m/e：239.1(M+H)+。 Step B : 4-Bromo-N-(3-hydroxybutyl)pyridiniumamine (311 mg, 1.14 mmol), bis(pinacolyl)diboron (434 mg, 1.71 mmol), butyldi-1 - adamantylphosphine n-BuPAd 2 (82 mg, 0.23 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (106 mg, 0.12 mmol) and potassium acetate (341 mg, 3.47 mmol) in anhydrous N The stirred mixture in N-dimethylacetamide (2.5 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain (2-((3-hydroxybutyl)aminecarbamoyl)pyridin-4-yl) Acid, which is used without purification. Mass spectrum (positive mode) m/e: 239.1 (M+H) + .

製備preparation

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(212 mg，5.30 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將1,3-丙二醇(0.26 mL，3.6 mmol)逐滴添加至冷反 應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.74 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-40%乙酸乙酯之己烷)純化淡黃色殘餘物，得到無色油狀物，其凝固成3-((5-溴吡啶-2-基)氧基)丙-1-醇(386.2 mg，1.664 mmol，96%產率)，其未經進一步純化即使用。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 8.17(1H,d,J=2.5 Hz),7.67(1H,dd,J=8.8,2.5 Hz),6.67(1H,d,J=8.8 Hz),4.42(2H,t,J=6.1 Hz),3.70(2H,t,J=6.0 Hz),1.86-2.08(3H,m)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (212 mg, 5.30 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice-water bath. After 20 minutes, 1,3-propanediol (0.26 mL, 3.6 mmol) was added dropwise to the cold reaction solution by a syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.74 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified on EtOAc (EtOAc EtOAc EtOAc Propyl-1-ol (386.2 mg, 1.664 mmol, 96% yield) was used without further purification. 1 H NMR (400 MHz, methylene chloride-d 2 ) δ δ 8.17 (1H, d, J = 2.5 Hz), 7.67 (1H, dd, J = 8.8, 2.5 Hz), 6.67 (1H, d, J = 8.8 Hz), 4.42 (2H, t, J = 6.1 Hz), 3.70 (2H, t, J = 6.0 Hz), 1.86-2.08 (3H, m).

步驟B：將3-((5-溴吡啶-2-基)氧基)丙-1-醇(397 mg，1.71 mmol)、雙(頻哪醇根基)二硼(652 mg，2.57 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(123 mg，0.34 mmol)、參(二亞苄基丙酮)二鈀(0)(161 mg，0.18 mmol)及乙酸鉀(510 mg，5.19 mmol)於無水N,N-二甲基乙醯胺(3.5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經鑑別含有3-((5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)氧基)丙-1-醇，其未經純化即使用。質譜(正模式)m/e：280.1(M+H)+。 Step B : 3-((5-Bromopyridin-2-yl)oxy)propan-1-ol (397 mg, 1.71 mmol), bis (pinadol) diboron (652 mg, 2.57 mmol), Butyl di-adamantylphosphine n-BuPAd 2 (123 mg, 0.34 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (161 mg, 0.18 mmol) and potassium acetate (510 mg, 5.19) Methylene) The stirred mixture in anhydrous N,N-dimethylacetamide (3.5 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain 3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)pyridin-2-yl)oxy)propan-1-ol, which was used without purification. Mass spectrum (positive mode) m/e: 280.1 (M+H) + .

製備preparation

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(211 mg，5.28 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20 分鐘後，由注射器將3-(甲基磺醯基)-1-丙醇(500 mg，3.62 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.74 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，將2-丙醇添加至泡沫狀白色固體中，接著在非真空下於旋轉蒸發器上加熱混合物至50℃。20分鐘後，在減壓下移除溶劑至約2 mL體積。過濾固體，接著用乙醚沖洗兩次，得到呈白色固體狀之5-溴-2-(3-(甲基磺醯基)丙氧基)吡啶(500 mg，1.7 mmol，98%產率)，其未經純化即使用。1H NMR(500 MHz,DMSO-d6)δ ppm 8.28(1H,d,J=2.2 Hz),7.91(1H,dd,J=8.8,2.4 Hz),6.85(1H,d,J=8.8 Hz),4.34(2H,t,J=6.5 Hz),3.20-3.30(2H,m),3.01(3H,s),2.09-2.18(2H,m)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (211 mg, 5.28 mmol) in anhydrous cyclopentylmethyl ether (10 mL) was cooled in ice water. After 20 minutes, 3-(methylsulfonyl)-1-propanol (500 mg, 3.62 mmol) was added dropwise to the cold reaction solution by syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.74 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentration, 2-propanol was added to a foamy white solid which was then warmed to 50[deg.] C. After 20 minutes, the solvent was removed under reduced pressure to a volume of approximately 2 mL. The solid was filtered, EtOAc (EtOAc m. It is used without purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.28 (1H, d, J = 2.2 Hz), 7.91 (1H, dd, J = 8.8, 2.4 Hz), 6.85 (1H, d, J = 8.8 Hz ), 4.34 (2H, t, J = 6.5 Hz), 3.20-3.30 (2H, m), 3.01 (3H, s), 2.09-2.18 (2H, m).

步驟B：將5-溴-2-(3-(甲基磺醯基)丙氧基)吡啶(320 mg，1.09 mmol)、雙(頻哪醇根基)二硼(420 mg，1.65 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(79.9 mg，0.223 mmol)、參(二亞苄基丙酮)二鈀(0)(104 mg，0.11 mmol)及乙酸鉀(326 mg，3.32 mmol)於無水N,N-二甲基乙醯胺(4 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經鑑別含有2-(3-(甲基磺醯基)丙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶，其未經純化即使用。質譜(正模式)m/e：342.1(M+H)+。 Step B : 5-Bromo-2-(3-(methylsulfonyl)propoxy)pyridine (320 mg, 1.09 mmol), bis(pinacolyl)diboron (420 mg, 1.65 mmol), Butyl di-1-adamantylphosphine n-BuPAd 2 (79.9 mg, 0.223 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (104 mg, 0.11 mmol) and potassium acetate (326 mg, 3.32) The stirred mixture in mmol of anhydrous N,N-dimethylacetamide (4 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain 2-(3-(methylsulfonyl)propoxy)-5-(4,4,5,5-tetramethyl-1,3 2-diboron 2-yl)pyridine, which was used without purification. Mass spectrum (positive mode) m/e: 342.1 (M+H) + .

製備：preparation:

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(245 mg，6.14 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將3-甲氧基-1-丙醇(0.38 mL，3.97 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加4-溴-2-氟吡啶(0.2 mL，1.95 mmol)。4-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至50℃。1小時後，使溫度升至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-15%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之4-溴-2-(3-甲氧基丙氧基)吡啶(368 mg，1.5 mmol，77%產率)，其未經進一步純化即使用。1H NMR(500 MHz,DMSO-d6)δ ppm 8.06(1H,d,J=5.4 Hz),7.21(1H,dd,J=5.4,1.7 Hz),7.10(1H,d,J=1.5 Hz),4.30(2H,t,J=6.5 Hz),3.44(2H,t,J=6.2 Hz),3.21-3.24(3H,m),1.90-1.96(2H,m)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (245 mg, 6.14 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice water bath. After 20 minutes, 3-methoxy-1-propanol (0.38 mL, 3.97 mmol) was added dropwise to the cold reaction solution by syringe. After 1 hour, 4-bromo-2-fluoropyridine (0.2 mL, 1.95 mmol) was added dropwise at 0 °C. After the addition of 4-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 50 ° C. After 1 hour, the temperature was raised to 85 °C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the title compound was purified mjjjjjjjjj (368 mg, 1.5 mmol, 77% yield) which was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.06 (1H, d, J = 5.4 Hz), 7.21. (1H, dd, J = 5.4, 1.7 Hz), 7.10 (1H, d, J = 1.5 Hz) ), 4.30 (2H, t, J = 6.5 Hz), 3.44 (2H, t, J = 6.2 Hz), 3.21-3.24 (3H, m), 1.90-1.96 (2H, m).

步驟B：將4-溴-2-(3-甲氧基丙氧基)吡啶(368 mg，1.5 mmol)、雙(頻哪醇根基)二硼(571 mg，2.25 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(109 mg，0.30 mmol)、參(二亞苄基丙酮)二鈀(0)(142 mg，0.15 mmol)及乙酸鉀(443 mg，4.51 mmol)於無水N,N-二甲基乙醯胺(5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經鑑別含有(2-(3-甲氧基丙氧基)吡啶-4-基)酸，其未經純化即使用。質譜(正模式)m/e：212.1(M+H)+。 Step B : 4-Bromo-2-(3-methoxypropoxy)pyridine (368 mg, 1.5 mmol), bis (pinacolyl) diboron (571 mg, 2.25 mmol), butyl di- 1-adamantylphosphine n-BuPAd 2 (109 mg, 0.30 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (142 mg, 0.15 mmol) and potassium acetate (443 mg, 4.51 mmol) in anhydrous The stirred mixture in N,N-dimethylacetamide (5 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain (2-(3-methoxypropoxy)pyridin-4-yl) Acid, which is used without purification. Mass spectrum (positive mode) m/e: 212.1 (M+H) + .

製備preparation

步驟A：將含有5-溴菸鹼酸(231 mg，1.15 mmol)及HATU(889 mg，2.34 mmol)之乾燥小瓶抽真空且用氬氣回填三次。在氬氣保護下，由注射器各別地依序添加無水DMF(5 mL)、二異丙基乙胺(0.8 mL，4.6 mmol)。在0℃下於氬氣下攪拌混合物。30分鐘後，分數份添加N-(2-胺基乙基)甲烷磺醯胺鹽酸鹽(328 mg，1.88 mmol)。添加完成後，在23℃下攪拌反應物且用TLC及LC-MS監測。17小時後，用水稀釋反應物，接著用乙酸乙酯萃取三次。彙集有機物，接著用飽和碳酸氫鈉水溶液洗滌三次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，在矽膠上(含0-10%甲醇之二氯甲烷)純化殘餘物，得到呈淡褐色固體狀之5-溴-N-(2-(甲基磺醯胺基)乙基)菸鹼醯胺(110 mg，0.34 mmol，29.9%產率)，其未經進一步純化即使用。1H NMR(500 MHz,DMSO-d6)δ ppm 8.98(1H,d,J=1.7 Hz),8.81-8.89(2H,m),8.43(1H,t,J=2.1 Hz),7.18(1H,t,J=6.1 Hz),3.39(2H,q,J=6.4 Hz),3.14(2H,q,J=6.4 Hz),2.92(3H,s)。 Step A : A dry vial containing 5-bromonicotinic acid (231 mg, 1.15 mmol) and HATU (889 mg, 2.34 mmol) was vacuumed and backfilled three times with argon. Anhydrous DMF (5 mL) and diisopropylethylamine (0.8 mL, 4.6 mmol) were added sequentially from a syringe under argon. The mixture was stirred at 0 ° C under argon. After 30 minutes, N-(2-aminoethyl)methanesulfonamide hydrochloride (328 mg, 1.88 mmol) was added in portions. After the addition was complete, the reaction was stirred at <RTI ID=0.0></RTI><RTIgt; After 17 hours, the reaction was diluted with water and then extracted three times with ethyl acetate. The organics were combined, washed three times with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, EtOAc (EtOAc m.) Amidino)ethyl)nicotinamide (110 mg, 0.34 mmol, 29.9% yield) was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.98 (1H, d, J = 1.7 Hz), 8.81-8.89 (2H, m), 8.43 (1H, t, J = 2.1 Hz), 7.18 (1H) , t, J = 6.1 Hz), 3.39 (2H, q, J = 6.4 Hz), 3.14 (2H, q, J = 6.4 Hz), 2.92 (3H, s).

步驟B：將5-溴-N-(2-(甲基磺醯胺基)乙基)菸鹼醯胺(110 mg，0.34 mmol)、雙(頻哪醇根基)二硼(132 mg，0.52 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(25 mg，0.07 mmol)、參(二亞苄基丙酮)二鈀(0)(32 mg，0.035 mmol)及乙酸鉀(104 mg，1.06 mmol)於無水N,N-二甲基乙醯胺(3 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷卻反應物至室溫，接著經鑑別含有(5-((2-(甲基磺醯胺基)乙基)胺甲醯基)吡啶-3-基)酸，其未經純化即使用。質譜(正模式)m/e：288.1(M+H)+。 Step B : 5-Bromo-N-(2-(methylsulfonylamino)ethyl)nicotinium amide (110 mg, 0.34 mmol), bis(pinacolyl)diboron (132 mg, 0.52) Ment), butyldi-1-adamantylphosphine n-BuPAd 2 (25 mg, 0.07 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (32 mg, 0.035 mmol) and potassium acetate (104) The mixture was stirred three times with argon and three times under vacuum in EtOAc (3 mL). The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain (5-((2-(methylsulfonamido)ethyl)aminecarbazinyl)pyridin-3-yl) Acid, which is used without purification. Mass spectrum (positive mode) m/e: 288.1 (M+H) + .

實例843Example 843

1-(5-((2-乙基吡啶-3-基)氧基)-6'-(2-羥基乙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(5-((2-ethylpyridin-3-yl)oxy)-6'-(2-hydroxyethoxy)-[3,3'-bipyridyl]-6-yl)-3- Methyl urea

步驟A：將1-(5-溴-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(167 mg，0.48 mmol)、三環己基膦(28 mg，0.10 mmol)、參(二亞苄基丙酮)二鈀(0)(44 mg，0.048 mmol)及1.3 M磷酸三鉀(1.2 mL，1.56 mmol)添加至含有2-((5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)氧基)乙醇(340 mg，1.28 mmol)於1,4-二噁烷(6 mL)中之小瓶中。將燒瓶脫氣且用氬氣回填。加熱所得反應物且用TLC及LC-MS監測。19小時後，冷卻反應物至室溫，接著經裝填有1.5 g矽藻土之40 mL拋棄式過濾漏斗(Chemglass目錄號：OP-06603-12)過濾。濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-10%甲醇之二氯甲烷)，得到棕色膜狀物，藉由溶解於4.5 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為1-(5-((2-乙基吡啶-3-基)氧基)-6'-(2-羥基乙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(75.8 mg，0.185 mmol，38.8%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.05(1H,d,J=4.2 Hz),8.73(1H,s),8.40(1H,d,J=2.4 Hz),8.36(1H,d,J=2.2 Hz),8.32(1H,dd,J=4.4,1.5 Hz),7.93(1H,dd,J=8.7,2.6 Hz),7.48(1H,d,J=2.2 Hz),7.20-7.29(2H,m),6.86(1H,d,J=8.8 Hz),4.82(1H,t,J=5.5 Hz),4.28(2H,t,J=5.1 Hz),3.70(2H,q,J=5.4 Hz),2.87(2H,q,J=7.6 Hz),2.82(3H,d,J=4.6 Hz),1.24(3H,t, J=7.6 Hz)。質譜(ESI)m/z=410.0(M+H)。 Step A : 1-(5-Bromo-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (167 mg, 0.48 mmol), tricyclic Hexylphosphine (28 mg, 0.10 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (44 mg, 0.048 mmol) and 1.3 M tripotassium phosphate (1.2 mL, 1.56 mmol) were added to contain 2-(( 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridin-2-yl)oxy)ethanol (340 mg, 1.28 mmol) in a small vial of 1,4-dioxane (6 mL). The flask was degassed and backfilled with argon. The resulting reaction was heated and monitored by TLC and LC-MS. After 19 hours, the reaction was cooled to room temperature and then filtered through a 40 mL disposable filter funnel (Chemglass catalog number: OP-06603-12) packed with 1.5 g of diatomaceous earth. After concentration, the residue was diluted with methylene chloride and then applied to a silica gel column (dichloromethane containing 0-10% methanol) to give a brown membrane which was dissolved in 4.5 mL DMF using reverse phase HPLC The membrane was further purified (water containing 10-90% acetonitrile (premixed with 0.1% TFA) (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as 1-(5-((2-ethylpyridin-3-yl)oxy)-6'-(2-hydroxyethoxy)-[ 3,3'-bipyridyl]-6-yl)-3-methylurea (75.8 mg, 0.185 mmol, 38.8% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.05 (1H, d, J = 4.2 Hz), 8.73 (1H, s), 8.40 (1H, d, J = 2.4 Hz), 8.36 (1H, d , J = 2.2 Hz), 8.32 (1H, dd, J = 4.4, 1.5 Hz), 7.93 (1H, dd, J = 8.7, 2.6 Hz), 7.48 (1H, d, J = 2.2 Hz), 7.20-7.29 (2H,m), 6.86 (1H, d, J = 8.8 Hz), 4.82 (1H, t, J = 5.5 Hz), 4.28 (2H, t, J = 5.1 Hz), 3.70 (2H, q, J = 5.4 Hz), 2.87 (2H, q, J = 7.6 Hz), 2.82 (3H, d, J = 4.6 Hz), 1.24 (3H, t, J = 7.6 Hz). Mass Spectrum (ESI) m/z = 410.0 (M+H).

實例844Example 844

1-(5-((1-乙基-1H-吡唑-5-基)氧基)-6'-(2-羥基乙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(5-((1-ethyl-1H-pyrazol-5-yl)oxy)-6'-(2-hydroxyethoxy)-[3,3'-bipyridyl]-6-yl -3-methylurea

步驟A：將5-溴-2-氯-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶(267 mg，0.88 mmol)、三環己基膦(50 mg，0.18 mmol)、參(二亞苄基丙酮)二鈀(0)(82 mg，0.089 mmol)及1.3 M磷酸三鉀(2.1 mL，2.7 mmol)添加至含有2-((5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)氧基)乙醇(340 mg，1.28 mmol)於1,4-二噁烷(6 mL)中之小瓶中。將燒瓶脫氣且用氬氣回填。加熱所得反應物至90℃且用TLC及LC-MS監測。4.5小時後，冷卻反應物至室溫且在23℃下攪拌隔夜。17.5小時後，經裝填有1.5 g矽藻土之40 mL拋棄式過濾漏斗(Chemglass目錄號：OP-06603-12)過濾黑色混合物。濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-15%甲醇之二氯甲烷)，得到棕色膜狀物，藉由溶解於6.5 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為2-((6'-氯-5'-((1-乙基-1H-吡唑-5-基)氧基)-[3,3'-聯吡啶]-6-基)氧基)乙醇(56.2 mg，0.156 mmol，17.64%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 8.67(1H,d,J=2.2 Hz),8.56(1H,dd,J=2.6,0.6 Hz),8.06-8.13(2H,m),7.38(1H,d,J=2.0 Hz),6.94(1H,dd,J=8.7,0.6 Hz),5.80(1H,d,J=2.0 Hz),4.86(1H,br.s.),4.29-4.34(2H,m),4.10(2H,q,J=7.2 Hz),3.72(2H,t,J=5.1 Hz),1.37(3H,t,J=7.2 Hz)。質譜(正模式)m/e：361.0(M+H)+。 Step A : 5-Bromo-2-chloro-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridine (267 mg, 0.88 mmol), tricyclohexylphosphine (50 mg, 0.18 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (82 mg, 0.089 mmol) and 1.3 M tripotassium phosphate (2.1 mL, 2.7 mmol) were added to contain 2-((5-(4,4) ,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridin-2-yl)oxy)ethanol (340 mg, 1.28 mmol) in a small vial of 1,4-dioxane (6 mL). The flask was degassed and backfilled with argon. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After 4.5 hours, the reaction was cooled to room temperature and stirred at 23 ° C overnight. After 17.5 hours, the black mixture was filtered through a 40 mL disposable filter funnel (Chemglass Cat. No.: OP-06603-12) packed with 1.5 g of diatomaceous earth. After concentration, the residue was diluted with methylene chloride, then applied to a silica gel column (with 0-15% methanol in dichloromethane) to give a brown membrane which was dissolved in 6.5 mL of DMF using reverse phase HPLC The membrane was further purified (water containing 10-90% acetonitrile (premixed with 0.1% TFA) (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as 2-((6--chloro-5'-((1-ethyl-1H-pyrazol-5-yl)oxy)-[3 , 3'-bipyridyl]-6-yl)oxy)ethanol (56.2 mg, 0.156 mmol, 17.64% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.67 (1H, d, J = 2.2 Hz), 8.56 (1H, dd, J = 2.6, 0.6 Hz), 8.06-8.13 (2H, m), 7.38 (1H,d, J =2.0 Hz), 6.94 (1H, dd, J = 8.7, 0.6 Hz), 5.80 (1H, d, J = 2.0 Hz), 4.86 (1H, br.s.), 4.29-4.34 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 3.72 (2H, t, J = 5.1 Hz), 1.37 (3H, t, J = 7.2 Hz). Mass spectrum (positive mode) m/e: 361.0 (M+H) + .

步驟B：組合1-甲基脲(23 mg，0.31 mmol)、經研磨之磷酸鉀(101 mg，0.47 mmol)、5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-1,4'-聯吡唑、t-But-BippyPhos(16 mg，0.032 mmol)及參(二亞苄基丙酮)二鈀(0)(15 mg，0.016 mmol)，接著將燒瓶抽真空且用氬氣回填。在氬氣保護下，由注射器添加無水1,2-二甲氧基乙烷(1.5 mL)。將反應物充氣10分鐘，隨後加熱混合至50℃，維持45分鐘。45分鐘後，在氬氣保護下，由注射器將含2-((6'-氯-5'-((1-乙基-1H-吡唑-5-基)氧基)-[3,3'-聯吡啶]-6-基)氧基)乙醇(56 mg，0.16 mmol)之無水1,2-二甲氧基乙烷(1.5 mL)添加至混合物中。添加完成後，加熱反應物至75℃且用TLC及LC-MS監測。17小時後，在減壓下濃縮反應物，接著藉由取乾物加載於矽膠管柱上(含0-10%甲醇之二氯甲烷)純化，得到棕色膜狀物，藉由溶解於3.2 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將灰白色固體鑑別為116707-025-001或1-(5-((1-乙基-1H-吡唑-5-基)氧基)-6'-(2-羥基乙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(11.3 mg，0.028 mmol，18.21%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 8.94-9.07(2H,m),8.43-8.47(1H,m),8.40(1H,d,J=2.0 Hz),7.98(1H,dd,J=8.7,2.6 Hz),7.77(1H,d,J=2.0 Hz),7.36(1H,d,J=2.0 Hz),6.90(1H,d,J=8.8 Hz),5.73(1H,d,J=2.2 Hz),4.84(1H,br.s.),4.27-4.33(2H,m),4.12(2H,q,J=7.1 Hz),3.72(2H,br.s.), 2.82(3H,d,J=4.6 Hz),1.35(3H,t,J=7.2 Hz)。質譜(ESI)m/z=399.1(M+H)。 Step B : Combination of 1-methylurea (23 mg, 0.31 mmol), ground potassium phosphate (101 mg, 0.47 mmol), 5-(di-t-butylphosphino)-1', 3', 5'-Triphenyl-1'H-1,4'-bipyrazole, t-But-BippyPhos (16 mg, 0.032 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (15 mg, 0.016 mmol) The flask was then evacuated and backfilled with argon. Anhydrous 1,2-dimethoxyethane (1.5 mL) was added by syringe under argon. The reaction was aerated for 10 minutes and then heated to 50 ° C for 45 minutes. After 45 minutes, under the protection of argon, the syringe will contain 2-((6'-chloro-5'-((1-ethyl-1H-pyrazol-5-yl)oxy)-[3,3 '-Bipyridyl]-6-yl)oxy)ethanol (56 mg, 0.16 mmol) in anhydrous 1,2-dimethoxyethane (1.5 mL) was added to the mixture. After the addition was completed, the reaction was heated to 75 ° C and was monitored by TLC and LC-MS. After 17 hours, the reaction was concentrated under reduced pressure and then purified to dryness eluted eluted eluted eluted eluted elution The membrane was further purified using reverse phase HPLC (water containing 10-90% acetonitrile (premixed with 0.1% TFA) (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, the pale-white solid was identified as 116707-025-001 or 1-(5-((1-ethyl-1H-pyrazol-5-yl)oxy)-6'- (2-Hydroxyethoxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (11.3 mg, 0.028 mmol, 18.21% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.94-9.07 (2H, m), 8.43-8.47 (1H, m), 8.40 (1H, d, J = 2.0 Hz), 7.98 (1H, dd, J = 8.7, 2.6 Hz), 7.77 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 2.0 Hz), 6.90 (1H, d, J = 8.8 Hz), 5.73 (1H, d, J = 2.2 Hz), 4.84 (1H, br.s.), 4.27-4.33 (2H, m), 4.12 (2H, q, J = 7.1 Hz), 3.72 (2H, br.s.), 2.82 (3H , d, J = 4.6 Hz), 1.35 (3H, t, J = 7.2 Hz). Mass Spectrum (ESI) m/z = 399.1 (M+H).

實例845Example 845

4-(2,6-二氟苯氧基)-N-(2-羥基乙基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-甲醯胺 4-(2,6-Difluorophenoxy)-N-(2-hydroxyethyl)-6-(3-methylureido)-[3,4'-bipyridine]-2'-formamidine amine

步驟A：將含有4-溴吡啶甲酸(406 mg，2.01 mmol)及HATU(1.53 g，4.03 mmol)之乾燥小瓶抽真空且用氬氣回填三次。在氬氣保護下，由注射器各別地依序添加無水DMF(10 mL)、二異丙基乙胺(1.4 mL，8.05 mmol)。在23℃下於氬氣下攪拌混合物。30分鐘後，由注射器逐滴添加2-((四氫-2H-哌喃-2-基)氧基)乙胺(440 mg，3.03 mmol)。添加完成後，在23℃下攪拌反應物且用TLC及LC-MS監測。17小時後，用水稀釋反應物，接著用乙酸乙酯萃取三次。彙集有機物，接著用飽和碳酸氫鈉水溶液洗滌三次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，在矽膠上(含0-50%乙酸乙酯之己烷)純化殘餘物，得到呈黃色油狀之4-溴-N-(2-((四氫-2H-哌喃-2-基)氧基)乙基)吡啶醯胺(423 mg，1.28 mmol，64.0%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.33-8.43(3H,m),7.62(1H,dd,J=5.1,2.0 Hz),4.60(1H,dd,J=4.6,2.7 Hz),3.80-3.92(2H,m),3.58-3.70(3H,m),3.43-3.54(1H,m),1.78-1.91(1H,m),1.66-1.77(1H,m),1.44-1.63(4H,m)。 Step A : A dry vial containing 4-bromopicolinic acid (406 mg, 2.01 mmol) and HATU (1.53 g, 4.03 mmol) was vacuumed and backfilled three times with argon. Anhydrous DMF (10 mL) and diisopropylethylamine (1.4 mL, 8.05 mmol) were added sequentially from a syringe under argon. The mixture was stirred under argon at 23 °C. After 30 minutes, 2-((tetrahydro-2H-piperidin-2-yl)oxy)ethylamine (440 mg, 3.03 mmol) was added dropwise from a syringe. After the addition was complete, the reaction was stirred at <RTI ID=0.0></RTI><RTIgt; After 17 hours, the reaction was diluted with water and then extracted three times with ethyl acetate. The organics were combined, washed three times with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous MgSO.sub.4, EtOAc (EtOAc m. -2H-Pylan-2-yl)oxy)ethyl)pyridiniumamine (423 mg, 1.28 mmol, 64.0% yield). 1 H NMR (500 MHz, methylene chloride-d 2 ) δ </ RTI></RTI> 8.33-8.43 (3H, m), 7.62 (1H, dd, J = 5.1, 2.0 Hz), 4.60 (1H, dd, J = 4.6, 2.7 Hz), 3.80-3.92 (2H, m), 3.58-3.70 (3H, m), 3.43-3.54 (1H, m), 1.78-1.91 (1H, m), 1.66-1.77 (1H, m), 1.44- 1.63 (4H, m).

步驟B：將4-溴-N-(2-((四氫-2H-哌喃-2-基)氧基)乙基)吡啶醯胺 (423 mg，1.28 mmol)、雙(頻哪醇根基)二硼(492 mg，1.94 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(316 mg，0.39 mmol)及乙酸鉀(387 mg，3.94 mmol)於無水1,4-二噁烷(7 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至85℃且用LC-MS及TLC監測。18小時後，冷卻反應物至室溫，接著鑑別為N-(2-((四氫-2H-哌喃-2-基)氧基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶醯胺，其未經純化即使用。質譜(正模式)m/e：211.1(M+H)+。(注意：LC-MS據推測對應於(2-((2-羥基乙基)胺甲醯基)吡啶-4-基)酸) Step B : 4-Bromo-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridiniumamine (423 mg, 1.28 mmol), bis (pinadol) a complex of diboron (492 mg, 1.94 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with methylene chloride (316 mg, 0.39 mmol) and acetic acid Potassium (387 mg, 3.94 mmol) in dry 1,4-dioxane (7 mL). The mixture was heated to 85 ° C and monitored by LC-MS and TLC. After 18 hours, the reaction was cooled to room temperature and then identified to N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaboron 2-yl)pyridiniumamine, which was used without purification. Mass spectrum (positive mode) m/e: 211.1 (M+H) + . (Note: LC-MS is presumably corresponding to (2-((2-hydroxyethyl))aminomethyl)pyridin-4-yl) acid)

步驟C：將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(483 mg，1.35 mmol)、三環己基膦(32 mg，0.11 mmol)、參(二亞苄基丙酮)二鈀(0)(52 mg，0.057 mmol)及1.3 M磷酸三鉀(1.3 mL，1.69 mmol)添加至含有N-(2-((四氫-2H-哌喃-2-基)氧基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶醯胺(207 mg，0.55 mmol)於1,4-二噁烷(7 mL)中之小瓶中。將燒瓶脫氣且用氬氣回填。加熱所得反應物至90℃且用TLC及LC-MS監測。19小時後，冷卻反應物至室溫，接著經裝填有1.5 g矽藻土之40 mL拋棄式過濾漏斗(Chemglass目錄號：OP-06603-12)過濾。濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-20%甲醇之二氯甲烷)，得到棕色膜狀物，將其鑑別為4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-N-(2-((四氫-2H-哌喃-2-基)氧基)乙基)-[3,4'-聯吡啶]-2'-甲醯胺(178 mg，0.34 mmol，61.2%產率)。質譜(正模式)m/e：528.1(M+H)+。 Step C : 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (483 mg, 1.35 mmol), tricyclohexylphosphine (32) Mg, 0.11 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (52 mg, 0.057 mmol) and 1.3 M tripotassium phosphate (1.3 mL, 1.69 mmol) were added to contain N-(2-((4) Hydrogen-2H-piperidin-2-yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridiniumamine (207 mg, 0.55 mmol) in a small vial of 1,4-dioxane (7 mL). The flask was degassed and backfilled with argon. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After 19 hours, the reaction was cooled to room temperature and then filtered through a 40 mL disposable filter funnel (Chemglass catalog number: OP-06603-12) packed with 1.5 g of diatomaceous earth. After concentration, the residue was diluted with dichloromethane, and then applied to a silica gel column (dichloromethane containing 0-20% methanol) to give a brown film which was identified as 4-(2,6-difluoro Phenoxy)-6-(3-methylureido)-N-(2-((tetrahydro-2H-piperidin-2-yl)oxy)ethyl)-[3,4'-bipyridine -2'-carbamamine (178 mg, 0.34 mmol, 61.2% yield). Mass spectrum (positive mode) m/e: 528.1 (M+H) + .

步驟D：將4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-N-(2-((四氫-2H-哌喃-2-基)氧基)乙基)-[3,4'-聯吡啶]-2'-甲醯胺(178 mg，0.34 mmol)及對甲苯磺酸吡錠(43 mg，0.17 mmol)於乙醇(10 mL)中之溶液加熱至55℃。用TLC及LC-MS監測反應。3.5小時後，冷卻反應物至23℃且攪拌 隔夜。18.5小時後，在減壓下濃縮反應物，接著藉由取乾物加載於矽膠管柱上(含0-10%甲醇之二氯甲烷)純化棕色殘餘物，得到棕色膜狀物，藉由溶解於4.2 mL DMF中，使用逆相HPLC(含25-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為4-(2,6-二氟苯氧基)-N-(2-羥基乙基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-甲醯胺(78.2 mg，0.18 mmol，52.3%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.38(1H,s),8.70-8.79(2H,m),8.41(1H,s),8.33(1H,d,J=1.0 Hz),7.87(1H,dd,J=5.0,1.8 Hz),7.46-7.55(1H,m),7.35-7.46(3H,m),7.14(1H,s),4.81(1H,br.s.),3.54(2H,d,J=3.9 Hz),3.40(2H,q,J=6.0 Hz),2.66(2H,d,J=4.4 Hz)。質譜(ESI)m/z=444.1(M+H)。 Step D : 4-(2,6-Difluorophenoxy)-6-(3-methylureido)-N-(2-((tetrahydro-2H-pyran-2-yl)oxy) Ethyl)-[3,4'-bipyridyl]-2'-formamide (178 mg, 0.34 mmol) and p-toluenesulfonate (43 mg, 0.17 mmol) in ethanol (10 mL) The solution was heated to 55 °C. The reaction was monitored by TLC and LC-MS. After 3.5 hours, the reaction was cooled to 23 ° C and stirred overnight. After 18.5 hours, the reaction was concentrated under reduced pressure, and then the brown residue was purified eluted from EtOAc EtOAc EtOAc The membrane was further purified using reverse phase HPLC (25-90% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA) in 4.2 mL DMF. The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as 4-(2,6-difluorophenoxy)-N-(2-hydroxyethyl)-6-(3-methylureido) -[3,4'-bipyridyl]-2'-formamide (78.2 mg, 0.18 mmol, 52.3% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.38 (1H, s), 8.70-8.79 (2H, m), 8.41 (1H, s), 8.33 (1H, d, J = 1.0 Hz), 7.87 (1H, dd, J = 5.0, 1.8 Hz), 7.46-7.55 (1H, m), 7.35-7.46 (3H, m), 7.14 (1H, s), 4.81 (1H, br.s.), 3.54 ( 2H,d, J = 3.9 Hz), 3.40 (2H, q, J = 6.0 Hz), 2.66 (2H, d, J = 4.4 Hz). Mass Spectrum (ESI) m/z = 444.1 (M+H).

遵循實例845中之程序，製備以下化合物： Following the procedure in Example 845 , the following compounds were prepared:

實例848Example 848

1-(4-(2,6-二氟苯氧基)-6'-(2,3-二羥基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲 基脲 1-(4-(2,6-Difluorophenoxy)-6'-(2,3-dihydroxypropoxy)-[3,3'-bipyridyl]-6-yl)-3-A Base urea

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(219 mg，5.47 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將丙酮縮甘油(Solketal)(0.44 mL，3.54 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.74 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。17小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-10%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之5-溴-2-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)吡啶(488 mg，1.69 mmol，97%產率)，其未經進一步純化即使用。1H NMR(400 MHz，二氯甲烷-d2)δ ppm 8.17(1H,dd,J=2.5,0.6 Hz),7.64-7.72(1H,m),6.70(1H,dd,J=8.8,0.6 Hz),4.39-4.48(1H,m),4.24-4.38(2H,m),4.10(1H,dd,J=8.4,6.5 Hz),3.80(1H,dd,J=8.4,6.3 Hz),1.41(3H,s),1.35(3H,s)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (219 mg, 5.47 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in ice water. After 20 minutes, Solketal (0.44 mL, 3.54 mmol) was added dropwise to the cold reaction solution by syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.74 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified mjjjjjjjjjj , 3-dioxolan-4-yl)methoxy)pyridine (488 mg, 1.69 mmol, 97% yield). 1 H NMR (400 MHz, methylene chloride-d 2 ) δ δ 8.17 (1H, dd, J = 2.5, 0.6 Hz), 7.64 - 7.72 (1H, m), 6.70 (1H, dd, J = 8.8, 0.6 Hz), 4.39-4.48 (1H, m), 4.24 - 4.38 (2H, m), 4.10 (1H, dd, J = 8.4, 6.5 Hz), 3.80 (1H, dd, J = 8.4, 6.3 Hz), 1.41 (3H, s), 1.35 (3H, s).

步驟B：將5-溴-2-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)吡啶(556 mg，1.93 mmol)、雙(頻哪醇根基)二硼(737 mg，2.90 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(140 mg，0.39 mmol)、參(二亞苄基丙酮)二鈀(0)(178 mg，0.19 mmol)及乙酸鉀(561 mg，5.71 mmol)於無水N,N-二甲基乙醯胺(4 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。21小時後，冷 卻反應物至室溫，接著經鑑別含有2-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶，其未經純化即使用。質譜(正模式)m/e：336.1(M+H)+。 Step B : 5-Bromo-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridine (556 mg, 1.93 mmol), bis ( Pinapol base) diboron (737 mg, 2.90 mmol), butyl di-1-adamantylphosphine n-BuPAd 2 (140 mg, 0.39 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (178 mg, 0.19 mmol) and potassium acetate (561 mg, 5.71 mmol) in EtOAc (3 mL) EtOAc. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 21 hours, the reaction was cooled to room temperature and then identified to contain 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridine, which was used without purification. Mass spectrum (positive mode) m/e: 336.1 (M+H) + .

步驟C：將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(206 mg，0.57 mmol)及4.0 M碳酸鉀水溶液(0.44 mL，1.76 mmol)添加至含有2-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(646 mg，1.93 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(140 mg，0.39 mmol)及參(二亞苄基丙酮)二鈀(0)(178 mg，0.19 mmol)於N,N-二甲基乙醯胺(4 mL)中之小瓶中。將燒瓶脫氣且用氬氣回填。加熱所得反應物至90℃且用TLC及LC-MS監測。19小時後，冷卻反應物至室溫，接著用鹽水稀釋。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-40%乙酸乙酯之二氯甲烷)，得到黃色膜狀物，用乙醚濕磨該膜狀物，得到呈白色固體狀之1-(4-(2,6-二氟苯氧基)-6'-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(115.0 mg，0.236 mmol，41.2%產率)。質譜(正模式)m/e：487.1(M+H)+。 Step C : 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (206 mg, 0.57 mmol) and aq. 0.44 mL, 1.76 mmol) was added to the solution containing 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridine (646 mg, 1.93 mmol), butyldi-1-adamantylphosphine n-BuPAd 2 (140 mg, 0.39 mmol), and bis(dibenzylideneacetone)dipalladium (0) ( 178 mg, 0.19 mmol) in a small bottle of N,N-dimethylacetamide (4 mL). The flask was degassed and backfilled with argon. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After 19 hours, the reaction was cooled to room temperature then diluted with brine. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentrating, the residue was diluted with methylene chloride, and then applied to a silica gel column (0-40% ethyl acetate in methylene chloride) to give a yellow film which was wet-ground with diethyl ether. 1-(4-(2,6-Difluorophenoxy)-6'-((2,2-dimethyl-1,3-dioxolan-4-yl) was obtained as a white solid Methoxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (115.0 mg, 0.236 mmol, 41.2% yield). Mass spectrum (positive mode) m/e: 487.1 (M+H) + .

步驟D：在0℃下，向1-(4-(2,6-二氟苯氧基)-6'-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(115 mg，0.24 mmol)於4：1四氫呋喃(1.6 mL)/水(0.4 mL)中之經攪拌溶液中逐滴添加三氟乙酸(0.1 mL，1.35 mmol)。使所得溶液升溫至23℃且用TLC及LC-MS監測。3.5天後，藉由添加濃氫氧化銨溶液小心中和反應物，接著在減壓下移除THF。用水稀釋殘餘物，接著用二氯甲烷萃取三次。彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，用乙腈濕磨殘餘物，得到呈白色固體狀之1-(4-(2,6-二氟苯氧基)-6'-(2,3-二羥基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(47 mg，0.11 mmol，44.8%產 率)。1H NMR(400 MHz,DMSO-d6)δ ppm 9.21(1H,s),8.36(1H,d,J=2.2 Hz),8.23(1H,s),7.93(1H,dd,J=8.6,2.3 Hz),7.33-7.56(4H,m),7.02(1H,s),6.93(1H,d,J=8.6 Hz),4.92(1H,br.s.),4.64(1H,br.s.),4.32(1H,dd,J=11.0,4.5 Hz),4.19(1H,dd,J=10.9,6.6 Hz),3.82(1H,br.s.),3.44(2H,br.s.),2.65(3H,d,J=4.3 Hz)。質譜(ESI)m/z=447.1(M+H)。 Step D : To a solution of 1-(4-(2,6-difluorophenoxy)-6'-((2,2-dimethyl-1,3-dioxolane) at 0 °C 4-yl)methoxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (115 mg, 0.24 mmol) in 4:1 tetrahydrofuran (1.6 mL) / water (0.4 mL Trifluoroacetic acid (0.1 mL, 1.35 mmol) was added dropwise to the stirred solution. The resulting solution was warmed to 23 ° C and was monitored by TLC and LC-MS. After 3.5 days, the reaction was carefully neutralized by the addition of concentrated ammonium hydroxide solution, followed by removal of THF under reduced pressure. The residue was diluted with water and then extracted three times with dichloromethane. The organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentrating, the residue was triturated with EtOAc (EtOAc-EtOAc-EtOAc-EtOAc [3,3'-bipyridyl]-6-yl)-3-methylurea (47 mg, 0.11 mmol, 44.8% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.21 (1H, s), 8.36 (1H, d, J = 2.2 Hz), 8.23 (1H, s), 7.93 (1H, dd, J = 8.6, 2.3 Hz), 7.33 - 7.56 (4H, m), 7.02 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 4.92 (1H, br.s.), 4.64 (1H, br.s. ), 4.32 (1H, dd, J = 11.0, 4.5 Hz), 4.19 (1H, dd, J = 10.9, 6.6 Hz), 3.82 (1H, br.s.), 3.44 (2H, br.s.), 2.65 (3H, d, J = 4.3 Hz). Mass Spectrum (ESI) m/z = 447.1 (M+H).

實例849Example 849

1-(5'-氰基-6'-甲氧基-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(5'-Cyano-6'-methoxy-4-((5-methylpyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl)-3 -methylurea

步驟A：將5-溴-2-甲氧基菸鹼腈(252 mg，1.18 mmol)、雙(頻哪醇根基)二硼(452 mg，1.78 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(87 mg，0.24 mmol)、參(二亞苄基丙酮)二鈀(0)(110 mg，0.12 mmol)及乙酸鉀(351 mg，3.58 mmol)於無水N,N-二甲基乙醯胺(6 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。4小時後，冷卻反應物至室溫，接著將1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(165 mg，0.49 mmol)及4 M碳酸鉀水溶液(0.37 mL，1.48 mmol)添加至反應混合物中。將燒瓶脫氣且用氬氣回填。加熱所得反應物至90℃且用TLC及LC-MS監測。總共20小時後，冷卻反應物至室溫，接著用鹽水稀釋。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-8%甲醇之 二氯甲烷)，得到黃色膜狀物，用乙腈濕磨該膜狀物，得到呈白色固體狀之1-(5'-氰基-6'-甲氧基-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(81 mg，0.21 mmol，42.7%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.23(1H,s),8.72(1H,d,J=2.4 Hz),8.56(1H,d,J=2.4 Hz),8.32-8.44(2H,m),8.27(1H,s),7.61(2H,br.s.),6.93(1H,s),4.04(3H,s),2.66(3H,d,J=4.6 Hz),2.35(3H,s)。質譜(正模式)m/e：391.1(M+H)+。質譜(ESI)m/z=391.1(M+H)。 Step A : 5-Bromo-2-methoxynicotinonitrile (252 mg, 1.18 mmol), bis(pinacolyl)diboron (452 mg, 1.78 mmol), butyldi-1-adamantyl Phosphine n-BuPAd 2 (87 mg, 0.24 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (110 mg, 0.12 mmol) and potassium acetate (351 mg, 3.58 mmol) in anhydrous N,N- The stirred mixture in methyl acetamide (6 mL) was purified three times with argon and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 4 hours, the reaction was cooled to room temperature then 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea ( 165 mg, 0.49 mmol) and 4 M aqueous potassium carbonate (0.37 mL, 1.48 mmol) were added to the mixture. The flask was degassed and backfilled with argon. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After a total of 20 hours, the reaction was cooled to room temperature and then diluted with brine. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was diluted with dichloromethane, and then applied to a silica gel column (dichloromethane containing 0-8% methanol) to give a yellow film which was wet-milled with acetonitrile. 1-(5'-Cyano-6'-methoxy-4-((5-methylpyridin-3-yl)oxy)-[3,3'-bipyridine]-6- as a white solid 3-methylurea (81 mg, 0.21 mmol, 42.7% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.23 (1H, s), 8.72 (1H, d, J = 2.4 Hz), 8.56 (1H, d, J = 2.4 Hz), 8.32-8.44 (2H , m), 8.27 (1H, s), 7.61 (2H, br.s.), 6.93 (1H, s), 4.04 (3H, s), 2.66 (3H, d, J = 4.6 Hz), 2.35 (3H) , s). Mass spectrum (positive mode) m/e: 391.1 (M+H) + . Mass Spectrum (ESI) m/z = 391.1 (M+H).

遵循實例849中之程序，製備以下化合物： Following the procedure in Example 849 , the following compounds were prepared:

製備preparation

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(278 mg，6.95 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將N-(2-羥基乙基)甲烷磺醯胺(482 mg，3.47 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加5-溴-2-氟吡啶(0.2 mL，1.74 mmol)。5-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心加熱至85℃。用TLC及LC-MS監測反應。4小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-40%乙酸乙酯之己烷)純化淡黃色殘餘物，得到無色油狀物，其凝固成N-(2-((5-溴吡啶-2-基)氧基)乙基)甲烷磺醯胺(133 mg，0.45 mmol，25.9%產率)，其未經進一步純化即使用。1H NMR(500 MHz,DMSO-d6)δ ppm 8.29(1H,d,J=2.4 Hz),7.92(1H,dd,J=8.8,2.7 Hz),7.26(1H,s),6.85(1H,d,J=8.8 Hz),4.29(2H,t,J=5.6 Hz),3.27-3.37(2H,m),2.93(3H,s)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (278 mg, 6.95 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice water bath. After 20 minutes, N-(2-hydroxyethyl)methanesulfonamide (482 mg, 3.47 mmol) was added dropwise to the cold reaction solution by a syringe. After 1 hour, 5-bromo-2-fluoropyridine (0.2 mL, 1.74 mmol) was added dropwise at 0 °C. After the addition of 5-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully heated to 85 ° C. The reaction was monitored by TLC and LC-MS. After 4 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the pale yellow residue was purified mjjjjjjjjj (Ethyloxy)ethyl)methanesulfonamide (133 mg, 0.45 mmol, 25.9% yield) was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.29 (1H, d, J = 2.4 Hz), 7.92 (1H, dd, J = 8.8, 2.7 Hz), 7.26 (1H, s), 6.85 (1H) , d, J = 8.8 Hz), 4.29 (2H, t, J = 5.6 Hz), 3.27-3.37 (2H, m), 2.93 (3H, s).

實例855Example 855

1-(4-(2,6-二氟苯氧基)-2'-(2-羥基乙氧基)-[3,4'-聯吡啶]-6-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-2'-(2-hydroxyethoxy)-[3,4'-bipyridyl]-6-yl)-3-methylurea

步驟A：在冰水浴中冷卻含有60%氫化鈉於礦物油中之分散液(235 mg，5.89 mmol)於無水環戊基甲基醚(10 mL)中之乾燥小瓶。20分鐘後，由注射器將2-(四氫-2H-哌喃-2-基氧基)乙醇(0.53 mL，3.9 mmol)逐滴添加至冷反應溶液中。1小時後，在0℃下逐滴添加4-溴-2-氟吡啶(0.2 mL，1.95 mmol)。4-溴-2-氟吡啶添加完成後，使混合物升溫至23℃，接著小心升溫至85℃。用TLC及LC-MS監測反應。3小時後，冷卻反應物至室溫且攪拌隔夜。17小時後，用水小心淬滅反應物。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾並濃縮後，在矽膠上(含0-15%乙酸乙酯之己烷)純化淡黃色殘餘物，得到呈無色油狀之4-溴-2-(2-((四氫-2H-哌喃-2-基)氧基)乙氧基)吡啶(541 mg，1.79 mmol，92%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 7.97(1H,d,J=5.4 Hz),7.04(1H,dd,J=5.5,1.6 Hz),6.96-7.01(1H,m),4.62-4.67(1H,m),4.38-4.52(2H,m),3.99(1H,ddd,J=11.5,5.9,3.4 Hz),3.80-3.89(1H,m),3.74(1H,ddd,J=11.4,6.4,3.7 Hz),3.43-3.52(1H,m),1.74-1.85(1H,m),1.66-1.73(1H,m),1.45-1.62(4H,m)。 Step A : A dry vial containing 60% sodium hydride in mineral oil (235 mg, 5.89 mmol) in anhydrous cyclopentyl methyl ether (10 mL) was cooled in an ice water bath. After 20 minutes, 2-(tetrahydro-2H-piperidin-2-yloxy)ethanol (0.53 mL, 3.9 mmol) was added dropwise to a cold reaction solution by syringe. After 1 hour, 4-bromo-2-fluoropyridine (0.2 mL, 1.95 mmol) was added dropwise at 0 °C. After the addition of 4-bromo-2-fluoropyridine was completed, the mixture was allowed to warm to 23 ° C, then carefully warmed to 85 ° C. The reaction was monitored by TLC and LC-MS. After 3 hours, the reaction was cooled to rt and stirred overnight. After 17 hours, the reaction was carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentrating, the title compound was purified mjjjjjjjjj Methyl-2-yl)oxy)ethoxy)pyridine (541 mg, 1.79 mmol, 92% yield) was used without further purification. 1 H NMR (500 MHz, methylene chloride-d 2 ) δ δ 7.97 (1H, d, J = 5.4 Hz), 7.04 (1H, dd, J = 5.5, 1.6 Hz), 6.96-7.01 (1H, m) , 4.62-4.67 (1H, m), 4.38-4.52 (2H, m), 3.99 (1H, ddd, J = 11.5, 5.9, 3.4 Hz), 3.80-3.89 (1H, m), 3.74 (1H, ddd, J = 11.4, 6.4, 3.7 Hz), 3.43 - 3.52 (1H, m), 1.74-1.85 (1H, m), 1.66-1.73 (1H, m), 1.45-1.62 (4H, m).

步驟B：將4-溴-2-(2-((四氫-2H-哌喃-2-基)氧基)乙氧基)吡啶(332 mg，1.10 mmol)、雙(頻哪醇根基)二硼(419 mg，1.65 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(80 mg，0.22 mmol)、參(二亞苄基丙酮)二鈀(0)(103 mg，0.11 mmol)及乙酸鉀(327 mg，3.33 mmol)於無水N,N-二甲基乙醯胺(5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。加熱混合物至90℃且用LC-MS及TLC監測。3小時後，冷卻反應 物至室溫，接著將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(150.9 mg，0.421 mmol)及4.0 M碳酸鉀水溶液(0.33 mL，1.320 mmol)添加至反應混合物中。將燒瓶脫氣且用氬氣回填。加熱所得反應物至90℃且用TLC及LC-MS監測。19小時後，冷卻反應物至室溫，接著用鹽水稀釋。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-40%乙酸乙酯之二氯甲烷)，得到呈黃色膜狀之1-(4-(2,6-二氟苯氧基)-2'-(2-((四氫-2H-哌喃-2-基)氧基)乙氧基)-[3,4'-聯吡啶]-6-基)-3-甲基脲(75 mg，0.15 mmol，36%產率)。質譜(正模式)m/e：501.1(M+H)+。 Step B : 4-Bromo-2-(2-((tetrahydro-2H-piperidin-2-yl)oxy)ethoxy)pyridine (332 mg, 1.10 mmol), bis (pinadol) Diboron (419 mg, 1.65 mmol), butyldi-1-adamantylphosphine n-BuPAd 2 (80 mg, 0.22 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (103 mg, 0.11) The mixture of mmol and potassium acetate (327 mg, 3.33 mmol) in anhydrous N,N-dimethylacetamide (5 mL) was purified with argon three times and three times under vacuum. The mixture was heated to 90 ° C and monitored by LC-MS and TLC. After 3 hours, the reaction was cooled to room temperature then 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (150.9 mg, 0.421) Methyl acetate and 4.0 M aqueous potassium carbonate (0.33 mL, 1.320 mmol) were added to the mixture. The flask was degassed and backfilled with argon. The resulting reaction was heated to 90 ° C and was monitored by TLC and LC-MS. After 19 hours, the reaction was cooled to room temperature then diluted with brine. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was diluted with methylene chloride and then applied to a silica gel column (0-40% ethyl acetate in dichloromethane) to give 1-(4-(2,6) as a yellow film. -difluorophenoxy)-2'-(2-((tetrahydro-2H-piperidin-2-yl)oxy)ethoxy)-[3,4'-bipyridyl]-6-yl) -3-methylurea (75 mg, 0.15 mmol, 36% yield). Mass spectrum (positive mode) m/e: 501.1 (M+H) + .

步驟C：將1-(4-(2,6-二氟苯氧基)-2'-(2-((四氫-2H-哌喃-2-基)氧基)乙氧基)-[3,4'-聯吡啶]-6-基)-3-甲基脲(75 mg，0.15 mmol)及對甲苯磺酸吡錠PPTS(18 mg，0.07 mmol)於乙醇(5 mL)中之溶液加熱至55℃。用TLC及LC-MS監測反應。2.5小時後，冷卻反應物至23℃且攪拌隔夜。18.5小時後，在減壓下濃縮反應物，接著藉由取乾物加載於矽膠管柱上(含0-8%甲醇之二氯甲烷)純化棕色殘餘物，得到黃色膜狀物，用乙腈濕磨該膜狀物，得到呈白色固體狀之1-(4-(2,6-二氟苯氧基)-2'-(2-羥基乙氧基)-[3,4'-聯吡啶]-6-基)-3-甲基脲(22 mg，0.05 mmol，35.6%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.30(1H,s),8.32(1H,s),8.22(1H,d,J=5.4 Hz),7.35-7.53(4H,m),7.24(1H,dd,J=5.4,1.0 Hz),7.04(1H,s),7.07(1H,s),4.83(1H,t,J=5.6 Hz),4.31(2H,t,J=5.1 Hz),3.72(2H,q,J=5.4 Hz),2.64(3H,d,J=4.6 Hz)。質譜(正模式)m/e：417.1(M+H)+。 Step C : 1-(4-(2,6-Difluorophenoxy)-2'-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-[ A solution of 3,4'-bipyridyl]-6-yl)-3-methylurea (75 mg, 0.15 mmol) and p-toluenesulfonate PPTS (18 mg, 0.07 mmol) in ethanol (5 mL) Heat to 55 °C. The reaction was monitored by TLC and LC-MS. After 2.5 hours, the reaction was cooled to 23 ° C and stirred overnight. After 18.5 hours, the reaction was concentrated under reduced pressure. EtOAc (EtOAc m. The film was obtained as 1-(4-(2,6-difluorophenoxy)-2'-(2-hydroxyethoxy)-[3,4'-bipyridine]- as a white solid. 6-yl)-3-methylurea (22 mg, 0.05 mmol, 35.6% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.30 (1H, s), 8.32 (1H, s), 8.22 (1H, d, J = 5.4 Hz), 7.35-7.53 (4H, m), 7.24 (1H, dd, J = 5.4, 1.0 Hz), 7.04 (1H, s), 7.07 (1H, s), 4.83 (1H, t, J = 5.6 Hz), 4.31 (2H, t, J = 5.1 Hz) , 3.72 (2H, q, J = 5.4 Hz), 2.64 (3H, d, J = 4.6 Hz). Mass spectrum (positive mode) m/e: 417.1 (M+H) + .

遵循實例853中之程序，製備以下化合物： Following the procedure in Example 853 , the following compounds were prepared:

實例859Example 859

1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(噠嗪-4-基)吡啶-2-基)脲 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(pyridazin-4-yl)pyridin-2-yl)urea

步驟A：將1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(117 mg，0.35 mmol)、4-(三丁基錫烷基)噠嗪(260 mg，0.70 mmol)及肆(三苯基膦)鈀(43 mg，0.037 mmol)於無水甲苯(2 mL)中之混合物用氮氣脫氣。加熱混合物至90℃且用TLC及LC-MS監測。37小時後，冷卻反應物至室溫，接著在減壓下濃縮。將矽膠添加至褐色殘餘物 中，接著加載於矽膠管柱上(含0-15%甲醇之二氯甲烷)，得到膜狀物，用乙腈濕磨該膜狀物，得到呈白色固體狀之1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(噠嗪-4-基)吡啶-2-基)脲(24 mg，0.07 mmol，20.60%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.52-9.61(1H,m),9.34(1H,s),9.23-9.31(1H,m),8.44(1H,s),8.33-8.42(2H,m),7.98(1H,dd,J=5.4,2.2 Hz),7.64(1H,s),7.54(1H,br.s.),7.01(1H,s),2.66(3H,d,J=4.6 Hz),2.35(3H,s)。質譜(正模式)m/e：337.1(M+H)+。 Step A : 1-(5-Bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (117 mg, 0.35 mmol), 4- A mixture of (tributylstannyl)pyridazine (260 mg, 0.70 mmol) and hydrazine (triphenylphosphine)palladium (43 mg, 0.037 mmol) in anhydrous toluene (2 mL). The mixture was heated to 90 ° C and monitored by TLC and LC-MS. After 37 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. The tannin extract was added to the brown residue, which was then loaded onto a ruthenium tube column (containing 0-15% methanol in dichloromethane) to give a film which was triturated with acetonitrile to give a white solid. -methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(pyridazin-4-yl)pyridin-2-yl)urea (24 mg, 0.07 mmol, 20.60 %Yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.52-9.61 (1H, m), 9.34 (1H, s), 9.23-9.31 (1H, m), 8.44 (1H, s), 8.33-8.42 ( 2H,m), 7.98 (1H, dd, J = 5.4, 2.2 Hz), 7.64 (1H, s), 7.54 (1H, br.s.), 7.01 (1H, s), 2.66 (3H, d, J =4.6 Hz), 2.35 (3H, s). Mass spectrum (positive mode) m/e: 337.1 (M+H) + .

遵循實例859中之程序，製備以下化合物： Following the procedure in Example 859 , the following compounds were prepared:

遵循實例170中之程序，製備以下化合物： Following the procedure in Example 170, the following compounds were prepared:

遵循實例197中之程序，製備以下化合物： Following the procedure in Example 197, the following compounds were prepared:

實例865Example 865

1-乙基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(嗎啉基甲基)吡啶-2-基)脲 1-ethyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(morpholinylmethyl)pyridin-2-yl)urea

向2-(二環己基膦基)-2',4',6'-三異丙基-1,1'-聯苯、X-Phos(28 mg，0.059 mmol)、乙酸鈀(II)三聚體(20 mg，0.029 mmol)、1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-乙基脲(100 mg，0.28 mmol)及(嗎啉-4-基)甲基三氟硼酸鉀(120 mg，0.58 mmol)於無水環戊基甲基醚(2.5 mL)中之經攪拌溶液中添加碳酸銫(278 mg，0.85 mmol)。加熱反應混合物至95℃且用TLC及LC-MS監測。19小時後，將水(0.5 mL)添加至混合物中。用TLC及LC-MS監測反應。41小時後，冷卻反應物 至室溫，接著添加水以淬滅反應物。用二氯甲烷萃取混合物三次，接著彙集有機物且經無水硫酸鎂乾燥。過濾並在減壓下濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠管柱上(含0-15%甲醇之二氯甲烷)，得到黃色膜狀物，藉由溶解於4.2 mL DMF中，使用逆相HPLC(含5-30%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將灰白色固體鑑別為1-乙基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(嗎啉基甲基)吡啶-2-基)脲(13.9 mg，0.037 mmol，13.21%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.05(1H,s),8.33(1H,s),8.24(1H,d,J=2.2 Hz),8.11(1H,s),7.86(1H,br.s.),7.43(1H,s),6.86(1H,s),3.45-3.59(6H,m),3.07-3.15(2H,m),2.36-2.44(4H,m),2.34(3H,s),1.04(3H,t,J=7.1 Hz)。質譜(ESI)m/z=372.1(M+H)。 To 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, X-Phos (28 mg, 0.059 mmol), palladium (II) acetate Polymer (20 mg, 0.029 mmol), 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-ethylurea (100 mg, Add cesium carbonate (278 mg, 0.28 mmol) and (morpholin-4-yl)methyltrifluoroborate (120 mg, 0.58 mmol) in anhydrous cyclopentylmethyl ether (2.5 mL). 0.85 mmol). The reaction mixture was heated to 95 ° C and was monitored by TLC and LC-MS. After 19 hours, water (0.5 mL) was added to the mixture. The reaction was monitored by TLC and LC-MS. After 41 hours, the reaction was cooled to room temperature then water was added to quench the reaction. The mixture was extracted three times with dichloromethane, then the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was diluted with methylene chloride, and then applied to a silica gel column (with 0-15% methanol in dichloromethane) to give a yellow film obtained by dissolving in 4.2 mL DMF The membrane was further purified using reverse phase HPLC (5-30% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, EtOAc m. Pyridin-2-yl)urea (13.9 mg, 0.037 mmol, 13.21% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.05 (1H, s), 8.33 (1H, s), 8.24 (1H, d, J = 2.2 Hz), 8.11 (1H, s), 7.86 (1H) , br.s.), 7.43 (1H, s), 6.86 (1H, s), 3.45-3.59 (6H, m), 3.07-3.15 (2H, m), 2.36-2.44 (4H, m), 2.34 ( 3H, s), 1.04 (3H, t, J = 7.1 Hz). Mass Spectrum (ESI) m/z = 3721. (M+H).

遵循865中之程序，製備以下化合物： Following the procedure in 865, the following compounds were prepared:

實例870Example 870

1-(4-((6-溴-5-甲基吡啶-3-基)氧基)-6'-(2-羥基-2-甲基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(4-((6-bromo-5-methylpyridin-3-yl)oxy)-6'-(2-hydroxy-2-methylpropoxy)-[3,3'-bipyridine ]-6-yl)-3-methylurea

向1-(4-氟-6'-(2-羥基-2-甲基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(0.25 g，0.75 mmol)、6-溴-5-甲基吡啶-3-醇(0.155 g，0.823 mmol)於DMF(2.50 mL)中之經攪拌溶液中添加碳酸銫(0.365 g，1.12 mmol)。加熱所得反應物至100℃，維持4小時。冷卻反應物至室溫且用水淬滅。過濾沈澱物且在真空下乾燥，得到白色固體1-(4-((6-溴-5-甲基吡啶-3-基)氧基)-6'-(2-羥基-2-甲基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 (0.114 g，0.227 mmol，30.3%產率)。質譜(ESI)m/z=502.1,504.1(M+H)。1H NMR(DMSO-d6)δ 9.19(s,1H),8.34(d,J=2.4 Hz,1H),8.17-8.28(m,2H),7.95(dd,J=8.7,2.6 Hz,1H),7.80(d,J=2.4 Hz,1H),7.74(br.s,1H),6.94(s,1H),6.91(d,J=8.6 Hz,1H),4.63(s,1H),4.07(s,2H),2.69(d,J=4.6 Hz,3H),2.36(s,3H),1.20(s,6H)。 To 1-(4-fluoro-6'-(2-hydroxy-2-methylpropoxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (0.25 g, 0.75 To a stirred solution of 6-bromo-5-methylpyridin-3-ol (0.155 g, 0.823 mmol) in DMF (2.50 mL). The resulting reaction was heated to 100 ° C for 4 hours. The reaction was cooled to room temperature and quenched with water. The precipitate was filtered and dried under vacuum to give 1-(4-((6-bromo-5-methylpyridin-3-yl)oxy)-6'- (2-hydroxy-2-methylpropane) as a white solid. Oxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (0.114 g, 0.227 mmol, 30.3% yield). Mass Spectrum (ESI) m/z = 5021. 1 H NMR (DMSO-d 6 ) δ 9.19 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.17-8.28 (m, 2H), 7.95 (dd, J = 8.7, 2.6 Hz, 1H) ), 7.80 (d, J = 2.4 Hz, 1H), 7.74 (br.s, 1H), 6.94 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.63 (s, 1H), 4.07 (s, 2H), 2.69 (d, J = 4.6 Hz, 3H), 2.36 (s, 3H), 1.20 (s, 6H).

遵循實例870中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 870 , the following compounds were prepared using the appropriate reagents:

遵循實例870中之程序，製備以下化合物： Following the procedure in Example 870 , the following compounds were prepared:

遵循實例870中之程序，製備以下化合物： Following the procedure in Example 870 , the following compounds were prepared:

實例870Example 870

1-(4-((6-溴-5-甲基吡啶-3-基)氧基)-6'-(2-羥基-2-甲基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(4-((6-bromo-5-methylpyridin-3-yl)oxy)-6'-(2-hydroxy-2-methylpropoxy)-[3,3'-bipyridine ]-6-yl)-3-methylurea

向1-(4-氟-6'-(2-羥基-2-甲基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(0.25 g，0.75 mmol)、6-溴-5-甲基吡啶-3-醇(0.155 g，0.823 mmol)於DMF(2.50 mL)中之經攪拌溶液中添加碳酸銫(0.365 g，1.12 mmol)。加熱所得反應物至100℃，維持4小時。冷卻反應物至室溫且用水淬滅。過濾沈澱物且在真空下乾燥，得到白色固體1-(4-((6-溴-5-甲基吡啶-3-基)氧基)-6'-(2-羥基-2-甲基丙氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(0.114 g，0.227 mmol，30.3%產率)。質譜(ESI)m/z=502.1,504.1 (M+H)。1H NMR(DMSO-d6)δ 9.19(s,1H),8.34(d,J=2.4 Hz,1H),8.17-8.28(m,2H),7.95(dd,J=8.7,2.6 Hz,1H),7.80(d,J=2.4 Hz,1H),7.74(br.s,1H),6.94(s,1H),6.91(d,J=8.6 Hz,1H),4.63(s,1H),4.07(s,2H),2.69(d,J=4.6 Hz,3H),2.36(s,3H),1.20(s,6H)。 To 1-(4-fluoro-6'-(2-hydroxy-2-methylpropoxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (0.25 g, 0.75 To a stirred solution of 6-bromo-5-methylpyridin-3-ol (0.155 g, 0.823 mmol) in DMF (2.50 mL). The resulting reaction was heated to 100 ° C for 4 hours. The reaction was cooled to room temperature and quenched with water. The precipitate was filtered and dried under vacuum to give 1-(4-((6-bromo-5-methylpyridin-3-yl)oxy)-6'- (2-hydroxy-2-methylpropane) as a white solid. Oxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (0.114 g, 0.227 mmol, 30.3% yield). Mass Spectrum (ESI) m/z = 5021. 1 H NMR (DMSO-d 6 ) δ 9.19 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.17-8.28 (m, 2H), 7.95 (dd, J = 8.7, 2.6 Hz, 1H) ), 7.80 (d, J = 2.4 Hz, 1H), 7.74 (br.s, 1H), 6.94 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.63 (s, 1H), 4.07 (s, 2H), 2.69 (d, J = 4.6 Hz, 3H), 2.36 (s, 3H), 1.20 (s, 6H).

遵循實例870中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 870 , the following compounds were prepared using the appropriate reagents:

遵循實例198中之程序，製備以下化合物： Following the procedure in Example 198, the following compounds were prepared:

製備IIPreparation II

2-(6-胺基-4-((5-甲基吡啶-3-基)氧基)吡啶-3-基)乙醇 2-(6-Amino-4-((5-methylpyridin-3-yl)oxy)pyridin-3-yl)ethanol

向玻璃微波反應容器中饋入含1-(5-(2-羥基乙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.150 g，0.496 mmol)及碳酸銫(0.323 g，0.992 mmol)之DMF(2 mL)。攪拌反應混合物，且在120℃下於Discover型微波反應器(CEM,Matthews,NC)中加熱60分鐘。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至20% MeOH之CH2Cl2梯度溶離進行層析來純化，得到2-(6-胺基-4-((5-甲基吡啶-3-基)氧基)吡啶-3-基)乙醇(0.055 g，0.224 mmol，45.2%產率)。質譜(ESI)m/z=246.2(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.29(s,1H),8.21(s,1H),7.77(s,1H),7.47(s,1H),5.83(s,1H),3.75(t,J=6.8 Hz,2H),2.79(s,2H),2.40(s,3H)。 Feeding a glass microwave reaction vessel with 1-(5-(2-hydroxyethyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methyl Urea (0.150 g, 0.496 mmol) and cesium carbonate (0.323 g, 0.992 mmol) in DMF (2 mL). The reaction mixture was stirred and heated at 120 ° C for 60 minutes in a Discover type microwave reactor (CEM, Matthews, NC). The crude material was absorbed onto a silica gel plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 20% MeOH in CH 2 Cl 2 to afford 2 -(6-Amino-4-((5-methylpyridin-3-yl)oxy)pyridin-3-yl)ethanol (0.055 g, 0.224 mmol, 45.2% yield). Mass Spectrum (ESI) m/z =246.2 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.29 (s, 1H), 8.21. (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 5.83 (s, 1H), 3.75 ( t, J = 6.8 Hz, 2H), 2.79 (s, 2H), 2.40 (s, 3H).

實例958Example 958

4-氟-3-((5-(2-羥基乙基)-2-(3-甲基脲基)吡啶-4-基)氧基)苯甲酸 4-fluoro-3-((5-(2-hydroxyethyl)-2-(3-methylureido)pyridin-4-yl)oxy)benzoic acid

將4-氟-3-((5-(2-羥基乙基)-2-(3-甲基脲基)吡啶-4-基)氧基)苯甲酸甲酯(0.190 g，0.523 mmol)置於4：1 THF：水之溶液(2.5 mL)中，接著添加10% NaOH水溶液(0.418 mL，1.046 mmol)。在室溫下攪拌反應混合物2小時。用1 N HCl水溶液酸化反應物，接著用9：1 DCM：IPA萃取。收集有機萃取物且經MgSO4乾燥。過濾溶液且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之4-氟-3-((5-(2-羥基乙基)-2-(3-甲基脲基)吡啶-4-基)氧基)苯甲酸(0.127 g，0.364 mmol，69.5%產率)。質譜(ESI)m/z=350.0(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.12-8.19(m,2H),8.08(dd,J=7.6,2.2 Hz,1H),7.57(dd,J=9.8,8.8 Hz,1H),6.36(br,s,1H),3.91(t,J=6.1 Hz,2H),3.03(t,J=6.1 Hz,2H),2.80(s,3H)。 Methyl 4-fluoro-3-((5-(2-hydroxyethyl)-2-(3-methylureido)pyridin-4-yl)oxy)benzoate (0.190 g, 0.523 mmol) In a 4:1 THF: water solution (2.5 mL), a 10% aqueous NaOH solution (0.418 mL, 1.46 mmol) was then added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was acidified with 1 N aqueous HCl then extracted with 9:1 DCM:EtOAc. The organic extracts were collected and dried over MgSO 4. The solution was filtered and concentrated in vacuo. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column (12 g), at 0% to 10% MeOH gradient of CH 2 Cl 2 eluting chromatographed to afford 4-Fluoro-3-((5-(2-hydroxyethyl)-2-(3-methylureido)pyridin-4-yl)oxy)benzoic acid as a white solid (0.127 g, 0.364 mmol, 69.5% yield). Mass Spectrum (ESI) m/z =353. 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.12 - 8.19 (m, 2H), 8.08 (dd, J = 7.6, 2.2 Hz, 1H), 7.57 (dd, J = 9.8, 8.8 Hz, 1H), 6.36 (br, s, 1H), 3.91 (t, J = 6.1 Hz, 2H), 3.03 (t, J = 6.1 Hz, 2H), 2.80 (s, 3H).

實例959Example 959

4-氟-3-((5-(2-羥基乙基)-2-(3-甲基脲基)吡啶-4-基)氧基)-N-(3-甲氧基丙基)苄醯胺 4-fluoro-3-((5-(2-hydroxyethyl)-2-(3-methylureido)pyridin-4-yl)oxy)-N-(3-methoxypropyl)benzyl Guanamine

向50 mL圓底燒瓶中添加含4-氟-3-((5-(2-羥基乙基)-2-(3-甲基脲基)吡啶-4-基)氧基)苯甲酸(0.050 g，0.143 mmol)、3-甲氧基丙胺(0.016 mL，0.157 mmol)、HBTU(0.060 g，0.157 mmol)及二異丙基乙胺(0.075 mL，0.429 mmol)之DMF(5 mL)。在室溫下攪拌反應混合物18小時。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH及0.1% NH4OH之CH2Cl2梯度溶離進 行層析來純化。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘梯度5%至95%)進一步純化產物，得到呈白色固體狀之4-氟-3-((5-(2-羥基乙基)-2-(3-甲基脲基)吡啶-4-基)氧基)-N-(3-甲氧基丙基)苄醯胺(0.020 g，0.048 mmol，33.2%產率)。質譜(ESI)m/z=421.1(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.12(s,1H),7.80-7.96(m,2H),7.51(dd,J=9.9,8.7 Hz,1H),6.37(s,1H),3.89(t,J=6.2 Hz,2H),3.41-3.51(m,4H),3.34(s,3H),3.00(t,J=6.4 Hz,2H),2.80(s,3H),1.87(五重峰，J=6.5 Hz,2H)。質譜(ESI)m/z=446.2(M+H)。 Add 4-fluoro-3-((5-(2-hydroxyethyl)-2-(3-methylureido)pyridin-4-yl)oxy)benzoic acid (0.050) to a 50 mL round bottom flask g, 0.143 mmol), 3-methoxypropylamine (0.016 mL, 0.157 mmol), EtOAc (0.060 g, 0.157 mmol) and diisopropylethylamine (0.075 mL, 0.429 mmol) DMF (5 mL). The reaction mixture was stirred at room temperature for 18 hours. The crude material was absorbed onto a silicone plug and the layer was preliminarily filled with a 2D to 10% MeOH and 0.1% NH 4 OH in a gradient of CH 2 Cl 2 by prefilling a cartridge (12 g) via Redi-Sep. Analyze for purification. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient over 25 minutes from 5 to 95%) The product was further purified, to give a white solid of 4-fluoro-3 - (( 5-(2-Hydroxyethyl)-2-(3-methylureido)pyridin-4-yl)oxy)-N-(3-methoxypropyl)benzylamine (0.020 g, 0.048 mmol , 33.2% yield). Mass Spectrum (ESI) m/z = 4221. (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.12 (s, 1H), 7.78-7.96 (m, 2H), 7.51 (dd, J = 9.9, 8.7 Hz, 1H), 6.37 (s, 1H), 3.89 (t, J = 6.2 Hz, 2H), 3.41-3.51 (m, 4H), 3.34 (s, 3H), 3.00 (t, J = 6.4 Hz, 2H), 2.80 (s, 3H), 1.87 (five Heavy peak, J = 6.5 Hz, 2H). Mass Spectrum (ESI) m/z = 446.2 (M+H).

遵循實例959中之程序，製備以下化合物： Following the procedure in Example 959, the following compounds were prepared:

實例1017Example 1017

反-2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸乙酯 Ethyl trans-2-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylate

步驟A：向250 mL圓底燒瓶中添加含1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.0 g，8.06 mmol)、2-乙氧基羰基乙烯基酸頻哪醇酯(2.53 mL，11.29 mmol)、二氯雙(三苯基膦)鈀(ii)(0.566 g，0.806 mmol)及碳酸鈉(4.27 g，40.3 mmol)之4：1二噁烷：水混合物(75 mL)。用氬氣淨化反應物，接著在80℃下於氬氣下加熱18小時。用水稀釋反應混合物且用含10% MeOH之CH2Cl2萃取。經MgSO4乾燥有機萃取物。過濾溶液且在真空中濃縮。用乙醚濕磨粗產物，得到灰白色固體。使濾液 吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(80 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，將其與經濕磨之固體合併，得到(E)-3-(4-氟-6-(3-甲基脲基)吡啶-3-基)丙烯酸乙酯(1.5 g，5.61 mmol，69.6%產率)。質譜(ESI)m/z=268.0(M+H)。 Step A : To a 250 mL round bottom flask was added 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (2.0 g, 8.06 mmol), 2-ethoxycarbonylvinyl Acid pinacol ester (2.53 mL, 11.29 mmol), dichlorobis(triphenylphosphine)palladium (ii) (0.566 g, 0.806 mmol) and sodium carbonate (4.27 g, 40.3 mmol) of 4:1 dioxane : Water mixture (75 mL). The reaction was purged with argon and then heated at 80 ° C under argon for 18 hours. The reaction mixture was diluted with water and extracted with 2 Cl 2 containing the CH 10% MeOH. The organic was dried over MgSO 4 extracts. The solution was filtered and concentrated in vacuo. The crude product was triturated with ether to give an off-white solid. The filtrate was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexanes. The combined solids were combined to give (E) <RTI ID=0.0>#</RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; Mass Spectrum (ESI) m/z = 268.0 (M+H).

步驟B：向含60%氫化鈉之礦物油(0.072 g，1.800 mmol)於DMSO(4 mL)中之溶液中添加三甲基氧化鋶碘(0.392 g，1.779 mmol)。在室溫下攪拌反應混合物1小時。添加含(E)-3-(4-氟-6-(3-甲基脲基)吡啶-3-基)丙烯酸乙酯(0.317 g，1.186 mmol)之DMSO(3 mL)。在室溫下攪拌反應混合物24小時。用水稀釋反應混合物，用EtOAc萃取。經MgSO4乾燥有機萃取物。過濾溶液且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，得到呈白色固體狀之反-2-(4-氟-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸乙酯(0.0933 g，0.332 mmol，28.0%產率)。質譜(ESI)m/z=282.1(M+H)。 Step B : To a solution of 60% sodium hydride in mineral oil (0.072 g, 1.800 mmol) in DMSO (4 mL) The reaction mixture was stirred at room temperature for 1 hour. Ethyl (E)-3-(4-fluoro-6-(3-methylureido)pyridin-3-yl)acrylate (0.317 g, 1.186 mmol) in DMSO (3 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over MgSO 4 extracts. The solution was filtered and concentrated in vacuo. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc (EtOAc) Ethyltrans-2-(4-fluoro-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylate (0.0933 g, 0.332 mmol, 28.0% yield). Mass Spectrum (ESI) m/z = 2821. (M+H).

步驟C：向螺旋蓋小瓶中添加含反-2-(4-氟-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸乙酯(0.205 g，0.729 mmol)、3-羥基-5-甲基吡啶(0.113 g，1.004 mmol)及氟化銫(0.040 ml，1.093 mmol)之乙腈(4 mL)。在80℃下攪拌反應混合物2天。藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至4% MeOH之CH2Cl2梯度溶離進行層析來純化粗產物，得到呈白色固體狀之反-2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸乙酯(0.0566 g，0.153 mmol，20.97%產率)。質譜(ESI)m/z=371.2(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.48(s,1H),8.40(d,J=2.4 Hz,1H),7.97(s,1H),7.73(s,1H),6.42(s,1H),4.15(q,J=7.1 Hz,2H),2.80(3H,s),2.54-2.65(m,1H),2.47(s,3H),1.94-2.07(m,1H),1.56-1.63(m,1H),1.53(dd,J=8.6,6.6 Hz,1H),1.23(t,J=7.1 Hz,3H)。 Step C : Add ethyl trans-2-(4-fluoro-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylate (0.205 g, 0.729 mmol) to a screw cap vial, 3- Hydroxy-5-methylpyridine (0.113 g, 1.004 mmol) and cesium fluoride (0.040 ml, 1.093 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at 80 ° C for 2 days. By via Redi-Sep pre-packed silica gel column (12 g), at 0% to 4% MeOH gradient of CH 2 Cl 2 eluting crude product was purified by chromatography, to give a white solid of trans-2- (4-((5-Methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylate (0.0566 g, 0.153 mmol, 20.97%) rate). Mass Spectrum (ESI) m/z = 371.2 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.48 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 6.42 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.80 (3H, s), 2.54-2.65 (m, 1H), 2.47 (s, 3H), 1.94-2.07 (m, 1H), 1.56-1.63 (m, 1H), 1.53 (dd, J = 8.6, 6.6 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H).

實例1018Example 1018

1-(5-環丙基-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-cyclopropyl-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.112 g，0.317 mmol)呈懸浮液形式置於10：1甲苯：水(3：0.3 mL)中且用氬氣脫氣。添加環丙基三氟硼酸鉀(0.188 g，1.269 mmol)、乙酸鈀(10.68 mg，0.048 mmol)及磷酸鉀(0.202 g，0.951 mmol)，繼而添加2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯苯(RuPhos)(0.044 g，0.095 mmol)。在100℃下於氬氣氛圍下攪拌反應物18小時。冷卻反應物至室溫。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以0%至5% MeOH/DCM梯度溶離進行層析來純化，得到呈白色固體狀之1-(5-環丙基-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.048 g，0.153 mmol，48.2%產率)。質譜(ESI)m/z=315.1(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.17(d,J=2.45 Hz,1H),7.99(d,J=2.20 Hz,1H),7.89(s,1H),7.24(t,J=2.32 Hz,1H),6.49(s,1H),3.89(s,3H),2.82(s,3H),1.87-2.08(m,1H),0.94(dd,J=1.83,8.44 Hz,2H),0.74(dd,J=1.47,5.38 Hz,2H)。 1-(5-Bromo-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.112 g, 0.317 mmol) as a suspension In 10:1 toluene: water (3: 0.3 mL) and degassed with argon. Add cyclopropyltrifluoroborate (0.188 g, 1.269 mmol), palladium acetate (10.68 mg, 0.048 mmol) and potassium phosphate (0.202 g, 0.951 mmol), followed by 2-dicyclohexylphosphino-2',6 '-Diisopropoxy-1,1'-biphenyl (RuPhos) (0.044 g, 0.095 mmol). The reaction was stirred at 100 ° C under argon for 18 hours. The reaction was cooled to room temperature. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of EtOAc/EtOAc (EtOAc) 1-(5-Cyclopropyl-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.048 g, 0.153 mmol, 48.2% yield ). Mass Spectrum (ESI) m/z = 315.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.17 (d, J = 2.45 Hz, 1H), 7.99 (d, J = 2.20 Hz, 1H), 7.89 (s, 1H), 7.24 (t, J = 2.32 Hz, 1H), 6.49 (s, 1H), 3.89 (s, 3H), 2.82 (s, 3H), 1.87-2.08 (m, 1H), 0.94 (dd, J = 1.83, 8.44 Hz, 2H), 0.74 (dd, J = 1.47, 5.38 Hz, 2H).

實例1019Example 1019

1-(5-(反-2-(羥基甲基)環丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(trans-2-(hydroxymethyl)cyclopropyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

向50 mL圓底燒瓶中添加含反-2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸乙酯(0.025 g，0.067 mmol)之THF(1 mL)。在0℃下添加含1.5 M氫化二異丁基鋁之甲苯(0.10 mL，0.150 mmol)，且在0℃下攪拌反應混合物。1小時後，再添加含1.5 M氫化二異丁基鋁之甲苯(0.10 mL，0.150 mmol)。再攪拌反應物1小時。用洛瑟耳氏鹽(Rochelle's salt)水溶液淬滅反應物，且用EtOAc萃取。收集有機萃取物且經MgSO4乾燥。過濾溶液且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之1-(5-(反-2-(羥基甲基)環丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.020 g，0.061 mmol，90%產率)。質譜(ESI)m/z=329.2(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.30(s,1H),8.22(d,J=2.45 Hz,1H),7.91(s,1H),7.48(s,1H),6.44(s,1H),3.53(dd,J=2.93,6.36 Hz,2H),2.77-2.86(m,3H),2.41(s,3H),1.82-1.97(m,1H),1.42(d,J=7.83 Hz,1H),1.01(td,J=5.07,8.44 Hz,1H),0.91(td,J=5.20,8.93 Hz,1H)。藉由超臨界流體層析(250×30 mm AD-H管柱，使用42 g/min MeOH+(20 mM NH3)+78 g/min CO2)分離外消旋物質。 Adding trans-2-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopropane to a 50 mL round bottom flask Ethyl formate (0.025 g, 0.067 mmol) in THF (1 mL). Toluene (0.10 mL, 0.150 mmol) containing 1.5 M diisobutylaluminum hydride was added at 0 ° C, and the reaction mixture was stirred at 0 °C. After 1 hour, additional 1.5 M toluene (0.10 mL, 0.150 mmol) of diisobutylaluminum hydride was added. The reaction was stirred for an additional 1 hour. The reaction was quenched with aqueous EtOAc (EtOAc)EtOAc. The organic extracts were collected and dried over MgSO 4. The solution was filtered and concentrated in vacuo. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 . 1-(5-(trans-2-(hydroxymethyl)cyclopropyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- as a white solid Methyl urea (0.020 g, 0.061 mmol, 90% yield). Mass Spectrum (ESI) m/z = 329.2 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.30 (s, 1H), 8.22 (d, J = 2.45 Hz, 1H), 7.91 (s, 1H), 7.48 (s, 1H), 6.44 (s, 1H), 3.53 (dd, J = 2.93, 6.36 Hz, 2H), 2.77-2.86 (m, 3H), 2.41 (s, 3H), 1.82-1.97 (m, 1H), 1.42 (d, J = 7.83 Hz) , 1H), 1.01 (td, J = 5.07, 8.44 Hz, 1H), 0.91 (td, J = 5.20, 8.93 Hz, 1H). By supercritical fluid chromatography (250 × 30 mm AD-H column, using 42 g / min MeOH + (20 mM NH 3) +78 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1022Example 1022

1-(5-(反-2-(2-羥基丙-2-基)環丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(trans-2-(2-hydroxypropan-2-yl)cyclopropyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 -methylurea

用甲苯使含反-2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸乙酯(0.025 g，0.067 mmol)之圓底燒瓶共沸，接著用氬氣淨化。將反應物首先溶解於THF(1 mL)中且冷卻至0℃。向溶液中逐滴添加1.6 M甲基鋰於乙醚中之溶液(0.316 ml，0.506 mmol)。5分鐘後，使反應物升溫至室溫且攪拌1小時。混合物變成黃色。用飽和氯化銨溶液淬滅反應物且用EtOAc萃取。收集有機層且經MgSO4乾燥。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之外消旋1-(5-(反-2-(2-羥基丙-2-基)環丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.022 g，0.062 mmol，91%產率)。質譜(ESI)m/z=357.3(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.27-8.37(m,1H),8.22(d,J=2.45 Hz,1H),7.91(s,1H),7.49(s,1H),6.41(s,1H),2.81(s,3H),2.41(s,3H),2.04(td,J=5.17,8.99 Hz,1H),1.27(s,6H),1.22(td,J=5.72,8.62 Hz,1H),1.04(td,J=4.52,10.27 Hz,1H),0.91(td,J=5.04,8.99 Hz,1H)。藉由超臨界流體層析(250×30 mm OJ-H管柱，使用24 g/min MeOH+(20 mM NH3)+96 g/min CO2)分離外消旋物質。 Ethyl trans-2-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylate (0.025) A round bottom flask of g, 0.067 mmol) was azeotroped and then purged with argon. The reaction was first dissolved in THF (1 mL) and cooled to 0 °C. A solution of 1.6 M methyllithium in diethyl ether (0.316 ml, 0.506 mmol) was added dropwise to the solution. After 5 minutes, the reaction was allowed to warm to rt and stirred 1 hr. The mixture turned yellow. The reaction was quenched with saturated aq. The organic layer was collected and dried over MgSO 4. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 . Racemic 1-(5-(trans-2-(2-hydroxypropan-2-yl)cyclopropyl)-4-((5-methylpyridin-3-yl)oxy)pyridine as a white solid 2-yl)-3-methylurea (0.022 g, 0.062 mmol, 91% yield). Mass Spectrum (ESI) m/z = 357.3 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.27-8.37 (m, 1H), 8.22 (d, J = 2.45 Hz, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 6.41 ( s, 1H), 2.81 (s, 3H), 2.41 (s, 3H), 2.04 (td, J = 5.17, 8.99 Hz, 1H), 1.27 (s, 6H), 1.22 (td, J = 5.72, 8.62 Hz , 1H), 1.04 (td, J = 4.52, 10.27 Hz, 1H), 0.91 (td, J = 5.04, 8.99 Hz, 1H). By supercritical fluid chromatography (250 × 30 mm OJ-H column, using 24 g / min MeOH + (20 mM NH 3) +96 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1025Example 1025

1-(5-(3-羥基丙-1-烯-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(3-hydroxyprop-1-en-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：在室溫下，於氮氣下，由注射器向NaI(2.998 g，20.0 mmol)於15 mL乙腈中之經攪拌溶液中逐滴添加TMS-Cl(2.530 mL，20.0 mmol)，繼而添加H2O(0.180 mL，10.0 mmol)及丙-2-炔-1-醇(0.532 mL，10 mmol)。攪拌1小時後，藉由添加水(20 mL)淬滅反應物。用Et2O萃取混合物。合併有機層，且用10%亞硫酸氫鈉溶液、飽和碳酸氫鈉及鹽水洗滌。經MgSO4乾燥有機層，過濾且濃縮，得到呈 黃色油狀之2-碘丙-2-烯-1-醇(0.920 g，5.00 mmol，50%產率)。 Step A : TMS-Cl (2.530 mL, 20.0 mmol) was added dropwise from a syringe to a stirred solution of NaI (2.998 g, 20.0 mmol) in 15 mL of acetonitrile under nitrogen at room temperature, followed by H 2 O (0.180 mL, 10.0 mmol) and prop-2-yn-1-ol (0.532 mL, 10 mmol). After stirring for 1 hour, the reaction was quenched by water (20 mL). The mixture was extracted with Et 2 O. The organic layers were combined and washed with aq. 10% sodium hydrogen hydrogen sulfate, saturated sodium hydrogen carbonate and brine. The organic layer was dried over MgSO 4, filtered and concentrated to give a yellow oil of 2-iodo-2-en-1-ol (0.920 g, 5.00 mmol, 50 % yield).

步驟B：在0℃下，於氮氣下，向2-碘丙-2-烯-1-醇(0.920 g，5.00 mmol)於10 mL DCM中之經攪拌溶液中添加咪唑(0.409 g，6.00 mmol)，繼而添加TBDMS-Cl(0.829 g，5.50 mmol)於DCM(5 mL)中之溶液。使反應物升溫至室溫且攪拌18小時。用DCM稀釋反應物，且用2 N HCl水溶液、10%亞硫酸氫鈉及飽和碳酸氫鈉洗滌。合併有機層，經MgSO4乾燥，過濾且濃縮。藉由經SNAP矽膠管柱(50 g)，用戊烷溶離進行層析來純化粗物質，得到第三丁基(2-碘烯丙氧基)二甲基矽烷(0.654 g，2.19 mmol，43.9%產率)。 Step B : Add imidazole (0.409 g, 6.00 mmol) to a stirred solution of 2-iodoprop-2-en-1-ol (0.920 g, 5.00 mmol) in 10 mL DCM at 0 ° C. Then, a solution of TBDMS-Cl (0.829 g, 5.50 mmol) in DCM (5 mL) was added. The reaction was allowed to warm to rt and stirred for 18 h. The reaction was diluted with DCM and washed with aq. EtOAc EtOAc. The combined organic layers were dried with MgSO 4 The crude material was purified by chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) %Yield).

步驟C：在室溫下，於氮氣下，向1-甲基-3-(4-(5-甲基吡啶-3-基氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)脲(0.443 g，1.15 mmol)於4：1二噁烷：水(11 mL)中之經攪拌懸浮液中依序添加第三丁基(2-碘烯丙氧基)二甲基矽烷(0.344 g，1.15 mmol)、碳酸鈉(0.611 g，5.76 mmol)。用氮氣淨化混合物10分鐘。添加Pd(PPh3)4(0.133 g，0.115 mmol)，且加熱反應物至80℃。18小時後，冷卻反應物至室溫且分配於DCM與水之間。合併有機層，經MgSO4乾燥，過濾且濃縮。藉由經SNAP矽膠管柱(50 g)，以含30%丙酮之己烷梯度溶離進行層析來純化粗物質，得到1-(5-(3-(第三丁基二甲基矽烷氧基)丙-1-烯-2-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.320 g，0.747 mmol，64.8%產率)。質譜(ESI)m/z=428.9(M+H)。 Step C : 1-methyl-3-(4-(5-methylpyridin-3-yloxy)-5-(4,4,5,5-tetramethyl) at room temperature under nitrogen Base-1,3,2-dioxaboron Benzyl-2-pyridin-2-yl)urea (0.443 g, 1.15 mmol) in a stirred suspension of 4:1 dioxane: water (11 mL). Allyloxy) dimethyl decane (0.344 g, 1.15 mmol), sodium carbonate (0.611 g, 5.76 mmol). The mixture was purged with nitrogen for 10 minutes. Pd(PPh 3 ) 4 (0.133 g, 0.115 mmol) was added and the reaction was heated to 80 °C. After 18 hours, the reaction was cooled to rt and partitioned between DCM and water. The combined organic layers were dried with MgSO 4 The crude material was purified by chromatography on a SNAP cartridge (50 g) eluting with a gradient of 30% acetone in hexanes to afford 1-(5-(3-(t-butyl dimethyl decyloxy). )prop-1-en-2-yl)-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (0.320 g, 0.747 mmol, 64.8% yield) ). Mass Spectrum (ESI) m/z = 428.9 (M+H).

步驟D：向25 mL圓底燒瓶中添加含1-(5-(3-((第三丁基二甲基矽烷基)氧基)丙-1-烯-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.200 g，0.467 mmol)及1.0 M氟化四丁基銨於THF中之溶液(0.467 mL，0.467 mmol)之THF(1 mL)。在室溫下攪拌反應混合物1.5小時。用飽和NH4Cl稀釋反應混合物且用EtOAc萃取。用水洗滌有機萃取物且經MgSO4乾燥。過濾溶液且在真空中濃縮，得到呈黃色油狀之粗物 質。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之1-(5-(3-羥基丙-1-烯-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.147 g，0.468 mmol，100%產率)。質譜(ESI)m/z=315.1(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.33(s,1H),8.24(d,J=2.4 Hz,1H),8.13(s,1H),7.52(s,1H),6.50(s,1H),5.51(d,J=1.7 Hz,1H),5.23-5.38(m,1H),4.45(s,2H),2.85(s,3H),2.42(s,3H)。 Step D : Add to a 25 mL round bottom flask containing 1-(5-(3-((t-butyldimethyl)alkyl)oxy)prop-1-en-2-yl)-4-(( a solution of 5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.200 g, 0.467 mmol) and 1.0 M tetrabutylammonium fluoride in THF (0.467 mL, 0.467 mmol) of THF (1 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with saturated NH 4 Cl and extracted with EtOAc. Dried over MgSO 4 organic extracts were washed with water and. The solution was filtered and concentrated in vacuo to give a crude material. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column (12 g), at 0% to 10% MeOH gradient of CH 2 Cl 2 eluting chromatographed to afford 1-(5-(3-hydroxyprop-1-en-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- as a white solid Methyl urea (0.147 g, 0.468 mmol, 100% yield). Mass Spectrum (ESI) m/z = 315.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.33 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 6.50 (s, 1H), 5.51 (d, J = 1.7 Hz, 1H), 5.23-5.38 (m, 1H), 4.45 (s, 2H), 2.85 (s, 3H), 2.42 (s, 3H).

實例1026Example 1026

1-(5-(1-羥基丙-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(1-hydroxypropan-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

向小瓶中添加含1-(5-(3-羥基丙-1-烯-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.060 g，0.191 mmol)及濕的10重量%(以乾物計)鈀/活性碳(0.020 g，0.019 mmol)之1：1 EtOH：MeOH(4 ml)。用H2(g)淨化反應混合物且在室溫下攪拌3天。經針筒栓塞(syringe plug)過濾反應混合物且濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之1-(5-(1-羥基丙-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.023 g，0.073 mmol，38.1%產率)。質譜(ESI)m/z=317.1(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.31(s,1H),8.23(d,J=2.4 Hz,1H),8.10(s,1H),7.50(s,1H),6.42(s,1H),3.81(dd,J=10.6,6.7 Hz,1H),3.69(dd,J=10.6,6.7 Hz,1H),3.21-3.25(m,1H),2.82(s,3H),2.41(s,3H),1.35(d,J=7.1 Hz,3H)。藉由超臨界流體層析(250 mm×21 mm Lux-2管柱，使用17.5 g/min EtOH(20 mM NH3)+32.5 g/min CO2)分離外消旋物質。 Add 1-(5-(3-hydroxyprop-1-en-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 to the vial Methyl urea (0.060 g, 0.191 mmol) and wet 10% by weight (dry basis) palladium/activated carbon (0.020 g, 0.019 mmol) in 1:1 EtOH:MeOH (4 ml). The reaction mixture was purified with H 2 (g) and stirred at room temperature for 3 days. The reaction mixture was filtered through a syringe plug and concentrated. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 . 1-(5-(1-hydroxypropan-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea as a white solid 0.023 g, 0.073 mmol, 38.1% yield). Mass Spectrum (ESI) m/z = 317.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.31 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.50 (s, 1H), 6.42 (s, 1H), 3.81 (dd, J = 10.6, 6.7 Hz, 1H), 3.69 (dd, J = 10.6, 6.7 Hz, 1H), 3.21-3.25 (m, 1H), 2.82 (s, 3H), 2.41 (s) , 3H), 1.35 (d, J = 7.1 Hz, 3H). By supercritical fluid chromatography (250 mm × 21 mm Lux- 2 column, using 17.5 g / min EtOH (20 mM NH 3) +32.5 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1029Example 1029

(Z)-1-(4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)-3-甲基脲 (Z)-1-(4-((1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)-5-(2-ethoxyethylene) Pyridin-2-yl)-3-methylurea

步驟A：向1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(1.18 g，4.76 mmol)及(Z)-三丁基(2-乙氧基乙烯基)錫烷(2.062 mL，5.71 mmol)於甲苯(25 mL)中之經攪拌溶液中添加Pd(PPh3)4(0.550 g，0.476 mmol)。加熱反應物至110℃且繼續攪拌16小時。濃縮混合物，且藉由經Redi-Sep預裝填矽膠管柱(40 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析 來純化粗產物，得到呈黃色粉末狀之(Z)-1-(5-(2-乙氧基乙烯基)-4-氟吡啶-2-基)-3-甲基脲(0.291 g，1.216 mmol，25.6%產率)。質譜(ESI)m/z=240.1(M+H)。 Step A : To 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (1.18 g, 4.76 mmol) and (Z)-tributyl(2-ethoxyvinyl) Pd(PPh 3 ) 4 (0.550 g, 0.476 mmol) was added to a stirred solution of stanane (2.062 mL, 5.71 mmol) in toluene (25 mL). The reaction was heated to 110 ° C and stirring was continued for 16 hours. The mixture was concentrated and purified by chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) 1-(5-(2-ethoxyvinyl)-4-fluoropyridin-2-yl)-3-methylurea (0.291 g, 1.216 mmol, 25.6% yield). Mass Spectrum (ESI) m/z = 240.1 (M+H).

步驟B：在23℃下，向含有5-羥基-1,6-二甲基吡啶-2(1H)-酮(0.120 g，0.862 mmol)於無水DMF(1.2 mL)中之小瓶中分數份添加(Z)-1-(5-(2-乙氧基乙烯基)-4-氟吡啶-2-基)-3-甲基脲(0.140 g，0.585 mmol)及碳酸銫(0.572 g，1.756 mmol)。鹼添加完成後，加熱反應物至100℃且用LC-MS監測。6小時後，冷卻反應物至室溫。用水稀釋反應混合物且用EtOAc萃取。經MgSO4乾燥有機萃取物。過濾溶液且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈淡黃色固體狀之(Z)-1-(4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)-3-甲基脲(0.157 g，0.438 mmol，74.9%產率)。質譜(ESI)m/z=359.1(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.84(1H,s),7.37(1H,d,J=9.8 Hz),6.54(1H,d,J=9.5 Hz),6.44(1H,d,J=7.1 Hz),6.35(1H,s),5.53(1H,d,J=7.1 Hz),4.05(2H,d,J=7.1 Hz),3.62(3H,s),2.82(3H,s),2.28(3H,s),1.37(3H,t,J=7.1 Hz)。 Step B : Add a fraction of a vial containing 5-hydroxy-1,6-lutidine-2(1H)-one (0.120 g, 0.862 mmol) in anhydrous DMF (1.2 mL) at 23 °C (Z)-1-(5-(2-ethoxyvinyl)-4-fluoropyridin-2-yl)-3-methylurea (0.140 g, 0.585 mmol) and cesium carbonate (0.572 g, 1.756 mmol) ). After the addition of the base was completed, the reaction was heated to 100 ° C and was monitored by LC-MS. After 6 hours, the reaction was cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over MgSO 4 extracts. The solution was filtered and concentrated in vacuo. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column (12 g), at 0% to 10% MeOH gradient of CH 2 Cl 2 eluting chromatographed to afford (Z)-1-(4-((1,2-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-5-(2) Ethoxyvinyl)pyridin-2-yl)-3-methylurea (0.157 g, 0.438 mmol, 74.9% yield). Mass Spectrum (ESI) m/z = 359.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.84 (1H, s), 7.37 (1H, d, J = 9.8 Hz), 6.54 (1H, d, J = 9.5 Hz), 6.44 (1H, d, J = 7.1 Hz), 6.35 (1H, s), 5.53 (1H, d, J = 7.1 Hz), 4.05 (2H, d, J = 7.1 Hz), 3.62 (3H, s), 2.82 (3H, s) , 2.28 (3H, s), 1.37 (3H, t, J = 7.1 Hz).

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

實例1032Example 1032

2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)乙酸第三丁酯 T-butyl 2-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)acetate

將含有1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.500 g，1.483 mmol)、1,2,3,4,5-五苯基-1'-(二第三丁基膦基)二茂鐵(Q-Phos)(0.105 g，0.148 mmol)、雙(亞苄基丙酮)鈀(0)(0.043 g，0.074 mmol)之乾燥小瓶用氬氣淨化。由注射器添加無水THF(8 mL)。5分鐘後，逐滴添加氯化(2-(第三丁氧基)-2-側氧基乙基)鋅(II)(8.90 ml，4.45 mmol)。鋅溶液添加完成後，將小瓶封蓋，且加熱混合物至65℃並攪拌18小時。LC-MS顯示仍存在一些起始物質。再添加1,2,3,4,5-五苯基-1'-(二第三丁基膦基)二茂鐵(Q-Phos)(0.105 g，0.148 mmol)、雙(亞苄基丙酮)鈀(0)(0.043 g，0.074 mmol)及氯化(2-(第三丁氧基)-2-側氧基乙基)鋅(II)(3.0 ml，1.5 mmol)。在65℃下攪拌反應混合物。6小時後，再添加氯化(2-(第三丁氧基)-2-側氧基乙基)鋅(II)(3.0 ml，1.5 mmol)，且攪拌反應混合物隔夜。濃縮反應混合物，用水稀釋且用DCM萃取。用飽和NaCl洗滌有機萃取物且經MgSO4乾燥。過濾溶液且在真空中濃縮，得到粗物質，使其吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(40 g)，以含0%至2.5% MeOH 之CH2Cl2梯度溶離進行層析來純化，得到呈灰白色固體狀之2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)乙酸第三丁酯(0.476 g，1.278 mmol，86%產率)。質譜(ESI)m/z=373.1(M+H)。1H NMR(500 MHz,MeOH-d 4)δ 8.34(s,1H),8.22(d,J=2.4 Hz,1H),8.08(s,1H),7.50(s,1H),6.44(s,1H),3.64(s,2H),2.83(s,3H),2.41(s,3H),1.42(s,9H)。 Will contain 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.500 g, 1.48 mmol), 1,2, 3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene (Q-Phos) (0.105 g, 0.148 mmol), bis(benzylideneacetone)palladium(0) ( A dry vial of 0.043 g, 0.074 mmol) was purged with argon. Anhydrous THF (8 mL) was added from a syringe. After 5 minutes, (2-(t-butoxy)-2-oxoethyl)zinc(II) chloride (8.90 ml, 4.45 mmol) was added dropwise. After the zinc solution was added, the vial was capped and the mixture was heated to 65 ° C and stirred for 18 hours. LC-MS showed some starting material still present. Add 1,2,3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene (Q-Phos) (0.105 g, 0.148 mmol), bis(benzylideneacetone) Palladium (0) (0.043 g, 0.074 mmol) and (2-(t-butoxy)-2-oxoethyl)zinc(II) chloride (3.0 ml, 1.5 mmol). The reaction mixture was stirred at 65 °C. After 6 hours, additional (2-(t-butoxy)-2-oxoethyl)zinc(II) chloride (3.0 ml, 1.5 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated, diluted with water and dried with DC. Dried over MgSO 4 and with organic extracts were washed with saturated NaCl. The solution was filtered and concentrated in vacuo to give the crude material was absorbed on silica plug, and by by Redi-Sep pre-packed silica gel column (40 g), containing CH 0% to 2.5% MeOH of 2 Cl 2 chromatography eluting gradient to afford an off-white solid of 2- (4 - ((5-methyl-pyridin-3-yl) oxy) -6- (3-methyl-ureido) pyridin-3 Base) tert-butyl acetate (0.476 g, 1.278 mmol, 86% yield). Mass Spectrum (ESI) m/z = 373.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.34 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.50 (s, 1H), 6.44 (s, 1H), 3.64 (s, 2H), 2.83 (s, 3H), 2.41 (s, 3H), 1.42 (s, 9H).

遵循實例1032中之程序，製備以下化合物： Following the procedure in Example 1032 , the following compounds were prepared:

實例1034Example 1034

1-(5-(2-羥基-2-甲基丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(2-hydroxy-2-methylpropyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

在0℃下，向裝有含2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)乙酸第三丁酯(0.033 g，0.089 mmol)之THF(1 mL)之圓底燒瓶中逐滴添加甲基鋰溶液(0.52 mL，0.572 mmol)。形成黃色沈澱。在0℃下攪拌混合物1小時。用飽和NH4Cl(水溶液)淬滅反應物且用DCM萃取。收集有機萃取物且經MgSO4乾燥。過濾溶液且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色 油狀之1-(5-(2-羥基-2-甲基丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.009 g，0.027 mmol，30.7%產率)。質譜(ESI)m/z=331.1(M+H)。1H NMR(500 MHz,MeOH-d 4 )δ 8.32(s,1H),8.21(s,1H),8.09(s,1H),7.49(s,1H),6.42(s,1H),3.35(s,2H),2.82(s,3H),2.41(s,3H),1.26(s,6H)。 At 0 ° C, charged with 2-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)acetate A solution of methyllithium (0.52 mL, 0.572 mmol) was added dropwise to a THF (1 mL) EtOAc. A yellow precipitate formed. The mixture was stirred at 0 ° C for 1 hour. With saturated NH 4 Cl (aq) The reaction was quenched and extracted with DCM. The organic extracts were collected and dried over MgSO 4. The solution was filtered and concentrated in vacuo. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 . 1-(5-(2-hydroxy-2-methylpropyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methyl as a white oil Urea (0.009 g, 0.027 mmol, 30.7% yield). Mass Spectrum (ESI) m/z = 331.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.32 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.49 (s, 1H), 6.42 (s, 1H), 3.35 ( s, 2H), 2.82 (s, 3H), 2.41 (s, 3H), 1.26 (s, 6H).

遵循實例486中之程序，製備以下化合物： Following the procedure in Example 486, the following compounds were prepared:

實例1036Example 1036

1-(5-(2-羥基丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(2-hydroxypropyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

用氬氣淨化裝有1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.100 g，0.297 mmol)之小瓶。添加THF(3 mL)，且冷卻溶液至-78℃。添加甲基鋰溶液(0.539 mL，0.593 mmol)，接著在5分鐘後，添加丁基鋰於己烷中之溶液(0.318 mL，0.445 mmol)。使混合物升溫至0℃且攪拌25分鐘。使橙色溶液冷卻返回至-78℃。添加環氧丙烷(0.042 ml，0.593 mmol)，且使反應混合物緩慢升溫至室溫。攪拌反應混合物18小時。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行 層析來純化，接著藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘梯度5%至95%)進一步純化，得到呈白色油狀之1-(5-(2-羥基丙基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲2,2,2-三氟乙酸鹽(0.008 g，0.019 mmol，6.27%產率)。質譜(ESI)m/z=317.0(M+H)。1H NMR(500 MHz,MeOH-d 4 )δ 8.42(s,1H),8.32(s,1H),8.18(d,J=6.8 Hz,1H),6.93(d,J=5.4 Hz,1H),6.60(br.s.,1H),3.92-4.11(m,1H),2.84-2.90(m,1H),2.82(s,3H),2.75-2.81(m,1H),2.49(s,3H),1.22(d,J=6.1 Hz,3H)。 Purification with argon containing 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.100 g, 0.297 mmol) Vial. THF (3 mL) was added and the solution was cooled to -78 °C. A solution of methyllithium (0.539 mL, 0.593 mmol) was added followed by a solution of butyl lithium in hexane (0.318 mL, 0.445 mmol). The mixture was warmed to 0 ° C and stirred for 25 minutes. The orange solution was allowed to cool back to -78 °C. Propylene oxide (0.042 ml, 0.593 mmol) was added and the reaction mixture was slowly warmed to room temperature. The reaction mixture was stirred for 18 hours. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (12 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 , followed by by a reverse phase preparative HPLC, containing the CH 0.1% TFA 3 CN / H 2 O for further purification (gradient over 25 minutes from 5 to 95%), as a white oil of 1- (5- (2-hydroxy-propyl 4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea 2,2,2-trifluoroacetate (0.008 g, 0.019 mmol, 6.27 %Yield). Mass Spectrum (ESI) m/z = 317.0 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.42 (s, 1H), 8.32 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 5.4 Hz, 1H) , 6.60 (br.s., 1H), 3.92-4.11 (m, 1H), 2.84-2.90 (m, 1H), 2.82 (s, 3H), 2.75-2.81 (m, 1H), 2.49 (s, 3H) ), 1.22 (d, J = 6.1 Hz, 3H).

實例1037Example 1037

1-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸第三丁酯 T-butyl 1-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylate

向25 mL圓底燒瓶中添加含有2-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)乙酸第三丁酯(0.160 g，0.430 mmol)及含60%氫化鈉之礦物油(0.069 g，1.718 mmol)的THF(4 mL)。攪拌反應混合物5分鐘，接著添加TMS-Cl(0.110 mL，0.859 mmol)。10分鐘後，添加1,2-二溴乙烷(0.037 mL，0.430 mmol)，且攪拌反應混合物18小時。添加雙(三甲基矽烷基)胺基鋰(0.859 mL，0.859 mmol)，且在室溫下攪拌反應混合物1小時。用飽和NH4Cl稀釋反應混合物且用DCM萃取。經MgSO4乾燥有機萃取物。過濾溶液且在真空中濃縮，得到粗物質。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化。藉由逆 相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘梯度5%至95%)進一步純化產物，得到呈白色玻璃狀之1-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環丙烷甲酸第三丁酯(0.005 g，0.010 mmol，2.35%產率)。質譜(ESI)m/z=399.3(M+H)。1H NMR(500 MHz,MeOH-d 4 )δ 8.43(s,1H),8.30(s,1H),8.09(s,1H),7.61(s,1H),6.40(s,1H),2.80(s,3H),2.45(s,3H),1.55-1.70(m,2H),1.39(s,9H),1.20-1.34(m,2H)。 Adding a third tributyl 2-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)acetate to a 25 mL round bottom flask Ester (0.160 g, 0.430 mmol) and THF (4 mL). The reaction mixture was stirred for 5 min then TMS-CI (0.110 mL, &lt After 10 minutes, 1,2-dibromoethane (0.037 mL, 0.430 mmol) was added and the mixture was stirred for 18 hr. Lithium bis(trimethyldecyl)amine (0.859 mL, 0.859 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Diluted with saturated NH 4 Cl and the reaction mixture was extracted with DCM. The organic was dried over MgSO 4 extracts. The solution was filtered and concentrated in vacuo to give a crude material. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column (4 g), containing CH 0% to 10% MeOH gradient of 2 Cl 2 chromatography eluting. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient over 25 minutes from 5 to 95%) The product was further purified, to give a white glassy form of 1- (4 - ((5 -Methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopropanecarboxylic acid tert-butyl ester (0.005 g, 0.010 mmol, 2.35% yield). Mass Spectrum (ESI) m/z = 399.3 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.43 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 6.40 (s, 1H), 2.80 ( s, 3H), 2.45 (s, 3H), 1.55-1.70 (m, 2H), 1.39 (s, 9H), 1.20-1.34 (m, 2H).

實例1038Example 1038

1-(4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-(2-氟乙基)吡啶-2-基)-3-甲基脲 1-(4-((1,2-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-5-(2-fluoroethyl)pyridine-2- 3-methylurea

向裝有含1-(4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-(2-羥基乙基)吡啶-2-基)-3-甲基脲(0.012 g，0.036 mmol)之DCM(1 mL)之小瓶中逐滴添加deoxo-fluor(9.97 μl，0.054 mmol)。在室溫下攪拌橙色溶液1小時。接著用塑膠量筒中之飽和碳酸氫鈉溶液淬滅反應混合物。將所得混合物轉移至分液漏斗中且用DCM萃取。經MgSO4乾燥經合併之有機層。過濾溶液且在真空中濃縮，得到呈白色油狀之粗物質。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈白色固體狀之1-(4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-(2-氟乙基)吡啶-2-基)-3-甲基脲(0.004 g，0.012 mmol，33.1%產率)。質譜(ESI)m/z=335.0(M+H)。1H NMR(400 MHz,DMSO-d 6)δ 8.97(s,1H),8.02(s,1H),7.36(d,J=9.8 Hz,1H),6.70(s,1H),6.40(d,J=9.8 Hz,1H),4.73(t,J=6.4 Hz,1H),4.61(t,J=6.4 Hz,1H),3.49(s,3H),3.06(t,J=6.3 Hz,1H),3.00(t,J=6.3 Hz,1H),2.67(d,J=4.7 Hz,3H),2.20(s,3H)。 To a solution containing 1-(4-((1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)-5-(2-hydroxyethyl) Deoxo-fluor (9.97 μl, 0.054 mmol) was added dropwise to a vial of pyridine-2-yl)-3-methylurea (0.012 g, 0.036 mmol) in DCM (1 mL). The orange solution was stirred at room temperature for 1 hour. The reaction mixture was then quenched with a saturated sodium bicarbonate solution in a plastic graduated cylinder. The resulting mixture was transferred to a sep. funnel and extracted with DCM. The combined organic layers were dried over the MgSO. The solution was filtered and concentrated in vacuo to give a crude material. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column (4 g), eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 . 1-(4-((1,2-Dimethyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-5-(2-fluoroethyl) as a white solid Pyridin-2-yl)-3-methylurea (0.004 g, 0.012 mmol, 33.1% yield). Mass Spectrum (ESI) m/z = 335.0 (M+H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.97 (s, 1H), 8.02 (s, 1H), 7.36 (d, J = 9.8 Hz, 1H), 6.70 (s, 1H), 6.40 (d, J = 9.8 Hz, 1H), 4.73 (t, J = 6.4 Hz, 1H), 4.61 (t, J = 6.4 Hz, 1H), 3.49 (s, 3H), 3.06 (t, J = 6.3 Hz, 1H) , 3.00 (t, J = 6.3 Hz, 1H), 2.67 (d, J = 4.7 Hz, 3H), 2.20 (s, 3H).

實例1039Example 1039

1-(5-(羥基甲基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(hydroxymethyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：將圓底燒瓶中之1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.200 g，0.593 mmol)溶解於THF(6 mL)中且用氬氣吹洗。在-78℃下添加甲基鋰溶液(1.078 mL，1.186 mmol)，且攪拌所得混合物5分鐘。添加丁基鋰溶液(1.271 mL，1.780 mmol)且攪拌20分鐘。添加DMF(0.115 mL，1.483 mmol)，且使反應混合物升溫至室溫並攪拌1小時。用飽和NH4Cl稀釋反應混合物且用EtOAc萃取。經MgSO4乾燥有機萃取物。過濾溶液且在真空中濃縮，得到粗物質。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，得到1-(5-甲醯基-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.128 g，0.447 mmol，75%產率)。 Step A : 1-(5-Bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.200 g, 0.593) in a round bottom flask Methyl) was dissolved in THF (6 mL) and washed with argon. A solution of methyllithium (1.078 mL, 1.186 mmol) was added at -78 °C, and the resulting mixture was stirred for 5 min. A solution of butyl lithium (1.271 mL, 1.780 mmol) was added and stirred for 20 minutes. DMF (0.115 mL, 1.383 mmol) was added and the mixture was warmed to room temperature and stirred 1 hr. The reaction mixture was diluted with saturated NH 4 Cl and extracted with EtOAc. The organic was dried over MgSO 4 extracts. The solution was filtered and concentrated in vacuo to give a crude material. The crude material was taken up on a silica gel plug and purified by chromatography on a pad of hexane (0% to 100% EtOAc) eluting with EtOAc (EtOAc) 5-Mercapto-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.128 g, 0.447 mmol, 75% yield).

步驟B：向1-(5-甲醯基-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.060 g，0.210 mmol)於MeOH(2 mL)中之溶液中添加硼氫化鈉(0.016 g，0.419 mmol)。在室溫下攪拌反應混合物2小時，接著在真空中濃縮。藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化粗產物，得到呈白色固體狀之1-(5-(羥基甲基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.007 g，0.024 mmol，11.59%產率)。質譜(ESI)m/z=389.0(M+H)。1H NMR(500 MHz,MeOH-d 4 )δ 8.33(s,1H),8.26(d,J=2.4 Hz,1H),8.19(s,1H),7.53(s,1H),6.43(s,1H),4.70(s,2H),2.82(s,3H),2.42(s,3H)。 Step B : To 1-(5-Methylmercapto-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.060 g, 0.210 mmol) Sodium borohydride (0.016 g, 0.419 mmol) was added to a solution in MeOH (2 mL). The reaction mixture was stirred at room temperature for 2 hr then concentrated in vacuo. Performed by gradient chromatography eluting Redi-Sep pre-packed silica gel column (12 g), at 0% to 10% MeOH CH 2 Cl 2 to the crude product was purified to give a white solid of 1- (5 -(Hydroxymethyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.007 g, 0.024 mmol, 11.59% yield). Mass Spectrum (ESI) m/z = 389.0 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.33 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.53 (s, 1H), 6.43 (s, 1H), 4.70 (s, 2H), 2.82 (s, 3H), 2.42 (s, 3H).

實例1040Example 1040

1-(5-(6,6-二甲基-3,6-二氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(6,6-Dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine- 2-yl)-3-methylurea

步驟A：向100 mL圓底燒瓶中添加含二異丙胺(1.1 mL，7.72 mmol)之THF(12 mL)且冷卻至-78℃。在-78℃下逐滴添加丁基鋰(5.25 ml，8.40 mmol)(1.6 M，於己烷中)且攪拌10分鐘。接著將混合物自乾冰浴中上提10分鐘，接著返回至乾冰浴中。將2,2-二甲基-四氫-哌喃-4-酮(0.930 ml，6.89 mmol)溶解於THF(12 mL)中，接著在-78℃下緩慢添加至LDA溶液中且攪拌45分鐘。緩慢添加溶解於THF(12 mL)中之N-苯基雙-三氟甲烷磺醯亞胺(2.71 g，7.58 mmol)，且在0℃下攪拌反應混合物2小時。用水淬滅反應混合物，且用己烷及乙醚萃取。經MgSO4乾燥經合併之有機層。過濾溶液且在真空中濃縮，得到呈橙色油狀之粗物質三氟甲烷磺酸6,6-二甲基-3,6-二氫-2H-哌喃-4-基酯與三氟甲烷磺酸2,2-二甲基-3,6-二氫-2H-哌喃-4-基酯之混合物(1.65 g，6.34 mmol，92%產率)。 Step A : To a 100 mL round bottom flask was added diisopropylamine (1.1 mL, 7.72 mmol) in THF (12 mL) and cooled to -78. Butyllithium (5.25 ml, 8.40 mmol) (1.6 M in hexanes) was added dropwise at -78 °C and stirred for 10 min. The mixture was then lifted from the dry ice bath for 10 minutes and then returned to a dry ice bath. 2,2-Dimethyl-tetrahydro-piperidone-4-one (0.930 ml, 6.89 mmol) was dissolved in THF (12 mL), then slowly added to the LDA solution at -78 °C and stirred for 45 min. . N-phenylbis-trifluoromethanesulfonimide (2.71 g, 7.58 mmol) dissolved in THF (12 mL) was slowly added, and the mixture was stirred at 0 ° C for 2 hr. The reaction mixture was quenched with water and extracted with EtOAc EtOAc. The combined organic layers were dried over the MgSO. Filtration of the solution and concentration in vacuo afforded the crude material, methylene trifluoromethanesulfonate, 6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl ester and trifluoromethanesulfonate as an orange oil. Mixture of acid 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl ester (1.65 g, 6.34 mmol, 92% yield).

步驟B：將三氟甲烷磺酸2,2-二甲基-3,6-二氫-2H-哌喃-4-基酯與三氟甲烷磺酸6,6-二甲基-3,6-二氫-2H-哌喃-4-基酯之混合物(1.65 g，6.34 mmol)、雙(頻哪醇根基)二硼(2.0 g，7.88 mmol)、(1,1'-雙(二苯基膦基)二茂鐵)二氯鈀(ii)(0.518 g，0.634 mmol)及乙酸鉀(1.867 g，19.02 mmol)於含二噁烷(30 mL)之圓底燒瓶中組合。在80℃下加熱此混合物2天。冷卻反應混合物，經矽藻土襯墊過濾且用乙酸乙酯洗滌。濃縮濾液且經矽膠襯墊用20% EtOAc：己烷過濾，定量地得到2-(2,2-二甲基-3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼與2-(6,6-二甲基-3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼之混合物。 Step B : 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate and 6,6-dimethyl-3,6 trifluoromethanesulfonate a mixture of dihydro-2H-pyran-4-yl ester (1.65 g, 6.34 mmol), bis(pinacolyl)diboron (2.0 g, 7.88 mmol), (1,1'-bis(diphenyl) The phosphinyl)ferrocene)dichloropalladium (ii) (0.518 g, 0.634 mmol) and potassium acetate (1.867 g, 19.02 mmol) were combined in a round bottom flask containing dioxane (30 mL). This mixture was heated at 80 ° C for 2 days. The reaction mixture was cooled, filtered over EtOAc EtOAc EtOAc The filtrate was concentrated and filtered through a pad of EtOAc EtOAc EtOAc (EtOAc) ,5,5-tetramethyl-1,3,2-dioxaboron And 2-(6,6-dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron a mixture.

步驟C：向小瓶中添加含2-(2,2-二甲基-3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼與2-(6,6-二甲基-3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼之混合物(0.283 g，1.186 mmol)、1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.200 g，0.593 mmol)、三環己基膦(0.033 g，0.119 mmol)、Pd2(dba)3(0.054 g，0.059 mmol)及K3PO4(1.369 mL，1.780 mmol)之二噁烷(4 mL)。在90℃下攪拌異質混合物18小時。使反應混合物冷卻至室溫且經MgSO4乾燥。使溶液吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至5% MeOH之CH2Cl2梯度溶離進行層析來純化，得到呈黃色油狀之1-(5-(2,2-二甲基-3,6-二氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲與1-(5-(6,6-二甲基-3,6-二氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲之混合物(0.200 g，0.543 mmol，92%產率)。藉由層析(LUX-2(2×15 cm)LUX-2(15×0.46 cm)，使用30%甲醇(NH4OH)/CO2)分離異構體，得到1-(5-(6,6-二甲基-3,6-二氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=369.1(M+H)。1H NMR(500 MHz,MeOH-d 4 )δ 8.28(s,1H),8.16(br.s.,1H),8.06(s,1H),7.41(s,1H),6.56(s,1H),5.84(s,1H),3.81(t,J=5.4 Hz,2H),2.83(s,3H),2.39-2.42(m,2H),2.39(s,3H),1.25(s,6H)。 Step C : Add 2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1 to the vial. 3,2-dioxaboron And 2-(6,6-dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron a mixture (0.283 g, 1.186 mmol), 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.200 g, 0.593 mmol), tricyclohexylphosphine (0.033 g, 0.119 mmol), Pd 2 (dba) 3 (0.054 g, 0.059 mmol) and K 3 PO 4 (1.369 mL, 1.780 mmol) of dioxane (4 mL). The heterogeneous mixture was stirred at 90 ° C for 18 hours. The reaction mixture was cooled to room temperature and dried over MgSO 4. The solution was absorbed on silica plug, and purified by chromatography by eluting a gradient of Redi-Sep pre-packed silica gel column (12 g), at 0% to 5% MeOH of CH 2 Cl 2, to give a yellow Oily 1-(5-(2,2-dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4-((5-methylpyridin-3-yl)oxyl Pyridin-2-yl)-3-methylurea with 1-(5-(6,6-dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4-(5 Mixture of -methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.200 g, 0.543 mmol, 92% yield). The isomer was separated by chromatography (LUX-2 (2×15 cm) LUX-2 (15×0.46 cm) using 30% methanol (NH 4 OH)/CO 2 ) to give 1-(5-(6) ,6-Dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- Methyl urea. Mass Spectrum (ESI) m/z = 369.1 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.28 (s, 1H), 8.16 (br.s., 1H), 8.06 (s, 1H), 7.41 (s, 1H), 6.56 (s, 1H) , 5.84 (s, 1H), 3.81 (t, J = 5.4 Hz, 2H), 2.83 (s, 3H), 2.39-2.42 (m, 2H), 2.39 (s, 3H), 1.25 (s, 6H).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1044Example 1044

1-(5-(2,2-二甲基四氫-2H-哌喃-4-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(2,2-Dimethyltetrahydro-2H-piperidin-4-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl) -3-methylurea

向高壓反應容器中添加含1-(5-(6,6-二甲基-3,6-二氫-2H-哌喃-4-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.073 g，0.190 mmol)、10重量%鈀/活性碳(0.202 g，0.190 mmol)之2.5：1 EtOH：DCM(7 mL)。用H2(g)淨化反應混合物一次，接著在800 psi H2(g)下攪拌3天。經針筒過濾器過濾反應溶液，且在減壓下濃縮濾液。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經20分鐘梯度5%至95%)純化粗物質，得到產物之三氟乙酸鹽。經Strata高效聚合固相萃取(SPE)過濾三氟乙酸鹽，得到呈白色固體狀之1-(5-(2,2-二甲基四氫-2H-哌喃-4-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.030 g，0.077 mmol，41%產率)。質譜(ESI)=387.3(M+H)。1H NMR(500 MHz,MeOH-d 4 )δ 8.19(d,J=2.4 Hz,1H),8.08(s,1H),8.00(d,J=2.2 Hz,1H),7.27(t,J=2.3 Hz,1H),6.47(s,1H),3.88-3.92(m,3H),3.78-3.87(m,2H),3.36(d,J=8.3 Hz,1H),2.82(s,3H),1.82(dd,J=9.8,4.4 Hz,3H),1.68(s,1H),1.31(s,3H),1.26(s,3H)。藉由超臨界流體層析(250 mm×21 mm AD-H管柱，使用19 g/min MeOH(+20 mM氨)+35 g/min CO2)分離外消旋物質。 Add 1-(5-(6,6-dimethyl-3,6-dihydro-2H-piperidin-4-yl)-4-((5-methoxypyridine-3) to a high pressure reaction vessel -yl)oxy)pyridin-2-yl)-3-methylurea (0.073 g, 0.190 mmol), 10% by weight palladium/activated carbon (0.202 g, 0.190 mmol) 2.5:1 EtOH: DCM (7 mL ). The reaction mixture was purified with H 2 (g) first, followed by stirring at 800 psi H 2 (g) 3 days. The reaction solution was filtered through a syringe filter, and the filtrate was concentrated under reduced pressure. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (20 min 5-95% gradient) to give crude material, trifluoroacetate salt of the product. The trifluoroacetate was filtered through Strata High Performance Polymeric Solid Phase Extraction (SPE) to give 1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- as a white solid. ((5-Methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.030 g, 0.077 mmol, 41% yield). Mass Spectrum (ESI) = 387.3 (M+H). 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.19 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.27 (t, J = 2.3 Hz, 1H), 6.47 (s, 1H), 3.88-3.92 (m, 3H), 3.78-3.87 (m, 2H), 3.36 (d, J = 8.3 Hz, 1H), 2.82 (s, 3H), 1.82 (dd, J = 9.8, 4.4 Hz, 3H), 1.68 (s, 1H), 1.31 (s, 3H), 1.26 (s, 3H). By supercritical fluid chromatography (250 mm × 21 mm AD- H column, using 19 g / min MeOH (+20 mM ammonia) +35 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

實例1047Example 1047

1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(2-側氧基環丁基)吡啶-2-基)脲 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(2-oxocyclocyclobutyl)pyridin-2-yl)urea

向含有攪拌棒之烘乾小瓶中饋入Pd2(dba)3(0.056 g，0.061 mmol)、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)(Xantphos)(0.078 g，0.135 mmol)、磷酸鉀(0.326 g，1.535 mmol) 及1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.207 g，0.614 mmol)。將小瓶用氬氣淨化。依序添加THF(6 mL)及環丁酮(0.069 mL，0.921 mmol)。用螺旋蓋將小瓶密封，且攪拌混合物並在80℃下加熱2天。使反應混合物冷卻至室溫。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以0%至10% MeOH/DCM梯度溶離進行層析來純化，且藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經20分鐘梯度5%至95%)進一步純化，得到1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(2-側氧基環丁基)吡啶-2-基)脲(0.065 g，0.199 mmol，32.4%產率)。質譜(ESI)=327.1(M+H)。 Feeding Pd 2 (dba) 3 (0.056 g, 0.061 mmol), (9,9-dimethyl-9H-dibenzopyran-4,5-diyl) double into a drying vial containing a stir bar (Diphenylphosphine) (Xantphos) (0.078 g, 0.135 mmol), potassium phosphate (0.326 g, 1.535 mmol) and 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy) Pyridin-2-yl)-3-methylurea (0.207 g, 0.614 mmol). The vial was purged with argon. THF (6 mL) and cyclobutanone (0.069 mL, 0.921 mmol) were added sequentially. The vial was sealed with a screw cap and the mixture was stirred and heated at 80 °C for 2 days. The reaction mixture was allowed to cool to room temperature. The crude material was absorbed onto a silicone plug and purified by chromatography on a Redi-Sep prefilled cartridge column (12 g), eluting with a 0% to 10% MeOH/DCM gradient, and prepared by reverse phase. HPLC type, the use of 0.1% TFA in CH 3 CN / H 2 O for further purification (20 min 5-95% gradient), to give 1-methyl-3- (4 - ((5-methyl-pyridin-3 -yl)oxy)-5-(2-oxocyclocyclobutyl)pyridin-2-yl)urea (0.065 g, 0.199 mmol, 32.4% yield). Mass Spectrum (ESI) = 327.1 (M+H).

1H NMR(500 MHz,MeOH-d 4 )δ 8.34(s,1H),8.22(d,J=2.2 Hz,1H),8.03(s,1H),7.50(s,1H),6.44(s,1H),4.62-4.72(m,1H),3.23-3.28(m,1H),2.98-3.10(m,1H),2.81(s,3H),2.46-2.58(m,1H),2.42(s,3H),2.27-2.38(m,1H)。 1 H NMR (500 MHz, MeOH- d 4 ) δ 8.34 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 6.44 (s, 1H), 4.62-4.72 (m, 1H), 3.23-3.28 (m, 1H), 2.98-3.10 (m, 1H), 2.81 (s, 3H), 2.46-2.58 (m, 1H), 2.42 (s, 3H), 2.27-2.38 (m, 1H).

遵循實例1047中之程序，製備以下化合物： Following the procedure in Example 1047 , the following compounds were prepared:

實例1049Example 1049

1-(5-(順-2-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(cis-2-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

向小瓶中添加含1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(2-側氧基環丁基)吡啶-2-基)脲(0.029 g，0.089 mmol)及硼氫化鈉(6.72 mg，0.178 mmol)之MeOH(1 mL)。在室溫下攪拌反應混合物2小時。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-(5-((1R,2R)-2-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.016 g，0.049 mmol，54.8%產率)。質譜(ESI)=329.0(M+H)。1H NMR(400 MHz,MeOH-d 4 )δ 8.47-8.55(m,1H),8.41(d,J=2.3 Hz,1H),8.09(s,1H),7.75(t,J=1.7 Hz,1H),6.39(s,1H),4.26(q,J=7.6 Hz,1H),3.57(q,J=8.9 Hz,1H),2.80(s,3H),2.44-2.52(m,3H),2.26-2.36(m,1H),2.13-2.24(m,1H),1.95(dt,J=10.4,9.0 Hz,1H),1.62-1.77(m,1H)。 Add 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(2-oxo-cyclobutyl)pyridin-2-yl)urea to the vial (0.029 g, 0.089 mmol) and sodium borohydride (6.72 mg, 0.178 mmol) MeOH (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column (4 g), containing CH 0% to 10% MeOH of 2 Cl 2 gradient eluting chromatographed to give 1 -(5-((1R,2R)-2-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.016 g, 0.049 mmol, 54.8% yield). Mass Spectrum (ESI) = 329.0 (M+H). 1 H NMR (400 MHz, MeOH- d 4 ) δ 8.47 - 8.55 (m, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 7.75 (t, J = 1.7 Hz, 1H), 6.39 (s, 1H), 4.26 (q, J = 7.6 Hz, 1H), 3.57 (q, J = 8.9 Hz, 1H), 2.80 (s, 3H), 2.44-2.52 (m, 3H), 2.26-2.36 (m, 1H), 2.13 - 2.24 (m, 1H), 1.95 (dt, J = 10.4, 9.0 Hz, 1H), 1.62-1.77 (m, 1H).

遵循實例1049中之程序，製備以下化合物： Following the procedure in Example 1049 , the following compounds were prepared:

實例1064Example 1064

1-(5-((3S,4R)-4-氟-3-甲氧基四氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((3S,4R)-4-fluoro-3-methoxytetrahydro-2H-piperid-3-yl)-4-((5-methylpyridin-3-yl)oxy Pyridin-2-yl)-3-methylurea

向小瓶中添加含1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.147 mmol)及Selectfluor(0.060 g，0.162 mmol)之MeOH(3 mL)。在40℃下攪拌反應混合物18小時。在真空中濃縮溶液，得到粗物質，且使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(4 g)，以含0%至5% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-(5-(4-氟-3-甲氧基四氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.041 g，0.105 mmol，71.5%產率)。藉由超臨界流體層析分離異構體，得到1- (5-((3S,4R)-4-氟-3-甲氧基四氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)=391.0(M+H)。 Add 1-(5-(5,6-dihydro-2H-piperidin-3-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl to the vial -3-methylurea (0.050 g, 0.147 mmol) and EtOAc (3 mL) EtOAc (EtOAc) The reaction mixture was stirred at 40 ° C for 18 hours. The solution was concentrated in vacuo to give the crude material, and absorbed crude material on silica plug, and by by Redi-Sep pre-packed silica gel column (4 g), at 0% to 5% MeOH CH 2 Cl of 2 gradient elution was carried out by chromatography to give 1-(5-(4-fluoro-3-methoxytetrahydro-2H-piperidin-3-yl)-4-((5-methylpyridine-3- Alkyloxypyridin-2-yl)-3-methylurea (0.041 g, 0.105 mmol, 71.5% yield). The isomers were separated by supercritical fluid chromatography to give 1-(5-((3S,4R)-4-fluoro-3-methoxytetrahydro-2H-pyran-3-yl)-4-( (5-Methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) = 391.0 (M+H).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1068Example 1068

1-(5-((3S,4S)-4-氟-3-羥基四氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((3S,4S)-4-fluoro-3-hydroxytetrahydro-2H-piperid-3-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine -2-yl)-3-methylurea

向小瓶中添加含1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.054 g，0.159 mmol)及Selectfluor (0.072 g，0.193 mmol)之10：1乙腈(1.5 ml)與水(0.15 ml)之混合物。在室溫下攪拌反應混合物18小時。在真空中濃縮反應混合物，接著使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-(5-(4-氟-3-羥基四氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.133 mmol，84%產率)。藉由超臨界流體層析(250 mm×30 mm AD-H管柱，使用20 g/min EtOH(+20 mM氨)+30 g/min CO2)分離異構體，接著藉由超臨界流體層析(250 mm×30 mm IC管柱，使用40 g/min MeOH(20 mM氨)+40 g/min CO2)進一步純化，得到1-(5-((3S,4S)-4-氟-3-羥基四氫-2H-哌喃-3-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)=377.1(M+H)。1H NMR(400 MHz,CDCl3)δ 1.96-2.11(m,1 H)2.30(br.s.,1 H)2.41(s,3 H)2.84(d,J=4.70 Hz,3 H)3.44-3.64(m,1 H)3.83(dd,J=11.74,8.02 Hz,1 H)3.96-4.15(m,2 H)5.32-5.62(m,1 H)6.11(s,1 H)7.26(br.s.,1 H)8.19-8.48(m,2 H)8.54(s,1 H)。 Add 1-(5-(5,6-dihydro-2H-piperidin-3-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl to the vial a mixture of 3-methylurea (0.054 g, 0.159 mmol) and Selectfluor (0.072 g, 0.193 mmol) in 10:1 acetonitrile (1.5 ml) and water (0.15 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, then the crude material was taken up on a silica gel plug and eluted with a gradient of 0% to 10% MeOH in CH 2 Cl 2 by prefilled with a Redi-Sep cartridge (12 g). Purification by chromatography gave 1-(5-(4-fluoro-3-hydroxytetrahydro-2H-piperidin-3-yl)-4-((5-methylpyridin-3-yl)oxy) Pyridin-2-yl)-3-methylurea (0.050 g, 0.133 mmol, 84% yield). Separation of isomers by supercritical fluid chromatography (250 mm × 30 mm AD-H column using 20 g/min EtOH (+20 mM ammonia) + 30 g/min CO 2 ) followed by supercritical fluid Chromatography (250 mm × 30 mm IC column, 40 g / min MeOH (20 mM ammonia) + 40 g / min CO 2 ) was further purified to give 1-(5-((3S,4S)-4-fluoro 3-Hydroxytetrahydro-2H-piperid-3-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) = 377.1 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 1.96-2.11 (m, 1 H) 2.30 (br.s., 1 H) 2.41 (s, 3 H) 2.84 (d, J = 4.70 Hz, 3 H) 3.44 -3.64 (m, 1 H) 3.83 (dd, J = 11.74, 8.02 Hz, 1 H) 3.96-4.15 (m, 2 H) 5.32-5.62 (m, 1 H) 6.11 (s, 1 H) 7.26 (br .s., 1 H) 8.19-8.48 (m, 2 H) 8.54 (s, 1 H).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1075Example 1075

1-(5-(5-羥基環己-1-烯-1-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(5-Hydroxycyclohex-1-en-1-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methyl Urea

步驟A：將1-(4-((5-甲氧基吡啶-3-基)氧基)-5-(1,4-二氧雜螺[4.5]癸-7-烯-7-基)吡啶-2-基)-3-甲基脲(142 mg，0.344 mmol)溶解於乙腈(1.0 mL)中，且添加數滴水，繼而添加四氟硼酸鋰(45.2 mg，0.482 mmol)。攪拌反應物2小時，且僅觀測到痕量所要產物。再添加1等分試樣之四氟硼酸鋰(45.2 mg，0.482 mmol)且再添加數滴水，且攪拌18小時。再添加5.0 mL乙腈且攪拌反應物2.5天，且顯示未向產物進展。接著濃縮反應混合物至約0.3 mL體積，且再添加1等分試樣之四氟硼酸鋰(45.2 mg，0.482 mmol)並攪拌18小時。最後，加熱反應混合物至80℃且攪拌6.5小時。現完全消耗起始物質。冷卻反應混合物至室溫且用二氯甲烷及乙腈稀釋。添加水，且分離各層。經硫酸鎂乾燥有機層。濃縮濾液，得到粗1-(4-((5-甲氧基吡啶-3-基)氧基)-5-(5-側氧基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=369.1 (M+H)。 Step A : 1-(4-((5-Methoxypyridin-3-yl)oxy)-5-(1,4-dioxaspiro[4.5]indole-7-ene-7-yl) Pyridin-2-yl)-3-methylurea (142 mg, 0.344 mmol) was dissolved in acetonitrile (1. <RTI ID=0.0></RTI><RTIID=0.0> The reaction was stirred for 2 hours and only traces of desired product were observed. An additional aliquot of lithium tetrafluoroborate (45.2 mg, 0.482 mmol) was added and a few more drops of water were added and stirred for 18 hours. An additional 5.0 mL of acetonitrile was added and the reaction was stirred for 2.5 days and showed no progress toward the product. The reaction mixture was then concentrated to a volume of about 0.3 mL, and an additional aliquot of lithium tetrafluoroborate (45.2 mg, 0.482 mmol) was added and stirred for 18 hours. Finally, the reaction mixture was heated to 80 ° C and stirred for 6.5 hours. The starting material is now completely consumed. The reaction mixture was cooled to room temperature and diluted with dichloromethane and EtOAc. Water was added and the layers were separated. The organic layer was dried over magnesium sulfate. The filtrate was concentrated to give crude 1-(4-((5-methoxypyridin-3-yl)oxy)-5-(5-oxooxycyclohex-1-en-1-yl)pyridine-2- Base)-3-methylurea. Mass Spectrum (ESI) m/z = 369.1 (M+H).

步驟B：將1-(4-((5-甲氧基吡啶-3-基)氧基)-5-(5-側氧基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲(127 mg，0.345 mmol)溶解於甲醇(2.0 mL)中且冷卻至0℃。接著添加硼氫化鈉(52.2 mg，1.379 mmol)，且在0℃下攪拌反應物30分鐘。接著用飽和碳酸氫鈉溶液淬滅反應物，接著在真空中濃縮。接著用水稀釋該物質，接著用EtOAc(3×20 mL)萃取。用鹽水(1×25 mL)洗滌經合併之有機層且經硫酸鎂乾燥。藉由逆相製備型HPLC，使用Phenomenex Luna管柱(5微米，C8(2)，100 Å，150×21.2 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度5%至95%)純化粗物質，得到所要產物之三氟乙酸鹽。使產物吸收於矽膠栓塞上，且藉由以含1%至10% 2 M氨之MeOH溶液之DCM溶離進行層析再純化，得到1-(5-(5-羥基環己-1-烯-1-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(9 mg，0.024 mmol，7.05%產率)。質譜(ESI)m/z=371.2(M+H)。1H NMR(400 MHz,CDCl3)δ 8.83(1H,br.s.),8.26-8.44(1H,m),8.20(1H,d,J=2.5 Hz),8.03(1H,d,J=2.2 Hz),7.95(1H,s),6.90(1H,t,J=2.3 Hz),6.21(1H,s),5.89-5.98(1H,m),4.35(1H,m,J=3.3 Hz),3.87(3H,s),2.87(3H,d,J=4.7 Hz),2.26-2.48(2H,m),1.90-2.01(1H,m),1.79-1.89(2H,m),1.63-1.76(4H,m)。 Step B : 1-(4-((5-Methoxypyridin-3-yl)oxy)-5-(5-oxocyclohex-1-en-1-yl)pyridin-2-yl -3 Methylurea (127 mg, 0.345 mmol) was dissolved in methanol (2.0 mL) and cooled to 0. Sodium borohydride (52.2 mg, 1.379 mmol) was then added and the reaction was stirred at 0 °C for 30 min. The reaction was then quenched with saturated aqueous sodium bicarbonate then concentrated in vacuo. The material was then diluted with water then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. By reverse phase preparative HPLC, a Phenomenex Luna column (5 micron, C8 (2), 100 Å, 150 x 21.2 mm, CH 3 CN/H 2 O with 0.1% TFA, gradient 5% to 25 minutes over 25 minutes) 95%) The crude material was purified to give the desired product as the trifluoroacetic acid salt. The product was absorbed onto a silicone plug and re-purified by chromatography in DCM containing 1% to 10% 2 M ammonia in MeOH to give 1-(5-(5-hydroxycyclohex-1-ene)- 1-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (9 mg, 0.024 mmol, 7.05% yield). Mass Spectrum (ESI) m/z = 371.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (1H, br. s.), 8.26-8.44 (1H, m), 8.20 (1H, d, J = 2.5 Hz), 8.03 (1H, d, J = 2.2 Hz), 7.95 (1H, s), 6.90 (1H, t, J = 2.3 Hz), 6.21 (1H, s), 5.89-5.98 (1H, m), 4.35 (1H, m, J = 3.3 Hz) , 3.87 (3H, s), 2.87 (3H, d, J = 4.7 Hz), 2.26-2.48 (2H, m), 1.90-2.01 (1H, m), 1.79-1.89 (2H, m), 1.63-1.76 (4H, m).

遵循實例1143中之程序，製備以下化合物： Following the procedure in Example 1143 , the following compounds were prepared:

實例1082Example 1082

1-(5-溴-4-((2,5-二側氧基吡咯啶-1-基)甲基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-((2,5-di-oxypyrrolidin-1-yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：向硝基甲烷(1.087 ml，20.16 mmol)於DMF(100 mL)中之溶液中添加氫化鈉(60%分散液)(0.363 g，15.12 mmol)，且攪拌混合物15分鐘。接著添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.50 g，10.08 mmol)，且在130℃下加熱所得溶液。加熱反應物2.5小時，接著冷卻至室溫。接著用水(125 mL)稀釋混合物且用乙酸乙酯(1×150 mL)萃取。在高真空下濃縮水層，得到經濃縮之殘餘物。將殘餘物溶解於極少量水中，且用10% MeOH：DCM(3×100 mL)萃取。經硫酸鎂乾燥經合併之有機層且濃縮濾液，得到粗的所要產物1-(5-溴-4-(硝基甲基)吡啶-2-基)-3-甲基脲(2.0 g，7.0 mmol，70%產率)。質譜(ESI)m/z=288.9,290.8(M+H)。 Step A : To a solution of nitromethane (1.087 ml, 20.16 mmol) in DMF (100 mL) Then 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (2.50 g, 10.08 mmol) was added, and the resulting solution was heated at 130 °C. The reaction was heated for 2.5 hours and then cooled to room temperature. The mixture was then diluted with water (125 mL) and ethyl acetate (1×150 mL). The aqueous layer was concentrated under high vacuum to give a concentrated residue. The residue was dissolved in a very small amount of water and extracted with 10% MeOH:EtOAc (EtOAc) The combined organic layers were dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ M, 70% yield). Mass Spectrum (ESI) m/z = 288.9, 290.8 (M+H).

步驟B：將1-(5-溴-4-(硝基甲基)吡啶-2-基)-3-甲基脲(1.5 g，5.3 mmol)於乙酸(27 ml)中製漿，且冷卻漿液至10℃。添加鋅粉(1.7 g，27 mmol)，且經8.5小時之時段使漿液緩慢升溫至室溫。接著再用乙酸(50 ml)稀釋反應漿液，接著過濾。用乙酸洗滌固體，且在減壓下濃縮經合併之濾液，得到所要粗產物之乙酸鹽。使粗物質吸附於矽膠栓塞上，且藉由用含7.5%至10% 2 M氨之甲醇溶液之DCM溶離進行層析來純化，得到1-(4-(胺基甲基)-5-溴吡啶-2-基)-3-甲基脲(320 mg，1.2 mmol，23%產率)。質譜(ESI)m/z=260.9(M+H)。 Step B : Slurry with 1-(5-bromo-4-(nitromethyl)pyridin-2-yl)-3-methylurea (1.5 g, 5.3 mmol) in acetic acid (27 ml) The slurry was allowed to reach 10 °C. Zinc powder (1.7 g, 27 mmol) was added and the slurry was slowly warmed to room temperature over a period of 8.5 hours. The reaction slurry was then diluted with acetic acid (50 ml) and filtered. The solid was washed with acetic acid, and the combined filtrate was concentrated under reduced pressure to give the desired crude product. The crude material was adsorbed onto a silica gel plug and purified by chromatography with DCM containing 7.5% to 10% ammonia in methanol to give 1-(4-(aminomethyl)-5-bromo. Pyridin-2-yl)-3-methylurea (320 mg, 1.2 mmol, 23% yield). Mass Spectrum (ESI) m/z = 260.9 (M+H).

步驟C：向玻璃微波反應容器中饋入含1-(4-(胺基甲基)-5-溴吡啶-2-基)-3-甲基脲(250 mg，0.97 mmol)及丁二酸酐(120 mg，1.2 mmol)之DMF(1.3 mL)，且在100℃下置於Discover型微波反應器(CEM,Matthews,NC)中30分鐘。冷卻反應混合物，且添加乙酸酐 (0.36 ml，3.9 mmol)。接著再加熱此混合物至100℃，維持30分鐘。接著冷卻反應物，且用水(30 mL)及乙酸乙酯(50 mL)稀釋。分離各層，且用二氯甲烷(1×50 mL)萃取水層。合併有機層，且用飽和碳酸氫鈉(3×25 mL)及水(3×25 mL)萃取混合物，且經硫酸鎂乾燥。使粗物質吸附於矽膠栓塞上，且藉由用含2.5%至6% MeOH之DCM溶離進行層析來純化，得到1-(5-溴-4-((2,5-二側氧基吡咯啶-1-基)甲基)吡啶-2-基)-3-甲基脲(150 mg，0.44 mmol，45%產率)。質譜(ESI)m/z=342.9(M+H)。1H NMR(400 MHz,CDCl3)δ 9.37(1H,s),8.88(1H,br.q,J=1.8,1.8,1.8 Hz),8.20(1H,s),6.54(1H,s),4.70(1H,s),2.93(2H,d,J=4.9 Hz),2.86(3H,br.s.)。 Step C : Feeding a glass microwave reaction vessel with 1-(4-(aminomethyl)-5-bromopyridin-2-yl)-3-methylurea (250 mg, 0.97 mmol) and succinic anhydride (120 mg, 1.2 mmol) in DMF (1.3 mL) and placed in a Discover-type microwave reactor (CEM, Matthews, NC) for 30 min at 100 °C. The reaction mixture was cooled and acetic anhydride (0.36 ml, 3.9 mmol). This mixture was then heated again to 100 ° C for 30 minutes. The reaction was then cooled and diluted with water (30 mL) &EtOAc. The layers were separated and the aqueous extracted with dichloromethane (1×50 mL). The combined organic layers were extracted with EtOAc EtOAc EtOAc (EtOAc) The crude material was adsorbed onto a silica gel plug and purified by chromatography eluting with 2.5% to 6% MeOH in MeOH to afford 1-(5-bromo-4-((2,5-di- oxypyrrole) Pyridin-1-yl)methyl)pyridin-2-yl)-3-methylurea (150 mg, 0.44 mmol, 45% yield). Mass Spectrum (ESI) m/z = 342.9 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (1H, s), 8.88 (1H, br.q, J = 1.8, 1.8, 1.8 Hz), 8.20 (1H, s), 6.54 (1H, s), 4.70 (1H, s), 2.93 (2H, d, J = 4.9 Hz), 2.86 (3H, br.s.).

製備preparation

5-氟嘧啶-2-甲腈 5-fluoropyrimidine-2-carbonitrile

向10 ml微波小瓶中饋入2-氯-5-氟嘧啶(840 mg，6.3 mmol)、Pd2(dba)3(230 mg，0.25 mmol)、1,1'-雙(二苯基膦基)二茂鐵(280 mg，0.51 mmol)、氰化鋅(480 mg，4.1 mmol)及鋅粉(100 mg，1.6 mmol)及二甲基乙醯胺(4.0 mL)。接著將混合物用氬氣充氣。將小瓶安裝於Discover型微波反應器(CEM,Matthews,NC)中且在100℃下加熱10小時。用EtOAc(50 mL)稀釋反應混合物，接著用鹽水(3×50 mL)洗滌。經硫酸鎂乾燥有機層且蒸發至乾燥。使粗物質吸附於矽膠栓塞上，且藉由用含0%至50%乙酸乙酯之己烷溶離進行層析來純化，得到5-氟嘧啶-2-甲腈(190 mg，1.5 mmol，24%產率)。1H NMR(CDCl3)δ 8.74(s,2H)。 To a 10 ml microwave vial was fed 2-chloro-5-fluoropyrimidine (840 mg, 6.3 mmol), Pd 2 (dba) 3 (230 mg, 0.25 mmol), 1,1'-bis (diphenylphosphino) Ferrocene (280 mg, 0.51 mmol), zinc cyanide (480 mg, 4.1 mmol) and zinc powder (100 mg, 1.6 mmol) and dimethylacetamide (4.0 mL). The mixture was then aerated with argon. The vials were mounted in a Discover type microwave reactor (CEM, Matthews, NC) and heated at 100 °C for 10 hours. The reaction mixture was diluted with EtOAc (50 mL)EtOAcEtOAc. The organic layer was dried over MgSO.sub.4 and evaporated to dry. The crude material was adsorbed onto a silica gel plug and purified by chromatography with 0% to 50% ethyl acetate in hexane to give 5-fluoropyrimidine-2-carbonitrile (190 mg, 1.5 mmol, 24). %Yield). 1 H NMR (CDCl 3 ) δ 8.74 (s, 2H).

實例1083Example 1083

1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea

將1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(1.40 g，5.6 mmol)及苄醇(0.88 mL，8.5 mmol)溶解於DMF(56 mL)中。將60%氫化鈉分散液(340 mg，8.5 mmol)小心添加至溶液中。接著在65℃下攪拌所得深棕色溶液2.5天。接著冷卻反應物至室溫且傾倒至300 mL水中。過濾所得漿液且用水洗滌。將濕沈澱物溶解於550 mL含10% MeOH之DCM混合物中，接著經硫酸鎂乾燥。濃縮濾液，得到粗1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(1.6 g，4.6 mmol，82%產率)。質譜(ESI)m/z=336.2(M+H),338.2(M+H)。1H NMR(DMSO-d6)δ 9.24(s,1H),8.18(s,1H),7.36-7.49(m,7H),5.21(s,2H),2.70(d,J=4.7 Hz,3H)。 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (1.40 g, 5.6 mmol) and benzyl alcohol (0.88 mL, 8.5 mmol) were dissolved in DMF (56 mL). A 60% sodium hydride dispersion (340 mg, 8.5 mmol) was carefully added to the solution. The resulting dark brown solution was then stirred at 65 ° C for 2.5 days. The reaction was then cooled to room temperature and poured into 300 mL water. The resulting slurry was filtered and washed with water. The wet precipitate was dissolved in 550 mL of a 10% MeOH mixture of DCM and dried over magnesium sulfate. The filtrate was concentrated to give crude 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (1.6 g, 4.6 mmol, 82% yield). Mass Spectrum (ESI) m/z = 336.2 (M+H) 1 H NMR (DMSO-d 6 ) δ 9.24 (s, 1H), 8.18 (s, 1H), 7.36-7.49 (m, 7H), 5.21. (s, 2H), 2.70 (d, J = 4.7 Hz, 3H ).

製備preparation

5-氯-N,N-二甲基吡嗪-2-甲醯胺 5-chloro-N,N-dimethylpyrazine-2-carboxamide

步驟A：將5-氯吡嗪-2-甲酸(600 mg，3.8 mmol)於亞硫醯氯(15 mL，210 mmol)中製漿，且添加兩滴DMF。攪拌反應混合物18小時，接著在真空下濃縮，得到粗5-氯吡嗪-2-羰基氯，其直接用於形成醯胺。將粗酸氯化物(370 mg，2.1 mmol)溶解於DCM(20 mL)中。添加二甲胺(9.5 ml，19.0 mmol)及三乙胺(0.53 ml，3.8 mmol)，且攪拌所得混合物18小時。接著用0.1 N檸檬酸溶液(25 mL)淬滅反應物。分離各層，且用水(1×25 ml)洗滌有機層，接著經硫酸鎂乾燥。濃縮濾液，且使粗物質吸附於矽膠栓塞上，且藉由用含0%至100% EtOAc之DCM 溶離進行層析來純化，得到5-氯-N,N-二甲基吡嗪-2-甲醯胺(180 mg，0.970 mmol，46%產率)。質譜(ESI)m/z=185.9(M+H)。1H NMR(CDCl3)δ 8.76(d,J=1.4 Hz,1H),8.55(d,J=1.4 Hz,1H),3.17(s,3H),3.14(s,3H)。 Step A : 5-Chloropyrazine-2-carboxylic acid (600 mg, 3.8 mmol) was slurried in sulphur chloride (15 mL, 210 mmol) and two drops of DMF were added. The reaction mixture was stirred for 18 hours then concentrated under vacuum to give crude 5-chloropyrazine-2-carbonyl chloride which was directly used to form the amine. The crude acid chloride (370 mg, 2.1 mmol) was dissolved in DCM (20 mL). Dimethylamine (9.5 ml, 19.0 mmol) and triethylamine (0.53 ml, 3.8 mmol) were added, and the mixture was stirred for 18 hr. The reaction was then quenched with 0.1 N citric acid (25 mL). The layers were separated, and the organic layer was washed with water (1×25 ml). The filtrate was concentrated, and the crude material was taken on a silica gel plug eluting eluting with EtOAc EtOAc EtOAc Formamide (180 mg, 0.970 mmol, 46% yield). Mass Spectrum (ESI) m/z = 185.9 (M+H). 1 H NMR (CDCl 3 ) δ 8.76 (d, J = 1.4 Hz, 1H), 8.55 (d, J = 1.4 Hz, 1H), 3.17 (s, 3H), 3.14 (s, 3H).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

實例1084Example 1084

1-(5-(1,5-二羥基戊-3-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(1,5-dihydroxypent-3-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

將5-羥基-3-(4-((5-甲氧基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)戊酸甲酯(35 mg，0.087 mmol)溶解於THF(1.0 mL)中且冷卻至0℃。接著逐滴添加三乙基硼氫化鋰(1.0 M，於THF中)(0.36 mL，0.36 mmol)。澄清溶液變成黃色且在0℃下攪拌45分鐘。接著在0℃下藉由逐滴添加過氧硫酸鉀(270 mg，0.43 mmol)溶液(溶解於8.0 mL水中)淬滅反應物。接著用乙酸乙酯及二氯甲烷萃取混合物，接著用鹽水洗滌。濃縮水層，接著與DMSO(5 mL)一起劇烈攪拌以自鹽中萃取產物。接著過濾DMSO層。藉由逆相製備型HPLC，使用Phenomenex Luna管柱(5微米，C8(2)，100 Å，150×21.2 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度5%至95%)純化粗物質，得到產物之三氟 乙酸鹽。使產物吸附於矽膠栓塞上，且藉由用含0%至10% 2 M氨之MeOH溶液之DCM進行層析再純化，得到1-(5-(1,5-二羥基戊-3-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(5.5 mg，0.015 mmol，17%產率)。質譜(ESI)m/z=377.2(M+H)。1H NMR(400 MHz,MeOH-d 4 )δ 8.19(1H,d,J=2.3 Hz),8.07(1H,s),8.00(1H,d,J=2.2 Hz),7.26(1H,t,J=2.3 Hz),6.47(1H,s),3.90(3H,s),3.44-3.62(4H,m),3.20-3.28(1H,m),2.82(3H,s),1.94-2.08(4H,m)。 Methyl 5-hydroxy-3-(4-((5-methoxypyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)pentanoate (35 mg , 0.087 mmol) dissolved in THF (1.0 mL) and cooled to 0 °C. Then lithium triethylborohydride (1.0 M in THF) (0.36 mL, 0.36 mmol) was added dropwise. The clear solution turned yellow and was stirred at 0 °C for 45 minutes. The reaction was then quenched by dropwise addition of a solution of potassium peroxodisulfate (270 mg, 0.43 mmol) (dissolved in 8.0 mL water) at 0 °C. The mixture was then extracted with ethyl acetate and dichloromethane, then brine. The aqueous layer was concentrated and then vigorously stirred with DMSO (5 mL) to extract product from salt. The DMSO layer was then filtered. By reverse phase preparative HPLC, a Phenomenex Luna column (5 micron, C8 (2), 100 Å, 150 x 21.2 mm, CH 3 CN/H 2 O with 0.1% TFA, gradient 5% to 25 minutes over 25 minutes) 95%) The crude material was purified to give the product trifluoroacetate. The product was adsorbed onto a silicone plug and re-purified by chromatography with DCM containing 0% to 10% 2M ammonia in MeOH to yield 1-(5-(1,5-dihydroxypent-3-yl) 4-((5-Methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (5.5 mg, 0.015 mmol, 17% yield). Mass Spectrum (ESI) m/z = 377.2 (M+H). 1 H NMR (400 MHz, MeOH- d 4 ) δ 8.19 (1H, d, J = 2.3 Hz), 8.07 (1H, s), 8.00 (1H, d, J = 2.2 Hz), 7.26 (1H, t, J = 2.3 Hz), 6.47 (1H, s), 3.90 (3H, s), 3.44 - 3.62 (4H, m), 3.20-3.28 (1H, m), 2.82 (3H, s), 1.94 - 2.08 (4H , m).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1087Example 1087

(+/-)-順-1-(5-((3R,4S)-3,4-二氘四氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (+/-)-cis-1-(5-((3R,4S)-3,4-dioxintetrahydro-2H-piperidin-4-yl)-4-((5-methylpyridine-3) -yl)oxy)pyridin-2-yl)-3-methylurea

將1-(5-(3,6-二氫-2H-哌喃-4-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(50 mg，0.140 mmol)溶解於6.0 mL 5：1氘化甲醇-d 4 ：乙酸乙酯之混合物中。接著添加10% Pd/C(150 mg，1.4 mmol)，且用氘氣吹洗反應燒瓶，接著在氣球壓力下保持2.5天。接著用氮氣吹洗混合物，且用乙酸乙酯稀釋，接著經矽藻土襯墊過濾。接著藉由中壓層析(二氧化矽，3.5至10% MeOH：DCM)純化粗產物，得到不純產物。藉由逆相製備型HPLC，使用Phenomenex Luna管柱(5微米，C8(2)，100 Å，150×21.2 mm，含0.1% TFA之CH3CN/H2O，經25分鐘梯度5%至95%)純化粗物質，得到所要產物之三氟乙酸鹽。接著藉由經SCX管柱，使用0至2 M氨之MeOH溶液作為溶離劑溶離使三氟乙酸鹽呈游離鹼形式，得到(15 mg，0.042 mmol，30%產率)，指定為順式對映異構體之混合物。質譜(ESI)m/z=362.2(M+H)。1H NMR(400 MHz，氯仿-d)δ ppm 8.93-9.16(1H,m),8.84(1H,br.s.),8.23(1H,d,J=2.3 Hz),8.05(1H,d,J=2.3 Hz),7.98(1H,s),6.87-6.99(1H,m),6.18(1H,s),4.09(2H,dd,J=11.4,4.2 Hz),3.86(3H,br.s.),3.49-3.62(2H,m),2.81(3H,d,J=4.7 Hz),1.78-1.97(3H,m)。 1-(5-(3,6-Dihydro-2H-piperidin-4-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3 -Methylurea (50 mg, 0.140 mmol) was dissolved in a mixture of 6.0 mL of 5:1 methanolic acid- d 4 :ethyl acetate. Then 10% Pd/C (150 mg, 1.4 mmol) was added and the reaction flask was purged with helium and then held under balloon pressure for 2.5 days. The mixture was then flushed with nitrogen and diluted with ethyl acetate then filtered thru a pad. The crude product is then purified by medium pressure chromatography (c.c., 3.5 to 10% MeOH: DCM) By reverse phase preparative HPLC, a Phenomenex Luna column (5 micron, C8 (2), 100 Å, 150 x 21.2 mm, CH 3 CN/H 2 O with 0.1% TFA, gradient 5% to 25 minutes over 25 minutes) 95%) The crude material was purified to give the desired product as the trifluoroacetic acid salt. The trifluoroacetate salt is then obtained as a free base by using a solution of 0 to 2 M ammonia in MeOH as a solvent to afford (15 mg, 0.042 mmol, 30% yield). a mixture of enantiomers. Mass Spectrum (ESI) m/z = 362.2 (M+H). 1H NMR (400 MHz, chloroform- d ) δ ppm 8.93-9.16 (1H, m), 8.84 (1H, br.s.), 8.23 (1H, d, J = 2.3 Hz), 8.05 (1H, d, J =2.3 Hz), 7.98 (1H, s), 6.87-6.99 (1H, m), 6.18 (1H, s), 4.09 (2H, dd, J = 11.4, 4.2 Hz), 3.86 (3H, br.s. ), 3.49-3.62 (2H, m), 2.81 (3H, d, J = 4.7 Hz), 1.78-1.97 (3H, m).

遵循實例1087中之程序，製備以下化合物： Following the procedure in Example 1087 , the following compounds were prepared:

實例1090Example 1090

(+/-)-1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環己基)吡啶-2-基)脲 (+/-)-1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-oxocyclohexyl)pyridin-2-yl)urea

將1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(1,4-二氧雜螺[4.5]癸-7-基)吡啶-2-基)脲(47 mg，0.12 mmol)溶解於EtOH(1.2 mL)中，且添加1.0 M HCl(0.35 mL，0.35 mmol)。攪拌所得溶液3.5天。濃縮反應物，用飽和碳酸氫鈉鹼化，接著用乙酸乙酯(3×25 mL)萃取。用鹽水(1×20 mL)洗滌經合併之有機層且經硫酸鎂乾燥。使粗物質吸附於矽膠栓塞上，且藉由用含6%至10% MeOH之DCM溶離進行層析來純化，得到1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環己基)吡啶-2-基)脲(41 mg，0.116 mmol，98%產率)。質譜(ESI)m/z=355.1(M+H)。1H NMR(400 MHz,CDCl3)δ 9.07(1H,m,J=3.9 Hz),8.89(1H,s),8.34(1H,d,J=0.8 Hz),8.25(1H,d,J=2.5 Hz),7.96(1H,s),7.16-7.26(1H,m),6.07(1H,s),3.25-3.43(1H,m),2.78(3H,d,J=4.9 Hz),2.57-2.70(2H,m),2.45-2.54(1H,m),2.39-2.44(1H,m),2.38(3H,s),2.07-2.22(2H,m),1.92-2.06(1H,m),1.73-1.89(1H,m)。 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(1,4-dioxaspiro[4.5]fluoren-7-yl)pyridine-2 -Base)urea (47 mg, 0.12 mmol) was dissolved in EtOH (1. The resulting solution was stirred for 3.5 days. The reaction was concentrated and basified with EtOAc (EtOAc) The combined organic layers were washed with brine (1×20 mL) and dried over magnesium sulfate. The crude material was adsorbed onto a silica gel plug and purified by chromatography with 6% to 10% MeOH in DCM to afford 1-methyl-3-(4-((5-methylpyridine-3-) ))oxy)-5-(3-oxocyclohexyl)pyridin-2-yl)urea (41 mg, 0.116 mmol, 98% yield). Mass Spectrum (ESI) m/z = 355.1 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.07 (1H, m, J = 3.9 Hz), 8.89 (1H, s), 8.34 (1H, d, J = 0.8 Hz), 8.25 (1H, d, J = 2.5 Hz), 7.96 (1H, s), 7.16-7.26 (1H, m), 6.07 (1H, s), 3.25-3.43 (1H, m), 2.78 (3H, d, J = 4.9 Hz), 2.57- 2.70(2H,m), 2.45-2.54(1H,m), 2.39-2.44(1H,m), 2.38(3H,s),2.07-2.22(2H,m),1.92-2.06(1H,m), 1.73-1.89 (1H, m).

自上述製備亦獲得以下化合物，但其中增添藉由超臨界流體層析(3×25 cm Whelk-D1(R,R)管柱，使用75 mL/min 25%異丙醇(0.2% EDA)/CO2)分離外消旋物質： The following compounds were also obtained from the above preparations, but were added by supercritical fluid chromatography (3 x 25 cm Whelk-D1 (R, R) column using 75 mL/min 25% isopropanol (0.2% EDA) / CO 2 ) separation of racemic materials:

實例1093Example 1093

1-(5-((1S,3S)-3-羥基環己基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((1S,3S)-3-hydroxycyclohexyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

將1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環己基)吡啶-2-基)脲(110 mg，0.31 mmol)溶解於THF(2.5 mL)中且冷卻至-78℃。接著逐滴添加三第二丁基(氫化)硼酸鋰(1.0 M，於THF中)(1.55 mL，1.55 mmol)，且經2.5小時之時段升溫至-20℃。用飽和氯化銨溶液淬滅反應物，且用乙酸乙酯(3×30 mL)萃取。用鹽水(1×20 mL)洗滌經合併之有機層，經硫酸鎂乾燥且在真空中濃縮。使粗物質吸附於矽膠栓 塞上，且藉由用含5%至10% MeOH之DCM溶離進行層析來純化，得到1-(5-(反-3-羥基環己基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(75 mg，0.210 mmol，68%)。藉由超臨界流體層析(2×25 cm OD-H管柱，使用60 mL/min 20% MeOH(0.1% NH4OH)/CO2)分離外消旋物質，得到1-(5-((1S,3S)-3-羥基環己基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=357.1(M+H)。1H NMR(400 MHz,CDCl3)δ 9.00(1H,br.s.),8.48(1H,s),8.32(1H,br.s.),8.24(1H,br.s.),7.94(1H,s),7.21(1H,br.t,J=1.0,1.0 Hz),6.05(1H,s),4.27(1H,br.t,J=1.0,1.0 Hz),3.36(1H,tt,J=12.3,3.1 Hz),2.81(3H,d,J=4.7 Hz),2.37(3H,s),2.01(1H,d,J=13.5 Hz),1.90-1.97(2H,m),1.73-1.89(4H,m),1.46-1.72(2H,m)。 1-Methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-oxocyclohexyl)pyridin-2-yl)urea (110 mg, 0.31 Methyl) was dissolved in THF (2.5 mL) and cooled to -78. Then, three second butyl(hydrogen)borates (1.0 M in THF) (1.55 mL, 1.55 mmol) were added dropwise and warmed to -20 °C over a period of 2.5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with brine (1×20 mL The crude material was adsorbed onto a silica gel plug and purified by chromatography with 5% to 10% MeOH in DCM to give 1-(5-(trans-3-hydroxycyclohexyl)-4-(5 Methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (75 mg, 0.210 mmol, 68%). The racemic material was separated by supercritical fluid chromatography (2 x 25 cm OD-H column using 60 mL/min 20% MeOH (0.1% NH 4 OH) / CO 2 ) to give 1-(5-( (1S,3S)-3-hydroxycyclohexyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 357.1 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (1H, br. s.), 8.48 (1H, s), 8.32 (1H, br.s.), 8.24 (1H, br.s.), 7.94 ( 1H, s), 7.21 (1H, br.t, J = 1.0, 1.0 Hz), 6.05 (1H, s), 4.27 (1H, br.t, J = 1.0, 1.0 Hz), 3.36 (1H, tt, J = 12.3, 3.1 Hz), 2.81 (3H, d, J = 4.7 Hz), 2.37 (3H, s), 2.01 (1H, d, J = 13.5 Hz), 1.90 - 1.97 (2H, m), 1.73 1.89 (4H, m), 1.46-1.72 (2H, m).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1095Example 1095

1-(5-環丁基-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-Cyclobutyl-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

將含有1-(5-溴-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (135.9 mg，0.385 mmol)、1,2,3,4,5-五苯基-1'-(二第三丁基膦基)二茂鐵Q-Phos(28.0 mg，0.039 mmol)及雙(二亞苄基丙酮)鈀(0)(13.8 mg，0.024 mmol)之乾燥小瓶抽真空且用氬氣回填。由注射器添加無水THF(3 mL)。約5分鐘後，逐滴添加含0.5 M溴化環丁基鋅之THF(1.93 mL，0.965 mmol)。1小時後，加熱混合物至60℃。3.5天後，冷卻反應物至室溫，接著在減壓下移除有機溶劑。用二氯甲烷稀釋殘餘物，接著在矽膠上(含0-7%甲醇之二氯甲烷)純化，得到粉紅色膜狀物，藉由溶解於3.7 mL DMF中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為1-(5-環丁基-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(54.3 mg，0.165 mmol，43.0%產率)。質譜(ESI)m/z=329.2(M+H)。1H NMR(500 MHz,DMSO-d6)δ 9.02(1H,s),8.23(1H,d,J=2.4 Hz),8.06(1H,s),8.00(1H,d,J=2.2 Hz),7.87(1H,br.s.),7.26(1H,t,J=2.3 Hz),6.75(1H,s),3.85(3H,s),3.64(1H，五重峰，J=8.9 Hz),2.64-2.68(3H,m),2.15-2.31(4H,m),1.93-2.04(1H,m),1.78-1.87(1H,m)。 Will contain 1-(5-bromo-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (135.9 mg, 0.385 mmol), 1,2 , 3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene Q-Phos (28.0 mg, 0.039 mmol) and bis(dibenzylideneacetone)palladium(0) ( A dry vial of 13.8 mg, 0.024 mmol) was evacuated and backfilled with argon. Anhydrous THF (3 mL) was added from a syringe. After about 5 minutes, THF (1.93 mL, 0.965 mmol) containing 0.5 M cyclobutylbutyl bromide was added dropwise. After 1 hour, the mixture was heated to 60 °C. After 3.5 days, the reaction was cooled to room temperature and then the organic solvent was removed under reduced pressure. The residue was diluted with methylene chloride, then purified on silica gel eluting with EtOAc EtOAc EtOAc EtOAc EtOAc The membrane was further purified by 90% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as 1-(5-cyclobutyl-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)- 3-methylurea (54.3 mg, 0.165 mmol, 43.0% yield). Mass Spectrum (ESI) m/z = 329.2 (M+H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.02 (1H, s), 8.23 (1H, d, J = 2.4 Hz), 8.06 (1H, s), 8.00 (1H, d, J = 2.2 Hz) , 7.87 (1H, br.s.), 7.26 (1H, t, J = 2.3 Hz), 6.75 (1H, s), 3.85 (3H, s), 3.64 (1H, quintuple, J = 8.9 Hz) , 2.64-2.68 (3H, m), 2.15-2.31 (4H, m), 1.93-2.04 (1H, m), 1.78-1.87 (1H, m).

遵循實例1095中之程序，製備以下化合物： Following the procedure in Example 1095 , the following compounds were prepared:

遵循製備15中之程序，製備以下化合物： Following the procedure in Preparation 15 , the following compounds were prepared:

製備preparation

向含有2-羥基乙基脲(3.26 g，31 mmol)於無水二氯甲烷(100 mL)中之圓底燒瓶中分數份依序添加咪唑(4.33 g，63 mmol)、氯化第三丁基二甲基矽烷(6.36 g，42 mmol)。在23℃下攪拌混濁混合物且用TLC及LC-MS監測。19小時後，用水稀釋反應物，接著用二氯甲烷萃取三次。彙集有機物，接著用飽和氯化銨水溶液洗滌一次，接著經無水硫酸鎂乾燥。過濾並濃縮後，無色殘餘物凝固成白色固體，將其鑑別為1-(2-((第三丁基二甲基矽烷基)氧基)乙基)脲(6.01 g，88%產率)，其未經純化即使用。1H NMR(500 MHz,DMSO-d6)δ ppm 5.87(1H,t,J=5.4 Hz),5.49(2H,br.s.),3.52(2H,t,J=6.0 Hz),3.04(2H,q,J=6.1 Hz),0.87(9H,s),0.04(6H,s)。質譜(正模式)m/e：219.1(M+H)+。 Addition of imidazole (4.33 g, 63 mmol), tributyl chloride, to a round bottom flask containing 2-hydroxyethylurea (3.26 g, 31 mmol) in dry dichloromethane (100 mL) Dimethyldecane (6.36 g, 42 mmol). The cloudy mixture was stirred at 23 ° C and monitored by TLC and LC-MS. After 19 hours, the reaction was diluted with water and then extracted three times with dichloromethane. The organics were combined and washed once with a saturated aqueous solution of ammonium chloride and then dried over anhydrous magnesium sulfate. After filtration and concentration, the colorless residue was crystallised to a white solid, which was identified as 1-(2-((t-butyl dimethyl decyl) oxy) ethyl) </RTI> (6.01 g, 88% yield) It is used without purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 5.87 (1H, t, J = 5.4 Hz), 5.49 (2H, br. s.), 3.52 (2H, t, J = 6.0 Hz), 3.04 ( 2H, q, J = 6.1 Hz), 0.87 (9H, s), 0.04 (6H, s). Mass spectrum (positive mode) m/e: 219.1 (M+H) + .

實例1102Example 1102

1-乙基-3-(4-((5-甲氧基吡啶-3-基)氧基)-5-(硫代嗎啉基甲基)吡啶-2-基)脲 1-ethyl-3-(4-((5-methoxypyridin-3-yl)oxy)-5-(thiomorpholinylmethyl)pyridin-2-yl)urea

將1-(5-溴-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-乙基脲(134.3 mg，0.366 mmol)、1-三氟硼酸鉀甲基硫代嗎啉(166.7 mg， 0.747 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(26.3 mg，0.073 mmol)、參(二亞苄基丙酮)二鈀(0)(33.9 mg，0.037 mmol)及碳酸鉀(156.6 mg，1.133 mmol)於N,N-二甲基乙醯胺(2.5 mL)及水(0.5 mL)中之經攪拌溶液脫氣且用氬氣回填。加熱反應混合物至100℃且用TLC及LC-MS監測。2.5天後，冷卻反應物至室溫，接著添加水以淬滅反應物。用二氯甲烷萃取混合物三次，接著彙集有機物且經無水硫酸鎂乾燥。過濾並在減壓下濃縮後，用二氯甲烷稀釋殘餘物，接著在矽膠上(含0-10%甲醇之二氯甲烷)純化，得到黃色膜狀物，藉由溶解於4 mL DMF中，使用逆相HPLC(含5-30%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將白色固體鑑別為1-乙基-3-(4-((5-甲氧基吡啶-3-基)氧基)-5-(硫代嗎啉基甲基)吡啶-2-基)脲(5.9 mg，0.015 mmol，4.00%產率)。質譜(ESI)m/z=404.2(M+H)。1H NMR(500 MHz,DMSO-d6)δ 9.02(1H,s),8.23(1H,d,J=2.4 Hz),8.10(1H,s),8.01(1H,d,J=2.0 Hz),7.85(1H,br.s.),7.26(1H,t,J=2.3 Hz),6.87(1H,s),3.85(3H,s),3.53(2H,s),3.08-3.16(2H,m),2.64-2.70(4H,m),2.54-2.60(4H,m),1.04(3H,t,J=7.2 Hz)。 1-(5-Bromo-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-ethylurea (134.3 mg, 0.366 mmol), 1-trifluoro Potassium borate methylthiomorpholine (166.7 mg, 0.747 mmol), butyldi-1-adamantylphosphine n-BuPAd 2 (26.3 mg, 0.073 mmol), ginseng (dibenzylideneacetone) dipalladium (0 (33.9 mg, 0.037 mmol) and potassium carbonate (156.6 mg, 1.133 mmol) in a stirred solution of N,N-dimethylacetamide (2.5 mL) and water (0.5 mL) with argon Backfill. The reaction mixture was heated to 100 ° C and was monitored by TLC and LC-MS. After 2.5 days, the reaction was cooled to room temperature and then water was added to quench the reaction. The mixture was extracted three times with dichloromethane, then the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentrating under reduced pressure, the residue was purified mjjjjjjjjjjjj The membrane was further purified using reverse phase HPLC (5-30% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, white solid was identified as 1-ethyl-3-(4-((5-methoxypyridin-3-yl)oxy)-5- (thiomorpholine) Methyl)pyridin-2-yl)urea (5.9 mg, 0.015 mmol, 4.40% yield). Mass Spectrum (ESI) m/z = 404.2 (M+H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.02 (1H, s), 8.23 (1H, d, J = 2.4 Hz), 8.10 (1H, s), 8.01 (1H, d, J = 2.0 Hz) , 7.85 (1H, br.s.), 7.26 (1H, t, J = 2.3 Hz), 6.87 (1H, s), 3.85 (3H, s), 3.53 (2H, s), 3.08-3.16 (2H, m), 2.64-2.70 (4H, m), 2.54-2.60 (4H, m), 1.04 (3H, t, J = 7.2 Hz).

遵循實例1102中之程序，製備以下化合物： Following the procedure in Example 1102 , the following compounds were prepared:

製備preparation

步驟A：將5-溴-2-碘吡啶(1.11 g，3.90 mmol)、3-丁炔-2-醇(0.42 mL，5.36 mmol)、反-二氯雙(三苯基膦)鈀(II)(274 mg，0.39 mmol)及 碘化銅(I)(149 mg，0.78 mmol)添加至小瓶中，接著脫氣且用氬氣回填。由注射器向小瓶中依序添加無水DMF(11 mL)、三乙胺(2.7 mL，19.4 mmol)。加熱所得反應物至50℃且用TLC及LC-MS監測。2.5小時後，冷卻反應物至室溫，接著用水稀釋。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，將殘餘物加載於矽膠管柱上(含0-65%乙酸乙酯之庚烷)，得到呈深黃色油狀之4-(5-溴吡啶-2-基)丁-3-炔-2-醇(701 mg，79%產率)，其未經進一步純化即使用。1H NMR(400 MHz,DMSO-d6)δ ppm 8.68(1H,dd,J=2.4,0.7 Hz),8.06(1H,dd,J=8.4,2.5 Hz),7.45(1H,dd,J=8.4,0.8 Hz),5.58(1H,d,J=5.5 Hz),4.55-4.65(1H,m),1.39(3H,d,J=6.7 Hz)。 Step A : 5-Bromo-2-iodopyridine (1.11 g, 3.90 mmol), 3-butyn-2-ol (0.42 mL, 5.36 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (274 mg, 0.39 mmol) and copper (I) iodide (149 mg, 0.78 mmol) were added to the vial, then degassed and backfilled with argon. Anhydrous DMF (11 mL) and triethylamine (2.7 mL, 19.4 mmol) were added sequentially from a syringe to a vial. The resulting reaction was heated to 50 ° C and was monitored by TLC and LC-MS. After 2.5 hours, the reaction was cooled to room temperature and then diluted with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentrating, the residue was applied to a silica gel column (0-65% ethyl acetate in heptane) to give 4-(5-bromopyridin-2-yl)butane-3 as a dark yellow oil. - alkyn-2-ol (701 mg, 79% yield) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.68 (1H, dd, J = 2.4, 0.7 Hz), 8.06 (1H, dd, J = 8.4, 2.5 Hz), 7.45 (1H, dd, J = 8.4, 0.8 Hz), 5.58 (1H, d, J = 5.5 Hz), 4.55 - 4.65 (1H, m), 1.39 (3H, d, J = 6.7 Hz).

步驟B：向含有4-(5-溴吡啶-2-基)丁-3-炔-2-醇(496 mg，2.19 mmol)於乙醇(12 mL)及三乙胺(0.3 mL，2.2 mmol)中之小瓶中添加氧化鉑(IV)(27 mg，0.12 mmol)。將燒瓶抽真空並用氮氣回填，且在23℃下攪拌。約5分鐘後，用氫氣置換氮氣。用TLC及LC-MS監測反應。2小時後，經矽藻土栓塞過濾混合物，依序用乙酸乙酯、乙醇沖洗該矽藻土栓塞。彙集有機物，接著在真空中濃縮，得到橙色膜狀物，用二氯甲烷稀釋該膜狀物，接著加載於矽膠上(含0-60%乙酸乙酯之庚烷)，得到呈淡黃色膜狀之4-(5-溴吡啶-2-基)丁-2-醇(304 mg，1.32 mmol，60.2%產率)，其未經進一步純化即使用。1H NMR(500 MHz，二氯甲烷-d2)δ ppm 8.54(1H,d,J=2.2 Hz),7.74(1H,dd,J=8.3,2.4 Hz),7.10(1H,d,J=8.3 Hz),3.77(1H,dqt,J=8.3,6.1,6.1,6.1,4.2,4.2 Hz),2.87(2H,t,J=7.3 Hz),2.76(1H,d,J=4.2 Hz),1.71-1.90(2H,m),1.18(3H,d,J=6.1 Hz)。 Step B : To a solution containing 4-(5-bromopyridin-2-yl)but-3-yn-2-ol (496 mg, 2.19 mmol) in ethanol (12 mL) and triethylamine (0.3 mL, 2.2 mmol) Platinum (IV) (27 mg, 0.12 mmol) was added to the vial. The flask was evacuated and backfilled with nitrogen and stirred at 23 °C. After about 5 minutes, the nitrogen was replaced with hydrogen. The reaction was monitored by TLC and LC-MS. After 2 hours, the mixture was filtered through a plug of diatomaceous earth, and the diatomaceous earth was plugged with ethyl acetate and ethanol in that order. The organics were combined and concentrated in vacuo to give abr. EtOAc (EtOAc). 4-(5-Bromopyridin-2-yl)butan-2-ol (304 mg, 1.32 mmol, 60.2% yield) was used without further purification. 1 H NMR (500 MHz, dichloromethane -d 2) δ ppm 8.54 (1H , d, J = 2.2 Hz), 7.74 (1H, dd, J = 8.3,2.4 Hz), 7.10 (1H, d, J = 8.3 Hz), 3.77 (1H, dqt, J = 8.3, 6.1, 6.1, 6.1, 4.2, 4.2 Hz), 2.87 (2H, t, J = 7.3 Hz), 2.76 (1H, d, J = 4.2 Hz), 1.71-1.90 (2H, m), 1.18 (3H, d, J = 6.1 Hz).

製備preparation

向4-溴吡啶-2-甲醛(532 mg，2.86 mmol)於二氯甲烷(20 mL)中之溶液中依序添加三乙胺(0.6 mL，4.3 mmol)、甲氧胺鹽酸鹽(252 mg，3.0 mmol)。在23℃下攪拌混合物且用TLC及LC-MS監測。3.5小時後，用二氯甲烷稀釋混合物，接著用水洗滌。用二氯甲烷再萃取水層兩次。彙集有機層，接著經無水硫酸鎂乾燥。過濾並濃縮後，將淡黃色膜狀物推測性地鑑別為順式與反式異構體之混合物或4-溴-2-吡啶甲醛O-甲基肟(106.9 mg，0.497 mmol，17.39%產率)，其未經純化即使用。質譜(ESI)m/z=215.3(M+H)。 To a solution of 4-bromopyridine-2-carbaldehyde (532 mg, 2.86 mmol) in dichloromethane (20 mL) EtOAc (EtOAc) Mg, 3.0 mmol). The mixture was stirred at 23 ° C and monitored by TLC and LC-MS. After 3.5 hours, the mixture was diluted with dichloromethane and then washed with water. The aqueous layer was extracted twice more with dichloromethane. The organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the pale yellow membrane was speculatively identified as a mixture of cis and trans isomers or 4-bromo-2-pyridinecarboxaldehyde O-methylindole (106.9 mg, 0.497 mmol, 17.39%) Rate), which is used without purification. Mass Spectrum (ESI) m/z = 215.3 (M+H).

實例1115Example 1115

1-(5-(4,5-二氫呋喃-2-基)-4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(4,5-Dihydrofuran-2-yl)-4-((1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy Pyridin-2-yl)-3-methylurea

將1-(5-溴-4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(121.0 mg，0.330 mmol)、2-(二環己基膦基)-2',4',6'-三異丙基-1,1'-聯苯、X-Phos(32.0 mg，0.067 mmol)及參(二亞苄基丙酮)二鈀(0)(15.7 mg，0.017 mmol)於無水THF(2 mL)中之經攪拌溶液脫氣且用氬氣回填。在氬氣保護下，由注射器將三丁基(4,5-二氫呋喃-2-基)錫烷(0.32 mL，1.005 mmol)添加至反應物中，接著在微波中加熱混合物至120℃。1小時後，冷卻反應物至室溫，接著在減壓下濃縮。用甲醇稀釋殘餘物，接著過濾。用甲醇沖洗固體三次，得到呈灰白色固體狀之1-(5-(4,5-二氫呋喃-2-基)-4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(104.0 mg，0.292 mmol，89%產率)。1H NMR(500 MHz,DMSO-d6)δ 9.10-9.17(1H,m),8.26-8.32(1H,m),7.74(1H,br.s.),7.34-7.42(1H,m),6.83(1H,s),6.39(1H,d,J=9.8 Hz),5.65(1H,t,J=2.8 Hz),4.38(2H,t,J=9.4 Hz),3.48(3H,s),2.80(2H,td,J=9.4,2.8 Hz),2.62-2.69(3H,m),2.18(3H,s)。 1-(5-Bromo-4-((1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)pyridin-2-yl)-3- Methylurea (121.0 mg, 0.330 mmol), 2-(dicyclohexylphosphino)-2', 4',6'-triisopropyl-1,1'-biphenyl, X-Phos (32.0 mg, 0.067 mmol) and hydrazine (dibenzylideneacetone) dipalladium (0) (15.7 mg, 0.017 mmol) in anhydrous THF (2 mL). Tributyl(4,5-dihydrofuran-2-yl)stannane (0.32 mL, 1.005 mmol) was added to the reaction by a syringe under argon, and then the mixture was heated to 120 ° C in a microwave. After 1 hour, the reaction was cooled to room temperature then concentrated under reduced pressure. The residue was diluted with methanol and then filtered. The solid was washed three times with methanol to give 1-(5-(4,5-dihydrofuran-2-yl)-4-((1,2-diethylfuran-2-yl)-4-( , 6-Dihydropyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (104.0 mg, 0.292 mmol, 89% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.10-9.17 (1H, m), 8.26-8.32 (1H, m), 7.74 (1H, br.s.), 7.34-7.42 (1H, m), 6.83(1H, s), 6.39 (1H, d, J = 9.8 Hz), 5.65 (1H, t, J = 2.8 Hz), 4.38 (2H, t, J = 9.4 Hz), 3.48 (3H, s), 2.80 (2H, td, J = 9.4, 2.8 Hz), 2.62-2.69 (3H, m), 2.18 (3H, s).

實例1116Example 1116

1-(6'-(3-羥基丁氧基)-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-(3-hydroxybutoxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl)-3- Methyl urea

向含有無水THF(3 mL)之小瓶中分數份添加雙(三甲基矽烷基)胺基鋰LHMDS(326.7 mg，1.952 mmol)。在冰水浴中冷卻小瓶。10分鐘後，在0℃下逐滴添加1,3-丁二醇(0.16 mL，1.775 mmol)。藉由自冰水浴中移出使反應物升溫至23℃。30分鐘後，分數份添加1-(6'-氟-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(150.4 mg，0.426 mmol)。小心加熱反應物至50℃且用TLC及LC-MS監測。4天後，冷卻反應物至室溫，接著用飽和氯化銨水溶液淬滅。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，用二氯甲烷稀釋殘餘物，接著加載於矽膠上(含20-70%預混合3：1乙酸乙酯：乙醇溶液之庚烷)，得到透明膜狀物，用乙腈濕磨該膜狀物，得到呈白色固體狀之1-(6'-(3-羥基丁氧基)-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(75.2 mg，0.178 mmol，41.7%產率)。質譜(ESI)m/z=424.1(M+H)。1H NMR(400 MHz,DMSO-d6)δ 9.17(1H,s),8.28- 8.38(3H,m),8.21(1H,s),7.89-7.97(1H,m),7.71(1H,d,J=3.7 Hz),7.55(1H,t,J=1.8 Hz),6.79-6.95(2H,m),4.54(1H,d,J=4.9 Hz),4.34(2H,t,J=6.7 Hz),3.73-3.86(1H,m),2.67(3H,d,J=4.5 Hz),2.33(3H,S),1.68-1.88(2H,m),1.11(3H,d,J=6.3 Hz)。藉由超臨界流體層析(2×15 cm AS-H管柱，使用50 mL/min 30%異丙醇(NH4OH)/CO2)分離外消旋物質。 To a fraction of a vial containing anhydrous THF (3 mL) was added bis(trimethylsulfonyl)amine lithium LHMDS (326.7 mg, 1.952 mmol). Cool the vial in an ice water bath. After 10 minutes, 1,3-butanediol (0.16 mL, 1.775 mmol) was added dropwise at 0 °C. The reaction was warmed to 23 °C by removal from the ice water bath. After 30 minutes, the fraction was added 1-(6'-fluoro-4-((5-methylpyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl)-3- Methyl urea (150.4 mg, 0.426 mmol). The reaction was carefully heated to 50 °C and was monitored by TLC and LC-MS. After 4 days, the reaction was cooled to rt then quenched with aq. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was diluted with methylene chloride, then applied to silica gel (20-70% pre-mixed 3:1 ethyl acetate: heptane in ethanol) to give a clear film which was wet-milled with acetonitrile The film gave 1-(6'-(3-hydroxybutoxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3'- as a white solid. Bipyridyl]-6-yl)-3-methylurea (75.2 mg, 0.178 mmol, 41.7% yield). Mass Spectrum (ESI) m/z = 424.1 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.17 (1H, s), 8.28 - 8.38 (3H, m), 8.21. (1H, s), 7.89-7.97 (1H, m), 7.71 (1H, d , J = 3.7 Hz), 7.55 (1H, t, J = 1.8 Hz), 6.79-6.95 (2H, m), 4.54 (1H, d, J = 4.9 Hz), 4.34 (2H, t, J = 6.7 Hz) ), 3.73-3.86 (1H, m), 2.67 (3H, d, J = 4.5 Hz), 2.33 (3H, S), 1.68-1.88 (2H, m), 1.11 (3H, d, J = 6.3 Hz) . The racemic material was separated by supercritical fluid chromatography (2 x 15 cm AS-H column using 50 mL/min 30% isopropanol (NH 4 OH) / CO 2 ).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1119Example 1119

(R)-1-(6'-((1-羥基丙-2-基)氧基)-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 (R)-1-(6'-((1-hydroxypropan-2-yl)oxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3'-linked Pyridyl]-6-yl)-3-methylurea

步驟A：向含有無水環戊基甲基醚(15 mL)之乾燥燒瓶中分數份添加雙(三甲基矽烷基)胺基鋰LHMDS(3.3969 g，20.30 mmol)。在冰 水浴中冷卻小瓶。10分鐘後，在0℃下逐滴添加1,2-丙二醇(1.2 mL，16.34 mmol)。藉由自冰水浴中移出使反應物升溫至23℃。30分鐘後，逐滴添加5-溴-2-氟吡啶(0.3 mL，2.91 mmol)，且反應溶液變混濁。小心加熱反應物至80℃且用TLC及LC-MS監測。2.5小時後，冷卻反應物至室溫，接著用飽和氯化銨水溶液淬滅。用二氯甲烷萃取三次後，彙集有機物，經無水硫酸鎂乾燥，過濾且濃縮。用二氯甲烷稀釋殘餘物，接著加載於矽膠上(含0-40%乙酸乙酯之庚烷)，得到1-((5-溴吡啶-2-基)氧基)丙-2-醇與2-((5-溴吡啶-2-基)氧基)丙-1-醇之混合物(219.5 mg，0.946 mmol，32.4%產率)。 Step A : To a fraction of dry flasks containing anhydrous cyclopentylmethyl ether (15 mL) was added bis(trimethylsulfonyl)amino lithium LHMDS (3.3969 g, 20.30 mmol). Cool the vial in an ice water bath. After 10 minutes, 1,2-propanediol (1.2 mL, 16.34 mmol) was added dropwise at 0 °C. The reaction was warmed to 23 °C by removal from the ice water bath. After 30 minutes, 5-bromo-2-fluoropyridine (0.3 mL, 2.91 mmol) was added dropwise, and the reaction solution became cloudy. The reaction was carefully heated to 80 ° C and was monitored by TLC and LC-MS. After 2.5 hours, the reaction was cooled to room rt then EtOAc EtOAc. After extracting three times with dichloromethane, the organics were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was diluted with dichloromethane, then loaded onto silica gel (0-40% ethyl acetate in heptane) to give 1-((5-bromopyridin-2-yl)oxy)propan-2-ol and Mixture of 2-((5-bromopyridin-2-yl)oxy)propan-1-ol (219.5 mg, 0.946 mmol, 32.4% yield).

步驟B：向含1-((5-溴吡啶-2-基)氧基)丙-2-醇與2-((5-溴吡啶-2-基)氧基)丙-1-醇之混合物(219.5 mg，0.946 mmol)之N,N-二甲基乙醯胺(5 mL)中添加雙(頻哪醇根基)二硼(362.7 mg，1.428 mmol)、丁基二-1-金剛烷基膦n-BuPAd2(68.9 mg，0.192 mmol)、參(二亞苄基丙酮)二鈀(0)(87.1 mg，0.095 mmol)及乙酸鉀(233.5 mg，2.379 mmol)。將所得溶液用氬氣淨化三次且置於真空下三次。加熱混合物至100℃且用LC-MS及TLC監測。4.5小時後，冷卻反應物至室溫。將1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(160.0 mg，0.475 mmol)及4.0 M碳酸鉀水溶液(0.36 mL，1.440 mmol)添加至反應混合物中。將燒瓶脫氣且用氬氣回填。加熱所得反應物至100℃且用TLC及LC-MS監測。22小時後，冷卻反應物至室溫，接著用鹽水稀釋。用二氯甲烷萃取三次後，彙集有機物，經無水硫酸鎂乾燥，過濾且濃縮。用二氯甲烷稀釋殘餘物，接著加載於矽膠上(含20-100%預混合3：1乙酸乙酯：乙醇溶液之庚烷)，得到黃色膜狀物，藉由溶解於4 mL DMSO中，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))進一步純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液 洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，藉由超臨界流體層析(250×30 mm AD-H管柱，使用40 mL/min MeOH+(20 mM NH3)+60 g/min CO2)分離異構體，接著藉由超臨界流體層析(250×30 mm OJ-H X OJ-H管柱，使用20 mL/min EtOH+(20 mM NH3)+80 g/min CO2)進一步純化，得到(R)-1-(6'-((1-羥基丙-2-基)氧基)-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(11.3 mg，0.028 mmol)。質譜(ESI)m/z=410.1(M+H)。1H NMR(500 MHz,DMSO-d6)δ 9.17(1H,s),8.28-8.37(3H,m),8.21(1H,s),7.93(1H,dd,J=8.6,2.4 Hz),7.72(1H,br.s.),7.56(1H,s),6.90(1H,s),6.83(1H,d,J=8.6 Hz),5.12-5.21(1H,m),4.81(1H,t,J=5.7 Hz),3.58(1H,dt,J=11.3,5.7 Hz),3.45-3.52(1H,m),2.67(3H,d,J=4.6 Hz),2.33(3H,s),1.24(3H,d,J=6.4 Hz)。 Step B : a mixture of 1-((5-bromopyridin-2-yl)oxy)propan-2-ol and 2-((5-bromopyridin-2-yl)oxy)propan-1-ol (219.5 mg, 0.946 mmol) of N,N-dimethylacetamide (5 mL) with bis(pinacolyl)diboron (362.7 mg, 1.428 mmol), butyldi-1-adamantyl Phosphine n-BuPAd 2 (68.9 mg, 0.192 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (87.1 mg, 0.095 mmol) and potassium acetate (233.5 mg, 2.379 mmol). The resulting solution was purged three times with argon and placed under vacuum three times. The mixture was heated to 100 ° C and monitored by LC-MS and TLC. After 4.5 hours, the reaction was cooled to room temperature. 1-(5-Bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (160.0 mg, 0.475 mmol) and 4.0 M aqueous potassium carbonate (0.36 mL, 1.440 mmol) was added to the reaction mixture. The flask was degassed and backfilled with argon. The resulting reaction was heated to 100 ° C and was monitored by TLC and LC-MS. After 22 hours, the reaction was cooled to room temperature then diluted with brine. After extracting three times with dichloromethane, the organics were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was diluted with dichloromethane, then loaded onto silica gel (20-100% pre-mixed 3:1 ethyl acetate: heptane in ethanol) to give a yellow film which was dissolved in 4 mL DMSO. The membrane was further purified using reverse phase HPLC (water containing 10-90% acetonitrile (premixed with 0.1% TFA) (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtration and concentration, separation by supercritical fluid chromatography (250×30 mm AD-H column using 40 mL/min MeOH + (20 mM NH 3 ) + 60 g/min CO 2 ) The isomer was further purified by supercritical fluid chromatography (250×30 mm OJ-H X OJ-H column using 20 mL/min EtOH+ (20 mM NH 3 ) + 80 g/min CO 2 ). Yield (R)-1-(6'-((1-hydroxypropan-2-yl)oxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3'- Bipyridyl]-6-yl)-3-methylurea (11.3 mg, 0.028 mmol). Mass Spectrum (ESI) m/z = 410.1 (M+H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.17 (1H, s), 8.28-8.37 (3H, m), 8.21. (1H, s), 7.93 (1H, dd, J = 8.6, 2.4 Hz), 7.72 (1H, br.s.), 7.56 (1H, s), 6.90 (1H, s), 6.83 (1H, d, J = 8.6 Hz), 5.12-5.21 (1H, m), 4.81 (1H, t , J = 5.7 Hz), 3.58 (1H, dt, J = 11.3, 5.7 Hz), 3.45-3.52 (1H, m), 2.67 (3H, d, J = 4.6 Hz), 2.33 (3H, s), 1.24 (3H,d, J =6.4 Hz).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1122Example 1122

1-(5-(5-氰基-1-甲基-1H-吡咯-2-基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3- 甲基脲 1-(5-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-4-(2,6-difluorophenoxy)pyridin-2-yl)-3- Methyl urea

將1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(156 mg，0.43 mmol)、(5-氰基-1-甲基-1H-吡咯-2-基)酸(131 mg，0.87 mmol)、肆(三苯基膦)鈀(0)(101 mg，0.09 mmol)及碳酸鉀(191 mg，1.38 mmol)添加至小瓶中，接著脫氣且用氬氣回填。由注射器向小瓶中添加四氫呋喃(3 mL)及水(1 mL)。加熱所得反應物至60℃且用TLC及LC-MS監測。17小時後，冷卻反應物至室溫，接著在減壓下濃縮。用二氯甲烷稀釋殘餘物，接著經數個0.45 μm GHP Acrodisc過濾。將物質加載於矽膠上(含0-50%預混合3：1乙酸乙酯：乙醇溶液之庚烷)，得到淡紫色膜狀物，使用逆相HPLC(含10-90%乙腈(預混有0.1% TFA)之水(含0.1% TFA))純化該膜狀物。合併含有所要產物之溶離份，接著在減壓下濃縮。用飽和碳酸氫鈉水溶液處理殘餘物。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，鑑別白色固體主要為所要產物。用乙腈處理白色固體，接著音波處理10分鐘。過濾固體且用乙腈沖洗兩次，得到呈白色固體狀之1-(5-(5-氰基-1-甲基-1H-吡咯-2-基)-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(15.0 mg，0.039 mmol，9.01%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.33(1H,s),8.13-8.17(1H,m),7.34-7.51(4H,m),7.04-7.09(2H,m),6.37(1H,d,J=4.2 Hz),3.66(3H,s),2.64(3H,d,J=4.6 Hz)。質譜(ESI)m/z=384.2(M+H)。 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (156 mg, 0.43 mmol), (5-cyano-1-methyl) keto-1H-pyrrol-2-yl) Acid (131 mg, 0.87 mmol), hydrazine (triphenylphosphine) palladium (0) (101 mg, 0.09 mmol) and potassium carbonate (191 mg, 1.38 mmol) were added to the vial, then degassed and backfilled with argon . Tetrahydrofuran (3 mL) and water (1 mL) were added to the vial from a syringe. The resulting reaction was heated to 60 ° C and was monitored by TLC and LC-MS. After 17 hours, the reaction was cooled to room temperature then concentrated under reduced pressure. The residue was diluted with dichloromethane and then filtered over several 0.45 [mu]m GHP Acrodis. The material was loaded onto silica gel (containing 0-50% premixed 3:1 ethyl acetate: heptane in ethanol) to give a lavender membrane using reverse phase HPLC (containing 10-90% acetonitrile (premixed) The membrane was purified by 0.1% TFA) water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the white solid was identified as the desired product. The white solid was treated with acetonitrile and then sonicated for 10 min. The solid was filtered and washed twice with EtOAc to give 1-(5-(5-cyano-1-methyl-1H-pyrrol-2-yl)-4-(2,6-difluorobenzene) as a white solid. Oxy)pyridin-2-yl)-3-methylurea (15.0 mg, 0.039 mmol, 9.01% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.33 (1H, s), 8.13-8.17 (1H, m), 7.34-7.51 (4H, m), 7.04-7.09 (2H, m), 6.37 ( 1H, d, J = 4.2 Hz), 3.66 (3H, s), 2.64 (3H, d, J = 4.6 Hz). Mass Spectrum (ESI) m/z = 384.2 (M+H).

實例1123Example 1123

1-(4-(3-氰基苯氧基)-5-環丙基吡啶-2-基)-3-甲基脲 1-(4-(3-cyanophenoxy)-5-cyclopropylpyridin-2-yl)-3-methylurea

步驟A：將1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.01 g，8.12 mmol)懸浮於1,4-二噁烷(55 mL)及水(5 mL)中，接著添加環丙基三氟硼酸鉀(4.46 g，30.1 mmol)、碳酸鉀(5.07 g，36.7 mmol)及[1,1-雙(二苯基膦基)二茂鐵]氯化鈀(II)與二氯甲烷之複合物(2.01 g，2.457 mmol)。使氬氣鼓泡通過混合物，持續10分鐘，接著加熱混合物至90℃。20小時後，冷卻反應物至室溫，接著分配於鹽水與乙酸乙酯之間。經無水硫酸鈉乾燥，過濾並濃縮後，在矽膠上(含0-30% 3：1乙酸乙酯：乙醇溶液之庚烷)純化殘餘物，得到黃色固體，用乙酸乙酯處理該固體。在旋轉蒸發器上加熱漿液至50℃。30分鐘後，冷卻混合物。過濾固體，接著用乙酸乙酯洗滌一次且用乙醚洗滌一次，得到呈白色固體狀之1-(5-環丙基-4-氟吡啶-2-基)-3-甲基脲(1.04 g，4.99 mmol，61.4%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.25(1H,s),7.91(1H,d,J=10.8 Hz),7.49(1H,br.s.),7.24(1H,d,J=12.7 Hz),2.64-2.73(3H,m),1.85(1H,tt,J=8.5,5.2 Hz),0.84-0.94(2H,m),0.65-0.78(2H,m)。質譜(正模式)m/e：210.1(M+H)+。 Step A : 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (2.01 g, 8.12 mmol) was suspended in 1,4-dioxane (55 mL) and water (5 In mL), followed by the addition of potassium cyclopropyltrifluoroborate (4.46 g, 30.1 mmol), potassium carbonate (5.07 g, 36.7 mmol) and [1,1-bis(diphenylphosphino)ferrocene] chloride Complex of palladium (II) with dichloromethane (2.01 g, 2.457 mmol). Argon was bubbled through the mixture for 10 minutes and then the mixture was heated to 90 °C. After 20 hours, the reaction was cooled to rt then partitioned between brine andEtOAc. After drying over anhydrous sodium sulfate, EtOAc (EtOAc)EtOAc. The slurry was heated to 50 ° C on a rotary evaporator. After 30 minutes, the mixture was cooled. The solid was filtered, washed with EtOAc EtOAc (EtOAc) 4.99 mmol, 61.4% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.25 (1H, s), 7.91 (1H, d, J = 10.8 Hz), 7.49 (1H, br.s.), 7.24 (1H, d, J =12.7 Hz), 2.64-2.73 (3H, m), 1.85 (1H, tt, J = 8.5, 5.2 Hz), 0.84-0.94 (2H, m), 0.65-0.78 (2H, m). Mass spectrum (positive mode) m/e: 210.1 (M+H) + .

步驟B：向1-(5-環丙基-4-氟吡啶-2-基)-3-甲基脲(101 mg，0.48 mmol)及3-氰基苯酚(75 mg，0.63 mmol)於DMF(2 mL)中之經攪拌溶液中分數份添加碳酸銫(259 mg，0.8 mmol)。加熱所得溶液至100℃且用LC-MS監測。18小時後，冷卻反應物至23℃，接著用水小心淬滅。用乙酸乙酯萃取三次後，彙集有機物，接著經無水硫酸鈉乾燥。過濾 並濃縮後，使用逆相HPLC(含10-95%乙腈(預混有0.1% TFA)之水(含0.1% TFA))純化該物質。合併含有所要產物之溶離份，接著在減壓下濃縮。用飽和碳酸氫鈉水溶液處理殘餘物。用二氯甲烷萃取三次後，彙集有機物，接著經無水硫酸鎂乾燥。過濾並濃縮後，將白色固體鑑別為1-(4-(3-氰基苯氧基)-5-環丙基吡啶-2-基)-3-甲基脲(15 mg，0.049 mmol，10.11%產率)。1H NMR(500 MHz,DMSO-d6)δ ppm 9.03(1H,s),7.87(1H,s),7.70-7.81(3H,m),7.67(1H,t,J=7.9 Hz),7.50(1H,ddd,J=8.3,2.4,1.0 Hz),6.79(1H,s),2.65(3H,d,J=4.6 Hz),1.88(1H,tt,J=8.5,5.3 Hz),0.82-0.88(2H,m),0.68-0.75(2H,m)。質譜(ESI)m/z=309.4(M+H)。 Step B : To 1-(5-cyclopropyl-4-fluoropyridin-2-yl)-3-methylurea (101 mg, 0.48 mmol) and 3-cyanophenol (75 mg, 0.63 mmol) in DMF Barium carbonate (259 mg, 0.8 mmol) was added in portions of the stirred solution in (2 mL). The resulting solution was heated to 100 ° C and monitored by LC-MS. After 18 hours, the reaction was cooled to 23 ° C then carefully quenched with water. After extracting three times with ethyl acetate, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the material was purified using reverse phase HPLC (10-95% acetonitrile (premixed with 0.1% TFA) in water (containing 0.1% TFA). The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate. After extracting three times with dichloromethane, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the white solid was identified as 1-(4-(3-cyanophenoxy)-5-cyclopropylpyridin-2-yl)-3-methylurea (15 mg, 0.049 mmol, 10.11 %Yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.03 (1H, s), 7.87 (1H, s), 7.70-7.81 (3H, m), 7.67 (1H, t, J = 7.9 Hz), 7.50 (1H,ddd, J = 8.3, 2.4, 1.0 Hz), 6.79 (1H, s), 2.65 (3H, d, J = 4.6 Hz), 1.88 (1H, tt, J = 8.5, 5.3 Hz), 0.82- 0.88 (2H, m), 0.68-0.75 (2H, m). Mass Spectrum (ESI) m/z = 309.4 (M+H).

遵循實例195中之程序，製備以下化合物： Following the procedure in Example 195, the following compounds were prepared:

實例1125Example 1125

1-(5-(1,4-二氧雜螺[4.5]癸-8-基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(1,4-Dioxaspiro[4.5]dec-8-ylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)- 3-methylurea

步驟A：向8-亞甲基-1,4-二氧雜螺[4.5]癸烷(0.087 mL，0.56 mmol)於經脫氣THF(1 mL)中之溶液中添加含0.5 M 9-BBN之THF(1.13 mL，0.564 mmol)。加熱混合物至回流，維持1小時，接著冷卻 至室溫。將混合物添加至含有5-溴-3-((2-乙基吡啶-3-基)氧基)吡啶醯胺(0.100 g，0.310 mmol)、二氯1,1'-雙(二苯基膦基)二茂鐵鈀(ii)(0.042 g，0.051 mmol)、K2CO3(0.213 g，1.54 mmol)、經脫氣DMF(2 mL)及經脫氣H2O(0.14 mL，7.8 mmol)之燒瓶中。在80℃下加熱所得混合物5小時。用飽和NaHCO3溶液稀釋混合物，用15% NaOH水溶液鹼化至PH 11，用EtOAc萃取且用鹽水洗滌。乾燥有機層且在真空中濃縮。藉由逆相製備型HPLC純化粗物質，得到5-(1,4-二氧雜螺[4.5]癸-8-基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶醯胺(0.060 g，0.15 mmol，29%產率)。質譜(ESI)m/z=398.2(M+H)。 Step A : Add 0.5 M 9-BBN to a solution of 8-methylene-1,4-dioxaspiro[4.5]decane (0.087 mL, 0.56 mmol) in degassed THF (1 mL) THF (1.13 mL, 0.564 mmol). The mixture was heated to reflux for 1 hour and then cooled to room temperature. Adding the mixture to 5-bromo-3-((2-ethylpyridin-3-yl)oxy)pyridiniumamine (0.100 g, 0.310 mmol), dichloro 1,1'-bis(diphenylphosphine) Ferrocenyl palladium (ii) (0.042 g, 0.051 mmol), K 2 CO 3 (0.213 g, 1.54 mmol), degassed DMF (2 mL) and degassed H 2 O (0.14 mL, 7.8 mmol In the flask. The resulting mixture was heated at 80 ° C for 5 hours. The solution was diluted with saturated NaHCO 3 mixture was basified with 15% NaOH aqueous solution to PH 11, extracted with EtOAc and washed with brine. The organic layer was dried and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC to give 5-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-3-((2-ethylpyridin-3-yl)oxy Pyridinamine (0.060 g, 0.15 mmol, 29% yield). Mass Spectrum (ESI) m/z = 398.2 (M+H).

步驟B：向5-(1,4-二氧雜螺[4.5]癸-8-基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶醯胺(60 mg，0.151 mmol)於乙腈(1.5 mL)與水(1.5 mL)之混合物中之溶液中添加甲胺(0.066 mL，0.755 mmol)及雙(三氟乙醯氧基)碘苯(68.2 mg，0.159 mmol)。在室溫下攪拌反應混合物1.8小時。用飽和NaHCO3稀釋反應混合物且用EtOAc萃取。收集有機層，乾燥且在真空中濃縮。藉由逆相HPLC，以10-40%梯度純化粗產物，得到1-(5-(1,4-二氧雜螺[4.5]癸-8-基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.044 g，0.10 mmol，68%產率)。質譜(ESI)m/z=427.3(M+H)。1H NMR(MeOH-d 4 )δ 8.35(dd,J=4.7,1.4 Hz,1H),7.84(d,J=1.8 Hz,1H),7.39(dd,J=8.2,1.6 Hz,1H),7.32(dd,J=8.2,4.7 Hz,1H),6.88(d,J=1.8 Hz,1H),3.89(s,4H),2.93(s,3H),2.86(q,J=7.6 Hz,2H),2.44(d,J=7.0 Hz,2H),1.69(d,J=12.3 Hz,2H),1.53-1.64(m,2H),1.43(td,J=13.2,4.0 Hz,3H),1.16-1.31(m,5H)。 Step B : to 5-(1,4-Dioxaspiro[4.5]dec-8-ylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridiniumamine (60 mg , 0.151 mmol) Methylamine (0.066 mL, 0.755 mmol) and bis(trifluoroethyloxy)iodobenzene (68.2 mg, 0.159 mmol) in a mixture of acetonitrile (1.5 mL) and water (1.5 mL) ). The reaction mixture was stirred at room temperature for 1.8 hours. The reaction mixture was diluted with saturated NaHCO 3 and extracted with with EtOAc. The organic layer was collected, dried and concentrated in vacuo. The crude product was purified by reverse phase HPLC on a 10-40% gradient to give 1-(5-(1,4-dioxaspiro[4.5]indole-8-ylmethyl)-3-((2-B) Pyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.044 g, 0.10 mmol, 68% yield). Mass Spectrum (ESI) m/z = 427.3 (M+H). 1 H NMR (MeOH- d 4 ) δ 8.35 (dd, J = 4.7, 1.4 Hz, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.2, 1.6 Hz, 1H), 7.32 (dd, J = 8.2, 4.7 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 3.89 (s, 4H), 2.93 (s, 3H), 2.86 (q, J = 7.6 Hz, 2H) ), 2.44 (d, J = 7.0 Hz, 2H), 1.69 (d, J = 12.3 Hz, 2H), 1.53-1.64 (m, 2H), 1.43 (td, J = 13.2, 4.0 Hz, 3H), 1.16 -1.31 (m, 5H).

遵循實例1125中之程序，製備以下化合物： Following the procedure in Example 1125 , the following compounds were prepared:

實例1127Example 1127

步驟A：向含1-(5-(1,4-二氧雜螺[4.5]癸-8-基甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(50 mg，0.117 mmol)之燒瓶中添加EtOH(3.5 mL)及1 N HCl(0.352 mL，0.352 mmol)。加熱反應混合物至65℃，維持2小時。用1 N NaOH水溶液中和反應混合物且濃縮。用鹽水稀釋混合物且用EtOAc萃取。收集有機層，乾燥且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，定量地得到1-(3-((2-乙基吡啶-3-基)氧基)-5-((4-側氧基環己基)甲基)吡啶-2-基)-3-甲基脲。 Step A : To a solution containing 1-(5-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-3-((2-ethylpyridin-3-yl)oxy)pyridine- To a flask of 2-yl)-3-methylurea (50 mg, 0.117 mmol) was added EtOH (3.5 mL) and 1 N HCl (0.352 mL, 0.352 mmol). The reaction mixture was heated to 65 ° C for 2 hours. The reaction mixture was neutralized with a 1 N aqueous NaOH solution and concentrated. The mixture was diluted with brine and extracted with EtOAc. The organic layer was collected, dried and concentrated in vacuo. The crude material was absorbed onto a silicone plug and purified by chromatography on a Didi-Sep prefilled cartridge column, eluting with a gradient of 0% to 10% MeOH in CH 2 Cl 2 to quantitatively afford 1-( 3-((2-Ethylpyridin-3-yl)oxy)-5-((4-oxocyclohexyl)methyl)pyridin-2-yl)-3-methylurea.

步驟B：向裝有1-(3-((2-乙基吡啶-3-基)氧基)-5-((4-側氧基環己基)甲基)吡啶-2-基)-3-甲基脲(43 mg，0.11 mmol)之燒瓶中添加NaBH4(17.0 mg，0.450 mmol)及MeOH(2.5 mL)。攪拌反應混合物1小時，接著在真空中濃縮。用NH4Cl稀釋反應混合物且用EtOAc萃取。收集有機層，乾燥且在真空中濃縮。藉由逆相HPLC純化粗物質，得到1-(3-((2-乙基吡啶-3-基)氧基)-5-((4-羥基環己基)甲基)吡啶-2-基)-3-甲基脲(28 mg，0.073 mmol，65%產率)。質譜(ESI)m/z=385.3(M+H)。藉由 超臨界流體層析(2×15 cm AD-H管柱，使用60 mL/min 15%異丙醇(0.1% NH4OH)/CO2)分離異構體。 Step B : To a solution of 1-(3-((2-ethylpyridin-3-yl)oxy)-5-((4-oxocyclohexyl)methyl)pyridin-2-yl)-3 - Add NaBH 4 (17.0 mg, 0.450 mmol ) and MeOH (2.5 mL) methylurea (43 mg, 0.11 mmol) of the flask. The reaction mixture was stirred for 1 hour then concentrated in vacuo. The reaction mixture was diluted with NH 4 Cl and extracted with EtOAc. The organic layer was collected, dried and concentrated in vacuo. The crude material was purified by reverse phase HPLC to give 1-(3-((2-ethylpyridin-3-yl)oxy)-5-((4-hydroxycyclohexyl)methyl)pyridin-2-yl) -3-methylurea (28 mg, 0.073 mmol, 65% yield). Mass Spectrum (ESI) m/z = 385.3 (M+H). By supercritical fluid chromatography (2 × 15 cm AD-H column, using 60 mL / min 15% isopropanol (0.1% NH 4 OH) / CO 2) separation of the isomers.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1130Example 1130

1-(5-((3-(苄氧基)環丁基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((3-(Benzyloxy)cyclobutyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3-methyl Urea

步驟A：向裝有3-(苄氧基)環丁酮(0.341 mL，2.168 mmol)之燒瓶中添加THF(5 mL)且冷卻降至0℃。緩慢添加0.5 M特貝試劑(Tebbe reagent)於甲苯中之溶液(4.34 mL，2.168 mmol)。使反應物升溫至室溫且攪拌30分鐘。添加乙醚以稀釋反應物，且用0.1 M NaOH水溶液淬滅直至氣體停止產生。經矽藻土過濾混合物，經MgSO4乾燥，接著在減壓下濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至20% EtOAc之己烷梯度溶離進行層析來純化，得到((3-亞甲基環丁氧基)甲基)苯(220 mg，1.26 mmol，58.2%產率)。 1H NMR(CDCl3)δ 7.18-7.30(m,5H),4.72-4.84(m,2H),4.38(s,2H),4.04(t,J=6.6 Hz,1H),2.74-2.90(m,2H),2.59-2.74(m,2H)。 Step A : To a flask containing 3-(benzyloxy)cyclobutanone (0.341 mL, 2.168 mmol) was added THF (5 mL) and cooled to 0 °C. A solution of 0.5 M Tebbe reagent in toluene (4.34 mL, 2.168 mmol) was slowly added. The reaction was allowed to warm to rt and stirred for 30 min. Diethyl ether was added to dilute the reaction and was quenched with 0.1 M aqueous NaOH until gas ceased. The mixture was filtered through diatomaceous earth, dried over MgSO 4, then concentrated under reduced pressure. The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium packed with 0% to 20% EtOAc in hexanes. Cyclobutoxy)methyl)benzene (220 mg, 1.26 mmol, 58.2% yield). 1 H NMR (CDCl 3 ) δ 7.18-7.30 (m, 5H), 4.72-4.84 (m, 2H), 4.38 (s, 2H), 4.04 (t, J = 6.6 Hz, 1H), 2.74-2.90 (m) , 2H), 2.59-2.74 (m, 2H).

步驟B：向((3-亞甲基環丁氧基)甲基)苯(110 mg，0.631 mmol)於THF(1 mL)中之溶液中添加含0.5 M 9-BBN之THF(1.26 ml，0.631 mmol)。加熱混合物至回流，維持1小時，接著冷卻至室溫。將混合物添加至含有5-溴-3-((2-乙基吡啶-3-基)氧基)吡啶醯胺(113 mg，0.350 mmol)、二氯1,1'-雙(二苯基膦基)二茂鐵鈀(ii)(46.9 mg，0.057 mmol)、K2CO3(238 mg，1.72 mmol)、經脫氣DMF(2 mL)、經脫氣H2O(0.16 ml)之燒瓶中。在80℃下加熱所得混合物5小時。用飽和NaHCO3溶液稀釋混合物，用15% NaOH水溶液鹼化至PH 11，用EtOAc萃取且用鹽水洗滌。乾燥有機層且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，得到5-((3-(苄氧基)環丁基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶醯胺(151 mg，0.362 mmol，63.0%產率)。質譜(ESI)m/z=418.2(M+H)。 Step B : To a solution of ((3-methylenecyclobutoxy)methyl)benzene (110 mg, 0.631 mmol) in THF (1 mL) 0.631 mmol). The mixture was heated to reflux for 1 hour and then cooled to room temperature. Adding the mixture to 5-bromo-3-((2-ethylpyridin-3-yl)oxy)pyridiniumamine (113 mg, 0.350 mmol), dichloro 1,1'-bis(diphenylphosphine) a flask of ferrocene palladium (ii) (46.9 mg, 0.057 mmol), K 2 CO 3 (238 mg, 1.72 mmol), degassed DMF (2 mL), degassed H 2 O (0.16 ml) in. The resulting mixture was heated at 80 ° C for 5 hours. The solution was diluted with saturated NaHCO 3 mixture was basified with 15% NaOH aqueous solution to PH 11, extracted with EtOAc and washed with brine. The organic layer was dried and concentrated in vacuo. The crude material was absorbed onto a silica gel plug and purified by chromatography on a ruthenium column containing 0% to 100% EtOAc in a pre-filled cartridge with Redi-Sep to give 5-((3-) Benzyloxy)cyclobutyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridiniumamine (151 mg, 0.362 mmol, 63.0% yield). Mass Spectrum (ESI) m/z = 418.2 (M+H).

步驟C：向5-((3-(苄氧基)環丁基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶醯胺(151 mg，0.362 mmol)於乙腈(3 mL)與水(3.00 mL)之混合物中之溶液中添加甲胺(0.158 mL，1.808 mmol)及雙(三氟乙醯氧基)碘苯(163 mg，0.380 mmol)。攪拌反應混合物1.8小時，接著用飽和NaHCO3溶液稀釋，且用EtOAc萃取。藉由逆相HPLC純化粗物質，得到1-(5-((3-(苄氧基)環丁基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(90 mg，0.20 mmol，56%)。質譜(ESI)m/z=447.3(M+H)。 Step C : To 5-((3-(Benzyloxy)cyclobutyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridiniumamine (151 mg, 0.362 mmol) Methylamine (0.158 mL, 1.808 mmol) and bis(trifluoroethyloxy)iodobenzene (163 mg, 0.380 mmol) were added to a mixture of acetonitrile (3 mL) and water (3.00 mL). The reaction mixture was stirred for 1.8 hours, then diluted with saturated NaHCO 3 solution, and extracted with EtOAc. The crude material was purified by reverse phase HPLC to give 1-(5-((3-(benzyloxy)cyclobutyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridine -2-yl)-3-methylurea (90 mg, 0.20 mmol, 56%). Mass Spectrum (ESI) m/z = 447.3 (M+H).

遵循實例1130中之程序，製備以下化合物： Following the procedure in Example 1130 , the following compounds were prepared:

實例1134Example 1134

向含1-(5-((3-(苄氧基)環丁基)甲基)-3-((2-乙基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(90 mg，0.202 mmol)之燒瓶中添加鈀/碳(32.2 mg，0.030 mmol)及MeOH。用氫氣淨化反應物且在氫氣氛圍下攪拌。18小時後，再添加Pd/C且對反應物再進行氫化。經矽藻土襯墊過濾反應混合物且濃縮。藉由逆相HPLC純化粗物質，得到1-(3-((2-乙基吡啶-3-基)氧基)-5-((3-羥基環丁基)甲基)吡啶-2-基)-3-甲基脲(26 mg，0.073 mmol，36%產率)。質譜(ESI)m/z=357.2(M+H)。藉由超臨界流體層析(2×15 cm AD-H管柱，使用65 mL/min 20% MeOH(0.1% NH4OH)/CO2)分離異構體。 To 1-(5-((3-(benzyloxy)cyclobutyl)methyl)-3-((2-ethylpyridin-3-yl)oxy)pyridin-2-yl)-3- Palladium on carbon (32.2 mg, 0.030 mmol) and MeOH were added to a methyl urea (90 mg, 0.202 mmol) flask. The reaction was purged with hydrogen and stirred under a hydrogen atmosphere. After 18 hours, additional Pd/C was added and the reaction was again hydrogenated. The reaction mixture was filtered through a pad of Celite and concentrated. The crude material was purified by reverse phase HPLC to give 1-(3-((2-ethylpyridin-3-yl)oxy)-5-((3-hydroxycyclobutyl)methyl)pyridin-2-yl )-3-methylurea (26 mg, 0.073 mmol, 36% yield). Mass Spectrum (ESI) m/z = 357.2 (M+H). By supercritical fluid chromatography (2 × 15 cm AD-H column, using 65 mL / min 20% MeOH ( 0.1% NH 4 OH) / CO 2) separation of the isomers.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1143Example 1143

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((1r,4r)-4-羥基-4-甲基環己基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)pyridine -2-yl)-3-methylurea

步驟A：向裝有1-(5-(1,4-二氧雜螺[4.5]癸-8-基甲基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲(137 mg，0.330 mmol)之燒瓶中添加EtOH(8 mL)及1 N HCl(0.989 mL，0.989 mmol)。加熱反應混合物至65℃，維持2小時。用1 N NaOH溶液中和反應混合物且濃縮。用鹽水稀釋混合物且用EtOAc萃取。收集有機層，乾燥且在真空中濃縮，得到1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((4-側氧基環己基)甲基)吡啶-2-基)-3-甲基脲(120 mg，0.323 mmol，98%產率)。 Step A : To the solution of 1-(5-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-3-((1-ethyl-1H-pyrazole-5-yl) To a flask of oxy)pyridin-2-yl)-3-methylurea (137 mg, 0.330 mmol) was added EtOH (8 mL) and 1 N HCl (0.989 mL, 0.989 mmol). The reaction mixture was heated to 65 ° C for 2 hours. The reaction mixture was neutralized with a 1 N NaOH solution and concentrated. The mixture was diluted with brine and extracted with EtOAc. The organic layer was collected, dried and concentrated in vacuo to give 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((4-oxocyclohexyl) Pyridin-2-yl)-3-methylurea (120 mg, 0.323 mmol, 98% yield).

步驟B：用甲苯使含1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((4-側氧基環己基)甲基)吡啶-2-基)-3-甲基脲(86 mg，0.232 mmol)之燒瓶共沸，接著用氮氣淨化。將反應物溶解於THF(2.5 mL)中且冷卻至0 ℃。向溶液中逐滴添加1.6 M甲基鋰於乙醚中之溶液(1.085 mL，1.737 mmol)。5分鐘後，使反應物升溫至室溫且攪拌1小時。反應物變成混濁的微紅色。用飽和氯化銨溶液淬滅反應物且用乙酸乙酯萃取。用鹽水洗滌有機層，經硫酸鎂乾燥且在真空中濃縮。藉由超臨界流體層析(2×25 cm AD-H管柱，使用65 mL/min 30% MeOH(0.1% NH4OH)/CO2)分離異構體，得到1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((1r,4r)-4-羥基-4-甲基環己基)甲基)吡啶-2-基)-3-甲基脲(9 mg，0.02 mmol，20%產率)。1H NMR(MeOH-d 4 )δ 7.89(s,1H),7.44(s,1H),7.20(s,1H),5.73(s,1H),4.03-4.23(m,2H),2.91(s,3H),2.47(d,J=4.3 Hz,2H),1.62(d,J=10.6 Hz,3H),1.22-1.49(m,12H)。 Step B : Using 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((4-oxocyclohexyl)methyl)pyridine-2 The flask of 3-methyl)urea (86 mg, 0.232 mmol) was azeotroped and then purified with nitrogen. The reaction was dissolved in THF (2.5 mL) and cooled to EtOAc. A solution of 1.6 M methyllithium in diethyl ether (1.085 mL, 1.737 mmol) was added dropwise to the solution. After 5 minutes, the reaction was allowed to warm to rt and stirred 1 hr. The reaction turned into a turbid reddish color. The reaction was quenched with saturated aq. The organic layer was washed with brine, dried over magnesium sulfate dried By supercritical fluid chromatography (2 × 25 cm AD-H column, using 65 mL / min 30% MeOH ( 0.1% NH 4 OH) / CO 2) separation of the isomers, to give 1- (3 - (( 1-ethyl-1H-pyrazol-5-yl)oxy)-5-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)pyridin-2-yl)-3 -methylurea (9 mg, 0.02 mmol, 20% yield). 1 H NMR (MeOH- d 4 ) δ 7.89 (s, 1H), 7.44 (s, 1H), 7.20 (s, 1H), 5.73 (s, 1H), 4.03-4.23 (m, 2H), 2.91 (s) , 3H), 2.47 (d, J = 4.3 Hz, 2H), 1.62 (d, J = 10.6 Hz, 3H), 1.22-1.49 (m, 12H).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

遵循實例449中之程序，製備以下化合物： Following the procedure in Example 449, the following compounds were prepared:

遵循實例467中之程序，製備以下化合物： Following the procedure in Example 467, the following compounds were prepared:

實例1155Example 1155

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((3-側氧基環丁基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((3-oxocyclocyclobutyl)methyl)pyridin-2-yl)-3- Methyl urea

向裝有1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((3-羥基環丁基)甲基)吡啶-2-基)-3-甲基脲(120 mg，0.347 mmol)之燒瓶中添加戴斯-馬丁高碘烷(Dess-martin periodinane)(192 mg，0.452 mmol)及CH2Cl2(6 mL)。在室溫下攪拌反應物1小時20分鐘，接著用飽和NaHCO3溶液淬滅且用乙酸乙酯萃取。用鹽水洗滌有機層，經硫酸鎂乾燥且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((3-側氧基環丁基)甲基)吡啶-2-基)-3-甲基脲(107 mg，0.312 mmol，90%產率)。質譜(ESI)m/z=344.1(M+H)。 To the solution of 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((3-hydroxycyclobutyl)methyl)pyridin-2-yl)-3 - methylurea (120 mg, 0.347 mmol) the flask was added Dess - Martin periodinane (Dess-martin periodinane) (192 mg, 0.452 mmol) and CH 2 Cl 2 (6 mL) . The reaction was stirred at room temperature for 1 hour 20 minutes, then quenched with quenched with saturated NaHCO 3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate dried The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column, containing CH 0% to 10% MeOH of 2 Cl 2 gradient eluting chromatographed to give 1- (3- ((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((3-o-oxocyclobutyl)methyl)pyridin-2-yl)-3-methylurea (107 Mg, 0.312 mmol, 90% yield). Mass Spectrum (ESI) m/z = 344.1 (M+H).

遵循製備1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((3-側氧基環丁基)甲基)吡啶-2-基)-3-甲基脲之程序，製備以下化合物： Following the preparation of 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((3-oxocyclocyclobutyl)methyl)pyridin-2-yl)- 3-methylurea procedure to prepare the following compounds:

實例1157Example 1157

1-(3-((2-乙基吡啶-3-基)氧基)-5-((3-羥基-3-(三氟甲基)環丁基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((2-ethylpyridin-3-yl)oxy)-5-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl)pyridin-2-yl) -3-methylurea

向燒瓶中饋入1-(3-((2-乙基吡啶-3-基)氧基)-5-((3-側氧基環丁基)甲基)吡啶-2-基)-3-甲基脲(47 mg，0.133 mmol)且冷卻至0℃。依序添加(三氟甲基)三甲基矽烷(0.098 mL，0.663 mmol)、含1.0 M氟化四丁基銨之THF(0.033 mL，0.033 mmol)，且在0℃下攪拌反應混合物20分鐘。使反應物升溫至室溫且攪拌18小時。再次冷卻反應物至0℃，且再添加(三氟甲基)三甲基矽烷(0.098 mL，0.663 mmol)及含1.0 M氟化四丁基銨之THF(0.033 mL，0.033 mmol)。使反應混合物升溫至室溫且攪拌18小時。添加(三氟甲基)三甲基矽烷(0.098 mL，0.663 mmol)、含1.0 M氟化四丁基銨之THF(0.033 mL，0.033 mmol)及水(20微升)，且攪拌反應混合物1天。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至50%)純化粗物質，得到1-(3-((2-乙基吡啶-3-基)氧基)-5-((3-羥基-3-(三氟甲基)環丁基)甲基)吡啶-2-基)-3-甲基脲(8 mg，0.019 mmol，14%產率)。質譜(ESI)m/z=425.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.36(dd,J=4.70,1.37 Hz,1 H)7.86(d, J=1.76 Hz,1 H)7.37-7.45(m,1 H)7.25-7.38(m,1 H)6.89(d,J=1.76 Hz,1 H)2.92(s,3 H)2.85(d,J=7.63 Hz,2 H)2.68(d,J=7.63 Hz,2 H)2.45-2.53(m,2 H)2.20(dt,J=16.14,8.17 Hz,1 H)1.77-1.87(m,2 H)1.23-1.29(m,3 H)。 The flask was fed with 1-(3-((2-ethylpyridin-3-yl)oxy)-5-((3-oxocyclocyclobutyl)methyl)pyridin-2-yl)-3 -Methylurea (47 mg, 0.133 mmol) and cooled to 0 °C. (Trifluoromethyl)trimethylnonane (0.098 mL, 0.663 mmol), THF (0.033 mL, 0.033 mmol) containing 1.0 M tetrabutylammonium fluoride, and the mixture was stirred at 0 ° C for 20 min. . The reaction was allowed to warm to rt and stirred for 18 h. The reaction was again cooled to 0&lt;0&gt;C, and (trifluoromethyl)trimethyl decane (0.098 <RTI ID=0.0></RTI><RTIgt; The reaction mixture was allowed to warm to rt and stirred for 18 h. Add (trifluoromethyl)trimethylnonane (0.098 mL, 0.663 mmol), THF (0.033 mL, 0.033 mmol) with 1.0 M tetrabutylammonium fluoride and water (20 μL), and stir the reaction mixture 1 day. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10-50%) to give the crude material to give 1- (3 - ((2-ethyl-pyridin-3-yl )oxy)-5-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)methyl)pyridin-2-yl)-3-methylurea (8 mg, 0.019 mmol, 14% yield) rate). Mass Spectrum (ESI) m/z = 425.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.36 (dd, J = 4.70, 1.37 Hz, 1 H) 7.86 (d, J = 1.76 Hz, 1 H) 7.37-7.45 (m, 1 H) 7.25-7.38 ( m,1 H)6.89 (d, J = 1.76 Hz, 1 H) 2.92 (s, 3 H) 2.85 (d, J = 7.63 Hz, 2 H) 2.68 (d, J = 7.63 Hz, 2 H) 2.45- 2.53 (m, 2 H) 2.20 (dt, J = 16.14, 8.17 Hz, 1 H) 1.77-1.87 (m, 2 H) 1.23-1.29 (m, 3 H).

實例1158Example 1158

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((S)-羥基((1r,3S)-3-羥基-3-甲基環丁基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((S)-hydroxy((1r,3S)-3-hydroxy-3-methylcyclobutane) Methyl)pyridin-2-yl)-3-methylurea

步驟A：向燒瓶中饋入1-(5-溴-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲(11.2 g，32.9 mmol)且與甲苯一起共沸。添加THF(400 mL)。在乾冰-丙酮浴中冷卻降溫。接著添加甲基鋰(41.2 mL，65.8 mmol)，且攪拌反應物8分鐘。反應物變成黃色。接著在劇烈攪拌下逐滴添加丁基鋰(15.80 mL，39.5 mmol)。添加30分鐘後，快速添加含(1r,3r)-3-((第三丁基二甲基矽烷基)氧基)-3-甲基環丁烷甲醛(8.05 g，35.2 mmol)之5 mL THF。在相同浴溫下攪拌反應物2小時40分鐘，且移除浴。在室溫下攪拌30分鐘後，反應物變成澄清溶液。用飽和NH4Cl淬滅反應物且用EtOAc萃取。乾燥EtOAc層並濃縮，且藉由在combiflash上，在7分鐘內以含0-70% EtOAc之己烷梯度，接著以含2-8% MeOH之DCM梯度進行矽膠層析來純化粗物質。得到9.56 g含有所要1-(5-((S)-((1r,3S)-3-((第三丁基二甲基矽烷基)氧基)-3-甲基環丁基)(羥基)甲基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲作為主要組分之混合物。 Step A : Feeding the flask with 1-(5-bromo-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-yl)-3-methylurea (11.2) g, 32.9 mmol) and azeotroped with toluene. Add THF (400 mL). Cool down in a dry ice-acetone bath. Methyllithium (41.2 mL, 65.8 mmol) was then added and the reaction was stirred for 8 min. The reaction turned yellow. Then butyl lithium (15.80 mL, 39.5 mmol) was added dropwise with vigorous stirring. After 30 minutes of addition, 5 mL of (1r,3r)-3-((t-butyldimethylmethylalkyl)oxy)-3-methylcyclobutanecarbaldehyde (8.05 g, 35.2 mmol) was quickly added. THF. The reaction was stirred at the same bath temperature for 2 hours and 40 minutes and the bath was removed. After stirring at room temperature for 30 minutes, the reaction became a clear solution. With saturated NH 4 Cl The reaction was quenched and extracted with EtOAc. The EtOAc layer was dried with EtOAc EtOAc EtOAc. 9.56 g of the desired 1-(5-((S)-((1r,3S)-3-((t-butyldimethylmethyl)alkyl)oxy)-3-methylcyclobutyl) A mixture of methyl)-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-yl)-3-methylurea as a main component.

步驟B：向含1-(5-((S)-((1r,3S)-3-((第三丁基二甲基矽烷基)氧基)-3-甲基環丁基)(羥基)甲基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲(14.0 g，28.6 mmol)之燒瓶中添加MeOH(200 mL)、甲烷磺酸(10 mL，154 mmol)。用氫氣淨化反應物且在雙層氫氣球下攪拌隔夜。經矽藻土過濾反應物。接著添加NaOH水溶液以將反應物PH值調整至約7。濃縮反應物以移除MeOH，接著添加EtOAc/水。用EtOAc萃取。乾燥EtOAc層並濃縮，且藉由在combiflash上以含0-70% EtOAc之己烷梯度，接著以含2-8% MeOH之DCM梯度進行矽膠層析來純化粗物質。質譜(ESI)m/z=376.1(M+H)。1H NMR(400 MHz,MeOH)δ ppm 7.93-8.06(m,1 H)7.46(d,J=2.15 Hz,1 H)7.33(d,J=1.76 Hz,1 H)5.78(d,J=1.96 Hz,1 H)4.46-4.52(m,1 H)4.12(q,J=7.24 Hz,2 H)2.93(br.s.,3 H)2.50-2.50(m,1 H)1.98-2.12(m,2 H)1.76-1.91(m,2 H)1.39(t,J=7.24 Hz,3 H)1.28(s,3 H)。 Step B : to 1-(5-((S)-((1r,3S)-3-((t-butyldimethylmethylalkyl)oxy)-3-methylcyclobutyl)) Add MeOH to a flask of methyl)-3-((1-ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-yl)-3-methylurea (14.0 g, 28.6 mmol) (200 mL), methanesulfonic acid (10 mL, 154 mmol). The reaction was purged with hydrogen and stirred overnight under a double hydrogen balloon. The reaction was filtered through celite. An aqueous NaOH solution was then added to adjust the pH of the reactants to about 7. The reaction was concentrated to remove MeOH then EtOAc / water. Extract with EtOAc. The EtOAc layer was dried with EtOAc EtOAc m. Mass Spectrum (ESI) m/z = 376.1 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 7.93-8.06 (m, 1 H) 7.46 (d, J = 2.15 Hz, 1 H) 7.33 (d, J = 1.76 Hz, 1 H) 5.78 (d, J = 1.96 Hz, 1 H) 4.46-4.52 (m, 1 H) 4.12 (q, J = 7.24 Hz, 2 H) 2.93 (br.s., 3 H) 2.50-2.50 (m, 1 H) 1.98-2.12 ( m, 2 H) 1.76-1.91 (m, 2 H) 1.39 (t, J = 7.24 Hz, 3 H) 1.28 (s, 3 H).

實例1159Example 1159

1-(5-(環丙基(羥基)甲基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(cyclopropyl(hydroxy)methyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

使1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(80 mg，0.237 mmol)與甲苯一起共沸且用氮氣淨化。添加THF(2.5 mL)，且冷卻反應物至-78℃。添加1.6 M甲基鋰(0.297 mL，0.475 mmol)，且攪拌反應混合物5分鐘。添加1.6 M丁基鋰(0.178 mL，0.285 mmol)，且攪拌混合物20分鐘，繼而添加環丙烷甲醛(0.044 mL， 0.593 mmol)。使浴自然地升至室溫且攪拌隔夜。反應物變成混濁的微紅色。用飽和氯化銨溶液淬滅反應物且用乙酸乙酯萃取。用鹽水洗滌有機層，經硫酸鎂乾燥且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至80% EtOAc之己烷、接著以含2%至8% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-(5-(環丙基(羥基)甲基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(30 mg，0.091 mmol，38.5%產率)。質譜(ESI)m/z=329.2(M+H)。1H NMR(MeOH)δ：8.29-8.39(m,2H),8.23(d,J=2.5 Hz,1H),7.44-7.55(m,1H),6.44(s,1H),4.40(d,J=7.8 Hz,1H),2.75-2.90(m,3H),2.42(s,3H),1.27-1.46(m,1H),0.59-0.70(m,1H),0.45-0.59(m,2H),0.31-0.45(m,1H)。 1-(5-Bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (80 mg, 0.237 mmol) was azeotroped with toluene and Purify with nitrogen. THF (2.5 mL) was added and the reaction was cooled to -78. 1.6 M methyllithium (0.297 mL, 0.475 mmol) was added and the reaction mixture was stirred for 5 min. 1.6 M butyllithium (0.178 mL, 0.285 mmol) was added and the mixture was stirred 20 min then cyclopropanecarbaldehyde (0.044 mL, 0.593 mmol). The bath was naturally warmed to room temperature and stirred overnight. The reaction turned into a turbid reddish color. The reaction was quenched with saturated aq. The organic layer was washed with brine, dried over magnesium sulfate dried The crude material was absorbed on silica plug, and by by Redi-Sep pre-packed silica gel column, containing hexanes 0% to sum to 80% EtOAc, followed by 2% to 8% MeOH gradient of CH 2 Cl 2 Purification by chromatography to give 1-(5-(cyclopropyl(hydroxy)methyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- Methyl urea (30 mg, 0.091 mmol, 38.5% yield). Mass Spectrum (ESI) m/z = 329.2 (M+H). 1 H NMR (MeOH) δ: 8.29-8.39 (m, 2H), 8.23 (d, J = 2.5 Hz, 1H), 7.44-7.55 (m, 1H), 6.44 (s, 1H), 4.40 (d, J = 7.8 Hz, 1H), 2.75-2.90 (m, 3H), 2.42 (s, 3H), 1.27-1.46 (m, 1H), 0.59-0.70 (m, 1H), 0.45-0.59 (m, 2H), 0.31-0.45 (m, 1H).

遵循實例1159中之程序，製備以下化合物： Following the procedure in Example 1159 , the following compounds were prepared:

實例1164Example 1164

1-(5-((1r,3r)-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((1r,3r)-3-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

將1-(5-(3-(苄氧基)-1-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(100 mg，0.230 mmol)、10%鈀/碳(73.5 mg，0.069 mmol)、甲烷磺酸(0.6 mL，9 mmol)、EtOH(3 mL)及MeOH(3 mL)於壓力管中組合。使壓力管在45 psi下氫化18小時。再添加甲烷磺酸(0.1 mL，1.5 mmol)及10%鈀/碳(73.5 mg，0.069 mmol)，且使反應混合物再氫化24小時。稍後，以與上述類似之程序使反應在雙層氫氣球下進行1-3天，每天用新的氫氣球替換氫氣球。不需要施加高壓。經矽藻土襯墊過濾反應混合物，用NaOH水溶液中和至弱鹼性且濃縮。將產物分配於EtOAc與水之間。收集有機層，經硫酸鎂乾燥且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-(5-((1r,3r)-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(59 mg，0.180 mmol，78%產率)。質譜(ESI)m/z=329.2(M+H)。 1H NMR(MeOH-d 4 )δ 8.27-8.36(m,1H),8.19(d,J=2.5 Hz,1H),8.07(s,1H),7.40-7.50(m,1H),6.41(s,1H),4.15-4.31(m,1H),3.07-3.21(m,1H),2.83(s,3H),2.66-2.79(m,2H),2.41(s,3H),1.98-2.17(m,2H)。 1-(5-(3-(Benzyloxy)-1-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-yl Combination of a urea (100 mg, 0.230 mmol), 10% palladium on carbon (73.5 mg, 0.069 mmol), methanesulfonic acid (0.6 mL, 9 mmol), EtOH (3 mL) and MeOH (3 mL) in a pressure tube . The pressure tube was hydrogenated at 45 psi for 18 hours. Methanesulfonic acid (0.1 mL, 1.5 mmol) and 10% palladium on carbon (73.5 mg, 0.069 mmol) were then added and the reaction mixture was then hydrogenated for 24h. Later, the reaction was carried out under a double-layer hydrogen balloon for 1-3 days in a procedure similar to the above, and the hydrogen balloon was replaced with a new hydrogen balloon every day. No need to apply high pressure. The reaction mixture was filtered through a pad of celite, neutralized with aqueous NaOH to weakly basic and concentrated. The product was partitioned between EtOAc and water. The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column, containing CH 0% to 10% MeOH of 2 Cl 2 gradient eluting chromatographed to give 1- (5- ((1r,3r)-3-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (59 mg, 0.180 mmol , 78% yield). Mass Spectrum (ESI) m/z = 329.2 (M+H). 1 H NMR (MeOH- d 4 ) δ 8.27-8.36 (m, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.07 (s, 1H), 7.40-7.50 (m, 1H), 6.41 (s) , 1H), 4.15-4.31 (m, 1H), 3.07-3.21 (m, 1H), 2.83 (s, 3H), 2.66-2.79 (m, 2H), 2.41 (s, 3H), 1.98-2.17 (m , 2H).

遵循實例1164中之程序，製備以下化合物： Following the procedure in Example 1164 , the following compounds were prepared:

遵循實例1154中之程序，製備以下化合物： Following the procedure in Example 1154 , the following compounds were prepared:

遵循實例1019中之程序，製備以下化合物： Following the procedure in Example 1019 , the following compounds were prepared:

實例1172Example 1172

1-(5-((1r,3r)-3-(苄氧基)環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((1r,3r)-3-(Benzyloxy)cyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- Methyl urea

步驟A：向燒瓶中饋入3-(苄氧基)環丁酮(1.00 g，5.67 mmol)及MeOH(24 mL)。添加硼氫化鈉(0.859 g，22.70 mmol)，且攪拌反應混合物1.5小時。用NH4Cl淬滅反應物且濃縮。將產物分配於水與EtOAc之間。收集有機層，經硫酸鎂乾燥且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱進行層析來純化，得 到(0.882 g，4.95 mmol，87%產率)。1H NMR(MeOH)δ：7.20-7.39(m,5H),4.84(s,2H),3.82(t,J=7.2 Hz,1H),3.55-3.71(m,1H),2.64(dtd,J=9.2,6.5,2.9 Hz,2H),1.77-1.95(m,2H)。 Step A : The flask was charged with 3-(benzyloxy)cyclobutanone (1.00 g, 5.67 mmol) and MeOH (24 mL). Sodium borohydride (0.859 g, 22.70 mmol) was added and the reaction mixture was stirred for 1.5 h. With NH 4 Cl The reaction was quenched and concentrated. The product was partitioned between water and EtOAc. The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo. The crude material was taken up on a silica gel plug and purified by chromatography on a EtOAc EtOAc EtOAc EtOAc (EtOAc). 1 H NMR (MeOH) δ: 7.20-7.39 (m, 5H), 4.84 (s, 2H), 3.82 (t, J = 7.2 Hz, 1H), 3.55 - 3.71 (m, 1H), 2.64 (dtd, J) = 9.2, 6.5, 2.9 Hz, 2H), 1.77-1.95 (m, 2H).

步驟B：向裝有3-(苄氧基)環丁醇(723 mg，4.06 mmol)之燒瓶中添加CH2Cl2(25 mL)、四溴化碳(3363 mg，10.14 mmol)及三乙胺(1.30 mL，9.33 mmol)。接著緩慢添加三苯基膦(2554 mg，9.74 mmol)。攪拌反應混合物1小時。用正戊烷稀釋混合物，接著傾倒至冰冷碳酸氫鈉溶液中。用鹽水洗滌有機相，經硫酸鎂乾燥且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含0%至25% EtOAc之己烷梯度溶離進行層析來純化，得到((3-溴環丁氧基)甲基)苯(906 mg，3.76 mmol，93%產率)。1H NMR(CDCl3)δ 7.29-7.43(m,5H),4.46-4.62(m,2H),4.43(s,2H),2.58-2.84(m,4H)。 Step B : Add CH 2 Cl 2 (25 mL), carbon tetrabromide (3363 mg, 10.14 mmol) and triethyl to a flask containing 3-(benzyloxy)cyclobutanol (723 mg, 4.06 mmol). Amine (1.30 mL, 9.33 mmol). Triphenylphosphine (2554 mg, 9.74 mmol) was then added slowly. The reaction mixture was stirred for 1 hour. The mixture was diluted with n-pentane and then poured into ice cold sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate dried The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium column containing 0% to 25% EtOAc in EtOAc (EtOAc). Oxy)methyl)benzene (906 mg, 3.76 mmol, 93% yield). 1 H NMR (CDCl 3 ) δ 7.29-7.43 (m, 5H), 4.46-4.62 (m, 2H), 4.43 (s, 2H), 2.58-2.84 (m, 4H).

步驟C：向燒瓶中添加氯化鋰(139 mg，3.28 mmol)，且在155℃下於高真空下乾燥燒瓶30分鐘。接著添加鋅(236 mg，3.60 mmol)，且在155℃下於高真空下再次乾燥燒瓶20分鐘。使燒瓶冷卻降至室溫，且在氮氣下添加無水THF(6 mL)，繼而添加1,2-二溴乙烷(0.014 mL，0.164 mmol)。用加熱槍將燒瓶短暫加熱至65℃且冷卻降溫，接著添加氯三甲基矽烷(4.16 μl，0.033 mmol)。短暫攪拌後，添加5滴1 M碘於THF中之溶液。短暫攪拌反應物，且添加含((3-溴環丁氧基)甲基)苯(790 mg，3.28 mmol)之THF(1 mL)。加熱反應混合物至50℃且加熱18小時，得到溴化(3-(苄氧基)環丁基)鋅(II)。 Step C : Lithium chloride (139 mg, 3.28 mmol) was added to the flask and the flask was dried at 155 ° C under high vacuum for 30 min. Zinc (236 mg, 3.60 mmol) was then added and the flask was again dried under high vacuum at 155 °C for 20 minutes. The flask was cooled to room temperature and anhydrous THF (6 mL) was added and then 1 ,2-dibromoethane (0.014 mL, 0.164 mmol). The flask was briefly heated to 65 ° C with a heat gun and cooled to cool, followed by the addition of chlorotrimethyl decane (4.16 μl, 0.033 mmol). After brief stirring, 5 drops of 1 M iodine in THF were added. The reaction was stirred briefly and THF (1 mL) (EtOAc (EtOAc) The reaction mixture was heated to 50 ° C and heated for 18 hours to give (3-(benzyloxy)cyclobutyl)zinc(II) bromide.

步驟D：向裝有1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(250 mg，0.741 mmol)之燒瓶中添加1,2,3,4,5-五苯基-1-(二第三丁基膦基)二茂鐵CTC-QPhos(58.0 mg，0.082 mmol)及雙(二亞苄基丙酮)鈀(0)(41.4 mg，0.072 mmol)。在高真空下用氮氣淨化混合物。依序添加經脫氣之THF(4 mL)、在先前步驟中當場產生之溴化(3-(苄 氧基)環丁基)鋅(II)(5.43 mL，2.97 mmol)。加熱反應物至回流，維持19小時。添加飽和氯化銨，且用乙酸乙酯萃取反應混合物。乾燥乙酸乙酯層並濃縮，且藉由矽膠層析(0-7% MeOH/DCM梯度分離)純化。藉由逆相HPLC進一步純化含有產物之溶離份，得到1-(5-((1r,3r)-3-(苄氧基)環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(40 mg，0.096 mmol，13%產率)。質譜(ESI)m/z=419.1(M+H)。1H NMR(MeOH-d 4 )δ 8.31(s,1H),8.18(s,1H),8.13(s,1H),7.46(s,1H),7.20-7.40(m,5H),6.40(s,1H),4.47(s,2H),4.29(t,J=5.9 Hz,1H),3.81(五重峰，J=7.8 Hz,1H),2.82(s,3H),2.45-2.60(m,4H),2.40(s,3H)。 Step D : To a solution of 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (250 mg, 0.741 mmol) Add 1,2,3,4,5-pentaphenyl-1-(di-t-butylphosphino)ferrocene CTC-QPhos (58.0 mg, 0.082 mmol) and bis(dibenzylideneacetone) to the flask. Palladium (0) (41.4 mg, 0.072 mmol). The mixture was purged with nitrogen under high vacuum. The degassed THF (4 mL) was added in the previous step to give (3-(benzyloxy)cyclobutyl)zinc(II) (5.43 mL, 2.97 mmol). The reaction was heated to reflux for 19 hours. Saturated ammonium chloride was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated and purified by silica gel chromatography (0-7% MeOH / DCM gradient). The product-containing fraction was further purified by reverse phase HPLC to give 1-(5-((1r,3r)-3-(benzyloxy)cyclobutyl)-4-((5-methylpyridine-3-) Ethyloxy)pyridin-2-yl)-3-methylurea (40 mg, 0.096 mmol, 13% yield). Mass Spectrum (ESI) m/z = 419.1 (M+H). 1 H NMR (MeOH- d 4 ) δ 8.31 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.46 (s, 1H), 7.20-7.40 (m, 5H), 6.40 (s) , 1H), 4.47(s, 2H), 4.29 (t, J = 5.9 Hz, 1H), 3.81 (five peaks, J = 7.8 Hz, 1H), 2.82 (s, 3H), 2.45-2.60 (m, 4H), 2.40 (s, 3H).

實例1173Example 1173

1-(5-((1r,3r)-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((1r,3r)-3-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

向裝有1-(5-(3-(苄氧基)環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(37 mg，0.088 mmol)之燒瓶中添加MeOH(3 mL)及鈀/碳(18.82 mg，0.018 mmol)。用氫氣淨化燒瓶，接著在H2(g)下攪拌。7小時後，添加H2SO4(0.15 mL)，且攪拌反應混合物18小時。經矽藻土襯墊過濾反應混合物，用NaOH水溶液中和至弱鹼性且濃縮。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至30%)純化粗物質，得到1-(5-((1s,3s)-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(9.3 mg，0.028 mmol，32%產率)。質譜(ESI)m/z=329.1(M+H)。1H NMR(MeOH-d 4 )δ 8.27-8.36(m,1H),8.19(d, J=2.5 Hz,1H),8.14(s,1H),7.46(s,1H),6.40(s,1H),4.36-4.50(m,1H),3.71-3.89(m,1H),2.82(s,3H),2.49-2.60(m,2H),2.32-2.46(m,5H)。 To the solution of 1-(5-(3-(benzyloxy)cyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (37 mg, 0.088 mmol) flask was charged with MeOH (3 mL) and palladium/carbon (18.82 mg, 0.018 mmol). The flask was purged with hydrogen and then stirred under H2 (g) . After 7 hours, H 2 SO 4 (0.15 mL) was added and the mixture was stirred for 18 hr. The reaction mixture was filtered through a pad of celite, neutralized with aqueous NaOH to weakly basic and concentrated. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10% to 30%) crude material was purified to give 1- (5 - ((1s, 3s) -3- hydroxycyclohexyl Butyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (9.3 mg, 0.028 mmol, 32% yield). Mass Spectrum (ESI) m/z = 329.1 (M+H). 1 H NMR (MeOH- d 4 ) δ 8.27-8.36 (m, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.46 (s, 1H), 6.40 (s, 1H) ), 4.36-4.50 (m, 1H), 3.71-3.89 (m, 1H), 2.82 (s, 3H), 2.49-2.60 (m, 2H), 2.32 - 2.46 (m, 5H).

實例1174Example 1174

1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環丁基)吡啶-2-基)脲 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-oxocyclocyclobutyl)pyridin-2-yl)urea

向燒瓶中饋入1-(5-((1r,3r)-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(100 mg，0.305 mmol)及戴斯-馬丁試劑(Dess-Martin)(168 mg，0.396 mmol)。接著添加CH2Cl2(7 mL)。反應物變成澄清溶液。在室溫下繼續攪拌1小時。接著添加飽和NaHCO3溶液，且用EtOAc萃取反應物。乾燥乙酸乙酯層並濃縮，且藉由逆相HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至40%)純化粗物質，在鹼化並萃取HPLC溶離份後得到72 mg呈白色固體狀之1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環丁基)吡啶-2-基)脲。質譜(ESI)m/z=327.0(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.34(d,J=0.98 Hz,1 H)8.25(d,J=2.54 Hz,1 H)8.19(br.s.,1 H)7.53(t,J=1.66 Hz,1 H)6.43-6.50(m,1 H)3.74-3.88(m,1 H)3.45-3.56(m,2 H)3.35-3.45(m,2 H)2.82(s,3 H)2.42(d,J=0.39 Hz,3 H)。 The flask was fed with 1-(5-((1r,3r)-3-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 -methylurea (100 mg, 0.305 mmol) and Dess-Martin (168 mg, 0.396 mmol). Then CH 2 Cl 2 (7 mL) was added. The reaction turned into a clear solution. Stirring was continued for 1 hour at room temperature. A saturated NaHCO 3 solution was then added and the reaction was extracted with EtOAc. The ethyl acetate layer was dried and concentrated, and by reverse phase HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10% to 40%) crude material was purified to give away parts of the solution was basified and extracted with HPLC 72 mg of 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-oxocyclobutyl)pyridin-2-yl as a white solid Urea. Mass Spectrum (ESI) m/z = 327.0 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.34 (d, J =0.98 Hz, 1 H) 8.25 (d, J = 2.54 Hz, 1 H) 8.19 (br.s., 1 H) 7.53 (t, J =1.66 Hz,1 H)6.43-6.50(m,1 H)3.74-3.88(m,1 H)3.45-3.56(m,2 H)3.35-3.45(m,2 H)2.82(s,3 H) 2.42 (d, J = 0.39 Hz, 3 H).

實例1175Example 1175

1-(5-((1r,3r)-3-氘-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((1r,3r)-3-indol-3-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3- Methyl urea

向裝有1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環丁基)吡啶-2-基)脲(53 mg，0.162 mmol)之燒瓶中依序添加硼氘化鈉(27.2 mg，0.650 mmol)及MeOH(2 mL)。在室溫下攪拌反應物3小時。添加水，繼而用EtOAc萃取。濃縮有機層且藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度10%至35%)純化，得到30 mg呈白色固體狀之1-(5-((1r,3r)-3-氘-3-羥基環丁基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=330.2(M+H)。1H NMR(400 MHz,MeOH)δ ppm 8.31(d,J=0.98 Hz,1 H)8.19(d,J=2.54 Hz,1 H)8.06(s,1 H)7.46(s,1 H)6.40(s,1 H)3.13(tt,J=10.25,7.65 Hz,1 H)2.83(s,3 H)2.67-2.77(m,2 H)2.41(s,3 H)1.99-2.12(m,2 H)。 To a solution containing 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-oxocyclocyclobutyl)pyridin-2-yl)urea Sodium borohydride (27.2 mg, 0.650 mmol) and MeOH (2 mL) were added sequentially to a flask of &lt;RTIgt; The reaction was stirred at room temperature for 3 hours. Water was added, followed by extraction with EtOAc. And the organic layer was concentrated by reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (gradient 10-35%) to afford 30 mg of a white solid of 1- (5 - (( 1r, 3r)-3-indol-3-hydroxycyclobutyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 330.2 (M+H). 1 H NMR (400 MHz, MeOH) δ ppm 8.31 (d, J =0.98 Hz, 1 H) 8.19 (d, J = 2.54 Hz, 1 H) 8.06 (s, 1 H) 7.46 (s, 1 H) 6.40 (s, 1 H) 3.13 (tt, J =10.25, 7.65 Hz, 1 H) 2.83 (s, 3 H) 2.67-2.77 (m, 2 H) 2.41 (s, 3 H) 1.99-2.12 (m, 2 H).

製備preparation

((2-(丙-2-炔-1-基氧基)乙氧基)甲基)苯 ((2-(prop-2-yn-1-yloxy)ethoxy)methyl)benzene

在0℃下，經15分鐘，向60%氫化鈉於礦物油中之分散液(1.511 g，37.8 mmol)於THF(110 mL)中之溶液中逐滴添加乙二醇單苄基醚(4.67 mL，32.9 mmol)。使反應混合物升溫至室溫。2小時後，逐滴添加80%炔丙基溴於甲苯中之溶液(3.54 mL，32.9 mmol)且攪拌18小時。過濾混合物，且在真空中濃縮溶劑。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱進行層析來純化，得到((2-(丙-2-炔-1-基氧基)乙氧基)甲基)苯(6.00 g，31.5 mmol，96%產率)。1H NMR(400 MHz,CDCl3)δ 7.13-7.38(5H,m),4.49(2H,s),4.09-4.19(2H,m),3.61-3.71(2H,m),3.51-3.61(2H,m),2.35(1H,t,J=2.3 Hz)。 Ethylene glycol monobenzyl ether (4.67) was added dropwise to a solution of 60% sodium hydride in mineral oil (1.511 g, 37.8 mmol) in THF (110 mL) over 15 min. mL, 32.9 mmol). The reaction mixture was allowed to warm to room temperature. After 2 hours, a solution of 80% propargyl bromide in toluene (3.54 mL, 32.9 mmol). The mixture was filtered and the solvent was concentrated in vacuo. The crude material was absorbed onto a silicone plug and purified by chromatography on a Redi-Sep prefilled cartridge column to give ((2-(prop-2-yn-1-yloxy)ethoxy)) Methyl)benzene (6.00 g, 31.5 mmol, 96% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.13-7.38 (5H, m), 4.49 (2H, s), 4.09-4.19 (2H, m), 3.61-3.71 (2H, m), 3.51-3.61 (2H , m), 2.35 (1H, t, J = 2.3 Hz).

製備preparation

3,4-二氫-2H-哌喃并[2,3-c]吡啶-5-醇 3,4-dihydro-2H-piperacino[2,3-c]pyridin-5-ol

步驟A：將3,5-二溴-4-吡啶甲醛(5.0 g，19 mmol)及(乙氧羰基亞甲基)三苯基磷烷(6.90 g，19.8 mmol)於氯仿(45.0 mL)中之混合物在室溫下攪拌1小時，接著在60℃下加熱18小時。在真空中濃縮反應混合物。在真空中濃縮反應混合物。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，用含10%至90% EtOAc之己烷溶離進行層析來純化，得到(E)-3-(3,5-二溴吡啶-4-基)丙烯酸乙酯(6.3 g，18 mmol，100%產率)。1H NMR(400 MHz,CDCl3)δ 8.69(2H,s),7.58(1H,d,J=16.2 Hz),6.56(1H,d,J=16.4 Hz),4.32(2H,q,J=7.0 Hz),1.37(3H,t,J=7.1 Hz)。 Step A : 3,5-Dibromo-4-pyridinecarboxaldehyde (5.0 g, 19 mmol) and (ethoxycarbonylmethylene)triphenylphosphane (6.90 g, 19.8 mmol) in chloroform (45.0 mL) The mixture was stirred at room temperature for 1 hour and then heated at 60 ° C for 18 hours. The reaction mixture was concentrated in vacuo. The reaction mixture was concentrated in vacuo. The crude material was absorbed onto a silicone plug and purified by chromatography on a cartridge packed with 10% to 90% EtOAc in hexanes pre-filled with Redi-Sep to give (E)-3-(3) Ethyl 5-dibromopyridin-4-yl)acrylate (6.3 g, 18 mmol, 100% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (2H, s), 7.58 (1H, d, J = 16.2 Hz), 6.56 (1H, d, J = 16.4 Hz), 4.32 (2H, q, J = 7.0 Hz), 1.37 (3H, t, J = 7.1 Hz).

步驟B：在-18℃下，向(E)-3-(3,5-二溴吡啶-4-基)丙烯酸乙酯(6.3 g，18.81 mmol)於乙醇(100.0 mL)中之溶液中添加硼氫化鈉(1.921 g，50.8 mmol)。在室溫下攪拌混合物1小時，接著在50℃下攪拌7小時。冷卻至室溫後，添加冰醋酸，接著在真空中濃縮混合物。將殘餘物溶解於乙酸乙酯中，且用1.0 M HCl水溶液、碳酸氫鈉及鹽水洗滌。經MgSO4乾燥有機層，過濾且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱進行層析來純化，得到3-(3,5-二溴吡啶-4-基)丙-1-醇(5.0 g，17 mmol，90%產率)。1H NMR(400 MHz,CDCl3)δ 8.58(2H,s),3.78(2H,t,J=6.3 Hz),3.01-3.17(2H,m),1.79-1.94(2H,m)。 Step B : Add to a solution of ethyl (E)-3-(3,5-dibromopyridin-4-yl)acrylate (6.3 g, 18.81 mmol) in ethanol (100.0 mL) at -18 °C Sodium borohydride (1.921 g, 50.8 mmol). The mixture was stirred at room temperature for 1 hour, followed by stirring at 50 ° C for 7 hours. After cooling to room temperature, glacial acetic acid was added, followed by concentration of the mixture in vacuo. The residue was dissolved in ethyl acetate and washed with EtOAc EtOAc. The organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The crude material was absorbed onto a silicone plug and purified by chromatography on a Redi-Sep prefilled cartridge column to give 3-(3,5-dibromopyridin-4-yl)propan-1-ol ( 5.0 g, 17 mmol, 90% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (2H, s), 3.78 (2H, t, J = 6.3 Hz), 3.01-3.17 (2H, m), 1.79-1.94 (2H, m).

步驟C：向3-(3,5-二溴吡啶-4-基)丙-1-醇(2.5 g，8.48 mmol)於DME(20 mL)中之溶液中添加氯化銅(i)(0.084 g，0.848 mmol)、2-胺基吡啶(0.080 g，0.848 mmol)及25重量%甲醇鈉於甲醇中之溶液(2.75 g，12.7 mmol)。在70℃下加熱反應混合物18小時。用飽和NaHCO3水溶液(30 mL)淬滅反應物，用乙酸乙酯(120 mL及60 mL)萃取。經MaSO4乾燥經合併之有機層，過濾且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含10%至90% EtOAc之己烷梯度溶離進行層析來純化，得到5-溴-3,4-二氫-2H-哌喃并[2,3-c]吡啶(1.2 g，5.61 mmol，66%產率)。1H NMR(400 MHz,CDCl3)δ 8.24(1H,s),8.09(1H,s),4.15-4.29(2H,m),2.76(2H,t,J=6.6 Hz),1.96-2.15(2H,m)。 Step C : Add copper chloride (i) (0.084) to a solution of 3-(3,5-dibromopyridin-4-yl)propan-1-ol (2.5 g, 8.48 mmol) in DME (20 mL) g, 0.848 mmol), 2-aminopyridine (0.080 g, 0.848 mmol) and a solution of 25% by weight sodium methoxide in methanol (2.75 g, 12.7 mmol). The reaction mixture was heated at 70 ° C for 18 hours. With saturated aqueous NaHCO 3 (30 mL) The reaction was quenched and extracted with ethyl acetate (120 mL and 60 mL). The organic layer was dried over MaSO 4 merger, filtered and concentrated in vacuo. The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium packed with 10% to 90% EtOAc in hexanes pre-filled with Redi-Sep to give 5-bromo-3,4 -Dihydro-2H-piperido[2,3-c]pyridine (1.2 g, 5.61 mmol, 66% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (1H, s), 8.09 (1H, s), 4.15 - 4.29 (2H, m), 2.76 (2H, t, J = 6.6 Hz), 1.96-2.15 ( 2H, m).

步驟D：向玻璃微波反應容器中饋入含5-溴-3,4-二氫-2H-哌喃并[2,3-c]吡啶(0.2 g，0.93 mmol)、N,N'-二甲基乙二胺(0.050 mL，0.467 mmol)、碘化銅(I)(0.018 g，0.093 mmol)及無水磷酸鉀(0.198 g，0.934 mmol)之水(2.0 mL)。攪拌反應混合物且在180℃下加熱30分鐘。用1.0 M HCl水溶液將混合物中和至pH 5-7，用水稀釋，用乙酸乙酯(2×30 mL)萃取，且經Na2SO4乾燥。過濾溶液且在真空中濃縮，得到3,4-二氫-2H-哌喃并[2,3-c]吡啶-5-醇(80.0 mg，0.529 mmol，56.6%產率)。質譜(ESI)m/z=152.1(M+H)。 Step D : feeding a 5-bromo-3,4-dihydro-2H-piperido[2,3-c]pyridine (0.2 g, 0.93 mmol), N, N'-di to a glass microwave reaction vessel Methylethylenediamine (0.050 mL, 0.467 mmol), copper (I) iodide (0.018 g, 0.093 mmol) and anhydrous potassium phosphate (0.198 g, 0.934 mmol) in water (2.0 mL). The reaction mixture was stirred and heated at 180 ° C for 30 minutes. The mixture was neutralized to pH 5-7, diluted with water and aqueous 1.0 M HCl, (2 × 30 mL) and extracted with ethyl acetate and dried over Na 2 SO 4. The solution was filtered and concentrated in vacuo to give 3,4-dihydro-2H-piped[2,3-c]pyridine-5-ol (80.0 mg, 0.529 mmol, 56.6% yield). Mass Spectrum (ESI) m/z = 1521. (M+H).

製備preparation

2-(丙-2-炔-1-基氧基)乙酸乙酯 2-(prop-2-yn-1-yloxy)ethyl acetate

在0℃下，向2-丙炔-1-醇(4.4 g，79 mmol)及重氮乙酸乙酯(5.44 mL，52.6 mmol)之混合物中添加氯化銦(iii)(1.745 g，7.89 mmol)。在 室溫下攪拌所得混合物40分鐘。用水(40 mL)淬滅反應物且用EtOAc(80 mL及20 mL)萃取。用鹽水(30 mL)洗滌經合併之有機層，經MgSO4乾燥，過濾且在真空中濃縮。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱，以含10%至90% EtOAc之己烷梯度溶離進行層析來純化，得到2-(丙-2-炔-1-基氧基)乙酸乙酯(3.89 g，27.4 mmol，52.0%產率)。1H NMR(400 MHz,CDCl3)δ 4.30(2H,d,J=2.3 Hz),4.22(2H,q,J=7.0 Hz),4.18(2H,s),2.47(1H,t,J=2.3 Hz),1.28(3H,t,J=7.1 Hz)。 Add indium chloride (iii) (1.745 g, 7.89 mmol) to a mixture of 2-propyn-1-ol (4.4 g, 79 mmol) and ethyl diazoacetate (5.44 mL, 52.6 mmol). ). The resulting mixture was stirred at room temperature for 40 minutes. The reaction was quenched with EtOAc (EtOAc) Combined organic layers were washed with brine (30 mL), dried over MgSO 4, filtered and concentrated in vacuo. The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium packed with 10% to 90% EtOAc in hexanes. Ethyl-1-yloxy)acetate (3.89 g, 27.4 mmol, 52.0% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 4.30 (2H, d, J = 2.3 Hz), 4.22 (2H, q, J = 7.0 Hz), 4.18 (2H, s), 2.47 (1H, t, J = 2.3 Hz), 1.28 (3H, t, J = 7.1 Hz).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

遵循實例1317中之程序，製備以下化合物： Following the procedure in Example 1317 , the following compounds were prepared:

製備preparation

2-甲基-1-(丙-2-炔-1-基氧基)丙-2-醇 2-methyl-1-(prop-2-yn-1-yloxy)propan-2-ol

在0℃下，向2-(丙-2-炔-1-基氧基)乙酸乙酯(1.78 g，12.52 mmol)於THF(20 mL)中之溶液中添加1.4 M溴化甲基鎂於甲苯/THF(75：25)中之溶液(19.68 mL，27.5 mmol)。在室溫下攪拌反應混合物1小時，接著用甲醇(2.0 mL)淬滅。用水(30 mL)稀釋混合物且用EtOAc(2×50 mL)萃取。經MgSO4乾燥經合併之有機層，過濾且在真空中濃縮，得 到2-甲基-1-(丙-2-炔-1-基氧基)丙-2-醇(1.56 g，12.2 mmol，97%產率)。1H NMR(400 MHz,CDCl3)δ 4.21(2H,d,J=2.3 Hz),3.37(2H,s),2.44(1H,s),2.22(1H,s),1.23(6H,s)。 Add 1.4 M methylmagnesium bromide to a solution of ethyl 2-(prop-2-yn-1-yloxy)acetate (1.78 g, 12.52 mmol) in THF (20 mL). Solution in toluene/THF (75:25) (19.68 mL, 27.5 mmol). The reaction mixture was stirred at room temperature for 1 h then quenched with EtOAc EtOAc. The mixture was diluted with water (30 mL) andEtOAcEtOAc The organic layer was dried over MgSO 4 merger, filtered and concentrated in vacuo to give 2-methyl-1- (prop-2-yn-1-yloxy) propan-2-ol (1.56 g, 12.2 mmol, 97% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 4.21 (2H, d, J = 2.3 Hz), 3.37 (2H, s), 2.44 (1H, s), 2.22 (1H, s), 1.23 (6H, s) .

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

製備preparation

((丁-3-炔-2-基氧基)甲基)苯 ((But-3-yne-2-yloxy)methyl)benzene

在0℃下，向60%氫化鈉於礦物油中之分散液(1.427 g，35.7 mmol)及碘化四正丁基銨(0.132 g，0.357 mmol)於THF(50.0 mL)中之溶液中緩慢添加含3-丁炔-2-醇(2.50 mL，35.7 mmol)之THF(5.0 mL)。在室溫下攪拌所得混合物30分鐘，接著添加含98%苄基溴(4.36 mL，35.7 mmol)之THF(5.0 mL)。在室溫下攪拌所得反應混合物18小時。過濾反應混合物。用鹽水(2×20 mL)洗滌濾液，經MgSO4乾燥，且在真空中濃縮，得到((丁-3-炔-2-基氧基)甲基)苯(5.65 g，35.5 mmol，99%產率)。1H NMR(400 MHz,CDCl3)δ 7.10-7.33(6H,m),4.71(1H,d,J=11.7 Hz),4.42(1H,d,J=11.5 Hz),4.12(1H,dd,J=6.7,2.0 Hz),2.37(1H,d,J=2.2 Hz),1.39(4H,d,J=6.7 Hz)。遵循上述程序，製備以下化合物： Slowly to a solution of 60% sodium hydride in mineral oil (1.427 g, 35.7 mmol) and tetra-n-butylammonium iodide (0.132 g, 0.357 mmol) in THF (50.0 mL) at 0 °C Add 3-butyn-2-ol (2.50 mL, 35.7 mmol) in THF (5.0 mL). The resulting mixture was stirred at room temperature for 30 min then EtOAc (EtOAc) (EtOAc) The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered. The filtrate was washed with brine (2 × 20 mL), dried over MgSO 4, and concentrated in vacuo to give ((but-3-yn-2-yloxy) methyl) benzene (5.65 g, 35.5 mmol, 99 % Yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.10-7.33 (6H, m), 4.71 (1H, d, J = 11.7 Hz), 4.42 (1H, d, J = 11.5 Hz), 4.12 (1H, dd, J = 6.7, 2.0 Hz), 2.37 (1H, d, J = 2.2 Hz), 1.39 (4H, d, J = 6.7 Hz). Following the above procedure, the following compounds were prepared:

實例1176Example 1176

(Z)-1-(5-(3-(苄氧基)丁-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (Z)-1-(5-(3-(Benzyloxy)but-1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl -3-methylurea

向1-(5-(3-(苄氧基)丁-1-炔-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.20 g，0.48 mmol)於1：1 MeOH：甲苯(30 mL)中之溶液中添加5重量%銠/碳(0.049 g，0.048 mmol)。將反應混合物抽真空且用氫氣回填三次。在室溫下於氫氣氛圍下攪拌18小時後，過濾混合物，且在真空中濃縮濾液。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O純化殘餘物，得到(Z)-1-(5-(3-(苄氧基)丁-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.125 g，0.299 mmol，62.2%產率)。質譜(ESI)m/z=419.1(M+H)。1H NMR(400 MHz,CDCl3)δ 8.52(1H,s),8.41(1H,d,J=2.3 Hz),7.60(1H,br.s.),7.51(1H,s),7.20-7.42(8H,m),6.47(1H,d,J=11.7 Hz),6.02(1H,dd,J=11.9,8.4 Hz),4.47(2H,s),4.27(1H,ddd,J=8.3,6.3,0.9 Hz),2.84(3H,d,J=4.5 Hz),2.51(3H,s),1.43(3H,d,J=6.3 Hz)。 To 1-(5-(3-(benzyloxy)but-1-yn-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 To a solution of methylurea (0.20 g, 0.48 mmol) in 1:1 MeOH:EtOAc (30 mL). The reaction mixture was evacuated and backfilled with hydrogen three times. After stirring at room temperature under a hydrogen atmosphere for 18 hours, the mixture was filtered, and the filtrate was concentrated in vacuo. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O The residue was purified to give (Z) -1- (5- (3- ( benzyloxy) -1-1-ene -yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.125 g, 0.299 mmol, 62.2% yield). Mass Spectrum (ESI) m/z = 419.1 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (1H, s), 8.41 (1H, d, J = 2.3 Hz), 7.60 (1H, br.s.), 7.51 (1H, s), 7.20-7.42 (8H, m), 6.47 (1H, d, J = 11.7 Hz), 6.02 (1H, dd, J = 11.9, 8.4 Hz), 4.47 (2H, s), 4.27 (1H, ddd, J = 8.3, 6.3 , 0.9 Hz), 2.84 (3H, d, J = 4.5 Hz), 2.51 (3H, s), 1.43 (3H, d, J = 6.3 Hz).

實例1177Example 1177

(Z)-1-(5-(3-(苄氧基)丙-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2- 基)-3-甲基脲 (Z)-1-(5-(3-(Benzyloxy)prop-1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine-2- 3-methylurea

向1-(5-(3-(苄氧基)丙-1-炔-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(114.0 mg，0.283 mmol)於MeOH(25 mL)中之溶液中添加林德拉催化劑鈀/碳酸鈣(鉛中毒)(60.3 mg，0.028 mmol)。將反應混合物抽真空且用氫氣回填三次。在室溫下於氫氣氛圍下攪拌18小時後，過濾混合物，且在真空中濃縮濾液。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O純化殘餘物，得到(Z)-1-(5-(3-(苄氧基)丙-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(70.0 mg，0.173 mmol，61.1%產率)。質譜(ESI)m/z=405.2(M+H)。1H NMR(400 MHz,CDCl3)δ 8.50(1H,s),8.31-8.42(1H,m),7.87(1H,s),7.47(1H,s),7.30-7.44(6H,m),6.62(1H,d,J=11.5 Hz),6.24(1H,d,J=11.5 Hz),4.57(2H,s),4.14(2H,dd,J=6.8,1.2 Hz),2.84(3H,d,J=4.7 Hz),2.49(3H,s)。 To 1-(5-(3-(benzyloxy)prop-1-yn-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 - A solution of methylurea (114.0 mg, 0.283 mmol) in MeOH (25 mL) was added to the lindane catalyst palladium/calcium carbonate (lead poisoning) (60.3 mg, 0.028 mmol). The reaction mixture was evacuated and backfilled with hydrogen three times. After stirring at room temperature under a hydrogen atmosphere for 18 hours, the mixture was filtered, and the filtrate was concentrated in vacuo. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O The residue was purified to give (Z) -1- (5- (3- ( benzyloxy) propan-1-1 -yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (70.0 mg, 0.173 mmol, 61.1% yield). Mass Spectrum (ESI) m/z = 405.2 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (1H, s), 8.31 - 8.42 (1H, m), 7.87 (1H, s), 7.47 (1H, s), 7.30-7.44 (6H, m), 6.62 (1H, d, J = 11.5 Hz), 6.24 (1H, d, J = 11.5 Hz), 4.57 (2H, s), 4.14 (2H, dd, J = 6.8, 1.2 Hz), 2.84 (3H, d , J = 4.7 Hz), 2.49 (3H, s).

遵循實例170中之程序，製備以下化合物： Following the procedure in Example 170, the following compounds were prepared:

藉由基本上遵循實例170中之程序且必要時繼之以對掌性管柱純化，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 170 and, if necessary, purifying the palm column:

遵循實例251中之程序，製備以下化合物： Following the procedure in Example 251, the following compounds were prepared:

實例1261Example 1261

1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環戊-1-烯-1-基)吡啶-2-基)脲 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-o-oxocyclopent-1-en-1-yl)pyridin-2-yl Urea

在氮氣流下，將1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3- 甲基脲(2.0 g，5.93 mmol)、2-環戊烯-1-酮(1.491 ml，17.80 mmol)、碳酸氫鈉(0.692 ml，17.80 mmol)及雙(三苯基膦)二氯化鈀(ii)(0.208 g，0.297 mmol)於1-甲基-2-吡咯啶酮(20 mL)中組合。將所得混合物密封且130℃下攪拌18小時。冷卻反應混合物至室溫，且經矽藻土襯墊過濾並用乙酸乙酯沖洗。濃縮濾液。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(300 g)，以含0%至10% MeOH之CH2Cl2梯度溶離進行層析來純化，得到1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環戊-1-烯-1-基)吡啶-2-基)脲(2.007 g，1.788 mmol，30.1%產率)。質譜(ESI)m/z=339.0(M+H)。1H NMR(CDCl3)δ 9.46(s,1H),9.06(br.s.,1H),8.36-8.49(m,2H),8.29(d,J=2.5 Hz,1H),7.29(s,1H),6.88(t,J=1.5 Hz,1H),6.17(s,1H),3.13(dd,J=5.1,3.1 Hz,2H),2.78(d,J=4.7 Hz,3H),2.51-2.61(m,2H),2.41(s,3H)。 1-(5-Bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (2.0 g, 5.93 mmol), 2 under a nitrogen stream -cyclopenten-1-one (1.491 ml, 17.80 mmol), sodium bicarbonate (0.692 ml, 17.80 mmol) and bis(triphenylphosphine)palladium dichloride (ii) (0.208 g, 0.297 mmol) in 1 -Methyl-2-pyrrolidone (20 mL) combined. The resulting mixture was sealed and stirred at 130 ° C for 18 hours. The reaction mixture was cooled to rt and filtered over EtOAc EtOAc. The filtrate was concentrated. The crude material was absorbed on silica plug, and purified by by Redi-Sep pre-packed silica gel column (300 g), containing CH 0% to 10% MeOH of 2 Cl 2 gradient eluting chromatographed to give 1 -methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-o-oxocyclopent-1-en-1-yl)pyridin-2-yl) Urea (2.007 g, 1.788 mmol, 30.1% yield). Mass Spectrum (ESI) m/z = 339.0 (M+H). 1 H NMR (CDCl 3 ) δ 9.46 (s, 1H), 9.06 (br.s., 1H), 8.36-8.49 (m, 2H), 8.29 (d, J = 2.5 Hz, 1H), 7.29 (s, 1H), 6.88 (t, J = 1.5 Hz, 1H), 6.17 (s, 1H), 3.13 (dd, J = 5.1, 3.1 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H), 2.51- 2.61 (m, 2H), 2.41 (s, 3H).

遵循實例1261中之程序，製備以下化合物： Following the procedure in Example 1261 , the following compounds were prepared:

實例1268Example 1268

1-(3-(2,6-二氟苯氧基)-4-(3-(羥基甲基)環戊基)苯基)-3-甲基脲 1-(3-(2,6-difluorophenoxy)-4-(3-(hydroxymethyl)cyclopentyl)phenyl)-3-methylurea

步驟A：在0℃下，向3-側氧基-1-環戊烷甲酸(5.9 g，46.0 mmol)於無水MeOH(46.0 mL)中之溶液中逐滴添加亞硫醯氯(16.79 mL，230 mmol)。在0℃下攪拌所得混合物8小時，接著在室溫下攪拌18小時。濃縮混合物。使粗物質吸收於矽膠栓塞上，且藉由經Redi-Sep預裝填矽膠管柱(300 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化，得到3-側氧基環戊烷甲酸甲酯(4.02 g，28.3 mmol，61.4%產率)。 Step A : To a solution of 3-oxo-l-cyclopentanecarboxylic acid (5.9 g, 46.0 mmol) in dry MeOH (46.0 mL) 230 mmol). The resulting mixture was stirred at 0 ° C for 8 hours, followed by stirring at room temperature for 18 hours. The mixture was concentrated. The crude material was taken up on a silica gel plug and purified by chromatography on a ruthenium packed with 0% to 100% EtOAc in hexanes (30 g). Methyloxycyclopentanecarboxylate (4.02 g, 28.3 mmol, 61.4% yield).

步驟B：在-78℃下，經20分鐘之時段，向二異丙胺(5.49 ml，39.1 mmol)於80 mL THF中之溶液中逐滴添加2.0 M丁基鋰於戊烷中之溶液(19.57 ml，39.1 mmol)。攪拌所得混合物30分鐘，同時逐漸升溫至室溫。再次冷卻混合物至-78℃，且添加3-側氧基環戊烷甲酸甲酯(3.71 g，26.1 mmol)於THF(20 mL)中之溶液。在-78℃下攪拌所得混合物30分鐘，隨後添加N-苯基雙-三氟甲烷磺醯亞胺(13.99 g，39.1 mmol)。攪拌所得混合物18小時，同時逐漸升溫至室溫。用600 mL乙酸乙酯稀釋混合物，分別用水、飽和碳酸氫鈉水溶液、鹽水洗滌。收集有機層，乾燥(無水Na2SO4)且濃縮。藉由經Redi-Sep預裝填矽膠管柱(330 g)，以含0%至100% EtOAc之己烷梯度溶離進行層析來純化殘餘物，得到3-(((三氟甲基)磺醯基)氧基)環戊-3-烯甲酸甲酯與3-(((三氟甲基)磺醯基)氧基)環戊-2-烯甲酸甲酯之混合物(4.11 g，15.0 mmol，57.4%產率)。 Step B : A solution of 2.0 M butyllithium in pentane (19.57) was added dropwise to a solution of diisopropylamine (5.49 ml, 39.1 mmol) in 80 mL of THF over a period of 20 min. Ml, 39.1 mmol). The resulting mixture was stirred for 30 minutes while gradually warming to room temperature. The mixture was again cooled to -78.degree. C., and a solution of &lt;RTI ID=0.0&gt;&gt; The resulting mixture was stirred at -78 °C for 30 min, then N-phenylbis-trifluoromethanesulfonimide (13.99 g, 39.1 mmol) was added. The resulting mixture was stirred for 18 hours while gradually warming to room temperature. The mixture was diluted with 600 mL of ethyl acetate and washed with water, sat. The organic layer was collected, dried (over anhydrous Na 2 SO 4) and concentrated. The residue was purified by chromatography on a pad of EtOAc (EtOAc) eluting with EtOAc (EtOAc) Mixture of methyl mercapto)oxy)cyclopent-3-enecarboxylate with methyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (4.11 g, 15.0 mmol , 57.4% yield).

步驟C：向2種3-(((三氟甲基)磺醯基)氧基)環戊-3-烯甲酸甲酯、3-(((三氟甲基)磺醯基)氧基)環戊-2-烯甲酸甲酯(164 mg，0.599 mmol) 於1,4-二噁烷(3 mL)中之混合物中添加1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(121 mg，0.299 mmol)、肆(三苯基膦)鈀(35 mg，0.030 mmol)及碳酸鉀(124 mg，0.898 mmol)。在100℃下攪拌反應混合物18小時，冷卻至室溫，經矽藻土襯墊過濾且用EtOAc沖洗。在真空中濃縮濾液。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘HPLC，梯度5%至95%)純化殘餘物，得到3-(2-(2,6-二氟苯氧基)-4-(3-甲基脲基)苯基)環戊-3-烯甲酸甲酯與3-(2-(2,6-二氟苯氧基)-4-(3-甲基脲基)苯基)環戊-2-烯甲酸甲酯之混合物(22.3 mg，0.0554 mmol)。質譜ESI(正模式)m/z=404.0(M+H)。 Step C : To two methyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-3-enecarboxylate, 3-(((trifluoromethyl)sulfonyl)oxy) Methyl cyclopent-2-enoate (164 mg, 0.599 mmol) in a mixture of 1,4-dioxane (3 mL) - 1-(4-(2,6-difluorophenoxy)- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridin-2-yl)-3-methylurea (121 mg, 0.299 mmol), hydrazine (triphenylphosphine) palladium (35 mg, 0.030 mmol) and potassium carbonate (124 mg, 0.898 mmol) . The reaction mixture was stirred at <RTI ID=0.0></RTI> EtOAc EtOAc. The filtrate was concentrated in vacuo. By reverse phase preparative HPLC, using 0.1% TFA in CH of 3 CN / H 2 O (over 25 minutes HPLC, gradient 5-95%) to give the residue, to give 3- (2- (2,6- Methyl fluorophenoxy)-4-(3-methylureido)phenyl)cyclopent-3-enecarboxylate with 3-(2-(2,6-difluorophenoxy)-4-(3) a mixture of methyl methylurea)phenyl)cyclopent-2-enecarboxylate (22.3 mg, 0.0554 mmol). Mass spectrum ESI (positive mode) m/z = 404.0 (M+H).

步驟D：在0℃下，向含3-(2-(2,6-二氟苯氧基)-4-(3-甲基脲基)苯基)環戊-2-烯甲酸甲酯與3-(2-(2,6-二氟苯氧基)-4-(3-甲基脲基)苯基)環戊-3-烯甲酸甲酯之混合物(0.0223 g，0.0554 mmol)之THF(2.0 mL)中逐滴添加氫化二異丁基鋁(0.166 mL，0.166 mmol)。在0℃下攪拌混合物3小時。再添加氫化二異丁基鋁(0.166 mL，0.166 mmol)，且攪拌反應混合物1小時。添加氯化銨及15 mL飽和洛瑟耳氏鹽水溶液。用乙酸乙酯(20 mL×4)萃取所得混合物。經無水硫酸鈉乾燥經合併之萃取物且濃縮，定量地得到(1-(3-(2,6-二氟苯氧基)-4-(3-(羥基甲基)環戊-1-烯-1-基)苯基)-3-甲基脲與1-(3-(2,6-二氟苯氧基)-4-(4-(羥基甲基)環戊-1-烯-1-基)苯基)-3-甲基脲之混合物。質譜(ESI)m/z=376.0(M+H)。 Step D : to methyl 3-(2-(2,6-difluorophenoxy)-4-(3-methylureido)phenyl)cyclopent-2-enecarboxylate at 0 ° C a mixture of methyl 3-(2-(2,6-difluorophenoxy)-4-(3-methylureido)phenyl)cyclopent-3-enecarboxylate (0.0223 g, 0.0554 mmol) in THF Diisobutylaluminum hydride (0.166 mL, 0.166 mmol) was added dropwise (2.0 mL). The mixture was stirred at 0 ° C for 3 hours. Additional diisobutylaluminum hydride (0.166 mL, 0.166 mmol) was added and the reaction mixture was stirred 1 hr. Ammonium chloride and 15 mL of a saturated aqueous solution of Lotll's salt were added. The resulting mixture was extracted with ethyl acetate (20 mL × 4). The combined extracts were dried over anhydrous sodium sulfate and concentrated to give (1-(3-(2,6-difluorophenoxy)-4-(3-(hydroxymethyl)cyclopent-1-ene quantitatively. 1-yl)phenyl)-3-methylurea with 1-(3-(2,6-difluorophenoxy)-4-(4-(hydroxymethyl)cyclopent-1-ene-1 a mixture of phenyl)-3-methylurea. Mass Spectrum (ESI) m/z = 376.0 (M+H).

步驟E：向含(1-(3-(2,6-二氟苯氧基)-4-(3-(羥基甲基)環戊-1-烯-1-基)苯基)-3-甲基脲與1-(3-(2,6-二氟苯氧基)-4-(4-(羥基甲基)環戊-1-烯-1-基)苯基)-3-甲基脲之混合物(0.024 g，0.064 mmol))之THF(4.5 mL)中添加20%氫氧化鈀/碳(4.41 mg，6.28 μmol)。在室溫下於H2(g)下攪拌反應混合物18小時。添加乙酸(0.060 mL，1.048 mmol)，且在室溫下於H2(g)下攪拌混合物3天。經矽藻土襯墊過濾混合物且濃縮。藉由 逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘梯度5%至95%)純化殘餘物，得到1-(3-(2,6-二氟苯氧基)-4-(3-(羥基甲基)環戊基)苯基)-3-甲基脲(15.8 mg，0.042 mmol，66%產率)。質譜(ESI)m/z=378.1(M+H)。 Step E : to (1-(3-(2,6-difluorophenoxy)-4-(3-(hydroxymethyl)cyclopent-1-en-1-yl)phenyl)-3- Methylurea and 1-(3-(2,6-difluorophenoxy)-4-(4-(hydroxymethyl)cyclopent-1-en-1-yl)phenyl)-3-methyl To a mixture of urea (0.024 g, 0.064 mmol) in THF (4.5 mL) was added 20% palladium hydroxide/carbon (4.41 mg, 6.28 μmol). The reaction mixture was stirred at room temperature under H 2 (g) for 18 h. Acetic acid (0.060 mL, 1.048 mmol) was added, and the mixture was stirred at room temperature under H2 (g) for 3 days. The mixture was filtered through a pad of Celite and concentrated. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (over 25 minute gradient 5-95%) to give the residue, to give 1- (3- (2,6-difluorophenyl Oxy)-4-(3-(hydroxymethyl)cyclopentyl)phenyl)-3-methylurea (15.8 mg, 0.042 mmol, 66% yield). Mass Spectrum (ESI) m/z = 378.1 (M+H).

遵循實例170中之程序，製備以下化合物： Following the procedure in Example 170, the following compounds were prepared:

實例1298Example 1298

1-(5-(3-羥基環戊基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(3-hydroxycyclopentyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：在室溫下，向七水合氯化鈰(0.824 g，2.211 mmol)及1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環戊-1-烯-1-基)吡啶-2-基)脲(0.187 g，0.553 mmol)於MeOH(11 mL)中之混合物中緩慢添加硼氫化鈉(0.019 ml，0.553 mmol)且攪拌1.5小時。用冰淬滅反應物且濃縮。經Redi-Sep預裝填矽膠管柱(12 g)，以含0%至10% MeOH之CH2Cl2梯度溶離對殘餘物進行層析，得到1-(5-(3-羥基環戊-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(71 mg，0.21 mmol，38%產率)。質譜(ESI)m/z=341.0(M+H)。 Step A : To cesium chloride heptahydrate (0.824 g, 2.211 mmol) and 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5- at room temperature Sodium borohydride (0.019 ml, slowly added to a mixture of (3-oxocyclopent-1-ene-1-yl)pyridin-2-yl)urea (0.187 g, 0.553 mmol) in MeOH (11 mL 0.553 mmol) and stirred for 1.5 hours. The reaction was quenched with ice and concentrated. 2 Cl 2 gradient eluting residue was subjected to chromatography Redi-Sep pre-packed silica gel column (12 g), at 0% to 10% MeOH of CH, to give 1- (5- (3-hydroxy-cyclopentyl - 1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (71 mg, 0.21 mmol, 38% yield) . Mass Spectrum (ESI) m/z = 341.0 (M+H).

步驟B：向1-(5-(3-羥基環戊-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.071 g，0.21 mmol)於THF(2 mL)中之溶液中添加氫氧化鈀/碳(0.029 g，0.042 mmol)。在氫氣氛圍下攪拌所得反應混合物3天。經矽藻土襯墊過濾反應混合物，用MeOH沖洗，且在真空中濃縮。藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(經25分鐘梯度5%至95%)純化殘餘物，得到1-(5-(3-羥基環戊基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.0065 g，0.019 mmol，9.1%產率)。質譜(ESI)m/z=343.0(M+H)。首先藉由超臨界流體層析(250 mm×30 mm Lux-2管柱，使用28 g/min MeOH(20 mM NH3)+52 g/min CO2)分離異構體，接著藉由超臨界流體層析(250 mm×21 mm AD-H管柱，使用17 g/min EtOH(20 mM NH3)+51 g/min CO2)分離外消 旋物質。 Step B : To 1-(5-(3-hydroxycyclopent-1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 To a solution of methylurea (0.071 g, 0.21 mmol) in THF (2 mL). The resulting reaction mixture was stirred under a hydrogen atmosphere for 3 days. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. By reverse phase preparative HPLC, using 0.1% TFA in of CH 3 CN / H 2 O (over 25 minute gradient 5-95%) to give the residue, to give 1- (5- (3-hydroxy-cyclopentyl) 4-((5-Methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.0065 g, 0.019 mmol, 9.1% yield). Mass Spectrum (ESI) m/z = 343.0 (M+H). Separation of the isomers by supercritical fluid chromatography (250 mm × 30 mm Lux-2 column using 28 g/min MeOH (20 mM NH 3 ) + 52 g/min CO 2 ) followed by supercritical fluid chromatography (250 mm × 21 mm AD- H column, using 17 g / min EtOH (20 mM NH 3) +51 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

遵循1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((3-側氧基環丁基)甲基) 吡啶-2-基)-3-甲基脲之程序，製備以下化合物： Follow 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((3-oxocyclocyclobutyl)methyl)pyridin-2-yl)-3 -Methylurea procedure to prepare the following compounds:

實例1307Example 1307

1-(5-(順-3-羥基-3-甲基環戊基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(cis-3-hydroxy-3-methylcyclopentyl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

在0℃下，向1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(3-側氧基環戊基)吡啶-2-基)脲(0.064 g，0.188 mmol)於無水THF(10.0 mL，123 mmol)中之溶液中逐滴添加含3.0 M溴化甲基鎂之乙醚(0.188 mL，0.564 mmol)。在0℃下攪拌所得混合物1小時。再添加含3.0 M溴化甲 基鎂之乙醚(0.188 mL，0.564 mmol)，且在0℃下攪拌反應混合物1小時。再添加含3.0 M溴化甲基鎂之乙醚(0.188 ml，0.564 mmol)，且再攪拌所得混合物1小時。用MeOH淬滅反應混合物且濃縮。經Redi-Sep預裝填矽膠管柱(24 g)，以含1%至10% MeOH之CH2Cl2梯度溶離對殘餘物進行層析，接著藉由逆相製備型HPLC，使用含0.1% TFA之CH3CN/H2O(梯度5%至95%)再純化，得到1-(5-(順-3-羥基-3-甲基環戊基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.0061 g，0.017 mmol，9.10%產率)。質譜(ESI)m/z=357.2(M+H)。藉由超臨界流體層析(250 mm×21 mm OJ-H管柱，使用6 g/min EtOH(20 mM NH3)+34 g/min CO2)分離外消旋物質。 To 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(3-oxocyclopentyl)pyridin-2-yl) at 0 °C A solution of 3.0 M methylmagnesium bromide (0.188 mL, 0.564 mmol) was added dropwise to a solution of EtOAc (EtOAc) The resulting mixture was stirred at 0 ° C for 1 hour. Further, diethyl ether (0.188 mL, 0.564 mmol) containing 3.0 M methylmagnesium bromide was added, and the mixture was stirred at 0 ° C for 1 hour. Further, diethyl ether (0.188 ml, 0.564 mmol) containing 3.0 M methylmagnesium bromide was added, and the resulting mixture was further stirred for 1 hour. The reaction mixture was quenched with MeOH and concentrated. By Redi-Sep pre-packed silica gel column (24 g), at 1% to 10% MeOH gradient of CH 2 Cl 2 fractions and the residue was subjected to chromatography, followed by reverse phase preparative HPLC, using 0.1% Further purification of CH 3 CN/H 2 O (gradient 5% to 95%) of TFA affords 1-(5-(cis-3-hydroxy-3-methylcyclopentyl)-4-((5-methyl) Pyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.0061 g, 0.017 mmol, 9.10% yield). Mass Spectrum (ESI) m/z = 357.2 (M+H). By supercritical fluid chromatography (250 mm × 21 mm OJ- H column using 6 g / min EtOH (20 mM NH 3) +34 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

遵循實例1307中之程序，製備以下化合物： Following the procedure in Example 1307, the following compounds were prepared:

製備preparation

4-甲基-8-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-酮 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-one

步驟A：將三苯基膦(0.976 g，3.72 mmol)、偶氮二甲酸二異丙酯(0.752 g，3.72 mmol)及4-溴-2-羥基-N-(2-羥基乙基)-N-甲基苄醯胺(0.680 g，2.481 mmol)於THF(138 mL)中之混合物在室溫下攪拌18小時。濃縮混合物，且將50 mL 2 N HCl水溶液添加至殘餘物中。用乙酸乙酯(80 mL×3)萃取所得混合物。分別用水、飽和碳酸氫鈉水溶液及鹽水洗滌經彙集之萃取物，乾燥(Na2SO4)且濃縮。經Redi-Sep預裝填矽膠管柱(40 g)，以含1%至100% EtOAc之己烷梯度溶離對殘餘物進行層析，得到8-溴-4-甲基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-酮(0.276 g，1.078 mmol，43.4%產率)。質譜(ESI)m/z=258.1(M+H)。 Step A : Triphenylphosphine (0.976 g, 3.72 mmol), diisopropyl azodicarboxylate (0.752 g, 3.72 mmol) and 4-bromo-2-hydroxy-N-(2-hydroxyethyl)- A mixture of N-methylbenzylamine (0.680 g, 2.481 mmol) in EtOAc (EtOAc) The mixture was concentrated and 50 mL of 2N aqueous HCl was added to the residue. The resulting mixture was extracted with ethyl acetate (80 mL × 3). With water, saturated aqueous sodium bicarbonate and brine The pooled extracts were dried (Na 2 SO 4) and concentrated. The residue was chromatographed with a gradient of 1% to 100% EtOAc in hexanes to afford 8-bromo-4-methyl-3,4-di. Hydrobenzo[f][1,4]oxazin-5(2H)-one (0.276 g, 1.078 mmol, 43.4% yield). Mass Spectrum (ESI) m/z = 258.1 (M+H).

步驟B：將8-溴-4-甲基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-酮(0.276 g，1.078 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(0.088 g，0.108 mmol)、雙(頻哪醇根基)二硼(0.547 g，2.155 mmol)及乙酸鉀(0.317 g，3.23 mmol)於1,4-二噁烷(10 mL)中之混合物用氮氣充氣5分鐘，隨後密封反應物且加熱至90℃，維持18小時。冷卻混合物室溫，過濾且用EtOAc沖洗。濃縮濾液。經Redi-Sep預裝填矽膠管柱(40 g)，以含1%至100% EtOAc之己烷梯度溶離對殘餘物進行層析，得到4-甲基-8-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-酮(0.197 g，0.650 mmol，60.3%產率)。1H NMR(CDCl3)δ 7.78(d,J=7.6 Hz,1H),7.57(dd,J=7.6,1.0 Hz,1H),7.37-7.51(m,1H),4.37(t,J=5.2 Hz,2H),3.48(t,J=5.2 Hz,2H),3.21(s,3H),1.34(s, 12H)。 Step B : 8-Bromo-4-methyl-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-one (0.276 g, 1.078 mmol), 1,1 '-Bis(diphenylphosphino)ferrocene-palladium dichloride (0.088 g, 0.108 mmol), bis(pinacolyl)diboron (0.547 g, 2.155 mmol) and potassium acetate (0.317 g, 3.23) A mixture of mmol) in 1,4-dioxane (10 mL) was agitated with nitrogen for 5 min then the mixture was sealed and warmed to <RTIgt; The mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated. The residue was chromatographed with a gradient of 1% to 100% EtOAc in hexanes to afford 4-methyl-8-(4,4,5, 5-tetramethyl-1,3,2-dioxaboron 2-yl)-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-one (0.197 g, 0.650 mmol, 60.3% yield). 1 H NMR (CDCl 3 ) δ 7.78 (d, J = 7.6 Hz, 1H), 7.57 (dd, J = 7.6, 1.0 Hz, 1H), 7.37-7.51 (m, 1H), 4.37 (t, J = 5.2 Hz, 2H), 3.48 (t, J = 5.2 Hz, 2H), 3.21 (s, 3H), 1.34 (s, 12H).

製備preparation

4,4,5,5-四甲基-2-(2,2,5,5-四甲基-2,5-二氫呋喃-3-基)-1,3,2-二氧硼 4,4,5,5-tetramethyl-2-(2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl)-1,3,2-dioxaboron

步驟A：在-78℃下，向2,2,5,5-四甲基四氫呋喃-3-酮(2.160 mL，14.07 mmol)於THF(70.3 mL，14.07 mmol)中之溶液中添加2.0 M二異丙基胺基鋰於庚烷/THF/乙苯中之溶液(10.55 mL，21.10 mmol)。攪拌混合物1小時，隨後添加n-苯基雙-三氟甲烷磺醯亞胺(7.54 g，21.10 mmol)。攪拌所得混合物18小時，同時逐漸升溫至室溫。用200 mL EtOAc稀釋混合物，且用水、飽和碳酸氫鈉水溶液及鹽水洗滌，乾燥(Na2SO4)並濃縮。經Redi-Sep預裝填矽膠管柱(120 g)，以含0%至30% EtOAc之己烷梯度溶離對殘餘物進行層析，得到三氟甲烷磺酸2,2,5,5-四甲基-2,5-二氫呋喃-3-基酯(0.628 g，2.29 mmol，16.2%產率)。 Step A : Add 2.0 M to a solution of 2,2,5,5-tetramethyltetrahydrofuran-3-one (2.160 mL, 14.07 mmol) in THF (70.3 mL, 14.07 mmol) at -78 °C A solution of isopropylamino lithium in heptane / THF / ethylbenzene (10.55 mL, 21.10 mmol). The mixture was stirred for 1 hour, then n-phenylbis-trifluoromethanesulfonimide (7.54 g, 21.10 mmol) was added. The resulting mixture was stirred for 18 hours while gradually warming to room temperature. The mixture was diluted with 200 mL EtOAc, and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na 2 SO 4) and concentrated. The residue was chromatographed on a Redi-Sep prefilled cartridge (120 g) eluting with a gradient of 0% to 30% EtOAc in hexanes to afford trifluoromethanesulfonic acid 2,2,5,5- Methyl-2,5-dihydrofuran-3-yl ester (0.628 g, 2.29 mmol, 16.2% yield).

步驟B：將1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(0.187 g，0.229 mmol)、雙(頻哪醇根基)二硼(0.756 g，2.98 mmol)、乙酸鉀(0.787 g，8.01 mmol)及三氟甲烷磺酸2,2,5,5-四甲基-2,5-二氫呋喃-3-基酯(0.628 g，2.29 mmol)於1,4-二噁烷(11 mL)中之混合物用氮氣充氣5分鐘，隨後密封反應物且加熱至90℃，維持18小時。冷卻混合物至室溫，過濾且用EtOAc沖洗。濃縮濾液。經Redi-Sep預裝填矽膠管柱(80 g)，以含0%至80% EtOAc之己烷梯度溶離對殘餘物進行層析，得到4,4,5,5-四甲基-2-(2,2,5,5-四甲基-2,5-二氫呋喃-3-基)-1,3,2-二氧硼(0.366 g，1.45 mmol，63.4%產率)。1H NMR(CDCl3)δ 6.29(s,1H),1.37(s,6H),1.31(s,6H),1.28(s,12H)。 Step B : 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.187 g, 0.229 mmol), bis(pinacolyl)diboron (0.756 g, 2.98 mmol), Potassium acetate (0.787 g, 8.01 mmol) and 2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (0.628 g, 2.29 mmol) at 1,4 The mixture in dioxane (11 mL) was aerated with nitrogen for 5 min then the reaction was sealed and warmed to 90 &lt;0&gt;C for 18 h. The mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated. The residue was chromatographed with a gradient of 0% to 80% EtOAc in hexanes to afford 4,4,5,5-tetramethyl-2-. (2,2,5,5-tetramethyl-2,5-dihydrofuran-3-yl)-1,3,2-dioxaboron (0.366 g, 1.45 mmol, 63.4% yield). 1 H NMR (CDCl 3 ) δ 6.29 (s, 1H), 1.37 (s, 6H), 1.31 (s, 6H), 1.28 (s, 12H).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

實例1317Example 1317

1-(5-(4-(羥基甲基)環己-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(4-(hydroxymethyl)cyclohex-1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 -methylurea

在0℃下，向4-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環己-3-烯甲酸乙酯(0.561 g，1.367 mmol)於THF(6.83 ml，1.367 mmol)中之溶液中添加含1.0 M氫化鋰鋁之THF(2.050 ml，2.050 mmol)。在0℃下攪拌所得混合物30分鐘，接著用飽和碳酸氫鈉水溶液淬滅。經矽藻土襯墊過濾混合物且用EtOAc沖洗。濃縮濾液。經Redi-Sep預裝填矽膠管柱(40 g)，以含1%至10% MeOH之CH2Cl2梯度溶離對殘餘物進行層析，得到1-(5-(4-(羥基甲基)環己-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.302 g，0.820 mmol，60.0%產率)。質譜(ESI)m/z=378.1(M+H)。1H NMR(CDCl3)δ 9.08(br.s.,1H),8.29(s,1H),8.22(d,J=2.5 Hz,1H),7.95(s,1H),7.12-7.22(m,1H),6.12(s,1H),5.74-5.90(m,1H),5.30(s,1H),3.44-3.66(m,2H),2.84(d,J=4.7 Hz,3H),2.39(br.s.,2H),2.36(s,3H),2.30(d,J=17.0 Hz,1H),1.88(m,2H),1.29-1.48(m,1H)。藉由超臨界流體層析(250 mm×21 mm Lux-2管柱，使用21 g/min MeOH(20 mM NH3)+49 g/min CO2)分離外消旋物質。 To 4-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclohex-3-enecarboxylic acid at 0 °C A solution of ethyl acetate (0.56 g, 1.367 mmol) in EtOAc (EtOAc (EtOAc) The resulting mixture was stirred at 0&lt;0&gt;C for 30 min then quenched with saturated aqueous sodium hydrogen sulfate. The mixture was filtered through a pad of Celite and rinsed with EtOAc. The filtrate was concentrated. By Redi-Sep pre-packed silica gel column (40 g), at 1% to 10% MeOH gradient of CH 2 Cl 2 fractions and the residue was subjected to chromatography to give 1- (5- (4- (hydroxymethyl Cyclohex-1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.302 g, 0.820 mmol, 60.0) %Yield). Mass Spectrum (ESI) m/z = 378.1 (M+H). 1 H NMR (CDCl 3 ) δ 9.08 (br.s., 1H), 8.29 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.12-7.22 (m, 1H), 6.12 (s, 1H), 5.74-5.90 (m, 1H), 5.30 (s, 1H), 3.44 - 3.66 (m, 2H), 2.84 (d, J = 4.7 Hz, 3H), 2.39 (br) .s., 2H), 2.36 (s, 3H), 2.30 (d, J = 17.0 Hz, 1H), 1.88 (m, 2H), 1.29-1.48 (m, 1H). By supercritical fluid chromatography (250 mm × 21 mm Lux- 2 column, using 21 g / min MeOH (20 mM NH 3) +49 g / min CO 2) separation of the racemic material.

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

遵循實例1317中之程序，製備以下化合物： Following the procedure in Example 1317 , the following compounds were prepared:

實例1325Example 1325

1-(5-(3-(羥基甲基)環戊-1-烯-1-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲與1-(5-(4-(羥基甲基)環戊-1-烯-1-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(1：1) 1-(5-(3-(Hydroxymethyl)cyclopent-1-en-1-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)- 3-methylurea with 1-(5-(4-(hydroxymethyl)cyclopent-1-en-1-yl)-4-((5-methoxypyridin-3-yl)oxy)pyridine -2-yl)-3-methylurea (1:1)

步驟A：將1-(4-溴-3-氟苯基)-3-甲基脲(2.50 g，10.12 mmol)、雙(頻哪醇根基)二硼(3.85 g，15.18 mmol)、乙酸鉀(2.98 g，30.4 mmol)及(1,1'-雙(二苯基膦基)二茂鐵)二氯鈀(ii)(0.413 g，0.506 mmol)於50 mL二噁烷中之經氬氣脫氣混合物在90℃下攪拌16小時。接著冷卻混合物至室溫且用200 mL乙酸乙酯稀釋。用50 mL飽和NH4Cl水溶液、水及鹽水洗滌所得混合物，乾燥(Na2SO4)且濃縮。藉由CombiFlash，在125 g矽膠管柱上純化殘餘物，得到1.18 g 1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯基)-3-甲基脲。1H NMR(CDCl3)δ 9.63(s,1H),9.24(s,1H),8.49(d,J=8.0 Hz,1H),6.62(d,J=12.0 Hz,1H),2.98(d,J=4.0 Hz,3H)及1.37(s,12H)。 Step A : 1-(4-Bromo-3-fluorophenyl)-3-methylurea (2.50 g, 10.12 mmol), bis(pinacolyl)diboron (3.85 g, 15.18 mmol), potassium acetate (2.98 g, 30.4 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (ii) (0.413 g, 0.506 mmol) in argon in 50 mL of dioxane The degassed mixture was stirred at 90 ° C for 16 hours. The mixture was then cooled to room temperature and diluted with 200 mL ethyl acetate. With 50 mL of saturated aqueous NH 4 Cl, the resulting mixture was washed with water and brine, dried (Na 2 SO 4) and concentrated. The residue was purified on a 125 g silica gel column using CombiFlash to give 1.18 g of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron). -2-yl)phenyl)-3-methylurea. 1 H NMR (CDCl 3 ) δ 9.63 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 12.0 Hz, 1H), 2.98 (d, J = 4.0 Hz, 3H) and 1.37 (s, 12H).

步驟B：將1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯基)-3-甲基脲(100 mg，0.340 mmol)、3-(((三氟甲基)磺醯基)氧基)-環戊-3-烯甲酸甲酯與3-(((三氟甲基)磺醯基)氧基)環戊-2-烯甲酸甲酯(1：1)(280 mg，1.02 mmol)、碳酸鉀(141 mg，1.02 mmol)、肆(三苯基膦)鈀(39 mg，0.034 mmol)、水(200 mL)及二噁烷(1.7 mL)之經氮氣脫氣混合物在85℃下攪拌18小時。接著冷卻混合物至室溫且直接進行HPLC純化，得到40 mg 3-(2-氟-4-(3-甲基脲基)苯基)環戊-2-烯甲酸甲酯與3-(2-氟-4-(3-甲基脲基)苯基)環戊-3-烯甲酸甲酯(1：1)之混合物。質譜(ESI)m/z=294.0(M+H)。 Step B : 1-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)phenyl)-3-methylurea (100 mg, 0.340 mmol), methyl 3-(((trifluoromethyl)sulfonyl)oxy)-cyclopent-3-enecarboxylate Methyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enoate (1:1) (280 mg, 1.02 mmol), potassium carbonate (141 mg, 1.02 mmol) A nitrogen degassed mixture of (triphenylphosphine)palladium (39 mg, 0.034 mmol), water (200 mL) and dioxane (1.7 mL) was stirred at 85 ° C for 18 hours. The mixture was then cooled to room temperature and directly purified by HPLC to give 40 mg of methyl 3-(2-fluoro-4-(3-methylureido)phenyl)cyclopent-2-enoate and 3-(2- A mixture of methyl fluoro-4-(3-methylureido)phenyl)cyclopent-3-enecarboxylate (1:1). Mass Spectrum (ESI) m/z = 294.0 (M+H).

步驟C：將3-(2-氟-4-(3-甲基脲基)苯基)環戊-2-烯甲酸甲酯與3-(2-氟-4-(3-甲基脲基)苯基)環戊-3-烯甲酸甲酯(1：1)之混合物(41 mg，0.14 mmol)、5-甲氧基-吡啶-3-醇(25 mg，0.21 mmol)及碳酸銫(69 mg，0.210)於1.5 mL 1-甲基-2-吡咯啶酮中之混合物在85℃下攪拌24小時。接著冷卻混合物至室溫且直接進行RP-HPLC純化，得到11.1 mg 3-(2-((5-甲氧基吡啶-3-基)氧基)-4-(3-甲基脲基)苯基)環戊-2-烯甲酸甲酯與3-(2-((5-甲氧基吡啶-3-基)氧基)-4-(3-甲基脲基)苯基)環戊-3-烯甲酸甲酯(1：1)之混合物。質譜(ESI)m/z=399.1(M+H)。 Step C : Methyl 3-(2-fluoro-4-(3-methylureido)phenyl)cyclopent-2-enoate with 3-(2-fluoro-4-(3-methylureido) a mixture of methyl phenyl)cyclopent-3-enecarboxylate (1:1) (41 mg, 0.14 mmol), 5-methoxy-pyridin-3-ol (25 mg, 0.21 mmol) and cesium carbonate ( A mixture of 69 mg, 0.210) in 1.5 mL of 1-methyl-2-pyrrolidone was stirred at 85 ° C for 24 hours. The mixture was then cooled to room temperature and directly subjected to RP-HPLC purification to give 11.1 mg of 3-(2-((5-methoxypyridin-3-yl)oxy)-4-(3-methylureido)benzene. Methyl cyclopent-2-enoate and 3-(2-((5-methoxypyridin-3-yl)oxy)-4-(3-methylureido)phenyl)cyclopentane- A mixture of methyl 3-enoate (1:1). Mass Spectrum (ESI) m/z = 399.1 (M+H).

步驟D：在0℃下，向3-(4-((5-甲氧基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)環戊-3-烯甲酸甲酯與3-(4-((5-甲氧基吡啶-3-基)氧基)- 6-(3-甲基脲基)吡啶-3-基)環戊-2-烯甲酸甲酯(1：1)之混合物(11.00 mg，0.014 mmol))於無水四氫呋喃(2.0 mL，24.66 mmol)中之溶液中逐滴添加1.0 M氫化二異丁基鋁於己烷中之溶液(0.083 mL，0.083 mmol)。在0℃下攪拌所得混合物1小時，接著用甲醇淬滅。對混合物直接進行RP-HPLC純化，得到6.2 mg 1-(5-(3-(羥基甲基)環戊-1-烯-1-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲與1-(5-(4-(羥基甲基)環戊-1-烯-1-基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(1：1)之混合物。質譜(ESI)m/z=371.2(M+H)。 Step D: To 3-(4-((5-methoxypyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)cyclopentane at 0 °C Methyl 3-enoate and 3-(4-((5-methoxypyridin-3-yl)oxy)- a mixture of methyl 6-(3-methylureido)pyridin-3-yl)cyclopent-2-enoate (1:1) (11.00 mg, 0.014 mmol) in anhydrous tetrahydrofuran (2.0 mL, 24.66 mmol) A solution of 1.0 M diisobutylaluminum hydride in hexane (0.083 mL, 0.083 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C for 1 hour then quenched with methanol. The mixture was directly subjected to RP-HPLC purification to give 6.2 mg of 1-(5-(3-(hydroxymethyl)cyclopent-1-en-1-yl)-4-((5-methoxypyridine-3- And oxy)pyridin-2-yl)-3-methylurea with 1-(5-(4-(hydroxymethyl)cyclopent-1-en-1-yl)-4-((5-A) A mixture of oxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (1:1). Mass Spectrum (ESI) m/z = 371.2 (M+H).

實例1326Example 1326

1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(2-甲基四氫呋喃-2-基)吡啶-2-基)脲 1-methyl-3-(4-((5-methylpyridin-3-yl)oxy)-5-(2-methyltetrahydrofuran-2-yl)pyridin-2-yl)urea

步驟A：使氬氣鼓泡通過1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.200 g，0.593 mmol)、2-烯丙基乙醇(0.306 ml，2.97 mmol)、二氯雙(三苯基-膦)鈀(ii)(0.042 g，0.059 mmol)及碳酸氫鈉(0.069 ml，1.780 mmol)於1-甲基-2-吡咯啶酮(2.97 ml，0.593 mmol)中之混合物，持續3分鐘，隨後將其密封且在130℃下攪拌隔夜。冷卻混合物至室溫，且藉由CombiFlash(ISCO)，在24 g矽膠管柱上，使用含0-10%甲醇之DCM梯度直接純化，得到混合物，再次藉由RP-HPLC純化該混合物，得到142 mg(E)-1-(5-(5-羥基戊-1-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲、(E)-1-(5-(5-羥基戊-2-烯-1-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲及1-(5-(5-羥基戊-1-烯-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲之混合物。質譜 (ESI)m/z=343.1(M+H)。 Step A : Bubbling argon through 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (0.200 g, 0.593) Ment), 2-allylethanol (0.306 ml, 2.97 mmol), dichlorobis(triphenyl-phosphine)palladium(ii) (0.042 g, 0.059 mmol) and sodium bicarbonate (0.069 ml, 1.780 mmol) A mixture of 1-methyl-2-pyrrolidone (2.97 ml, 0.593 mmol) was continued for 3 minutes, then sealed and stirred at 130 ° C overnight. The mixture was cooled to room temperature and directly purified by a CombiFlash (ISCO) eluting with EtOAc (EtOAc) Mg(E)-1-(5-(5-hydroxypent-1-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 -methylurea, (E)-1-(5-(5-hydroxypent-2-en-1-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine-2- 3-methylurea and 1-(5-(5-hydroxypent-1-en-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine-2- a mixture of benzyl-3-methylurea. Mass Spectrum (ESI) m/z = 343.1 (M+H).

步驟B：在室溫下，向1-(5-(5-羥基戊-1-烯-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(0.041 g，0.120 mmol)於四氫呋喃(5.0 mL，0.120 mmol)中之溶液中添加二碘(0.091 g，0.359 mmol)。在室溫下攪拌所得混合物且由LCMS監測。濃縮混合物且在真空下乾燥，得到粗產物，其含有1-(5-(2-(碘甲基)四氫呋喃-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲、1-(5-(3-碘四氫-2H-哌喃-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲及1-(5-(碘(四氫呋喃-2-基)甲基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲之混合物。質譜(ESI)m/z=469.0(M+H)。 Step B : To 1-(5-(5-hydroxypent-1-en-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine-2- at room temperature Diethyl iodide (0.091 g, 0.359 mmol) was added to a solution of EtOAc (MeOH) (EtOAc). The resulting mixture was stirred at room temperature and monitored by LCMS. The mixture is concentrated and dried under vacuum to give a crude material containing 1-(5-(2-(iodomethyl)tetrahydrofuran-2-yl)-4-((5-methylpyridin-3-yl)oxy. Pyridin-2-yl)-3-methylurea, 1-(5-(3-iodotetrahydro-2H-piperidin-2-yl)-4-((5-methylpyridin-3-yl) Oxy)pyridin-2-yl)-3-methylurea and 1-(5-(iodo(tetrahydrofuran-2-yl)methyl)-4-((5-methylpyridin-3-yl)oxy a mixture of pyridin-2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 469.0 (M+H).

步驟C：在室溫下，向1-(5-(2-(碘甲基)四氫呋喃-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲、1-(5-(3-碘四氫-2H-哌喃-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲及1-(5-(碘(四氫呋喃-2-基)甲基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲之混合物(0.015 g，0.032 mmol)於四氫呋喃(5.0 mL，0.032 mmol)中之溶液中添加2800阮尼鎳(raney 2800 nickel)於水中之漿液(0.050 mL，3.79 mmol)。在室溫下攪拌所得混合物隔夜。經矽藻土襯墊過濾混合物且用DCM洗滌，濃縮濾液且藉由RP-HPLC純化殘餘物，得到5.0 mg 1-甲基-3-(4-((5-甲基吡啶-3-基)氧基)-5-(2-甲基四氫呋喃-2-基)吡啶-2-基)脲。質譜(ESI)m/z=343.1(M+H)。 Step C : To 1-(5-(2-(iodomethyl)tetrahydrofuran-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine-2- at room temperature 3-methylurea, 1-(5-(3-iodotetrahydro-2H-piperidin-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridine- 2-yl)-3-methylurea and 1-(5-(iodo(tetrahydrofuran-2-yl)methyl)-4-((5-methylpyridin-3-yl)oxy)pyridine-2- A mixture of 2,3 methyl urea (0.015 g, 0.032 mmol) in tetrahydrofuran (5.0 mL, 0.032 mmol) was added 2800 Niney (Rney 2800 nickel) in water (0.050 mL, 3.79 mmol) ). The resulting mixture was stirred overnight at room temperature. The mixture was filtered through a pad of celite and washed with DCM, and the filtrate was concentrated, and the residue was purified by RP-HPLC to give 5.0 mg of 1-methyl-3-(4-((5-methylpyridin-3-yl) Oxy)-5-(2-methyltetrahydrofuran-2-yl)pyridin-2-yl)urea. Mass Spectrum (ESI) m/z = 343.1 (M+H).

遵循實例1326中之程序，製備以下化合物： Following the procedure in Example 1326 , the following compounds were prepared:

實例1331Example 1331

(R)-1-(4-(3-氯-2-氟苯氧基)-5-(四氫呋喃-2-基)吡啶-2-基)-3-甲基脲與(S)-1-(4-(3-氯-2-氟苯氧基)-5-(四氫呋喃-2-基)吡啶-2-基)-3-甲基脲 (R)-1-(4-(3-chloro-2-fluorophenoxy)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)-3-methylurea with (S)-1- (4-(3-Chloro-2-fluorophenoxy)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)-3-methylurea

步驟A：將N-乙基-N-異丙基丙-2-胺(0.100 g，0.267 mmol)、2,3-二氫呋喃(0.202 mL，2.67 mmol)、N-乙基-N-異丙基丙-2-胺(0.188 mL，1.07 mmol)、二乙醯氧基鈀(5.99 mg，0.027 mmol)及碳酸銀(52 mg，0.187 mmol)於1.35 mL DMF中之經氮氣脫氣混合物置於密封管中，且在100℃下攪拌17小時。冷卻混合物至室溫且直接進行 RP-HPLC純化，得到75 mg 1-(4-(3-氯-2-氟苯氧基)-5-(2,5-二氫呋喃-2-基)吡啶-2-基)-3-甲基脲。質譜(ESI)m/z=364.0(M+H)。 Step A : N-Ethyl-N-isopropylpropan-2-amine (0.100 g, 0.267 mmol), 2,3-dihydrofuran (0.202 mL, 2.67 mmol), N-ethyl-N- Propyl propyl-2-amine (0.188 mL, 1.07 mmol), diethoxyphosphonium palladium (5.99 mg, 0.027 mmol) and silver carbonate (52 mg, 0.187 mmol) in 1.35 mL DMF. Stir in a sealed tube and stir at 100 ° C for 17 hours. The mixture was cooled to room temperature and directly purified by RP-HPLC to give 75 mg of 1-(4-(3-chloro-2-fluorophenoxy)-5-(2,5-dihydrofuran-2-yl)pyridine. -2-yl)-3-methylurea. Mass Spectrum (ESI) m/z = 364.0 (M+H).

步驟B：在室溫下於氫氣球下攪拌1-(4-(3-氯-2-氟苯氧基)-5-(2,5-二氫呋喃-2-基)吡啶-2-基)-3-甲基脲(0.075 g，0.206 mmol)、5重量%銠/碳(1.710 μl，10.31 μmol)及甲醇(3.0 mL，0.206 mmol)之混合物，且由LCMS監測。完成後，經矽藻土襯墊過濾混合物。使用甲醇沖洗矽藻土數次。在真空中濃縮濾液且藉由RP-HPLC純化殘餘物，得到22.6 mg(R)-1-(4-(3-氯-2-氟苯氧基)-5-(四氫呋喃-2-基)吡啶-2-基)-3-甲基脲與(S)-1-(4-(3-氯-2-氟苯氧基)-5-(四氫呋喃-2-基)吡啶-2-基)-3-甲基脲(116351-33-1)。質譜(ESI)m/z=366.0(M+H)。 Step B : Stir 1-(4-(3-chloro-2-fluorophenoxy)-5-(2,5-dihydrofuran-2-yl)pyridin-2-yl under hydrogen balloon at room temperature A mixture of 3-methylurea (0.075 g, 0.206 mmol), 5% by weight of hydrazine/carbon (1.710 μl, 10.31 μmol) and methanol (3.0 mL, 0.206 mmol) was monitored by LCMS. After completion, the mixture was filtered through a pad of diatomaceous earth. Rinse the algae soil several times with methanol. The filtrate was concentrated in vacuo and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -2-yl)-3-methylurea with (S)-1-(4-(3-chloro-2-fluorophenoxy)-5-(tetrahydrofuran-2-yl)pyridin-2-yl)- 3-methylurea (116351-33-1). Mass Spectrum (ESI) m/z = 366.0 (M+H).

遵循實例1331中之程序，製備以下化合物： Following the procedure in Example 1331 , the following compounds were prepared:

遵循製備XXX中之程序，製備以下化合物： Following the procedure in Preparation XXX, the following compounds were prepared:

遵循實例1644中之程序，製備以下化合物： Following the procedure in Example 1644 , the following compounds were prepared:

遵循製備XXX中之程序，製備以下化合物： Following the procedure in Preparation XXX, the following compounds were prepared:

製備preparation

5-溴-2-甲基苯并[d]異噁唑-3(2H)-酮 5-bromo-2-methylbenzo[d]isoxazole-3(2H)-one

步驟A：在0℃下，向無水碳酸鈉(18.43 ml，18.43 mmol)及n-羥基甲胺鹽酸鹽(1.155 g，13.82 mmol)於四氫呋喃(23.04 ml，4.61 mmol)中之劇烈攪拌混合物中添加5-溴-2-羥基苄醯氯(1.085 g，4.61 mmol)於二氯甲烷(23.04 ml，4.61 mmol)中之溶液。在室溫下攪拌所得混合物18小時。冷卻混合物至0℃，且緩慢添加25 mL 2 N HCl水溶液。用EtOAc(40 mL×4)萃取所得混合物。經無水硫酸鈉乾燥經彙集之萃取物且在真空中濃縮。藉由CombiFlash，在40 g矽膠管柱上，使用含0-100% EtOAc之己烷梯度純化殘餘物，得到157 mg 116504-5-1。質譜(ESI)m/z=258.1(M+H)。 Step A : To a vigorous mixture of anhydrous sodium carbonate (18.43 ml, 18.43 mmol) and n-hydroxymethylamine hydrochloride (1.155 g, 13.82 mmol) in tetrahydrofuran (23.04 ml, 4.61 mmol) at 0 ° C A solution of 5-bromo-2-hydroxybenzylhydrazine chloride (1.085 g, 4.61 mmol) in dichloromethane (23.04 mL, 4. The resulting mixture was stirred at room temperature for 18 hours. The mixture was cooled to 0 ° C and 25 mL of 2N aqueous HCl was slowly added. The resulting mixture was extracted with EtOAc (40 mL×4). The pooled extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) Mass Spectrum (ESI) m/z = 258.1 (M+H).

步驟B：在0℃下，向5-溴-N,2-二羥基-N-甲基苄醯胺(0.157 g，0.638 mmol)、三苯基膦(0.222 ml，0.957 mmol)及四氫呋喃(6.38 ml， 0.638 mmol)之混合物中添加偶氮二甲酸二異丙酯(0.188 ml，0.957 mmol)。在室溫下攪拌所得混合物24小時。接著濃縮混合物，且藉由CombiFlash，在12 g矽膠管柱上，使用含0-80% EtOAc之己烷梯度純化殘餘物，得到11 mg 5-溴-N,2-二羥基-N-甲基苄醯胺。1H NMR(CDCl3)δ 7.96(d,J=4.0 Hz,1H),7.69(dd,J=8.0,4.0 Hz,1H),7.14(d,J=8.0 Hz,1H),3.68(s,3H)。 Step B : 5-Bromo-N,2-dihydroxy-N-methylbenzylamine (0.157 g, 0.638 mmol), triphenylphosphine (0.222 ml, 0.957 mmol) and tetrahydrofuran (6.38) at 0 °C To a mixture of ml, 0.638 mmol) was added diisopropyl azodicarboxylate (0.188 ml, 0.957 mmol). The resulting mixture was stirred at room temperature for 24 hours. The mixture was then concentrated, and the residue was purified eluting with EtOAc EtOAc EtOAc Benzylamine. 1 H NMR (CDCl 3 ) δ 7.96 (d, J = 4.0 Hz, 1H), 7.69 (dd, J = 8.0, 4.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.68 (s, 3H).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

製備preparation

7-溴-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪1,1-二氧化物 7-Bromo-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine 1,1-dioxide

步驟A：a)在冰浴下，向2-羥基乙硫醇(0333 mL，4.75 mmol)及5-溴-2-氯-3-氟吡啶(1.0 g，4.75 mmol)於47 mL DMF中之混合物中分數份緩慢添加氫化鈉(60%分散液，於礦物油中，0.418 g，10.45 mmol)。在室溫下攪拌所得混合物4小時。在冰-水浴下，向此溶液中緩慢添加單過氧硫酸鹽化合物過硫酸氫鉀(7.96 ml，14.25 mmol)。在室溫下攪拌所得混合物18小時。接著經矽藻土短柱過濾混合物。在真空中濃縮濾液。藉由CombiFlash，在40 g矽膠管柱上，使用含0-100% EtOAc之己烷梯度純化殘餘物，得到0.35 g 5-溴-2-氯-3-(乙烯基磺醯基)-吡啶。質譜(ESI)m/z=283.8(M+H)。1H NMR(CDCl3)δ 8.66(d,J=4.0,1H),8.57(d,J=4.0 Hz,1H),6.88(dd,J=16,8.0 Hz,1H),6.66(dd,J=16.0,4.0 Hz,1H),6.35(dd,J=8.0,4.0 Hz,1H)。 Step A : a) In an ice bath, 2-hydroxyethanethiol (0333 mL, 4.75 mmol) and 5-bromo-2-chloro-3-fluoropyridine (1.0 g, 4.75 mmol) in 47 mL DMF Sodium hydride (60% dispersion in mineral oil, 0.418 g, 10.45 mmol) was slowly added in portions of the mixture. The resulting mixture was stirred at room temperature for 4 hours. To the solution was slowly added a monoperoxysulfate compound potassium persulfate (7.96 ml, 14.25 mmol) under ice-water bath. The resulting mixture was stirred at room temperature for 18 hours. The mixture was then filtered through a short column of diatomaceous earth. The filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Mass Spectrum (ESI) m/z = 283.8 (M+H). 1 H NMR (CDCl 3 ) δ 8.66 (d, J = 4.0, 1H), 8.57 (d, J = 4.0 Hz, 1H), 6.88 (dd, J = 16, 8.0 Hz, 1H), 6.66 (dd, J =16.0, 4.0 Hz, 1H), 6.35 (dd, J=8.0, 4.0 Hz, 1H).

步驟B：使碳酸氫鈉(47.3 mg，0.563 mmol)、甲胺(2.0 M溶液，於甲醇中，225 μl，0.450 mmol)及5-溴-2-氯-3-(乙烯基磺醯基)吡啶(106 mg，0.375 mmol)於甲醇(3752 μl，0.375 mmol)中之混合物回流1小時。濃縮混合物，且藉由CombiFlash，在40 g矽膠管柱上，使用含0-100% EtOAc之己烷梯度純化殘餘物，得到100 mg 7-溴-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪1,1-二氧化物。質譜(ESI)m/z=278.8(M+H)。1H NMR(CDCl3)δ 8.32(d,J=4.0 Hz,1H),8.04(d,J=4.0 Hz,1H),3.93(m,2H),3.32(m,2H),3.23(s,3H)。 Step B : Sodium bicarbonate (47.3 mg, 0.563 mmol), methylamine (2.0 M solution in MeOH, 225 μl, 0.450 mmol) and 5-bromo-2-chloro-3-(vinylsulfonyl) A mixture of pyridine (106 mg, 0.375 mmol) in MeOH (EtOAc. The mixture was concentrated, and the residue was purified mjjjjjjjjjj 2H-pyrido[3,2-b][1,4]thiazine 1,1-dioxide. Mass Spectrum (ESI) m/z = 278.8 (M+H). 1 H NMR (CDCl 3 ) δ 8.32 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 4.0 Hz, 1H), 3.93 (m, 2H), 3.32 (m, 2H), 3.23 (s, 3H).

製備preparation

7-溴-2-甲基苯并[d]異噁唑-3(2H)-酮 7-bromo-2-methylbenzo[d]isoxazole-3(2H)-one

步驟A：向3-溴-2-氟苯甲酸(2.0 g，9.13 mmol)及乙二醯氯(2.398 ml，27.4 mmol)於20 mL DCM中之混合物中添加兩滴DMF。在室溫下攪拌所得混合物30分鐘，接著使其回流1小時。濃縮混合物且在真空下乾燥殘餘物，得到粗醯氯。在冰-水浴下，將粗醯氯溶解於20 mL DCM中，且將溶液添加至n-羥基甲胺鹽酸鹽(2.288 g，27.4 mmol)及碳酸鉀粉末(24.35 ml，36.5 mmol)於THF(18.26 ml，9.13 mmol)中之劇烈攪拌混合物中。在室溫下攪拌所得混合物18小時。濃縮混合物且將殘餘物溶解於200 mL乙酸乙酯中。用水(兩次)、飽和碳酸氫鈉水溶 液及鹽水洗滌溶液，經無水硫酸鈉乾燥且濃縮。在真空下乾燥殘餘物，得到2.25 g粗產物3-溴-2-氟-N-羥基-N-甲基苄醯胺。質譜(ESI)m/z=249.9(M+H)。 Step A : Two drops of DMF were added to a mixture of 3-bromo-2-fluorobenzoic acid (2.0 g, 9.13 mmol) and EtOAc (2.398 mL, 27.4 mmol) in 20 mL DCM. The resulting mixture was stirred at room temperature for 30 minutes and then refluxed for 1 hour. The mixture was concentrated and the residue was dried in vacuo to give crude EtOAc. The crude chloroform was dissolved in 20 mL of DCM in an ice-water bath, and the solution was added to n-hydroxymethylamine hydrochloride (2.288 g, 27.4 mmol) and potassium carbonate powder (24.35 ml, 36.5 mmol) in THF The mixture was vigorously stirred in (18.26 ml, 9.13 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water (twice), aq. The residue was dried under vacuum to give 2.25 g of crude product of 3-bromo-2-fluoro-N-hydroxy-N-methylbenzylamine. Mass Spectrum (ESI) m/z = 249.9 (M+H).

步驟B：將3-溴-2-氟-N-羥基-N-甲基苄醯胺(0.50 g，2.016 mmol)於dmf(4.03 ml，2.016 mmol)中之溶液冷卻至0℃，且分數份添加氫化鈉(60%分散液，於礦物油中，0.089 g，2.217 mmol)。在100℃下攪拌所得混合物18小時。冷卻混合物至室溫，且添加20 mL飽和NH4Cl水溶液。用乙酸乙酯(30 mL×4)萃取所得混合物。用水(30 mL×4)及鹽水洗滌經彙集之萃取物，經無水硫酸鈉乾燥且濃縮。藉由CombiFlash，在40 g矽膠管柱上，使用含0-100% EtOAc之己烷梯度純化殘餘物，得到172 mg 7-溴-2-甲基苯并[d]異噁唑-3(2H)-酮。質譜(ESI)m/z=229.6(M+H)。1H NMR(CDCl3)δ 7.74(dd,J=8.0,4.0 Hz,1H),7.71(dd,J=8.0,4.0 Hz,1H),7.14(dd,J=8.0,8.0 Hz,1H),3.70(s,3H)。 Step B : The solution of 3-bromo-2-fluoro-N-hydroxy-N-methylbenzylamine (0.50 g, 2.016 mmol) in dmf (4.03 ml, 2.016 mmol) was cooled to 0 ° C and fractions Sodium hydride (60% dispersion in mineral oil, 0.089 g, 2.217 mmol) was added. The resulting mixture was stirred at 100 ° C for 18 hours. The mixture was cooled to room temperature and add 20 mL of saturated aqueous NH 4 Cl. The resulting mixture was extracted with ethyl acetate (30 mL × 4). The combined extracts were washed with water (30 mL×4) and brine The residue was purified on a 40 g silica gel column using EtOAc EtOAc EtOAc EtOAc EtOAc )-ketone. Mass Spectrum (ESI) m/z = 229.6 (M+H). 1 H NMR (CDCl 3 ) δ 7.74 (dd, J = 8.0, 4.0 Hz, 1H), 7.71 (dd, J = 8.0, 4.0 Hz, 1H), 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 3.70 (s, 3H).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

製備preparation

8-溴-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶1,1-二氧化物 8-bromo-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine 1,1-dioxide

步驟A：在室溫下，向3-巰基-1-丙醇(0.431 ml，4.99 mmol)及碳酸銫(0.418 ml，5.23 mmol)於DMF(4.75 ml，4.75 mmol)中之混合物 中分數份緩慢添加5-溴-2-氯-3-氟吡啶(1.0 g，4.75 mmol)。在室溫下攪拌所得混合物3小時。添加甲醇(5.0 ml，124 mmol)及水(5.0 ml，278 mmol)，接著冷卻至0℃，隨後分數份添加單過氧硫酸鹽化合物過硫酸氫鉀(7.0 g，11.4 mmol)。在室溫下攪拌所得混合物16小時。過濾混合物，且用EtOAc洗滌沈澱物。分別用水(兩次)及鹽水洗滌濾液，經無水硫酸鈉乾燥且在真空中濃縮。在真空下乾燥殘餘物，得到1.35 g粗產物3-((5-溴-2-氯吡啶-3-基)磺醯基)丙-1-醇。質譜(ESI)m/z=316.0(M+H)。 Step A : fractions of a mixture of 3-mercapto-1-propanol (0.431 ml, 4.99 mmol) and cesium carbonate (0.418 ml, 5.23 mmol) in DMF (4.75 ml, 4. 5-Bromo-2-chloro-3-fluoropyridine (1.0 g, 4.75 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. Methanol (5.0 ml, 124 mmol) and water (5.0 ml, 278 mmol) were added, followed by cooling to 0 ° C, followed by fractional addition of monoperoxysulfate compound potassium persulfate (7.0 g, 11.4 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and the precipitate was washed with EtOAc. The filtrate was washed with water (twice) and brine, dried over anhydrous sodium sulfate and evaporated The residue was dried under vacuum to give 1.35 g of crude product 3-((5-bromo-2-chloropyridin-3-yl)sulfonyl)propan-1-ol. Mass Spectrum (ESI) m/z = 316.0 (M+H).

步驟B：在冰-水浴下，向3-((5-溴-2-氯吡啶-3-基)磺醯基)丙-1-醇(1.35 g，4.29 mmol)於二甲基甲醯胺omnisolv(42.9 ml，4.29 mmol)中之溶液中分數份添加氫化鈉(60%分散液，於礦物油中，0.180 g，4.51 mmol)。在100℃下攪拌所得混合物2小時。接著冷卻混合物至室溫。添加50 mL飽和NH4Cl水溶液，且用乙酸乙酯(50 mL×4)萃取所得混合物。用水及鹽水洗滌經彙集之萃取物，經無水硫酸鈉乾燥且濃縮。藉由CombiFalsh，在40 g矽膠管柱上，使用含0-10%甲醇之己烷梯度純化殘餘物，得到335 mg 8-溴-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶1,1-二氧化物。1H NMR(CDCl3)δ 8.53(d,J=4.0 Hz,1H),8.42(d,J=4.0 Hz,1H),4.45(dd,J=8.0,8.0 Hz,2H),3.43(dd,J=8.0,8.0 Hz,2H),2.50(m,2H)。 Step B : 3-((5-Bromo-2-chloropyridin-3-yl)sulfonyl)propan-1-ol (1.35 g, 4.29 mmol) in dimethylformamide under ice-water bath Sodium hydride (60% dispersion in mineral oil, 0.180 g, 4.51 mmol) was added in portions of omnisolv (42.9 ml, 4.29 mmol). The resulting mixture was stirred at 100 ° C for 2 hours. The mixture was then cooled to room temperature. 50 mL of a saturated aqueous NH 4 Cl solution was added, and the mixture was extracted with ethyl acetate (50 mL×4). The combined extracts were washed with water and brine, dried over anhydrous sodium The residue was purified by CombiFalsh on a 40 g silica gel column using a gradient of 0-10% methanol to afford 335 mg of 8-bromo-3,4-dihydro-2H-[1,4] sulphur Indeno[2,3-b]pyridine 1,1-dioxide. 1 H NMR (CDCl 3 ) δ 8.53 (d, J = 4.0 Hz, 1H), 8.42 (d, J = 4.0 Hz, 1H), 4.45 (dd, J = 8.0, 8.0 Hz, 2H), 3.43 (dd, J = 8.0, 8.0 Hz, 2H), 2.50 (m, 2H).

製備preparation

8-溴-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯1,1-二氧化物 8-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazinium 1,1-dioxide

步驟A：在室溫下，向n-甲基乙醇胺(0.586 ml，7.31 mmol)及三 乙胺(1.019 ml，7.31 mmol)於dcm(27.4 ml，5.48 mmol)中之混合物中添加5-溴-2-氟苯-1-磺醯氯(1.0 g，3.66 mmol)於10 mL DCM中之溶液。在室溫下攪拌所得混合物24小時。濃縮混合物且將殘餘物溶解於150 mL乙酸乙酯中。用1 N HCl水溶液、水、飽和碳酸氫鈉水溶液及鹽水洗滌溶液，經無水硫酸鈉乾燥且濃縮。在真空下乾燥殘餘物，得到1.14 g粗產物5-溴-2-氟-N-(2-羥基乙基)-N-甲基苯磺醯胺。質譜(ESI)m/z=311.8(M+H)。NMR(CDCl3)δ 7.99(m,1H),7.66(m,1H),7.11(dd,J=8.0,8.0 Hz,1H),3.78(dd,J=8.0,4.0 Hz,2H),3.32(dd,J=8.0,4.0 Hz,2H),2.95(s,3H)。 Step A : To a mixture of n-methylethanolamine (0.586 ml, 7.31 mmol) and triethylamine (1.019 ml, 7.31 mmol) in dcm (27.4 ml, 5.48 mmol) A solution of 2-fluorobenzene-1-sulfonium chloride (1.0 g, 3.66 mmol) in 10 mL DCM. The resulting mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was taken in 150 mL ethyl acetate. The solution was washed with aq. EtOAc EtOAc. The residue was dried under vacuum to give 1.14 g of crude product 5-bromo-2-fluoro-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide. Mass Spectrum (ESI) m/z = 311.8 (M+H). NMR (CDCl 3 ) δ 7.99 (m, 1H), 7.66 (m, 1H), 7.11 (dd, J = 8.0, 8.0 Hz, 1H), 3.78 (dd, J = 8.0, 4.0 Hz, 2H), 3.32 ( Dd, J = 8.0, 4.0 Hz, 2H), 2.95 (s, 3H).

步驟B：在0℃下，向5-溴-2-氟-N-(2-羥基乙基)-N-甲基苯磺醯胺(1.14 g，3.65 mmol)於DMF(36.5 ml，3.65 mmol)中之溶液中分數份添加氫化鈉(60%，於礦物油中，0.161 g，4.02 mmol)，且在110℃下攪拌所得混合物24小時。接著冷卻混合物至室溫，且添加50 mL飽和NH4Cl水溶液。用乙酸乙酯(30 mL×4)萃取混合物。用水、飽和碳酸氫鈉水溶液及鹽水洗滌經彙集之萃取物，經無水硫酸鈉乾燥且濃縮。藉由CombiFlash，在40 g矽膠管柱上，使用含0-100% EtOAc之己烷梯度純化殘餘物，得到0.43 g 8-溴-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯1,1-二氧化物。1H NMR(CDCl3)δ 7.92(d,J=4.0 Hz,1H),7.57(dd,J=8.0,4.0 HZ,1H),7.06(d,J=8.0 Hz,1H),4.17(m,2H),3.73(m,2H),2.79(s,3H)。 Step B : To a solution of 5-bromo-2-fluoro-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide (1.14 g, 3.65 mmol) in DMF (36.5 ml, 3.65 mmol) Sodium hydride (60% in mineral oil, 0.161 g, 4.02 mmol) was added in portions of the solution, and the mixture was stirred at 110 ° C for 24 hours. The mixture was then cooled to room temperature and add 50 mL of saturated aqueous NH 4 Cl. The mixture was extracted with ethyl acetate (30 mL×4). The combined extracts were washed with water, aq. The residue was purified by a CombiFlash eluting EtOAc EtOAc EtOAc EtOAc EtOAc [b][1,4,5] oxathiazide 1,1-dioxide. 1 H NMR (CDCl 3 ) δ 7.92 (d, J = 4.0 Hz, 1H), 7.57 (dd, J = 8.0, 4.0 HZ, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.17 (m, 2H), 3.73 (m, 2H), 2.79 (s, 3H).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

製備preparation

(7-溴-2,3-二氫-[1,4]二氧雜環己烯并[2,3-b]吡啶-3-基)甲醇 (7-Bromo-2,3-dihydro-[1,4]dioxine[2,3-b]pyridin-3-yl)methanol

步驟A：將5-溴-2-氯-3-氟吡啶(0.515 g，2.45 mmol)、丙酮縮甘油(0.356，2.69 mmol)及碳酸銫(0.877 g，2.69 mmol)於5.0 mL DMF中之混合物在80℃下攪拌20小時。冷卻混合物至室溫，且添加50 mL飽和NH4Cl水溶液。用乙酸乙酯(50 mL×4)萃取所得混合物。用水及鹽水洗滌經合併之萃取物，乾燥(Na2SO4)且濃縮。乾燥殘餘物，得到0.804 g粗產物5-溴-2-氯-3-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)吡啶。質譜(ESI)m/z=323.8(M+H)。 Step A : a mixture of 5-bromo-2-chloro-3-fluoropyridine (0.515 g, 2.45 mmol), acetone glycerol (0.356, 2.69 mmol) and cesium carbonate (0.877 g, 2.69 mmol) in 5.0 mL DMF Stir at 80 ° C for 20 hours. The mixture was cooled to room temperature and add 50 mL of saturated aqueous NH 4 Cl. The resulting mixture was extracted with ethyl acetate (50 mL × 4). The combined washed with water and brine, the extracts were dried (Na 2 SO 4) and concentrated. The residue was dried to give 0.84 g (yield: 5-bromo-2-chloro-3-((2,2-dimethyl-1,3-dioxa)- yl) methoxy) pyridine. Mass Spectrum (ESI) m/z = 323.8 (M+H).

步驟B：在室溫下，向5-溴-2-氯-3-((2,2-二甲基-1,3-二氧雜環戊烷-4-基)甲氧基)吡啶(0.804 g，2.492 mmol)於四氫呋喃(12.46 ml，2.492 mmol)中之溶液中添加6 mL 2 N HCl水溶液。在室溫下攪拌所得混合物18小時。濃縮混合物且乾燥，得到0.704 g粗產物3-((5-溴-2-氯吡啶-3-基)氧基)丙烷-1,2-二醇。質譜(ESI)m/z=283.9(M+H)。 Step B : to 5-bromo-2-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridine at room temperature ( 0.804 g, 2.492 mmol) of a solution of tetrahydrofuran (12.46 ml, 2.492 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated and dried to give &lt;RTI ID=0.0&gt;&gt; Mass Spectrum (ESI) m/z = 283.9 (M+H).

步驟C：將3-((5-溴-2-氯吡啶-3-基)氧基)丙烷-1,2-二醇(0.198 g，0.701 mmol)及碳酸銫(0.228 g，0.701 mmol)於7.0 mL DMF中之混合物在95℃下攪拌24小時。接著冷卻混合物至室溫，且藉由CombiFlash，在24 g矽膠管柱上，使用0-100% EtOAc/己烷梯度直接純化，得到33.2 mg(7-溴-2,3-二氫-[1,4]二氧雜環己烯并[2,3-b]吡啶-3-基)甲醇。質譜(ESI)m/z=247.9(M+H)。NMR(CDCl3)δ 7.87(d,J=4.0 Hz,1H),7.36(d,J=4.0 Hz,1H),3.87-4.51(m,5H),2.55(br s,1H)。 Step C : 3-((5-Bromo-2-chloropyridin-3-yl)oxy)propane-1,2-diol (0.198 g, 0.701 mmol) and cesium carbonate (0.228 g, 0.701 mmol) The mixture in 7.0 mL of DMF was stirred at 95 ° C for 24 hours. The mixture was then cooled to room temperature and directly purified on a 24 g silica gel column using a CombiFlash using a 0-100% EtOAc/hexane gradient to give 33.2 mg (7-bromo-2,3-dihydro-[1 4]dioxine[2,3-b]pyridin-3-yl)methanol. Mass Spectrum (ESI) m/z = 247.9 (M+H). NMR (CDCl 3 ) δ 7.87 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 4.0 Hz, 1H), 3.87-4.51 (m, 5H), 2.55 (br s, 1H).

遵循上述程序，製備以下化合物： Following the above procedure, the following compounds were prepared:

遵循實例197中之程序，製備以下化合物： Following the procedure in Example 197, the following compounds were prepared:

遵循實例198中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 198, the following compounds were prepared using the appropriate reagents:

遵循實例158中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 158, the following compounds were prepared using the appropriate reagents:

遵循實例174中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 174, the following compounds were prepared using the appropriate reagents:

實例1500Example 1500

4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-甲酸甲酯 Methyl 4-(2,6-difluorophenoxy)-6-(3-methylureido)-[3,4'-bipyridyl]-2'-carboxylate

向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.1 g，0.279 mmol)於DMF(0.022 ml，0.279 mmol)中之經攪拌溶液中依序添加4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶甲酸甲酯(0.147 g，0.558 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(ii)與二氯甲烷之複合物(0.023 g，0.028 mmol)及碳酸鉀(0.116 g，0.838 mmol)。在100℃下攪拌反應物且由LCMS監測。反應完成後，添加水以淬滅反應物，且依序用乙酸乙酯、二氯甲烷萃取混合物。在真空中濃縮經合併之有機物。在矽膠上(用含0-100%乙酸乙酯之二氯甲烷溶離)純化粗產物，得到4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-甲酸甲酯(0.014 g，0.034 mmol，12.10%)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.39(1H,s),8.81(1H,d,J=5.1 Hz),8.42(1H,s),8.33(1H,d,J=1.0 Hz),7.92(1H,dd,J=4.9,1.7 Hz),7.30-7.54(4H,m),7.15(1H,s),3.86-3.96(3H,m),2.66(3H,d,J=4.6 Hz)。質譜(ESI)m/z=415.0(M+H)。 To 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.1 g, 0.279 mmol) in DMF (0.022 ml, 0.279 mmol) Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in sequence to the stirred solution Methyl 2-methyl)picolinate (0.147 g, 0.558 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (ii) complex with dichloromethane (0.023 g , 0.028 mmol) and potassium carbonate (0.116 g, 0.838 mmol). The reaction was stirred at 100 ° C and monitored by LCMS. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate and dichloromethane. The combined organics were concentrated in vacuo. The crude product was purified on silica gel eluting with 0-100% ethyl acetate in dichloromethane to afford 4-(2,6-difluorophenoxy)-6-(3-methylureido)-[ Methyl 3,4'-bipyridyl]-2'-carboxylate (0.014 g, 0.034 mmol, 12.10%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.39 (1H, s), 8.81 (1H, d, J = 5.1 Hz), 8.42 (1H, s), 8.33 (1H, d, J = 1.0 Hz ), 7.92 (1H, dd, J = 4.9, 1.7 Hz), 7.30-7.54 (4H, m), 7.15 (1H, s), 3.86-3.96 (3H, m), 2.66 (3H, d, J = 4.6) Hz). Mass Spectrum (ESI) m/z = 415.0 (M+H).

遵循實例1500中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 1500 , the following compounds were prepared using the appropriate reagents:

實例1503Example 1503

1-(4-(2,6-二氟苯氧基)-5-(2-乙基苯并[d]噁唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(2-ethylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3-methylurea

步驟A：將大部分1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.211 g，0.59 mmol)、雙(頻哪醇根基)二硼(0.224 g，0.88 mmol)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(0.147 g，0.180 mmol)及乙酸鉀(0.176 g，1.79 mmol)於無水1,4-二噁烷(5 mL)中之經攪拌混合物用氬氣淨化三次且置於真空下三次。在100℃下加熱混合物16小時。此後，冷卻反應物至室溫，接著在減壓下濃縮。黑色殘餘物未經進一步純化即以1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(0.238 g，0.587 mmol，100%產率)使用。 Step A : The majority of 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.211 g, 0.59 mmol), double (frequency) Alkyl)diboron (0.224 g, 0.88 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.147 g, 0.180 mmol) The stirred mixture of potassium acetate (0.176 g, 1.79 mmol) in anhydrous 1,4-dioxane (5 mL) was purified three times with argon and three times under vacuum. The mixture was heated at 100 ° C for 16 hours. Thereafter, the reaction was cooled to room temperature and then concentrated under reduced pressure. The black residue was 1-(4-(2,6-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboride without further purification. 2-yl)pyridin-2-yl)-3-methylurea (0.238 g, 0.587 mmol, 100% yield) was used.

步驟B：將1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(0.108 g，0.265 mmol)、5-溴-2-乙基苯并 [d]噁唑(0.04 g，0.177 mmol)、三環己基膦(9.92 mg，0.035 mmol)及參(二亞苄基丙酮)二鈀(0)(0.016 g，0.018 mmol)添加至小瓶中，接著脫氣且用氮氣回填。由注射器向小瓶中添加1,4-二噁烷(1.769 ml)及1.3 M磷酸三鉀水溶液(0.113 g，0.531 mmol)。加熱所得反應物至100℃且由LCMS監測。一旦反應完成，即冷卻反應物至室溫，接著在減壓下濃縮。過濾殘餘物，接著加載於矽膠上(含0-60%預混合90：10二氯甲烷：甲醇之二氯甲烷)，得到固體1-(4-(2,6-二氟苯氧基)-5-(2-乙基苯并[d]噁唑-5-基)吡啶-2-基)-3-甲基脲(0.017 g，0.040 mmol，23%產率)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.14(1H,s),8.18(1H,s),7.80(1H,d,J=1.5 Hz),7.70(1H,d,J=8.3 Hz),7.45-7.53(2H,m),7.30-7.44(3H,m),6.96(1H,s),2.91(2H,q,J=7.6 Hz),2.59(3H,d,J=4.6 Hz),1.29(3H,t,J=7.6 Hz)。質譜(ESI)m/z=425.0(M+H)。 Step B : 1-(4-(2,6-Difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridin-2-yl)-3-methylurea (0.108 g, 0.265 mmol), 5-bromo-2-ethylbenzo[d]oxazole (0.04 g, 0.177 mmol), tricyclic Hexylphosphine (9.92 mg, 0.035 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (0.016 g, 0.018 mmol) were added to a vial, then degassed and backfilled with nitrogen. To the vial was added 1,4-dioxane (1.769 ml) and a 1.3 M aqueous solution of tripotassium phosphate (0.113 g, 0.531 mmol) from a syringe. The resulting reaction was heated to 100 ° C and was monitored by LCMS. Once the reaction was complete, the reaction was cooled to room temperature then concentrated under reduced pressure. The residue was filtered, then loaded onto silica gel (0-60% pre-mixed 90:10 dichloromethane: methanol in dichloromethane) to give the solid 1-(4-(2,6-difluorophenoxy)- 5-(2-Ethylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3-methylurea (0.017 g, 0.040 mmol, 23% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.14 (1H, s), 8.18 (1H, s), 7.80 (1H, d, J = 1.5 Hz), 7.70 (1H, d, J = 8.3 Hz ), 7.45-7.53 (2H, m), 7.30-7.44 (3H, m), 6.96 (1H, s), 2.91 (2H, q, J = 7.6 Hz), 2.59 (3H, d, J = 4.6 Hz) , 1.29 (3H, t, J = 7.6 Hz). Mass Spectrum (ESI) m/z = 425.0 (M+H).

遵循實例1503中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 1503 , the following compounds were prepared using the appropriate reagents:

製備preparation

三氟甲烷磺酸咪唑并[1,2-a]吡啶-8-基酯 Imidazo[13,2-a]pyridin-8-yl trifluoromethanesulfonate

向咪唑并[1,2-a]吡啶-8-醇(0.1 g，0.746 mmol)於二氯甲烷(3.73 ml，0.746 mmol)中之經攪拌溶液中添加三乙胺(0.114 ml，0.820 mmol)及4-二甲基胺基吡啶(9.11 mg，0.075 mmol)，繼而添加n-苯基雙-三氟甲烷磺醯亞胺(0.293 g，0.820 mmol)。繼續攪拌16小時，此後在減壓下濃縮反應物，得到三氟甲烷磺酸咪唑并[1,2-a]吡啶-8-基酯(0.198 g，0.744 mmol，100%產率)，其未經純化即使用。質譜(ESI)m/z=266.9(M+H) To a stirred solution of imidazo[1,2-a]pyridin-8-ol (0.1 g, 0.746 mmol) in dichloromethane (3.73 ml, 0.746 mmol) was added triethylamine (0.114 ml, 0.820 mmol) And 4-dimethylaminopyridine (9.11 mg, 0.075 mmol) followed by n-phenylbis-trifluoromethanesulfonimide (0.293 g, 0.820 mmol). Stirring was continued for 16 hours, after which time the reaction was concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; It is used after purification. Mass Spectrum (ESI) m/z = 266.9 (M+H)

遵循上述程序，使用適當試劑製備以下化合物： Following the above procedure, the following compounds were prepared using the appropriate reagents:

實例1518Example 1518

1-(4-(2,6-二氟苯氧基)-5-(咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(imidazo[1,2-a]pyridin-8-yl)pyridin-2-yl)-3-methylurea

將1-(4-(2,6-二氟苯氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)-3-甲基脲(0.1 g，0.247 mmol)、三氟甲烷磺酸咪唑并[1,2-a]吡啶-8-基酯(0.044 g，0.165 mmol)、三環己基膦(9.23 mg，0.033 mmol)及參(二亞苄基丙酮)二鈀(0)(0.015 g，0.016 mmol)添加至小瓶 中，接著脫氣且用氮氣回填。由注射器向小瓶中添加1,4-二噁烷(1.645 ml)及1.3 M磷酸三鉀水溶液(0.105 g，0.494 mmol)。加熱所得反應物至100℃，且由LCMS監測反應。反應完成後，冷卻混合物至室溫，接著在減壓下濃縮。過濾殘餘物，接著加載於矽膠上(含0-60%預混合90：10二氯甲烷：甲醇之二氯甲烷)，得到固體1-(4-(2,6-二氟苯氧基)-5-(咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)-3-甲基脲(0.0149 g，0.038 mmol，22.91%產率)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.27(1H,s),8.64(1H,s),8.59(1H,dd,J=6.7,1.1 Hz),8.05(1H,d,J=1.0 Hz),7.53-7.63(3H,m),7.34-7.52(5H,m),6.94-7.10(2H,m),2.67(4H,d,J=4.6 Hz),1.10(1H,t,J=7.1 Hz)。質譜(ESI)m/z=395.9(M+H)。 1-(4-(2,6-Difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridin-2-yl)-3-methylurea (0.1 g, 0.247 mmol), imidazo[1,2-a]pyridin-8-yl trifluoromethanesulfonate (0.044 g, 0.165 Methyl), tricyclohexylphosphine (9.23 mg, 0.033 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (0.015 g, 0.016 mmol) were added to a vial, then degassed and backfilled with nitrogen. To the vial was added 1,4-dioxane (1.645 ml) and a 1.3 M aqueous solution of tripotassium phosphate (0.105 g, 0.494 mmol) from a syringe. The resulting reaction was heated to 100 ° C and the reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was filtered, then loaded onto silica gel (0-60% pre-mixed 90:10 dichloromethane: methanol in dichloromethane) to give the solid 1-(4-(2,6-difluorophenoxy)- 5-(Imidazo[1,2-a]pyridin-8-yl)pyridin-2-yl)-3-methylurea (0.0149 g, 0.038 mmol, 22.91% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.27 (1H, s), 8.64 (1H, s), 8.59 (1H, dd, J = 6.7, 1.1 Hz), 8.05 (1H, d, J = 1.0 Hz), 7.53 - 7.63 (3H, m), 7.34 - 7.52 (5H, m), 6.94 - 7.10 (2H, m), 2.67 (4H, d, J = 4.6 Hz), 1.10 (1H, t, J =7.1 Hz). Mass Spectrum (ESI) m/z = 395.9 (M+H).

遵循實例1518中之程序，使用適當試劑製備以下化合物： Following the procedure in Example 1518 , the following compounds were prepared using the appropriate reagents:

實例1523Example 1523

1-(4-(2,6-二氟苯氧基)-5-(1H-吡唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea

向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.1 g，0.28 mmol)、1H-吡唑-5-三氟硼酸鉀(0.053 g，0.31 mmol)、Pd(OAc)2(6.27 mg，0.028 mmol)及Ru Phos預催化劑(0.041 g，0.056 mmol)於乙醇(2.79 ml)中之經攪拌溶液中添加碳酸鈉(0.059 g，0.56 mmol)。加熱反應混合物至85℃且繼續攪拌，由LCMS監測反應。反應完成後，在真空中濃縮反應物。藉由管柱層析，在矽膠上(含0%至50%二氯甲烷/10%甲醇之二氯甲烷)純化粗產物，得到所要產物1-(4-(2,6-二氟苯氧基)-5-(1H-吡唑-5-基)吡啶-2-基)-3-甲基脲(0.0028 g，8.11 μmol，2.90%產率)。1H NMR(500 MHz，二氯甲烷-d 2)δ ppm 8.56(1H,s),7.72(1H,d,J=2.2 Hz),7.37-7.44(1H,m),7.19(3H,t,J=8.3 Hz),6.90(1H,br.s.),2.82-2.86(3H,m)。質譜(ESI)m/z=346.0(M+H)。 To 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.1 g, 0.28 mmol), 1H-pyrazole-5-trifluoro Potassium borate (0.053 g, 0.31 mmol), Pd(OAc) 2 (6.27 mg, 0.028 mmol) and Ru Phos precatalyst (0.041 g, 0.056 mmol) in ethanol (2.79 ml). 0.059 g, 0.56 mmol). The reaction mixture was heated to 85 ° C and stirring was continued and the reaction was monitored by LCMS. After the reaction was completed, the reaction was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 0% to 50% dichloromethane / 10% methanol to give the desired product 1-(4-(2,6-difluorophenoxy) 5-(1H-pyrazol-5-yl)pyridin-2-yl)-3-methylurea (0.0028 g, 8.11 μmol, 2.90% yield). 1 H NMR (500 MHz, methylene chloride - d 2 ) δ δ 8.56 (1H, s), 7.72 (1H, d, J = 2.2 Hz), 7.37-7.44 (1H, m), 7.19 (3H, t, J = 8.3 Hz), 6.90 (1H, br.s.), 2.82-2.86 (3H, m). Mass Spectrum (ESI) m/z = 346.0 (M+H).

實例1524Example 1524

4-(2,6-二氟苯氧基)-N,N-二甲基-6-(3-甲基脲基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-甲醯胺 4-(2,6-Difluorophenoxy)-N,N-dimethyl-6-(3-methylureido)-5',6'-dihydro-[3,4'-bipyridine ]-1'(2'H)-formamide

步驟A：向1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲(0.1 g，0.28 mmol)於DMF(2.79 ml)中之經攪拌溶液中依序添加4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.173 g，0.56 mmol)、肆(三苯基膦)鈀(0)(0.032 g，0.028 mmol)及碳酸鉀(0.116 g，0.84 mmol)。在100℃下繼續攪拌直至由LCMS指示完成。添加水以淬滅反應物，且依序用乙酸乙酯、二氯甲烷萃取混合物。在真空中濃縮經合併之有機物。在矽膠上用含0-100%乙酸乙酯之己烷溶離來純化粗產物，得到所要化合物；4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-甲酸第三丁酯(0.076 g，0.165 mmol，59.1%產率)。質譜(ESI)m/z=461.0(M+H)。 Step A : To 1-(5-Bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea (0.1 g, 0.28 mmol) in DMF (2. Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in sequence to the stirred solution -2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.173 g, 0.56 mmol), hydrazine (triphenylphosphine) palladium (0) (0.032 g, 0.028 mmol) And potassium carbonate (0.116 g, 0.84 mmol). Stirring was continued at 100 °C until indicated by LCMS. Water was added to quench the reaction, and the mixture was extracted sequentially with ethyl acetate and dichloromethane. The combined organics were concentrated in vacuo. The crude product was purified by dissolving with 0-100% ethyl acetate in hexane to give the desired compound; 4-(2,6-difluorophenoxy)-6-(3-methylureido)- 5',6'-Dihydro-[3,4'-bipyridine]-1 '(2'H)-carboxylic acid tert-butyl ester (0.076 g, 0.165 mmol, 59.1% yield). Mass Spectrum (ESI) m/z = 461.0 (M+H).

步驟B：向4-(2,6-二氟苯氧基)-6-(3-甲基脲基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-甲酸第三丁酯(0.076 g，0.17 mmol)於二氯甲烷(1.65 ml)中之經攪拌溶液中添加tfa(0.127 ml，1.650 mmol)。在23℃下繼續攪拌1小時。在真空中濃縮反應物。粗產物未經進一步純化即使用。1-(4-(2,6-二氟苯氧基)-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)-3-甲基脲(0.059 g，0.164 mmol，99%產率)。 Step B : To 4-(2,6-difluorophenoxy)-6-(3-methylureido)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-T-butyl carboxylic acid (0.076 g, 0.17 mmol) EtOAc (EtOAc m. Stirring was continued for 1 hour at 23 °C. The reaction was concentrated in vacuo. The crude product was used without further purification. 1-(4-(2,6-Difluorophenoxy)-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl)-3-A Base urea (0.059 g, 0.164 mmol, 99% yield).

步驟C：將1-(4-(2,6-二氟苯氧基)-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)-3-甲基脲(0.056 g，0.16 mmol)、二異丙基乙胺(0.1 ml，0.57 mmol)及(二甲基胺基)羰基氯(0.015 ml，0.155 mmol)於二氯甲烷(1.55 ml)中之溶液在室溫下攪拌隔夜。在真空中濃縮反應混合物。藉由急驟層析，在矽膠管柱上，用含0-5% MeOH之二氯甲烷純化粗產物，得 到4-(2,6-二氟苯氧基)-N,N-二甲基-6-(3-甲基脲基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-甲醯胺(0.001 g，2.318 μmol，1.492%產率)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.12(1H,s),8.05(1H,s),7.34-7.57(4H,m),6.89(1H,s),5.98(1H,dt,J=3.1,1.7 Hz),3.85(2H,d,J=2.9 Hz),3.24-3.45(2H,m),2.68-2.85(6H,m),2.59-2.68(3H,m),2.52-2.59(2H,m)。質譜(ESI)m/z=432.0(M+H)。 Step C : 1-(4-(2,6-Difluorophenoxy)-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl) 3-methylurea (0.056 g, 0.16 mmol), diisopropylethylamine (0.1 ml, 0.57 mmol) and (dimethylamino)carbonyl chloride (0.015 ml, 0.155 mmol) in dichloromethane (1.55 The solution in ml) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography on EtOAc EtOAc EtOAc (EtOAc) 6-(3-methylureido)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carbenamide (0.001 g, 2.318 μmol, 1.492%) Yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.12 (1H, s), 8.05 (1H, s), 7.34-7.57 (4H, m), 6.89 (1H, s), 5.98 (1H, dt, J = 3.1, 1.7 Hz), 3.85 (2H, d, J = 2.9 Hz), 3.24-3.45 (2H, m), 2.68-2.85 (6H, m), 2.59-2.68 (3H, m), 2.52-2.59 (2H, m). Mass Spectrum (ESI) m/z = 432.0 (M+H).

實例1525Example 1525

1-(4-(2,6-二氟苯氧基)-5-(4-羥基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(4-hydroxycyclohex-1-en-1-yl)pyridin-2-yl)-3-methylurea

步驟A：向1-(4-(2,6-二氟苯氧基)-5-(1,4-二氧雜螺[4.5]癸-7-烯-8-基)吡啶-2-基)-3-甲基脲(0.036 g，0.086 mmol)於乙醇(3.97 mg)中之經攪拌溶液中添加HCl(7.86 μl，0.259 mmol)。在23℃下繼續攪拌。由LCMS監測反應。一旦反應完成，即在真空中濃縮有機物，且添加碳酸氫鈉水溶液，且用乙酸乙酯萃取所得混合物並在真空中濃縮。粗產物1-(4-(2,6-二氟苯氧基)-5-(4-側氧基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲(0.032 g，0.086 mmol，99%產率)。質譜(ESI)m/z=374.0(M+H)；將其視為足夠純的且用於下一步驟。 Step A : To 1-(4-(2,6-difluorophenoxy)-5-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)pyridin-2-yl HCl (7.86 μl, 0.259 mmol) was added to a stirred solution of 3-methylurea (0.036 g, 0.086 mmol) in ethanol (3.97 mg). Stirring was continued at 23 °C. The reaction was monitored by LCMS. Once the reaction was complete, the organics were concentrated in vacuo and aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate and concentrated in vacuo. The crude product 1-(4-(2,6-difluorophenoxy)-5-(4-oxocyclohex-1-en-1-yl)pyridin-2-yl)-3-methylurea (0.032 g, 0.086 mmol, 99% yield). Mass Spectrum (ESI) m/z = 374.0 (M+H);

步驟B：向1-(4-(2,6-二氟苯氧基)-5-(4-側氧基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲(0.032 g，0.086 mmol)於甲醇(0.86 ml)中之經攪拌溶液中添加硼氫化鈉(3.24 mg，0.086 mmol)。在23℃下繼續攪拌，直至由LCMS斷定完成。在真空中濃縮有機物。添加1 N HCl以淬滅反應物。此後，添加碳酸氫鈉水溶液，且用乙酸乙酯萃取反應物並在真空 中濃縮。在矽膠上用含0-100%乙酸乙酯之己烷溶離來純化粗產物，得到所要化合物。1-(4-(2,6-二氟苯氧基)-5-(4-羥基環己-1-烯-1-基)吡啶-2-基)-3-甲基脲(0.01 g，0.027 mmol，31%產率)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.07(1H,s),7.98(1H,s),7.54(1H,br.s.),7.31-7.50(3H,m),6.80-6.89(1H,m),5.69-5.84(1H,m),4.68(1H,d,J=3.9 Hz),3.80(1H,d,J=3.9 Hz),2.60-2.67(3H,m),2.35-2.49(3H,m),2.00-2.09(1H,m),1.79-1.89(1H,m),1.52-1.63(1H,m)。質譜(ESI)m/z=376.0(M+H)。 Step B : To 1-(4-(2,6-difluorophenoxy)-5-(4-oxocyclohex-1-en-1-yl)pyridin-2-yl)-3-yl Sodium borohydride (3.24 mg, 0.086 mmol) was added to a stirred solution of carbazide (0.032 g, 0.086 mmol). Stirring was continued at 23 ° C until completion by LCMS. The organics were concentrated in vacuo. 1 N HCl was added to quench the reaction. Thereafter, an aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate and concentrated in vacuo. The crude product was purified by dissolving on EtOAc (EtOAc EtOAc) 1-(4-(2,6-difluorophenoxy)-5-(4-hydroxycyclohex-1-en-1-yl)pyridin-2-yl)-3-methylurea (0.01 g, 0.027 mmol, 31% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.07 (1H, s), 7.98 (1H, s), 7.54 (1H, br.s.), 7.31-7.50 (3H, m), 6.80-6.89 (1H, m), 5.69-5.84 (1H, m), 4.68 (1H, d, J = 3.9 Hz), 3.80 (1H, d, J = 3.9 Hz), 2.60-2.67 (3H, m), 2.35- 2.49 (3H, m), 2.00-2.09 (1H, m), 1.79-1.89 (1H, m), 1.52-1.63 (1H, m). Mass Spectrum (ESI) m/z = 376.0 (M+H).

實例1526Example 1526

1-(4-(2,6-二氟苯氧基)-5-(4-羥基環己基)吡啶-2-基)-3-甲基脲 1-(4-(2,6-difluorophenoxy)-5-(4-hydroxycyclohexyl)pyridin-2-yl)-3-methylurea

步驟A：向1-(4-(2,6-二氟苯氧基)-5-(1,4-二氧雜螺[4.5]癸-7-烯-8-基)吡啶-2-基)-3-甲基脲(0.35 g，0.84 mmol)於乙醇(8.39 ml)中之溶液中添加鈀/碳(0.89 g，0.84 mmol)。在氫氣氛圍下攪拌所得反應混合物4週。經矽膠栓塞過濾反應混合物且在真空中濃縮，得到1-(4-(2,6-二氟苯氧基)-5-(1,4-二氧雜螺[4.5]癸-8-基)吡啶-2-基)-3-甲基脲(0.352 g，0.839 mmol，100%產率)。質譜(ESI)m/z=419.9(M+H)。 Step A : To 1-(4-(2,6-difluorophenoxy)-5-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)pyridin-2-yl Palladium on carbon (0.89 g, 0.84 mmol) was added to a solution of 3-methylurea (0.35 g, 0.84 mmol) in ethanol (8.39 ml). The resulting reaction mixture was stirred under a hydrogen atmosphere for 4 weeks. The reaction mixture was filtered through hydrazine gel and concentrated in vacuo to give 1-(4-(2,6-difluorophenoxy)-5-(1,4-dioxaspiro[4.5]indole-8-yl) Pyridin-2-yl)-3-methylurea (0.352 g, 0.839 mmol, 100% yield). Mass Spectrum (ESI) m/z = 419.9 (M+H).

步驟B：向1-(4-(2,6-二氟苯氧基)-5-(1,4-二氧雜螺[4.5]癸-8-基)吡啶-2-基)-3-甲基脲(0.352 g，0.84 mmol)於乙醇(8.39 ml)中之經攪拌溶液中添加HCl(2.52 ml)。在23℃下繼續攪拌反應混合物直至由LCMS斷定完成。此後，在真空中濃縮有機物。添加碳酸氫鈉水溶液，且用乙酸乙酯萃取所得混合物並在真空中濃縮。將粗產物視為足夠純的且 用於下一步驟。1-(4-(2,6-二氟苯氧基)-5-(4-側氧基環己基)吡啶-2-基)-3-甲基脲(0.315 g，0.84 mmol，100%產率)。質譜(ESI)m/z=376.0(M+H)。 Step B : To 1-(4-(2,6-difluorophenoxy)-5-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-2-yl)-3- To the stirred solution of methylurea (0.352 g, 0.84 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at 23 ° C until completion by LCMS. Thereafter, the organic matter was concentrated in a vacuum. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate and concentrated in vacuo. The crude product was considered to be sufficiently pure and used in the next step. 1-(4-(2,6-Difluorophenoxy)-5-(4-oxocyclohexyl)pyridin-2-yl)-3-methylurea (0.315 g, 0.84 mmol, 100% yield) rate). Mass Spectrum (ESI) m/z = 376.0 (M+H).

步驟C：向1-(4-(2,6-二氟苯氧基)-5-(4-側氧基環己基)吡啶-2-基)-3-甲基脲(0.040 g，0.107 mmol)於甲醇(1.066 ml)中之經攪拌溶液中添加硼氫化鈉(4.03 mg，0.107 mmol)。在23℃下繼續攪拌反應混合物直至由LCMS斷定完成。此後，在真空中濃縮有機物。添加1 N HCl以淬滅反應物。添加碳酸氫鈉水溶液，且用乙酸乙酯萃取反應物並在真空中濃縮。在矽膠上用含0-50%乙酸乙酯/乙醇(3/1)之庚烷溶離來純化粗產物，得到所要化合物。呈10：1非對映異構體混合物形式之1-(4-(2,6-二氟苯氧基)-5-(4-羥基環己基)吡啶-2-基)-3-甲基脲(0.015 g，0.040 mmol，37.3%產率)。1H NMR(500 MHz，二氯甲烷-d 2)δ ppm 9.04(1H,br.s.),8.19(1H,br.s.),7.96(1H,s),7.26(1H,tt,J=8.5,5.9 Hz),7.02-7.14(2H,m),5.91(1H,s),3.66(1H,t,J=10.5 Hz),2.93(1H,tt,J=12.2,3.1 Hz),2.75(3H,d,J=4.6 Hz),1.98-2.13(4H,m),1.64(2H,qd,J=12.8,2.7 Hz),1.47-1.58(2H,m),1.35-1.47(2H,m)。質譜(ESI)m/z=377.9(M+H)。 Step C : To 1-(4-(2,6-difluorophenoxy)-5-(4-oxocyclohexyl)pyridin-2-yl)-3-methylurea (0.040 g, 0.107 mmol Sodium borohydride (4.03 mg, 0.107 mmol) was added to a stirred solution in methanol (1.066 ml). The reaction mixture was stirred at 23 ° C until completion by LCMS. Thereafter, the organic matter was concentrated in a vacuum. 1 N HCl was added to quench the reaction. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate and concentrated in vacuo. The crude product was purified by dissolving on silica gel eluting with 0-50% ethyl acetate/ethanol (3/1) to give the desired compound. 1-(4-(2,6-difluorophenoxy)-5-(4-hydroxycyclohexyl)pyridin-2-yl)-3-methyl as a mixture of 10:1 diastereomers Urea (0.015 g, 0.040 mmol, 37.3% yield). 1 H NMR (500 MHz, dichloromethane - d 2 ) δ ppm 9.04 (1H, br. s.), 8.19 (1H, br. s.), 7.96 (1H, s), 7.26 (1H, tt, J = 8.5, 5.9 Hz), 7.02-7.14 (2H, m), 5.91 (1H, s), 3.66 (1H, t, J = 10.5 Hz), 2.93 (1H, tt, J = 12.2, 3.1 Hz), 2.75 (3H, d, J = 4.6 Hz), 1.98-2.13 (4H, m), 1.64 (2H, qd, J = 12.8, 2.7 Hz), 1.47-1.58 (2H, m), 1.35-1.47 (2H, m ). Mass Spectrum (ESI) m/z = 377.9 (M+H).

實例1527Example 1527

1-甲基-3-(4-((5-(丙-1-烯-2-基)吡啶-3-基)氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲 1-methyl-3-(4-((5-(prop-1-en-2-yl)pyridin-3-yl)oxy)-2'-(trifluoromethyl)-[3,4' -bipyridyl]-6-yl)urea

將1-(4-((5-氯吡啶-3-基)氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)-3-甲基脲(0.05 g，0.12 mmol)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧硼(0.040 g，0.24 mmol)、三環己基膦(6.62 mg，0.024 mmol)及參(二亞苄基丙酮)二鈀(0)(10.80 mg，0.012 mmol)添加至小瓶中，接著脫氣且用氮氣回填。由注射器向小瓶中添加1,4-二噁烷(1.18 ml)及1.3 M磷酸三鉀水溶液(0.075 g，0.35 mmol)。加熱所得反應物至100℃且由LCMS監測。反應完成後，冷卻反應物至室溫，添加水，且用乙酸乙酯萃取混合物。在減壓下濃縮有機物。過濾殘餘物，接著加載於矽膠上(含0-50%乙酸乙酯/乙醇(3/1)之庚烷)，得到固體1-甲基-3-(4-((5-(丙-1-烯-2-基)吡啶-3-基)氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲(0.0324 g，0.075 mmol，64.0%產率)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.36(1H,s),8.83(1H,d,J=5.1 Hz),8.73(1H,d,J=2.0 Hz),8.51(1H,d,J=2.7 Hz),8.44(1H,s),8.20(1H,s),8.06(1H,dd,J=5.0,1.1 Hz),7.94(1H,t,J=2.2 Hz),7.59(1H,br.s.),7.00(1H,s),5.67(1H,s),5.29(1H,s),2.67(3H,d,J=4.6 Hz),2.16(3H,s)。質譜(ESI)m/z=430.0(M+H)。 1-(4-((5-chloropyridin-3-yl)oxy)-2'-(trifluoromethyl)-[3,4'-bipyridyl]-6-yl)-3-methyl Urea (0.05 g, 0.12 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaboron (0.040 g, 0.24 mmol), tricyclohexylphosphine (6.62 mg, 0.024 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (10.80 mg, 0.012 mmol) were added to the vial, then degassed and used Nitrogen backfill. To the vial was added 1,4-dioxane (1.18 ml) and 1.3 M aqueous solution of tri-potassium phosphate (0.075 g, 0.35 mmol) from a syringe. The resulting reaction was heated to 100 ° C and was monitored by LCMS. After the reaction was completed, the reaction was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organics were concentrated under reduced pressure. The residue was filtered, then loaded onto silica gel (0-50% ethyl acetate / ethanol (3 / 1) of heptane) to give solid 1-methyl-3-(4-((5-(propyl-1) -en-2-yl)pyridin-3-yl)oxy)-2'-(trifluoromethyl)-[3,4'-bipyridyl]-6-yl)urea (0.0324 g, 0.075 mmol, 64.0 %Yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.36 (1H, s), 8.83 (1H, d, J = 5.1 Hz), 8.73 (1H, d, J = 2.0 Hz), 8.51 (1H, d , J = 2.7 Hz), 8.44 (1H, s), 8.20 (1H, s), 8.06 (1H, dd, J = 5.0, 1.1 Hz), 7.94 (1H, t, J = 2.2 Hz), 7.59 (1H) , br.s.), 7.00 (1H, s), 5.67 (1H, s), 5.29 (1H, s), 2.67 (3H, d, J = 4.6 Hz), 2.16 (3H, s). Mass Spectrum (ESI) m/z =437.

遵循上述程序，使用適當試劑製備以下化合物： Following the above procedure, the following compounds were prepared using the appropriate reagents:

實例1530Example 1530

1-甲基-3-(4-((5-丙基吡啶-3-基)氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲 1-methyl-3-(4-((5-propylpyridin-3-yl)oxy)-2'-(trifluoromethyl)-[3,4'-bipyridyl]-6-yl) Urea

向(E)-1-甲基-3-(4-((5-(丙-1-烯-1-基)吡啶-3-基)氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲(0.023 g，0.053 mmol)於甲醇(0.529 ml)及乙酸乙酯(0.529 ml)中之經攪拌溶液中添加10%鈀/活性碳(0.563 mg，5.29 μmol)。將所得反應物(0.107 mg，0.053 mmol)置於氫氣氛圍下，且在23℃下攪拌直至由LCMS斷定完成。此後，過濾反應物，且在減壓下濃縮有機物。過濾殘餘物，接著加載於矽膠上(含0-50%乙酸乙酯/乙醇(3/1)之庚烷)，得到白色固體1-甲基-3-(4-((5-丙基吡啶-3-基)氧基)-2'-(三氟甲基)-[3,4'-聯吡啶]-6-基)脲(0.0114 g，0.026 mmol，50.0%產率)。1H NMR(500 MHz,DMSO-d 6)δ ppm 9.38(1H,s),8.82(1H,d,J=4.9 Hz),8.40(2H,s),8.43(1H,s),8.16(1H,s),8.02(1H,d,J=4.6 Hz),7.53-7.66(2H,m),7.00(1H,s),2.56-2.72(5H,m),1.57-1.67 (2H,m),0.90(3H,t,J=7.2 Hz)。質譜(ESI)m/z=431.9(M+H)。 To (E)-1-methyl-3-(4-((5-(prop-1-en-1-yl)pyridin-3-yl)oxy)-2'-(trifluoromethyl)- [3,4'-Bipyridyl]-6-yl)urea (0.023 g, 0.053 mmol) was added 10% palladium/activated carbon in a stirred solution of methanol (0.529 ml) and ethyl acetate (0.529 ml). 0.563 mg, 5.29 μmol). The resulting reaction (0.107 mg, 0.053 mmol) was taken in a hydrogen atmosphere and stirred at 23 ° C until completion by LCMS. Thereafter, the reactant was filtered, and the organic matter was concentrated under reduced pressure. The residue was filtered, then loaded onto silica gel (0-50% ethyl acetate/ethanol (3/1) of heptane) to afford 1-methyl-3-(4-((5-propylpyridine) as a white solid. 3-yl)oxy)-2'-(trifluoromethyl)-[3,4'-bipyridyl]-6-yl)urea (0.0114 g, 0.026 mmol, 50.0% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.38 (1H, s), 8.82 (1H, d, J = 4.9 Hz), 8.40 (2H, s), 8.43 (1H, s), 8.16 (1H) , s), 8.02 (1H, d, J = 4.6 Hz), 7.53-7.66 (2H, m), 7.00 (1H, s), 2.56-2.72 (5H, m), 1.57-1.67 (2H, m), 0.90 (3H, t, J = 7.2 Hz). Mass Spectrum (ESI) m/z = 431.9 (M+H).

實例1531Example 1531

1-(4-((5-甲氧基吡啶-3-基)氧基)-5-((3-甲基嗎啉基)甲基)吡啶-2-基)-3-甲基脲 1-(4-((5-methoxypyridin-3-yl)oxy)-5-((3-methylmorpholinyl)methyl)pyridin-2-yl)-3-methylurea

步驟A：向1-(5-溴-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(4 g，12 mmol)於EtOH(150 mL)中之溶液中添加Pd(OAc)2(800 mg，2.4 mmol)、Dppf(1.4 g，2.4 mmol)及TEA(5 g，48 mmol)。在60℃下於CO氛圍(50 psi)下攪拌所得混合物48小時。過濾所得混合物並濃縮，且藉由管柱層析純化，得到呈黃色固體狀之4-((5-甲氧基吡啶-3-基)氧基)-6-(3-甲基脲基)菸鹼酸乙酯(2.4 g，6.94 mmol，61.5%產率)。 Step A : To 1-(5-Bromo-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (4 g, 12 mmol) in EtOH Pd(OAc) 2 (800 mg, 2.4 mmol), Dppf (1.4 g, 2.4 mmol) and TEA (5 g, 48 mmol) were added to the solution (150 mL). The resulting mixture was stirred at 60 ° C under a CO atmosphere (50 psi) for 48 hours. The resulting mixture was filtered, dried and purified eluting elut elut elut eluting Ethyl nicotinic acid (2.4 g, 6.94 mmol, 61.5% yield).

步驟B：經約30分鐘，向4-((5-甲氧基吡啶-3-基)氧基)-6-(3-甲基脲基)菸鹼酸乙酯(1.8 g，5.20 mmol)於THF(120 mL)中之經冷卻(0℃)溶液中分數小份添加LiAlH4(608 mg，15.6 mmol)。添加後，在室溫下攪拌反應混合物12小時。冷卻反應物至0℃，接著添加水以淬滅反應物。用乙酸乙酯萃取所得溶液，且乾燥經合併之有機層並濃縮，獲得1-(5-(羥基甲基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(1.1 g，3.61 mmol，69.4%產率)。 Step B : To a solution of 4-((5-methoxypyridin-3-yl)oxy)-6-(3-methylureido)nicotinate (1.8 g, 5.20 mmol) over ca. LiAlH 4 (608 mg, 15.6 mmol) was added in small portions of a cooled (0 ° C) solution in THF (120 mL). After the addition, the reaction mixture was stirred at room temperature for 12 hours. The reaction was cooled to 0 ° C then water was added to quench the reaction. The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried and concentrated to give 1-(5-(hydroxymethyl)-4-((5-methoxypyridin-3-yl)oxy)pyridine- 2-yl)-3-methylurea (1.1 g, 3.61 mmol, 69.4% yield).

步驟C：在0℃下，向1-(5-(羥基甲基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(1 g，3.28 mmol)於無水DCM(30 mL)及無水DMF(0.3 mL)中之溶液中逐滴添加SOCl2(0.83 mL)。使所得溶液升溫 至23℃。1小時後，濃縮反應物，獲得1-(5-(氯甲基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(800 mg，2.48 mmol，75.5%產率)。 Step C : To 1-(5-(hydroxymethyl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea at 0 °C (1 g, 3.28 mmol) SOCl 2 (0.83 mL) was added dropwise to a solution of anhydrous DCM (30 mL) and anhydrous DMF (0.3 mL). The resulting solution was allowed to warm to 23 °C. After 1 hour, the reaction was concentrated to give 1-(5-(chloromethyl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (800 mg, 2.48 mmol, 75.5% yield).

步驟D：在室溫下，向1-(5-(氯甲基)-4-((5-甲氧基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(200 mg，0.621 mmol)及3-甲基嗎啉(3當量)於DMF(15 mL)中之溶液中添加NaHCO3(203 mg，1.8 mmol)。在室溫下攪拌反應混合物隔夜。用水稀釋所得溶液且用EtOAc萃取。乾燥有機層，濃縮且藉由製備型HPLC純化，得到1-(4-((5-甲氧基吡啶-3-基)氧基)-5-((3-甲基嗎啉基)甲基)吡啶-2-基)-3-甲基脲。HPLC：>95%(254 nm)。1H NMR(400 MHz,MeOD)δ 8.46-8.30(m,3H),7.67-7.66(m,1H),6.67(s,1H),4.92-4.82(m,1H),4.41-4.38(m,1H),4.06(m,2H),3.98(m,3H),3.86(m,1H),3.66-3.56(m,3H),3.37-3.36(m,1H),2.82(s,3H),1.56-1.54(m,3H)。ESI-MS(M+1)：388.2，C19H25N5O4計算值387.2。 Step D : To 1-(5-(chloromethyl)-4-((5-methoxypyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea at room temperature (200 mg, 0.621 mmol) and 3-methylmorpholine (3 equivalents) in DMF was added NaHCO (15 mL) in a solution of 3 (203 mg, 1.8 mmol) . The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water and extracted with EtOAc. The organic layer was dried, concentrated and purified by preparative HPLC to afford 1-(4-((5-methoxypyridin-3-yl)oxy)-5-((3-methylmorpholinyl)methyl Pyridin-2-yl)-3-methylurea. HPLC: >95% (254 nm). 1 H NMR (400 MHz, MeOD) δ 8.46-8.30 (m, 3H), 7.67-7.66 (m, 1H), 6.67 (s, 1H), 4.92-4.82 (m, 1H), 4.41-4.38 (m, 1H), 4.06 (m, 2H), 3.98 (m, 3H), 3.86 (m, 1H), 3.66-3.56 (m, 3H), 3.37-3.36 (m, 1H), 2.82 (s, 3H), 1.56 -1.54 (m, 3H). ESI-MS (M + 1) : 388.2, C 19 H 25 N 5 O 4 387.2 calc.

遵循上述程序，使用適當試劑製備以下化合物： Following the above procedure, the following compounds were prepared using the appropriate reagents:

遵循製備II中之程序，但使用DMSO替代DMF，製備以下化合物： Following the procedure in Preparation II , but using DMSO instead of DMF, the following compounds were prepared:

藉由基本上遵循實例1660中之程序，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 1660:

藉由基本上遵循實例1660中之程序，但藉由對掌性層析(AD管柱，30% MeOH)分離所得外消旋體，製備以下化合物： The following compounds were prepared by essentially following the procedure in Example 1660 , but by separating the resulting racemate from palm chromatography (AD column, 30% MeOH):

藉由基本上遵循實例606中之程序，但最後藉由超臨界流體對掌性層析(AD-H，30% MeOH(0.1% NH4OH)/CO2，100巴)純化化合物，製備以下化合物： By substantially following the procedures of Example 606, but in the end by chiral supercritical fluid chromatography (AD-H, 30% MeOH (0.1% NH 4 OH) / CO 2, 100 bar) to give a compound, prepared by the following Compound:

遵循實例1127中之程序，製備以下化合物： Following the procedure in Example 1127 , the following compounds were prepared:

遵循製備32中之途徑，亦合成以下化合物： Following the route in Preparation 32, the following compounds were also synthesized:

製備VIPreparation VI

2,4-二氟-3-羥基苯甲酸甲酯 Methyl 2,4-difluoro-3-hydroxybenzoate

將2,4-二氟-3-羥基苯甲酸(4.0 g，23 mmol)置於MeOH(40 mL)中且冷卻至0℃。逐滴添加(重氮甲基)三甲基矽烷(29 ml，57 mmol)，接著在0℃下攪拌30分鐘。接著濃縮反應物，用DCM稀釋，且用1 M NaOH洗滌，乾燥(MgSO4)，過濾且濃縮，得到粗產物，藉由管柱層析(9：1 DCM：MeOH)純化該粗產物，得到產物2,4-二氟-3-羥基苯甲酸甲酯(2.8 g，65%產率)。 2,4-Difluoro-3-hydroxybenzoic acid (4.0 g, 23 mmol) was taken in MeOH (40 mL) and cooled to EtOAc. (Diazomethyl)trimethylnonane (29 ml, 57 mmol) was added dropwise, followed by stirring at 0 ° C for 30 min. The reaction was then concentrated, diluted with DCM, and washed with 1 M NaOH and dried (MgSO 4), filtered and concentrated to give the crude product by column chromatography (9: 1 DCM: MeOH) The crude product was purified to give Product 2,4-Difluoro-3-hydroxybenzoic acid methyl ester (2.8 g, 65% yield).

製備VIIPreparation VII

5-羥基-N,N,1-三甲基-1H-吡唑-3-甲醯胺 5-hydroxy-N,N,1-trimethyl-1H-pyrazole-3-carboxamide

在室溫下，向二甲胺(13 ml，26 mmol)(2 M，於THF中)之室溫溶液中逐滴添加AlMe3(13 ml，26 mmol)且攪拌15分鐘。接著添加5-羥基-1-甲基-1H-吡唑-3-甲酸甲酯(2.0 g，13 mmol)，且在室溫下攪拌30分鐘。冷卻反應物至0℃且用水緩慢淬滅，接著酸化至pH 3，且用3：1 DCM：IPA萃取。在矽膠上(500：30-500：45 DCM：MeOH)純化粗產物，得到5-羥基-N,N,1-三甲基-1H-吡唑-3-甲醯胺(1.1 g，51%產率)。 At room temperature, to dimethylamine (13 ml, 26 mmol) ( 2 M, in THF) at room temperature was added dropwise a solution of AlMe 3 (13 ml, 26 mmol ) and stirred for 15 minutes. Methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (2.0 g, 13 mmol) was then added and stirred at room temperature for 30 min. The reaction was cooled to 0 ° C and slowly quenched with water then acidified to pH 3 and extracted with 3:1 DCM: IPA. The crude product was purified on silica gel (500:30-500:45 DCM:MeOH) to afford 5-hydroxy-N,N,1-trimethyl-1H-pyrazole-3-carbamide (1.1 g, 51% Yield).

製備VIIIPreparation VIII

1-乙基-3-(甲氧基甲基)-1H-吡唑-5-醇 1-ethyl-3-(methoxymethyl)-1H-pyrazole-5-ol

在室溫下，將草酸乙肼(1.34 g，8.90 mmol)置於MeOH(10 mL)中。添加三乙胺(1.24 ml，8.90 mmol)且攪拌10分鐘，接著添加4-甲氧基-3-側氧基丁酸甲酯(1.18 ml，8.90 mmol)，且加熱至回流隔夜，接著傾倒至水中，酸化至pH 4，且用5：1 DCM：IPA萃取。乾燥(MgSO4)經合併之有機部分，過濾，濃縮且在矽膠上(500：15 DCM：MeOH)純化，得到1-乙基-3-(甲氧基甲基)-1H-吡唑-5-醇(1.0 g，72.0%產率)。 Ethyl oxalate (1.34 g, 8.90 mmol) was taken in MeOH (10 mL). Add triethylamine (1.24 ml, 8.90 mmol) and stir for 10 min then add methyl 4-methoxy-3-oxobutanoate (1.18 ml, 8.90 mmol) and warm to reflux overnight then poured In water, acidify to pH 4 and extract with 5:1 DCM:IPA. Dried (MgSO 4) the organic fractions were combined, filtered, and concentrated on silica gel (500: 15 DCM: MeOH) to give ethyl-3- (methoxymethyl-ylmethyl) -1H- pyrazol-5 - alcohol (1.0 g, 72.0% yield).

製備IXPreparation IX

2-(4-氟-3-羥基苯基)乙酸甲酯 Methyl 2-(4-fluoro-3-hydroxyphenyl)acetate

步驟A：將2-(4-氟-3-甲氧基苯基)乙酸(1.0 g，5.43 mmol)溶解於DCM(30 mL)中，且添加1 M BBr3(16.3 ml，16.3 mmol)，且在室溫 下攪拌反應物1小時。將反應物傾倒至NaHCO3水溶液中，且攪拌10分鐘並用乙醚萃取。用1 M HCl酸化水層，用DCM(×2)萃取，經硫酸鈉乾燥，過濾且濃縮，得到2-(4-氟-3-羥基苯基)乙酸(800 mg，4.70 mmol，86.6%產率)。 Step A : 2-(4-Fluoro-3-methoxyphenyl)acetic acid (1.0 g, 5.43 mmol) was dissolved in DCM (30 mL), and 1 M BBr 3 (16.3 ml, 16.3 mmol), The reaction was stirred at room temperature for 1 hour. The reaction was poured into aqueous NaHCO 3 solution, and stirred for 10 minutes and extracted with ether. The aqueous layer was acidified with EtOAc EtOAc (EtOAc)EtOAc. rate).

步驟B：將2-(4-氟-3-羥基苯基)乙酸(800 mg，4.70 mmol)溶解於MeOH(20 mL)中，且緩慢添加(重氮甲基)三甲基矽烷(2351 μl，4.70 mmol)，且在室溫下攪拌10分鐘。濃縮反應物，得到2-(4-氟-3-羥基苯基)乙酸甲酯(866 mg，4.70 mmol，100%產率)。 Step B : Dissolve 2-(4-fluoro-3-hydroxyphenyl)acetic acid (800 mg, 4.70 mmol) in MeOH (20 mL) and slowly add (diazomethyl)trimethyl decane (2351 μl) , 4.70 mmol), and stirred at room temperature for 10 minutes. The reaction was concentrated to give methyl 2-(4-fluoro-3-hydroxyphenyl)acetate (866 mg, 4.70 mmol, 100% yield).

製備XPreparation X

6-(2-羥基丙-2-基)-5-甲基吡啶-3-醇 6-(2-hydroxypropan-2-yl)-5-methylpyridin-3-ol

步驟A：將2,5-二溴-3-甲基吡啶(4.0 g，15.9 mmol)溶解於甲苯(150 mL)中且冷卻至-78℃。逐滴添加2.5 M丁基鋰(6.82 ml，17.1 mmol)且在-78℃下攪拌3小時。添加丙酮(1.41 ml，19.1 mmol)且在-78℃下攪拌2小時。將反應物傾倒至NH4Cl水溶液中，用EtOAc萃取，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含20% EtOAc之己烷)純化，得到呈透明無色油狀之2-(5-溴-3-甲基吡啶-2-基)丙-2-醇(2.6 g，11.3 mmol，70.9%產率)。 Step A : 2,5-Dibromo-3-methylpyridine (4.0 g, 15.9 mmol) was dissolved in toluene (150 mL) and cooled to -78. 2.5 M butyllithium (6.82 ml, 17.1 mmol) was added dropwise and stirred at -78 °C for 3 hours. Acetone (1.41 ml, 19.1 mmol) was added and stirred at -78 °C for 2 h. The reaction was poured into aqueous 4 Cl NH, extracted with EtOAc, and dried over sodium sulfate, filtered and concentrated. Purification on silica gel (20% EtOAc EtOAc) 70.9% yield).

步驟B：將2-(5-溴-3-甲基吡啶-2-基)丙-2-醇(100 mg，0.435 mmol)溶解於二噁烷：水(1：1，4 mL)中，且使氮氣鼓泡通過，持續5分鐘。添加氫氧化鉀(48.8 mg，0.869 mmol)、Pd2dba3(19.9 mg，0.0217 mmol)及二第三丁基(2',4',6'-三異丙基聯苯-2-基)膦(36.9 mg，0.0869 mmol)，且將反應物傾沒於90℃油浴中，維持2小時。冷卻反 應物至室溫，用乙醚稀釋，分配，用飽和NH4Cl中和水層，用固體NaCl使鹽析出，用EtOAc(×2)萃取，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含90% EtOAc之己烷)純化，得到6-(2-羥基丙-2-基)-5-甲基吡啶-3-醇(15 mg，0.0897 mmol，20.6%產率)。 Step B : Dissolving 2-(5-bromo-3-methylpyridin-2-yl)propan-2-ol (100 mg, 0.435 mmol) in dioxane: water (1:1, 4 mL). Nitrogen gas was bubbled through for 5 minutes. Potassium hydroxide (48.8 mg, 0.869 mmol), Pd 2 dba 3 (19.9 mg, 0.0217 mmol) and di-tert-butyl (2',4',6'-triisopropylbiphenyl-2-yl) were added. Phosphine (36.9 mg, 0.0869 mmol) and the reaction was poured into a 90 ° C oil bath for 2 h. The reaction was cooled to room temperature, diluted with ether, dispensing with saturated NH 4 Cl aqueous layer was neutralized, the salt precipitated with solid NaCl and extracted with EtOAc (× 2), dried over sodium sulfate, filtered and concentrated. Purification on silica gel (90% EtOAc in hexanes) gave 6-(2-hydroxypropan-2-yl)-5-methylpyridin-3-ol (15 mg, 0.0897 mmol, 20.6% yield).

製備XIPreparation XI

5-氟-3-甲基-2-(三氟甲基)吡啶 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine

將2-溴-5-氟-3-甲基吡啶(1.0 g，5.26 mmol)溶解於密封管中之無水DMF(25 mL)中，且使氮氣鼓泡通過，持續10分鐘。依序添加碘化銅(I)(1.00 g，5.26 mmol)、2,2-二氟-2-(氟磺醯基)乙酸甲酯(2.34 ml，18.4 mmol)。密封反應物且加熱至100℃。1小時後，冷卻反應物至室溫。小心打開密封蓋後，發生較大壓力釋放[保持於通風櫥中且面向窗框後方]。用EtOAc稀釋橙色混合物，經矽藻土過濾，分配於50%鹽水與EtOAc之間，用50%鹽水及鹽水洗滌，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含20-50% EtOAc之己烷)純化油狀物，得到600 mg粗5-氟-3-甲基-2-(三氟甲基)吡啶。 2-Bromo-5-fluoro-3-methylpyridine (1.0 g, 5.26 mmol) was dissolved in dry DMF (25 mL) EtOAc. Copper (I) iodide (1.00 g, 5.26 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.34 ml, 18.4 mmol) were added sequentially. The reaction was sealed and heated to 100 °C. After 1 hour, the reaction was cooled to room temperature. After careful opening of the sealing cap, a large pressure release occurs [maintained in the fume hood and facing the rear of the window frame]. The mixture was diluted with EtOAc (EtOAc)EtOAcEtOAcEtOAc. The oil was purified on EtOAc (EtOAc EtOAc EtOAc)

製備XIIPreparation of XII

5-羥基-1,4-二甲基吡啶-2(1H)-酮 5-hydroxy-1,4-dimethylpyridine-2(1H)-one

步驟A：將5-溴-2-甲氧基-4-甲基吡啶(4.47 g，22.1 mmol)於6 N HCl(28.6 ml，171 mmol)中之溶液在106℃下加熱24小時。用冰浴將 其冷卻至5℃。用固體碳酸鈉將溶液之pH值調整至約6.5。藉由過濾收集固體，且用水(5 ml)洗滌並乾燥，得到呈固體狀之5-溴-4-甲基吡啶-2(1H)-酮(3.7 g，88.9%)。 Step A : A solution of 5-bromo-2-methoxy-4-methylpyridine (4.47 g, 22.1 mmol) in 6 N EtOAc (2. It was cooled to 5 ° C with an ice bath. The pH of the solution was adjusted to about 6.5 with solid sodium carbonate. The solid was collected by filtration and washed with water (5 ml) and dried to afford 5-bromo-4-methylpyridine-2(1H)-one (3.7 g, 88.9%).

步驟B：在0℃下，向5-溴-4-甲基吡啶-2(1H)-酮(1.00 g，5.32 mmol)及K2CO3(1.84 g，13.3 mmol)於DMF(10 mL)中之溶液中添加MeI(0.40 ml，6.38 mmol)。在0℃下攪拌混合物12小時。接著使其升溫至周圍溫度，且在周圍溫度下再攪拌12小時。添加水(10 mL)。用乙酸乙酯(3×20 mL)萃取水層。用鹽水(20 mL)洗滌經合併之有機層，乾燥(硫酸鈉)，過濾且在減壓下濃縮。藉由急驟層析，在矽膠上(100：1乙酸乙酯：MeOH)純化所獲得之殘餘物，得到呈固體狀之5-溴-1,4-二甲基吡啶-2(1H)-酮(0.94 g，87.5%)。 Step B : To a solution of 5-bromo-4-methylpyridine-2(1H)-one (1.00 g, 5.32 mmol) and K 2 CO 3 (1.84 g, 13.3 mmol) in DMF (10 mL) MeI (0.40 ml, 6.38 mmol) was added to the solution. The mixture was stirred at 0 ° C for 12 hours. It was then allowed to warm to ambient temperature and stirred for an additional 12 hours at ambient temperature. Add water (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with EtOAc EtOAc m. The residue obtained was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc) (0.94 g, 87.5%).

步驟C：經10分鐘，向5-溴-1,4-二甲基吡啶-2(1H)-酮(0.34 g，1.66 mmol)及硼酸三甲酯(0.41 ml，3.65 mmol)於四氫呋喃(10 mL)中之溶液中逐滴添加含1.70 M t-BuLi(2.15 ml，3.65 mmol)之己烷。在-78℃下攪拌所得混合物2小時，且添加過氧乙酸(0.77 ml，3.65 mmol)。在-78℃下10分鐘後，使反應物升溫至0℃且攪拌1小時。用含亞硫酸鈉(0.84 g，6.63 mmol)之水(5 mL)處理反應物。在減壓下移除溶劑。將所得固體懸浮於4：1 CHCl3：IPA(30 mL)中且在周圍溫度下攪拌1小時。藉由過濾移除固體。在減壓下濃縮濾液，得到呈油狀之5-羥基-1,4-二甲基吡啶-2(1H)-酮(0.13 g，57.2%)。 Step C : To a solution of 5-bromo-1,4-dimethylpyridine-2(1H)-one (0.34 g, 1.66 mmol) and trimethyl borate (0.41 ml, 3.65 mmol) in tetrahydrofuran over 10 min. 1.70 M t -BuLi (2.15 ml, 3.65 mmol) of hexane was added dropwise to the solution in mL). The resulting mixture was stirred at -78.degree. C. for 2 hrs and then EtOAc (EtOAc (EtOAc) After 10 minutes at -78 °C, the reaction was warmed to 0 ° C and stirred 1 hr. The reaction was treated with sodium sulfite (0.84 g, 6.63 mmol) water (5 mL). The solvent was removed under reduced pressure. The obtained solid was suspended in 4:1 CHCl 3 :IPA (30 mL) and stirred at ambient temperature for 1 hour. The solids were removed by filtration. The filtrate was concentrated under reduced pressure to give 5-hydroxy-1,4-dimethylpyridine-2(1H)-one (0.13 g, 57.2%).

以下化合物均以類似方式製備。 The following compounds were all prepared in a similar manner.

遵循製備17中之程序，亦合成以下化合物： Following the procedure in Preparation 17, the following compounds were also synthesized:

製備XIIIPreparation XIII

1-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2(1H)-酮 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridine-2(1H)-one

步驟A：將5-溴吡啶-2-醇(1.0 g，5.75 mmol)溶解於DMF(15 mL)中，且添加60%氫化鈉(0.230 g，5.75 mmol)，且在室溫下攪拌反應物30分鐘。添加碘乙烷(0.511 ml，6.32 mmol)，且在室溫下攪拌反應 物。1小時後，將反應物分配於水與EtOAc之間，用EtOAc萃取，用鹽水洗滌，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含70% EtOAc之己烷)純化殘餘物，得到呈白色固體狀之5-溴-1-乙基吡啶-2(1H)-酮(619 mg，3.06 mmol，53.3%產率)。 Step A : Dissolve 5-bromopyridin-2-ol (1.0 g, 5.75 mmol) in DMF (15 mL) and add 60% sodium hydride (0.230 g, 5.75 mmol). 30 minutes. Iodoethane (0.511 ml, 6.32 mmol) was added and the reaction was stirred at room temperature. After 1 hr, EtOAc EtOAc m. The residue was purified with EtOAc EtOAc EtOAcjjjjjjj .

步驟B：將5-溴-1-乙基吡啶-2(1H)-酮(300 mg，1.48 mmol)溶解於二噁烷(7 mL)中。添加4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧硼)(566 mg，2.23 mmol)及乙酸鉀(437 mg，4.45 mmol)，且使氮氣鼓泡通過，持續5分鐘。添加PdCl2(dppf)．DCM(121 mg，0.148 mmol)，且加熱反應物至90℃隔夜。冷卻反應物至室溫，經矽藻土過濾，用EtOAc沖洗，濃縮且在矽膠上(含50% EtOAc之己烷)純化，得到呈琥珀色油狀之1-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2(1H)-酮(350 mg，1.40 mmol，94.6%產率)。 Step B : 5-Bromo-1-ethylpyridine-2(1H)-one (300 mg, 1.48 mmol) was dissolved in dioxane (7 mL). Add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron) (566 mg, 2.23 mmol) and potassium acetate (437 mg, 4.45 mmol), and nitrogen was bubbled through for 5 minutes. Add PdCl 2 (dppf). DCM (121 mg, 0.148 mmol), and the mixture was heated to 90 ° C overnight. The reaction was cooled to EtOAcqqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridine-2(1H)-one (350 mg, 1.40 mmol, 94.6% yield).

遵循製備XIII中之程序，亦合成以下化合物： Following the procedure in Preparation XIII, the following compounds were also synthesized:

製備XIVPrepare XIV

2-異丙氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)嘧啶 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyrimidine

步驟A：將丙-2-醇(1.19 ml，15.5 mmol)溶解於DMF(40 mL)中，在冰浴中冷卻，且添加60%氫化鈉(0.620 g，15.5 mmol)。使反應物升溫至室溫，添加5-溴-2-氯嘧啶(2.0 g，10.3 mmol)，且加熱反應物至80℃隔夜。用50%鹽水稀釋反應物，用EtOAc萃取，用鹽水洗滌，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含5% EtOAc之己烷)純化殘餘物，得到呈透明無色油狀之5-溴-2-異丙氧基嘧啶(0.43 g，1.98 mmol，19.2%產率)。 Step A : Propan-2-ol (1.19 ml, 15.5 mmol) was dissolved in DMF (40 mL). The reaction was allowed to warm to room rt. 5-bromo-2-chloropyrimidine (2.0 g, 10.3 mmol). The reaction was diluted with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc EtOAc EtOAc (EtOAc

步驟B：將5-溴-2-異丙氧基嘧啶(400 mg，1.84 mmol)溶解於二噁烷(10 mL)中。添加4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧硼)(702 mg，2.76 mmol)及乙酸鉀(543 mg，5.53 mmol)，且使氮氣鼓泡通過，持續5分鐘。添加PdCl2(dppf)．DCM(150 mg，0.184 mmol)，且加熱反應物至90℃隔夜。冷卻反應物至室溫，用EtOAc稀釋，經矽藻土過濾，用EtOAc沖洗，濃縮且在矽膠上(含15% EtOAc之己烷)純化，得到呈白色固體狀之2-異丙氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)嘧啶(422 mg，1.60 mmol，86.7%產率)。 Step B : 5-Bromo-2-isopropoxypyrimidine (400 mg, 1.84 mmol) was dissolved in dioxane (10 mL). Add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron) (702 mg, 2.76 mmol) and potassium acetate (543 mg, 5.53 mmol), and nitrogen was bubbled through for 5 minutes. Add PdCl 2 (dppf). DCM (150 mg, 0.184 mmol), and the mixture was heated to 90 ° C overnight. The reaction was cooled to EtOAcq~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyrimidine (422 mg, 1.60 mmol, 86.7% yield).

遵循製備XIV中之程序，亦合成以下化合物： Following the procedure in Preparation XIV, the following compounds were also synthesized:

遵循製備13中之程序，亦合成以下化合物： Following the procedure in Preparation 13, the following compounds were also synthesized:

製備XVPrepare XV

2-(5-((第三丁基二甲基矽烷基)氧基)吡啶-3-基)丙-2-醇 2-(5-((tert-butyldimethylmethylalkyl)oxy)pyridin-3-yl)propan-2-ol

步驟A：在室溫下，將5-羥基菸鹼酸甲酯(5.1 g，33.3 mmol)、咪唑(2.38 g，35.0 mmol)及TBDMS-Cl(5.27 g，35.0 mmol)於60 mL四氫呋喃中組合，且在氮氣下攪拌此物質。快速形成沈澱物。攪拌反應物隔夜。此後，在減壓下濃縮反應物。將殘餘物分配於EtOAc與飽和碳酸氫鈉之間。接著用1：1水：鹽水洗滌有機物兩次，用鹽水洗滌一次，經MgSO4乾燥，過濾，且在減壓下移除，得到5-(第三丁基二甲基矽烷氧基)菸鹼酸甲酯(8.8 g，32.8 mmol，99%產率)。 Step A : Combining methyl 5-hydroxynicotinate (5.1 g, 33.3 mmol), imidazole (2.38 g, 35.0 mmol) and TBDMS-Cl (5.27 g, 35.0 mmol) in 60 mL of tetrahydrofuran at room temperature And the material was stirred under nitrogen. Rapid formation of precipitates. The reaction was stirred overnight. Thereafter, the reactant was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated sodium hydrogen sulfate. Followed by 1: 1 water: organics were washed twice with brine, once with brine, dried over MgSO 4, filtered, and removed under reduced pressure to give 5- (tert-butyl-dimethyl silane-yloxy) nicotinic Methyl ester (8.8 g, 32.8 mmol, 99% yield).

步驟B：在10 mL THF中稀釋5-(第三丁基二甲基矽烷氧基)菸鹼酸甲酯(2.0 g，7.48 mmol)且冷卻至0℃，隨後緩慢添加MeMgBr(5.48 ml，16.5 mmol)。使反應物升溫至室溫，且1小時後，用飽和NH4Cl稀釋反應物且用EtOAc萃取。接著用1：1水：鹽水、鹽水洗滌有機物，經MgSO4乾燥，過濾，且在減壓下移除。在矽膠上(含20%丙酮之二氯甲烷)對粗物質進行層析，得到2-(5-(第三丁基二甲基矽烷氧基)吡啶-3-基)丙-2-醇(1.82 g，6.81 mmol，91%產率)。 Step B : Dilute 5-(t-butyldimethylammoniumoxy) nicotinic acid methyl ester (2.0 g, 7.48 mmol) in 10 mL THF and cool to 0 ° C then slowly add MeMgBr (5.48 ml, 16.5) Mm). After the reaction was allowed to warm to room temperature and 1 hour, the reaction was diluted with sat NH 4 Cl and extracted with EtOAc. The organics were washed with 1:1 water: brine, brine, dried MgSO 4 The crude material was chromatographed on silica gel eluting with 20% of ethyl acetate to afford 2-(5-(t-butyl dimethyl-decyloxy)pyridin-3-yl)propan-2-ol ( 1.82 g, 6.81 mmol, 91% yield).

製備XVIPrepare XVI

(5-((第三丁基二甲基矽烷基)氧基)吡啶-3-基)甲醇 (5-((Tert-butyldimethylmethylalkyl)oxy)pyridin-3-yl)methanol

步驟A：如製備XV步驟A，自5-羥基菸鹼酸甲酯(5.1 g，33.3 mmol)獲得5-(第三丁基二甲基矽烷氧基)菸鹼酸甲酯(1.82 g，6.81 mmol，91.0%產率)。 Step A : As of XV Step A, methyl 5-(t-butyldimethylsilyloxy)nicotinate (1.82 g, 6.81) was obtained from methyl 5-hydroxynicotinate (5.1 g, 33.3 mmol). M, 91.0% yield).

步驟B：在0℃下，於5 mL THF中組合氫化鋰鋁(III)(0.12 g，3.1 mmol)及5-(第三丁基二甲基矽烷氧基)菸鹼酸甲酯(1.5 g，5.6 mmol)，且繼續維持1小時。此後，用固體十水合硫酸鈉淬滅反應物且劇烈攪拌10分鐘。過濾粗物質，在減壓下濃縮，且在矽膠上(含25%丙酮之二氯甲烷)進行層析，得到(5-(第三丁基二甲基矽烷氧基)吡啶-3-基)甲醇(0.62 g，2.6 mmol，46%產率)。 Step B : Lithium aluminum (III) hydride (0.12 g, 3.1 mmol) and methyl 5-(t-butyldimethyl decyloxy) nicotinic acid (1.5 g) were combined in 5 mL of THF at 0 °C. , 5.6 mmol), and continued for 1 hour. Thereafter, the reaction was quenched with solid sodium sulfate decahydrate and stirred vigorously for 10 min. The crude material was filtered, concentrated under reduced pressure and purified eluting eluting eluting eluting Methanol (0.62 g, 2.6 mmol, 46% yield).

製備XVIIPreparation of XVII

1-(5-((第三丁基二甲基矽烷基)氧基)吡啶-3-基)乙醇 1-(5-((tert-butyldimethylmethylalkyl)oxy)pyridin-3-yl)ethanol

步驟A：在0℃下，於5 mL THF中組合氫化鋰鋁(III)(0.12 g，3.1 mmol)及5-(第三丁基二甲基矽烷氧基)菸鹼酸甲酯(1.5 g，5.6 mmol)， 且繼續維持1小時。此後，用固體十水合硫酸鈉淬滅反應物且劇烈攪拌10分鐘。接著過濾粗物質，在減壓下濃縮，且在矽膠上(含25%丙酮之二氯甲烷)純化，得到(5-(第三丁基二甲基矽烷氧基)吡啶-3-基)甲醇(0.62 g，2.6 mmol，46%產率)。 Step A : Lithium aluminum (III) hydride (0.12 g, 3.1 mmol) and methyl 5-(t-butyldimethylammoniumoxy) nicotinic acid (1.5 g) were combined in 5 mL of THF at 0 °C. , 5.6 mmol), and continued for 1 hour. Thereafter, the reaction was quenched with solid sodium sulfate decahydrate and stirred vigorously for 10 min. The crude material was then filtered, concentrated under reduced pressure and purified on silica gel eluting with 25% of ethyl acetate to afford (5-(t-butyl dimethyl decyloxy) pyridin-3-yl) (0.62 g, 2.6 mmol, 46% yield).

步驟B：在0℃下，於2 mL二氯甲烷中組合(5-(第三丁基二甲基矽烷氧基)吡啶-3-基)甲醇(0.200 g，0.835 mmol)及戴斯-馬丁高碘酸鹽(Dess-Martin periodenate)(0.390 g，0.919 mmol)。使反應進行8小時，接著用二氯甲烷稀釋，且用1：1飽和碳酸氫鈉：1 M Na2SO3洗滌。用二氯甲烷反萃取水相三次。合併有機物，經MgSO4乾燥，過濾，在減壓下移除，且在高真空下乾燥1小時。在矽膠上(含5%丙酮之二氯甲烷)純化粗物質，得到5-(第三丁基二甲基矽烷氧基)菸鹼醛(0.085 g，0.358 mmol，42.9%產率)。 Step B : Combine (5-(t-butyldimethylammonyloxy)pyridin-3-yl)methanol (0.200 g, 0.835 mmol) and Days-Martin in 2 mL of dichloromethane at 0 °C. Dess-Martin periodenate (0.390 g, 0.919 mmol). The reaction for 8 hours, then diluted with dichloromethane and washed with 1: 1 M Na 2 SO 3: 1 saturated sodium bicarbonate. The aqueous phase was back extracted three times with dichloromethane. The organics were combined, dried over MgSO 4, filtered, removed under reduced pressure, and dried under high vacuum for 1 hour. The crude material was purified on EtOAc (EtOAc EtOAc EtOAc)

步驟C：在1 mL THF中稀釋5-(第三丁基二甲基矽烷氧基)菸鹼醛(0.080 g，0.34 mmol)，且在冰浴中冷卻此物質5分鐘，隨後緩慢添加3 M MeMgBr(0.17 ml，0.51 mmol)。10分鐘後，用1：1飽和NH4Cl：水淬滅反應物且用EtOAc萃取三次。經MgSO4乾燥有機物，過濾且濃縮，得到1-(5-((第三丁基二甲基矽烷基)氧基)吡啶-3-基)乙醇(88 mg，0.31 mmol，93%產率)。 Step C : Dilute 5-(t-butyldimethylammoniumoxy)nicotinaldehyde (0.080 g, 0.34 mmol) in 1 mL THF and cool the material in ice bath for 5 min then slowly add 3 M MeMgBr (0.17 ml, 0.51 mmol). After 10 minutes, with 1: 1 saturated NH 4 Cl: The reaction was quenched with water and extracted three times with EtOAc. The organics were dried over MgSO 4, filtered and concentrated to give 1- (5 - ((tert-butyl dimethyl silicone alkyl) oxy) pyridin-3-yl) ethanol (88 mg, 0.31 mmol, 93 % yield) .

製備XVIIIPreparation of XVIII

2-甲基-1-((5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)氧基)丙-2-醇 2-methyl-1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)pyridin-2-yl)oxy)propan-2-ol

步驟A：將NaH(1.70 g，42.6 mmol)懸浮於冷卻至0℃之50 mL DMA中，隨後經由注射器緩慢添加2-羥基乙酸乙酯(4.03 ml，42.6 mmol)，且在添加期間將容器用氮氣充氣。使反應物升溫至室溫且攪拌1小時。此後，添加5-溴-2-氟吡啶(5.00 g，28.4 mmol)，且使反應在室溫下進行4小時。接著用水稀釋反應物且用EtOAc萃取兩次。接著依序用1：1飽和碳酸氫鈉：水、1：1鹽水：水、鹽水洗滌有機物，經MgSO4乾燥，過濾，且濃縮，得到2-(5-溴吡啶-2-基氧基)乙酸乙酯(7.48 g，28.8 mmol，100%產率)。 Step A : NaH (1.70 g, 42.6 mmol) was suspended in 50 mL of DMA cooled to 0 ° C, then ethyl 2-hydroxyacetate (4.03 ml, 42.6 mmol) was slowly added via syringe, and the container was used during the addition. Nitrogen gas. The reaction was allowed to warm to rt and stirred 1 hr. Thereafter, 5-bromo-2-fluoropyridine (5.00 g, 28.4 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 hours. The reaction was then diluted with water and extracted twice with EtOAc. Then washed sequentially with 1: 1 saturated sodium bicarbonate: water, 1: 1 brine: water, organics were washed with brine, dried over MgSO 4, filtered, and concentrated to give 2- (5-bromo-2-yloxy) Ethyl acetate (7.48 g, 28.8 mmol, 100% yield).

步驟B：在30 mL THF中稀釋2-(5-溴吡啶-2-基氧基)乙酸乙酯(5.0 g，19 mmol)，且冷卻此物質至0℃，隨後緩慢添加3 M MeMgBr(14 ml，42 mmol)。添加之後，使反應物升溫至室溫。1小時後，將飽和NH4Cl水溶液緩慢添加至反應物中，接著添加水。在室溫下攪拌此物質10分鐘，隨後添加300 mL EtOAc。分離各層，且用1：1水：鹽水、鹽水洗滌有機物兩次，經MgSO4乾燥，過濾並濃縮。在矽膠上(含2.5%丙酮之二氯甲烷)純化粗物質，得到1-(5-溴吡啶-2-基氧基)-2-甲基丙-2-醇(4.2 g，17 mmol，89%產率)。 Step B : Ethyl 2-(5-bromopyridin-2-yloxy)acetate (5.0 g, 19 mmol) was diluted in 30 mL THF and then cooled to 0 &lt;0&gt;C, then slowly 3 M MeMgBr (14) Ml, 42 mmol). After the addition, the reaction was allowed to warm to room temperature. After 1 hour, saturated aqueous NH 4 Cl was added slowly to the reaction, followed by addition of water. This material was stirred at room temperature for 10 minutes, then 300 mL of EtOAc was added. The layers were separated, and washed with 1: 1 water: brine, organics were washed twice with brine, dried over MgSO 4, filtered and concentrated. The crude material was purified on EtOAc (EtOAc: EtOAc: EtOAc) %Yield).

步驟C：在30 mL二噁烷中組合1-(5-溴吡啶-2-基氧基)-2-甲基丙-2-醇(4.2 g，17 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧硼)(6.5 g，26 mmol)及KOAc(5.0 g，51 mmol)，且將此物質用氬氣充氣5分鐘，隨後添加PdCl2(dppf)．DCM(1.4 g，1.7 mmol)，且再繼續充氣5分鐘，隨後密封反應物且加熱至100℃。次日，用1：1二氯甲烷：EtOAc稀釋反應物，且過濾此物質。依序用二氯甲烷及EtOAc洗滌濾餅。在減壓下移除有機物且在高真空下乾燥1小時。在矽膠上(含10%丙酮之二氯甲烷)純化殘餘物，得到2-甲基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基氧基)丙-2-醇(5.6 g，19 mmol，112%產率)。 Step C : Combine 1-(5-bromopyridin-2-yloxy)-2-methylpropan-2-ol (4.2 g, 17 mmol), 4, 4, 4' in 30 mL of dioxane. 4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron) (6.5 g, 26 mmol) and KOAc (5.0 g, 51 mmol), and this material was inflated with argon for 5 minutes, then PdCl 2 (dppf) was added. DCM (1.4 g, 1.7 mmol) and continued to aerate for another 5 minutes, then the reaction was sealed and heated to 100 °C. The next day, the reaction was diluted with 1:1 dichloromethane:EtOAc and filtered. The filter cake was washed sequentially with dichloromethane and EtOAc. The organics were removed under reduced pressure and dried under high vacuum for 1 hour. The residue was purified on silica gel (dichloromethane containing 10% acetone) to give 2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)pyridin-2-yloxy)propan-2-ol (5.6 g, 19 mmol, 112% yield).

遵循製備XVIII中之程序，亦合成以下化合物： Following the procedure in Preparation XVIII, the following compounds were also synthesized:

製備XXXPreparation XXX

2-((5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基)氧基)乙醇 2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)pyridin-2-yl)oxy)ethanol

步驟A：遵循製備XVIII步驟C，使2-(5-溴吡啶-2-基氧基)乙醇(4.0 g，18 mmol)轉化成2-(5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基氧基)乙醇(5.6 g，19 mmol，102%產率)。 Step A : Following the preparation of Step X of Preparation XVIII, 2-(5-bromopyridin-2-yloxy)ethanol (4.0 g, 18 mmol) was converted to 2-(5-(4,4,5,5-tetramethyl) Base-1,3,2-dioxaboron 2-yl)pyridin-2-yloxy)ethanol (5.6 g, 19 mmol, 102% yield).

製備XIXPrepare XIX

1-(5-溴-4-羥基吡啶-2-基)-3-甲基脲 1-(5-bromo-4-hydroxypyridin-2-yl)-3-methylurea

步驟A：在室溫下，於20 mL DMA中組合氫化鈉(1.209 g，30.24 mmol)及苯基甲醇(3.132 ml，30.24 mmol)，且在攪拌下繼續維持4小時。此後，添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(5.0 g，20.16 mmol)，且使反應在70℃下進行。經週末後，冷卻反應物至室溫，接著用120 mL水稀釋且劇烈攪拌。經由真空過濾收集固體且在真空烘箱中乾燥，得到1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(6.59 g，19.60 mmol，97.25%產率)。 Step A : Sodium hydride (1.209 g, 30.24 mmol) and phenylmethanol (3.132 ml, 30.24 mmol) were combined in 20 mL MeOH at room temperature and continued for 4 hours with stirring. Thereafter, 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (5.0 g, 20.16 mmol) was added, and the reaction was carried out at 70 °C. After the weekend, the reaction was cooled to room temperature then diluted with 120 mL water and stirred vigorously. The solid was collected via vacuum filtration and dried in vacuo to give 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (6.59 g, 19.60 mmol, 97.25% yield ).

步驟B：將1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(3.0 g，8.92 mmol)及2-胺基乙硫醇鹽酸鹽(1.52 g，13.4 mmol)溶解於6 M HCl(25 ml，150 mmol)中，且在攪拌下加熱至100℃隔夜。次日早晨，經由震盪將在容器頂部周圍所收集之固體引入水相中，接著在100℃下再攪拌16小時。此後，在冰浴中冷卻反應物，且用50% NaOH將pH值調整至14。接著用濃鹽酸將pH值調整至約5。經由真空過濾收集所得固體且用水洗滌。在真空烘箱中乾燥此物質，得到1-(5-溴-4-羥基吡啶-2-基)-3-甲基脲(2.6 g，8.49 mmmol，95%產率)。 Step B : 1-(4-(Benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (3.0 g, 8.92 mmol) and 2-aminoethylthiol hydrochloride (1.52) g, 13.4 mmol) was dissolved in 6 M HCl (25 mL, 150 mmol) and heated to 100 ° C overnight with stirring. The next morning, the solid collected around the top of the vessel was introduced into the aqueous phase via shaking, followed by stirring at 100 ° C for an additional 16 hours. Thereafter, the reaction was cooled in an ice bath and the pH was adjusted to 14 with 50% NaOH. The pH was then adjusted to about 5 with concentrated hydrochloric acid. The resulting solid was collected via vacuum filtration and washed with water. This material was dried in a vacuum oven to give 1-(5-bromo-4-hydroxypyridin-2-yl)-3-methylurea (2.6 g, 8.49 mmmol, 95% yield).

實例1546Example 1546

1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

在氮氣下攪拌1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(500 mg，2.02 mmol)、5-甲基吡啶-3-醇(330 mg，3.02 mmol)及碳酸鉀(836 mg，6.05 mmol)於無水二甲基乙醯胺(DMA)(5 mL)中之混合物，同時加熱至90℃，維持3小時。使混合物冷卻，用水(30 mL)稀釋，且藉由過濾收集固體。用水(50 mL)洗滌固體，接著在真空下乾燥，得到呈褐色固體狀之1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(540 mg， 79%產率)。MS(apci)m/z 337.0,339.0(M+H)。 Stir 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (500 mg, 2.02 mmol), 5-methylpyridin-3-ol (330 mg, 3.02 mmol) under nitrogen A mixture of potassium carbonate (836 mg, 6.05 mmol) in anhydrous dimethylacetamide (DMA) (5 mL) was then warmed to &lt The mixture was cooled, diluted with water (30 mL) andEtOAc was evaporated. The solid was washed with water (50 mL) EtOAc (EtOAc) -3-methylurea (540 mg, 79% yield). MS (apci) m/z 337.0, 339.0 (M+H).

遵循實例1546中之程序，亦合成以下化合物： Following the procedure in Example 1546, the following compounds were also synthesized:

實例1553Example 1553

1-(5-乙炔基-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-ethynyl-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

步驟A：用氮氣淨化1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(1000 mg，2.966 mmol)、乙炔基三甲基矽烷(1182 μL，8.304 mmol)、三乙胺(1240 μL，8.898 mmol)、雙(三苯基膦)氯化鈀(II)(104 mg，0.148 mmol)、三苯基膦(39 mg，0.148 mmol)及碘化銅(I)(14 mg，0.074 mmol)於無水二甲基甲醯胺(DMF)(2 mL)中之混合物，且密封於磁性攪拌小瓶中。在90℃下加熱混合物8小時。此後，再添加乙炔基三甲基矽烷、三乙胺、雙(三苯基膦)氯化鈀(II)、三苯基膦及碘化銅(I)之等分試樣(類似於初始添加量)。再繼續加熱5小時，屆時用水(20 mL)稀釋混合物且萃取至乙酸乙酯(3×20 mL)中。乾燥(硫酸鈉)經合併之萃取物，過濾且在真空下濃縮。在矽膠上(己烷/乙酸乙酯(4：1至1：0))純化該物質，得到呈灰白色固體狀之1-甲基-3-(4-(5-甲基吡啶-3-基氧基)-5-((三甲基矽烷基)乙炔基)吡啶-2-基)脲(780 mg，74%產率)。MS(apci)m/z 354.9(M+H)。 Step A : Purification of 1-(5-bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (1000 mg, 2.966 mmol) with nitrogen, Ethynyl trimethyl decane (1182 μL, 8.304 mmol), triethylamine (1240 μL, 8.988 mmol), bis(triphenylphosphine)palladium(II) chloride (104 mg, 0.148 mmol), triphenylphosphine (39 mg, 0.148 mmol) and a mixture of copper iodide (I) (14 mg, 0.074 mmol) in anhydrous dimethylformamide (DMF) (2 mL) and sealed in a magnetic stirring vial. The mixture was heated at 90 ° C for 8 hours. Thereafter, an aliquot of ethynyl trimethyl decane, triethylamine, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine and copper (I) iodide was added (similar to the initial addition). the amount). Heating was continued for a further 5 hours, at which time the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried (Na2SO4), filtered and evaporated. The material was purified on EtOAc (EtOAc/EtOAc (EtOAc:EtOAc) Oxy)-5-((trimethyldecyl)ethynyl)pyridin-2-yl)urea (780 mg, 74% yield). MS (apci) m/z 354.9 (M+H).

步驟B：向1-甲基-3-(4-(5-甲基吡啶-3-基氧基)-5-((三甲基矽烷基)乙炔基)吡啶-2-基)脲(838 mg，2.36 mmol)於甲醇(10 mL)中之混合物溶液中添加碳酸鉀(653 mg，4.73 mmol)，且在周圍溫度下攪拌混合物5小時。在氮氣流下移除甲醇。將殘餘物與含有甲醇(5%)之二氯甲烷(50 mL)混合。用水(30 mL)洗滌懸浮液，乾燥(硫酸鎂及硫酸鈉)，過濾且在減壓下濃縮，得到呈奶白色固體狀之1-(5-乙炔基-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(490 mg，73%產率)。MS(apci)m/z 282.9(M+H)。 Step B : To 1-methyl-3-(4-(5-methylpyridin-3-yloxy)-5-((trimethyldecyl)ethynyl)pyridin-2-yl)urea (838 Potassium carbonate (653 mg, 4.73 mmol) was added to a mixture solution of EtOAc (EtOAc) (EtOAc) The methanol was removed under a stream of nitrogen. The residue was mixed with dichloromethane (50 mL) containing methanol (5%). The suspension was washed with water (30 mL) EtOAc (EtOAc m. 3-yloxy)pyridin-2-yl)-3-methylurea (490 mg, 73% yield). MS (apci) m/z 282.9 (M+H).

實例1554Example 1554

1-(5-溴-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

將6-(三氟甲基)吡啶-3-醇(360 mg，2.21 mmol)溶解於DMA(5 mL)中，且添加氫化鈉(88.3 mg，2.21 mmol)，且在室溫下攪拌反應物10分鐘。添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(548 mg，2.21 mmol)，且加熱反應物至100℃隔夜。冷卻反應物至室溫，用水(25 mL)稀釋，攪拌10分鐘，過濾且乾燥。用CH2Cl2濕磨固體，過濾且乾燥，得到呈白色固體狀之1-(5-溴-4-(6-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(580 mg，1.48 mmol，67.2%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.33(s,1H),8.75(d,J=2.5 Hz,1H),8.41(s,1H),8.06(d,J=8.8 Hz,1H),7.94(dd,J=8.6,2.7 Hz,1H),7.32(m,1H),7.22(s,1H),2.64(d,J=4.7 Hz,3H)。質譜(apci)m/z=390.7,392.7(M+H)。 6-(Trifluoromethyl)pyridin-3-ol (360 mg, 2.21 mmol) was dissolved in EtOAc (5 mL) and sodium hydride (88.3 mg, 2.21 mmol). 10 minutes. 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (548 mg, 2.21 mmol) was added and the reaction was taken to 100 ° C overnight. The reaction was cooled to room temperature, diluted with water (25 mL) and stirred for 10 min, filtered and dried. Triturated with CH 2 Cl 2 The solid was filtered and dried to give a white solid of 1- (5-bromo-4- (6- (trifluoromethyl) pyridin-3-yloxy) pyridin-2-yl )-3-methylurea (580 mg, 1.48 mmol, 67.2% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.33 (s, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H) ), 7.94 (dd, J = 8.6, 2.7 Hz, 1H), 7.32 (m, 1H), 7.22 (s, 1H), 2.64 (d, J = 4.7 Hz, 3H). Mass spectrum (apci) m/z = 390.7, 392.7 (M+H).

實例1555Example 1555

3-((6'-乙氧基-6-(3-甲基脲基)-[3,3'-聯吡啶]-4-基)氧基)-4-氟苯甲酸甲酯 Methyl 3-((6'-ethoxy-6-(3-methylureido)-[3,3'-bipyridin]-4-yl)oxy)-4-fluorobenzoate

步驟A：使用與實例1554相同之方法，用4-氟-3-羥基苯甲酸甲酯替代6-(三氟甲基)吡啶-3-醇，獲得3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.713 g，1.79 mmol，44.4%產率)。 Step A : Using the same procedure as in Example 1554, substituting methyl 4-fluoro-3-hydroxybenzoate for 6-(trifluoromethyl)pyridin-3-ol afforded 3-(5-bromo-2-(3) Methyl methylureido)pyridin-4-yloxy)-4-fluorobenzoate (0.713 g, 1.79 mmol, 44.4% yield).

步驟B：在5 mL二噁烷中組合6-乙氧基吡啶-3-基酸(0.126 g，0.753 mmol)、3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.200 g，0.502 mmol)及K3PO4(0.753 ml，1.51 mmol)，且將此物質用氬氣充氣10分鐘，隨後添加PdCl2(dppf)*DCM(0.0615 g，0.0753 mmol)且繼續充氣5分鐘，隨後密封反應物且加熱至100℃隔夜。此後，用二氯甲烷稀釋反應物，直接加載於矽膠上(含10%-15%丙酮之二氯甲烷)，得到3-(6'-乙氧基-6-(3-甲基脲基)-3,3'-聯吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.143 g，0.308 mmol，61.4%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.05(s,1H),8.33(d,J=2.3 Hz,1H),8.19(s,1H),8.10(s,1H),7.95(m,1H),7.85(dd,J=7.6,1.9 Hz,1H),7.81(dd,J=8.6,2.3 Hz,1H),7.27(m,1H),6.80(d,J=8.6 Hz,1H),6.04(s,1H),4.40(q,J=7.0 Hz,2H),3.91(s,3H),2.83(d,J=4.7 Hz,3H),1.42,(t,J=7.0 Hz,3H)。質譜(apci)m/z=441.2(M+H)。 Step B : Combining 6-ethoxypyridin-3-yl in 5 mL of dioxane Acid (0.126 g, 0.753 mmol), methyl 3-(5-bromo-2-(3-methylureido)pyridin-4-yloxy)-4-fluorobenzoate (0.200 g, 0.502 mmol) K 3 PO 4 (0.753 ml, 1.51 mmol), and this material was then inflated with argon for 10 min, then PdCl 2 (dppf)*DCM (0.0615 g, 0.0753 mmol) was added and the aeration was continued for 5 minutes, then the reaction was sealed and Heat to 100 ° C overnight. Thereafter, the reaction was diluted with dichloromethane and directly loaded onto silica gel (dichloromethane containing 10% to 15% acetone) to give 3-(6'-ethoxy-6-(3-methylureido). Methyl-3,3'-bipyridin-4-yloxy)-4-fluorobenzoate (0.143 g, 0.308 mmol, 61.4% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.05 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.95 (m, 1H) ), 7.85 (dd, J = 7.6, 1.9 Hz, 1H), 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.27 (m, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.04 (s, 1H), 4.40 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 2.83 (d, J = 4.7 Hz, 3H), 1.42, (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 441.2 (M+H).

遵循實例1555中之程序，亦可合成以下化合物： Following the procedure in Example 1555, the following compounds were also synthesized:

遵循實例78中之程序，合成以下化合物： Following the procedure in Example 78, the following compounds were synthesized:

遵循實例145中之程序，亦合成以下化合物： Following the procedure in Example 145, the following compounds were also synthesized:

遵循實例155中之程序，亦合成以下化合物： Following the procedure in Example 155, the following compounds were also synthesized:

實例1586Example 1586

1-(5-(2-乙氧基嘧啶-5-基)-4-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(2-ethoxypyrimidin-5-yl)-4-(1-methyl-6-yloxy-1,6-dihydropyridin-3-yloxy)pyridine-2- 3-methylurea

將1-(5-溴-4-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(50 mg，0.14 mmol)懸浮於二噁烷(1 mL)中，且添加2 M K2CO3(142 μl，0.28 mmol)及2-乙氧基嘧啶-5-基酸(36 mg，0.21 mmol)，且使氮氣鼓泡通過反應物，持續5分鐘。添加PdCl2(dppf)*DCM(12 mg，0.014 mmol)，且加熱反應物至90℃，維持1小時。冷卻反應物至室溫，分配於水與DCM之間，用DCM、含10% MeOH之DCM萃取，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含15% MeOH之EtOAc)純化殘餘物，得到不純物質。在C18逆相管柱上(含5%至95% ACN之水)純化固體，得到呈白色固體狀之1-(5-(2-乙氧基嘧啶-5-基)-4-(1-甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(23 mg，0.058 mmol，41%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.99(s,1H0,8.67(s,2H),8.29(s,1H),8.09(s,1H),7.26-7.20(m,2H), 6.65(d,J=9.6 Hz,1H),6.24(s,1H),4.48(q,J=6.7 Hz,2H),3.55(s,3H),2.89(d,J=4.7 Hz,3H),1.47(t,J=6.7 Hz,3H)。質譜(APCI)m/z=396.8(M+H)。 1-(5-Bromo-4-(1-methyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3-methylurea (50 Mg, 0.14 mmol) suspended in dioxane (1 mL) with 2 MK 2 CO 3 (142 μl, 0.28 mmol) and 2-ethoxypyrimidin-5-yl Acid (36 mg, 0.21 mmol) and nitrogen was bubbled through the reaction for 5 min. PdCl 2 (dppf) * DCM (12 mg, 0.014 mmol) was added and the reaction was heated to 90 ° C for 1 hour. The reaction was cooled to EtOAc EtOAc (EtOAc m. The residue was purified on EtOAc (EtOAc EtOAc) The solid was purified on a C18 reverse phase column (water containing 5% to 95% ACN) to give 1-(5-(2-ethoxypyrimidin-5-yl)-4-(1- Methyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3-methylurea (23 mg, 0.058 mmol, 41% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.99 (s, 1H0, 8.67 (s, 2H), 8.29 (s, 1H), 8.09 (s, 1H), 7.26-7.20 (m, 2H), 6.65 ( d, J = 9.6 Hz, 1H), 6.24 (s, 1H), 4.48 (q, J = 6.7 Hz, 2H), 3.55 (s, 3H), 2.89 (d, J = 4.7 Hz, 3H), 1.47 ( t, J = 6.7 Hz, 3H) Mass Spectrum (APCI) m/z = 396.8 (M+H).

遵循實例1586中之程序，亦合成以下化合物： Following the procedure in Example 1586, the following compounds were also synthesized:

實例1604Example 1604

2-(4-(4-(3-氯-2-氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-1H-吡唑-1-基)乙酸 2-(4-(4-(3-Chloro-2-fluorophenoxy)-6-(3-methylureido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

將1-(5-溴-4-(3-氯-2-氟苯氧基)吡啶-2-基)-3-甲基脲(100 mg，0.267 mmol)溶解於密封管中之二噁烷(1 mL)中，且添加2 M碳酸鉀(400 μl，0.801 mmol)及2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H- 吡唑-1-基)乙酸乙酯(112 mg，0.400 mmol)，且使氮氣鼓泡通過，持續5分鐘。添加PdCl2(dppf)*DCM(21.8 mg，0.0267 mmol)，且使氮氣鼓泡通過，持續2分鐘，且將反應物密封並傾沒於100℃油浴中隔夜。冷卻反應物至室溫，添加水(10 mL)，且過濾所得固體。在C18逆相管柱上(含5%至95% ACN之水)純化固體，得到呈白色固體狀之2-(4-(4-(3-氯-2-氟苯氧基)-6-(3-甲基脲基)吡啶-3-基)-1H-吡唑-1-基)乙酸(15.3 mg，0.0364 mmol，13.7%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.12(s,1H),8.48(s,1H),9.09(s,1H),7.85(s,1H),7.68(m,1H),7.58(t,J=7.0 Hz,2H),7.42(t,J=7.2 Hz,1H),7.36(t,J=8.0 Hz,1H),6.90(s,1H),4.60(s,2H),2.65(d,J=4.5 Hz,3H)。質譜(APCI)m/z=420.1(M+H)。 Dissolving 1-(5-bromo-4-(3-chloro-2-fluorophenoxy)pyridin-2-yl)-3-methylurea (100 mg, 0.267 mmol) in dioxane in a sealed tube (1 mL) with 2 M potassium carbonate (400 μl, 0.801 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Ethyl-2-phenyl)-1H-pyrazol-1-yl)acetate (112 mg, 0.400 mmol) was bubbled with nitrogen for 5 min. PdCl 2 (dppf) * DCM (21.8 mg, 0.0267 mmol) was added and nitrogen was bubbled through for 2 min and the reaction was sealed and poured in a 100 ° C oil bath overnight. The reaction was cooled to room rt, water (10 mL) was evaporated and filtered. The solid was purified on a C18 reverse phase column (water containing 5% to 95% ACN) to give 2-(4-(4-chloro-2-fluorophenoxy)-6- as a white solid. (3-Methylureido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid (15.3 mg, 0.0364 mmol, 13.7% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.12 (s, 1H), 8.48 (s, 1H), 9.09 (s, 1H), 7.85 (s, 1H), 7.68 (m, 1H), 7.58 (t, J = 7.0 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.90 (s, 1H), 4.60 (s, 2H), 2.65 (d, J = 4.5 Hz, 3H). Mass Spectrum (APCI) m/z = 420.1 (M+H).

遵循實例155中之程序，用TBAF替代K2CO3且使用適當起始物質來製備以下化合物： Following the procedure in Example 155, TBAF was used in place of K 2 CO 3 and the appropriate starting materials were used to prepare the following compounds:

實例1608Example 1608

(R)-1-(6'-乙氧基-4-((5-(1-羥基乙基)吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 (R)-1-(6'-ethoxy-4-((5-(1-hydroxyethyl)pyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl -3-methylurea

步驟A：藉由對掌性層析(管柱：IC 20 mm×250 mm，流動速率：40 mL/min，MPA=60%(超臨界CO2)，MPB=40%(90：10：0.1 MeOH：異丙醇：DEA)分離實例1607所得之外消旋物質。此物質來自第一溶離峰且任意地指定立體化學。1H NMR(400 MHz,CDCl3)δ ppm 9.02(s,1H),8.47(s,1H),8.37(d,J=1.8 Hz,1H),8.30(d,J=2.5 Hz,1H),8.27(d,J=2.3 Hz,1H),6.79(d,J=8.6 Hz,1H),6.22(s,1H),4.98-4.91(m,1H),4.39(q,J=7.0 Hz,2H),3.33(s,1H),2.83(d,J=4.7 Hz,3H),1.49(d,J=6.4 Hz,3H),1.41(t,J=7.0 Hz,3H)。質譜(apci)m/z=410.1(M+H)。 Step A : by palm chromatography (column: IC 20 mm × 250 mm, flow rate: 40 mL/min, MPA = 60% (supercritical CO 2 ), MPB = 40% (90: 10: 0.1) MeOH: isopropanol: DEA) The racemic material obtained in Example 1607 was isolated. This material was obtained from the first elution peak and arbitrarily designated stereochemistry. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.02 (s, 1H) , 8.47 (s, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.22 (s, 1H), 4.98-4.91 (m, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.33 (s, 1H), 2.83 (d, J = 4.7 Hz, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 410.1 (M+H).

遵循上述程序，作為第二溶離峰分離以下化合物且任意地指定立體化學： Following the procedure described above, the following compounds were isolated as the second elution peak and the stereochemistry was arbitrarily assigned:

遵循實例155中之程序，用NaH替代K2CO3且使用適當起始物質來製備以下化合物： Follow the procedure of Example 155, was treated with NaH and substitute K 2 CO 3 following compounds were prepared using the appropriate starting materials:

實例1615Example 1615

1-(4-(3-氯-2-氰基苯氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲 1-(4-(3-Chloro-2-cyanophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea

步驟A：在室溫下，於20 mL DMA中組合60%氫化鈉(1.209 g，30.24 mmol)及苯基甲醇(3.132 ml，30.24 mmol)，且攪拌4小時。添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(5.0 g，20.16 mmol)，且在70℃下攪拌反應物72小時。冷卻反應物至室溫，且用120 mL水稀釋並劇烈攪拌。經由真空過濾收集固體且在真空烘箱中乾燥，得到1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(6.59 g，19.60 mmol，97.25%產率)。 Step A : 60% sodium hydride (1.209 g, 30.24 mmol) and phenylmethanol (3.132 ml, 30.24 mmol) were combined in 20 mL DMA at room temperature and stirred for 4 h. 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (5.0 g, 20.16 mmol) was added, and the reaction was stirred at 70 ° C for 72 hr. The reaction was cooled to room temperature and diluted with 120 mL water and stirred vigorously. The solid was collected via vacuum filtration and dried in vacuo to give 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (6.59 g, 19.60 mmol, 97.25% yield ).

步驟B：在30 mL二噁烷中組合1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(4.0 g，12 mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2- 基)-1H-吡唑(3.7 g，18 mmol)及碳酸鉀(18 ml，36 mmol)，且將此物質用氬氣充氣10分鐘。添加PdCl2(dppf)*DCM(1.5 g，1.8 mmol)，且將反應物充氣10分鐘，隨後將其密封且加熱至100℃，維持5小時。冷卻反應物至室溫，傾倒至水中且用EtOAc(3×100 ml)、DCM(1x100 mL)萃取，經硫酸鈉乾燥，過濾並濃縮。在矽膠上(含15%至30%丙酮之DCM w/0.5% NH4OH)純化固體，得到1-(4-(苄氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(2.0 g，5.9 mmol，50%產率)。 Step B : Combine 1-(4-(benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (4.0 g, 12 mmol), 1-methyl- in 30 mL of dioxane. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (3.7 g, 18 mmol) and potassium carbonate (18 ml, 36 mmol), and this material was then inflated with argon for 10 min. PdCl 2 (dppf) * DCM (1.5 g, 1.8 mmol) was added and the reaction was inflated for 10 min, then sealed and heated to 100 ° C for 5 h. The reaction was cooled to EtOAc EtOAc (EtOAc)EtOAc. The solid was purified on silica gel (15% to 30% acetone in DCM w / 0.5% NH 4 OH) to give 1-(4-(benzyloxy)-5-(1-methyl-1H-pyrazole-4 -yl)pyridin-2-yl)-3-methylurea (2.0 g, 5.9 mmol, 50% yield).

步驟C：將1-(4-(苄氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(2.0 g，5.9 mmol)及2-胺基乙硫醇鹽酸鹽(1.0 g，8.9 mmol)溶解於6 N HCl(28 ml，166 mmol)中，且加熱至90℃，維持12小時。向各別燒瓶中添加350 mL飽和K2CO3溶液。向此物質中逐滴添加反應溶液直至開始產生泡沫。再添加20 mL飽和K2CO3，繼而添加反應溶液直至產生泡沫。重複此過程直至所有反應溶液消耗且新溶液之pH值為7。添加DCM(500 mL)且劇烈攪拌。過濾溶劑混合物且乾燥固體，得到1-(4-羥基-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(1.2 g，4.6 mmol，78%產率)。 Step C : 1-(4-(Benzyloxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea (2.0 g, 5.9 mmol And 2-aminoethanethiol hydrochloride (1.0 g, 8.9 mmol) was dissolved in 6 N HCl (28 mL, 166 mmol) and warmed to 90 ° C for 12 h. 350 mL of saturated K 2 CO 3 solution was added to each flask. The reaction solution was added dropwise to this material until foaming started. An additional 20 mL of saturated K 2 CO 3 was added, followed by the addition of the reaction solution until foaming occurred. This process was repeated until all of the reaction solution was consumed and the pH of the new solution was 7. DCM (500 mL) was added and stirred vigorously. The solvent mixture was filtered and dried to give 1-(4-hydroxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea (1.2 g, 4.6 mmol , 78% yield).

步驟D：在2 mL DMA中組合2-氯-6-氟苄腈(38 mg，0.24 mmol)、1-(4-羥基-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(40 mg，0.16 mmol)及碳酸鉀(45 mg，0.32 mmol)，且將其加熱至80℃，維持3小時。冷卻反應物至室溫，且添加4 mL水並攪拌10分鐘。過濾沈澱物且乾燥。在劇烈攪拌下於Et2O中濕磨固體2小時，過濾且乾燥，得到1-(4-(3-氯-2-氰基苯氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(26 mg，40%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.20(s,1H),8.54(s,1H),8.11(s,1H),7.88(s,1H),7.80(t,J=8.2 Hz,1H),7.66(d,J=8.2 Hz,1H),7.46(m,1H),7.32(d,J=8.4 Hz,1H),7.08(s,1H),3.85(s,3H),2.66(d,J=4.3 Hz,3H)。質譜(apci)m/z=383.1(M+H)。 Step D : Combine 2-chloro-6-fluorobenzonitrile (38 mg, 0.24 mmol) in 1-mL DMA, 1-(4-hydroxy-5-(1-methyl-1H-pyrazol-4-yl) Pyridin-2-yl)-3-methylurea (40 mg, 0.16 mmol) and potassium carbonate (45 mg, 0.32 mmol), and warmed to 80 ° C for 3 hr. The reaction was cooled to room temperature and 4 mL water was added and stirred for 10 min. The precipitate was filtered and dried. The solid was wet-milled in Et 2 O for 2 hours with vigorous stirring, filtered and dried to give 1-(4-(3-chloro-2-cyanophenoxy)-5-(1-methyl-1H-pyridin Zol-4-yl)pyridin-2-yl)-3-methylurea (26 mg, 40% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.20 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.80 (t, J = 8.2 Hz, 1H) ), 7.66 (d, J = 8.2 Hz, 1H), 7.46 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 3.85 (s, 3H), 2.66 (d) , J = 4.3 Hz, 3H). Mass spectrum (apci) m/z = 383.1 (M+H).

遵循實例1615中之程序，亦合成以下化合物： Following the procedure in Example 1615, the following compounds were also synthesized:

實例1622Example 1622

1-(4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-5-(四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲 1-(4-(1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)-5-(tetrahydro-2H-pyran-4-yl) Pyridin-2-yl)-3-methylurea

將1-(5-(3,6-二氫-2H-哌喃-4-基)-4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(18 mg，0.049 mmol)懸浮於1：1 MeOH：EtOAc中，且添加10% Pd/C(18 mg)，且置於氫氣球壓力下隔夜。替換氫氣球，且加熱反應物至45℃，維持2天，同時不時地再填充氫氣球。冷卻反應物至室溫，經矽藻土過濾，濃縮且在矽膠上(含10% MeOH之EtOAc)純化，得到呈褐色固體狀之1-(4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-5-(四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲(13 mg，0.035 mmol，72%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.14(s,1H),8.13(s,1H),7.96(s,1H),7.10(d,J=9.8 Hz,1H),6.54(d,J=9.6 Hz,1H),5.94(s,1H),4.10(dd,J=11.2,3.9 Hz,2H),3.61-3.54(m,5H),3.12(m,1H),2.85(d,J=4.5 Hz,3H),2.23(s,3H),1.98-1.77(m,4H)。質譜(apci)m/z=372.9(M+H)。 1-(5-(3,6-Dihydro-2H-piperidin-4-yl)-4-(1,2-dimethyl-6-o-oxy-1,6-dihydropyridine-3 - oxy)pyridin-2-yl)-3-methylurea (18 mg, 0.049 mmol) was suspended in 1:1 MeOH:EtOAc, and 10% Pd / C (18 mg) Balloon pressure under the night. The hydrogen balloon was replaced and the reaction was heated to 45 ° C for 2 days while refilling the hydrogen balloon from time to time. The reaction was cooled to room temperature, EtOAc (EtOAc)EtOAc. Sideoxy-1,6-dihydropyridin-3-yloxy)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylurea (13 mg, 0.035 mmol, 72% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.14 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.10 (d, J = 9.8 Hz, 1H), 6.54 (d, J = 9.6 Hz, 1H), 5.94 (s, 1H), 4.10 (dd, J = 11.2, 3.9 Hz, 2H), 3.61-3.54 (m, 5H), 3.12 (m, 1H), 2.85 (d, J = 4.5 Hz, 3H), 2.23 (s, 3H), 1.98-1.77 (m, 4H). Mass spectrum (apci) m/z = 372.9 (M+H).

實例1623Example 1623

1-(6'-乙氧基-4-(1-甲基-2-側氧基-6-(三氟甲基)-1,2-二氫吡啶-4-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(6'-ethoxy-4-(1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yloxy)-3, 3'-bipyridyl-6-yl)-3-methylurea

步驟A：經50分鐘，向水浴中之3-胺基-4,4,4-三氟巴豆酸乙酯(10.0 g，54.61 mmol)於DCM(50 mL)及吡啶(5.18 g，5.3 mL，65.53 mmol)中之溶液中逐滴添加乙基丙二醯氯(10.28 g，8.74 mL，68.26 mmol)。在周圍溫度下攪拌混合物48小時。用EtOAc稀釋溶液，且用水、1 N HCl、飽和NaHCO3水溶液洗滌，乾燥(MgSO4)且濃縮至12.96 g呈黃橙色油狀粗3-(3-乙氧基-3-側氧基丙醯胺基)-4,4,4-三氟丁-2-烯酸乙酯，其未經進一步純化即繼續使用。 Step A : 3-Amino-4,4,4-trifluorocrotonate ethyl ester (10.0 g, 54.61 mmol) in DCM (50 mL) and pyridine (5.18 g, 5.3 mL, Ethylpropionyl chloride (10.28 g, 8.74 mL, 68.26 mmol) was added dropwise to the solution in 65.53 mmol. The mixture was stirred at ambient temperature for 48 hours. The solution was diluted with EtOAc, and washed with water, 1 N HCl, washed with saturated aqueous NaHC03, dried (MgSO 4) and concentrated to a yellow-orange oil 12.96 g crude 3- (3-ethoxy-3-oxoprop-XI Ethyl)-4,4,4-trifluorobut-2-enoate, which was used without further purification.

步驟B：經25分鐘，向在水浴上冷卻之粗3-(3-乙氧基-3-側氧基丙醯胺基)-4,4,4-三氟丁-2-烯酸乙酯(12.96 g，43.6 mmol)於EtOH(90 mL)中之溶液中逐份添加第三丁醇鉀(9.05 g，80.67 mmol)。添加完成後，在70℃下加熱混合物2小時，接著使其冷卻且在室溫下攪拌隔夜。 Step B : Crude 3-(3-ethoxy-3-oxopropoxyamino)-4,4,4-trifluorobut-2-enoate ethyl ester cooled to 25 min. (12.96 g, 43.6 mmol) Potassium tert-butoxide (9.05 g, 80.67 mmol) was added portionwise in a solution of EtOH (90 mL). After the addition was completed, the mixture was heated at 70 ° C for 2 hours, then allowed to cool and stirred at room temperature overnight.

在減壓下移除溶劑，且將黃橙色固體殘餘物於飽和檸檬酸溶液(100 mL)中攪拌30分鐘。過濾所得懸浮液且用檸檬酸溶液洗滌數次，得到呈淡粉紅色固體狀之粗4-羥基-2-側氧基-6-(三氟甲基)-1,2-二氫吡啶-3-甲酸乙酯(13 g)。 The solvent was removed under reduced pressure, and a yellow-yellow solid residue was stirred in saturated citric acid (100 mL) for 30 min. The resulting suspension was filtered and washed with citric acid solution several times to give crude 4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3 as a pale pink solid. - ethyl formate (13 g).

步驟C：向經攪拌之6 M HCl溶液(100 mL)中逐份添加4-羥基-2- 側氧基-6-(三氟甲基)-1,2-二氫吡啶-3-甲酸乙酯(13.0 g，51.8 mmol)，且在回流下加熱所得懸浮液隔夜。在冰浴中冷卻溶液且用氫氧化銨中和。藉由過濾收集所形成之沈澱物，且用冷水及己烷洗滌並乾燥，得到呈奶白色固體狀之4-羥基-6-(三氟甲基)吡啶-2(1H)-酮(6.62 g，37.0 mmol，71%產率)。 Step C : Partial addition of 4-hydroxy-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate B to a stirred 6 M HCl solution (100 mL) Ester (13.0 g, 51.8 mmol) and the resulting suspension was heated at reflux overnight. The solution was cooled in an ice bath and neutralized with ammonium hydroxide. The precipitate formed was collected by filtration, washed with cold water and hexanes and dried to give 4-hydroxy-6-(trifluoromethyl)pyridine-2(1H)-one as a milky white solid (6.62 g , 37.0 mmol, 71% yield).

步驟D：在0℃下，向4-羥基-6-(三氟甲基)吡啶-2(1H)-酮(1.75 g，9.77 mmol)及K2CO3(3.38 g，24.4 mmol)於DMF(20 mL)中之溶液中添加碘甲烷(0.730 mL，11.7 mmol)。在0℃下攪拌混合物，且緩慢升溫至周圍溫度並在周圍溫度下攪拌隔夜。向反應混合物中再饋入K2CO3(3.38 g，24.4 mmol)及MeI(2.77 g，1.22 mL，19.5 mmol)，且在室溫下攪拌混合物18小時。添加水(100 mL)，使得沈澱物分離，藉由過濾收集該沈澱物，用水洗滌且乾燥，得到呈奶白色固體狀之2,4-二甲氧基-6-(三氟甲基)吡啶(570 mg，2.75 mmol，28%產率)。用10% IPA-DCM(3×40 mL)萃取水層，且用鹽水洗滌經合併之萃取物，且乾燥(MgSO4)並濃縮。在矽膠上(含40% EtOAc之己烷)純化所獲得之殘餘物，得到呈白色固體狀之4-甲氧基-1-甲基-6-(三氟甲基)吡啶-2(1H)-酮(500 mg，2.41 mmol，24.7%產率)。 Step D : 4-hydroxy-6-(trifluoromethyl)pyridine-2(1H)-one (1.75 g, 9.77 mmol) and K 2 CO 3 (3.38 g, 24.4 mmol) in DMF at 0 °C Methyl iodide (0.730 mL, 11.7 mmol) was added to the solution in (20 mL). The mixture was stirred at 0 ° C and slowly warmed to ambient temperature and stirred overnight at ambient temperature. K 2 CO 3 (3.38 g, 24.4 mmol) and MeI (2.77 g, 1.22 mL, 19.5 mmol) were further added to the mixture, and the mixture was stirred at room temperature for 18 hr. Water (100 mL) was added to separate the precipitate, which was collected by filtration, washed with water and dried to give 2,4-dimethoxy-6-(trifluoromethyl)pyridine as a milky white solid. (570 mg, 2.75 mmol, 28% yield). The aqueous layer was extracted with 10% IPA-DCM (3 × 40 mL), washed with brine and the extracts were combined and dried (MgSO 4) and concentrated. The residue was purified on EtOAc (EtOAc EtOAcEtOAc - Ketone (500 mg, 2.41 mmol, 24.7% yield).

步驟E：將4-甲氧基-1-甲基-6-(三氟甲基)吡啶-2(1H)-酮(500 mg，2.41 mmol)於1.0 N NaOH(20 mL)及THF(7 mL)中之溶液在100℃下加熱72小時。在冰浴上冷卻混合物且用1 N HCl酸化，將pH值調整至3，接著用5% IPA-EtOAc萃取。用鹽水洗滌經合併之有機萃取物，接著乾燥(MgSO4)且濃縮，得到呈淡黃色固體狀之4-羥基-1-甲基-6-(三氟甲基)吡啶-2(1H)-酮(345 mg，1.79 mmol，74%產率)。 Step E : 4-Methoxy-1-methyl-6-(trifluoromethyl)pyridine-2(1H)-one (500 mg, 2.41 mmol) in 1.0 N NaOH (20 mL) The solution in mL) was heated at 100 ° C for 72 hours. The mixture was cooled on an ice-bath and EtOAc (EtOAc)EtOAc. Washed with brine the combined organic extracts were then dried (MgSO 4) and concentrated to give a light yellow solid of 4-hydroxyl-methyl-6- (trifluoromethyl) pyridin -2 (1H) - Ketone (345 mg, 1.79 mmol, 74% yield).

步驟F：將4-羥基-1-甲基-6-(三氟甲基)吡啶-2(1H)-酮(100 mg，0.518 mmol)溶解於DMA(2.5 mL)中，且添加60%氫化鈉(20.7 mg，0.518 mmol)，且在室溫下攪拌10分鐘。添加1-(5-溴-4-氟吡啶-2-基)- 3-甲基脲(107 mg，0.432 mmol)，且加熱反應物至100℃隔夜，接著加熱至120℃再次隔夜。冷卻反應物至室溫，且用水(8 mL)稀釋並劇烈攪拌20分鐘，過濾且乾燥，得到呈褐色固體狀之1-(5-溴-4-(1-甲基-2-側氧基-6-(三氟甲基)-1,2-二氫吡啶-4-基氧基)吡啶-2-基)-3-甲基脲(94 mg，0.223 mmol，51.7%產率)。 Step F : Dissolving 4-hydroxy-1-methyl-6-(trifluoromethyl)pyridine-2(1H)-one (100 mg, 0.518 mmol) in DMA (2.5 mL) with 60% hydrogenation Sodium (20.7 mg, 0.518 mmol) was stirred at room temperature for 10 min. 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (107 mg, 0.432 mmol) was added and the reaction was warmed to 100 &lt;0&gt;C overnight, then warmed to 120 &lt;0&gt;C overnight. The reaction was cooled to room temperature and then diluted with H~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -6-(Trifluoromethyl)-1,2-dihydropyridin-4-yloxy)pyridin-2-yl)-3-methylurea (94 mg, 0.223 mmol, 51.7% yield).

步驟G：將1-(5-溴-4-(1-甲基-2-側氧基-6-(三氟甲基)-1,2-二氫吡啶-4-基氧基)吡啶-2-基)-3-甲基脲(40 mg，0.095 mmol)溶解於二噁烷(1 mL)中，且添加2 M K2CO3(95 μl，0.19 mmol)及6-乙氧基吡啶-3-基酸(24 mg，0.14 mmol)，且使氮氣鼓泡通過混合物，持續5分鐘。添加PdCl2(dppf)*DCM(7.8 mg，0.0095 mmol)，且在100℃下攪拌反應物隔夜。冷卻反應物至室溫，分配於50%鹽水與EtOAc之間，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含90% EtOAc之己烷)純化，得到呈白色固體狀之1-(6'-乙氧基-4-(1-甲基-2-側氧基-6-(三氟甲基)-1,2-二氫吡啶-4-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(17 mg，0.037 mmol，39%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.88(s,1H),8.24(m,2H),8.19(m,1H),7.61(m,1H),6.76(d,J=8.6 Hz,1H),6.61(s,1H),6.47(d,J=2.5 Hz,1H),5.95(d,J=2.5 Hz,1H),4.37(q,J=7.0 Hz,2H),3.54(s,3H),2.96(d,J=4.1 Hz,3H),1.40(t,J=7.0 Hz,3H)。質譜(apci)m/z=463.7(M+H)。 Step G : 1-(5-Bromo-4-(1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-4-yloxy)pyridine- 2-Methyl)-3-methylurea (40 mg, 0.095 mmol) was dissolved in dioxane (1 mL) and 2 MK 2 CO 3 (95 μl, 0.19 mmol) and 6-ethoxy pyridine - 3-base Acid (24 mg, 0.14 mmol) and nitrogen was bubbled through the mixture for 5 min. PdCl 2 (dppf) * DCM (7.8 mg, 0.0095 mmol) was added and the mixture was stirred at 100 ° C overnight. The reaction was cooled to rt EtOAc (EtOAc m. Purify on silica gel (90% EtOAc in hexanes) to afford 1-(6'-ethoxy-4-(1-methyl-2-oxo-6-(trifluoro) Base,-1,2-dihydropyridin-4-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea (17 mg, 0.037 mmol, 39% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.88 (s, 1H), 8.24 (m, 2H), 8.19 (m, 1H), 7.61 (m, 1H), 6.76 (d, J = 8.6 Hz, 1H ), 6.61 (s, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.95 (d, J = 2.5 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 3.54 (s, 3H) ), 2.96 (d, J = 4.1 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 463.7 (M+H).

實例1624Example 1624

1-(5-環丙基-4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-Cyclopropyl-4-((1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)pyridin-2-yl)-3 -methylurea

步驟A：將5-羥基-1,6-二甲基吡啶-2(1H)-酮(1.6 g，11.5 mmol)及K2CO3(1.59 g，11.5 mmol)於DMA(35 mL)中攪拌5分鐘，且添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.19 g，8.84 mmol)，且加熱反應物至90℃隔夜。冷卻反應物至室溫，用水(250 mL)稀釋，攪拌10分鐘且過濾。用1：1 Et2O：DCM(100 mL)濕磨固體，且攪拌20分鐘並過濾，得到1.05 g產物。初始水層中有更多固體沈下。如上所述過濾並濕磨此等固體，總共得到呈褐色固體狀之1-(5-溴-4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(1.35 g，3.68 mmol，41.6%產率)。 Step A : Stirring 5-hydroxy-1,6-lutidine-2(1H)-one (1.6 g, 11.5 mmol) and K 2 CO 3 (1.59 g, 11.5 mmol) in DMA (35 mL) For 5 minutes, 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (2.19 g, 8.84 mmol) was added and the mixture was evaporated to EtOAc. The reaction was cooled to room temperature, diluted with water (250 mL), stirred for 10 min and filtered. With 1: 1 Et 2 O: DCM (100 mL) triturated solid, and stirred for 20 minutes and filtered to give 1.05 g of product. More solids sink in the initial water layer. The solids were filtered and wet-ground as described above to give a total of 1-(5-bromo-4-(1,2-dimethyl-6-oxo-1,6-dihydropyridine) as a brown solid. 3-Hydroxy)pyridin-2-yl)-3-methylurea (1.35 g, 3.68 mmol, 41.6% yield).

步驟B：將1-(5-溴-4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(250 mg，0.681 mmol)溶解於10：1甲苯：水(8 mL)中且使氮氣鼓泡通過。在鼓泡下，添加環丙基三氟硼酸鉀(403 mg，2.72 mmol)、二乙醯氧基鈀(22.9 mg，0.102 mmol)及K3PO4(434 mg，2.04 mmol)。添加二環己基(2',6'-二異丙氧基聯苯-2-基)膦(95.3 mg，0.204 mmol)，且使氮氣鼓泡通過，再持續1分鐘。密封反應物且加熱至100℃，維持30小時，且冷卻至室溫。用DCM稀釋反應物，經矽藻土過濾，用含10% MeOH之DCM洗滌。濃縮濾液且在矽膠上(含5%至10% MeOH之EtOAc)純化，得到淺黃色固體。用含25% DCM之Et2O濕磨固體，過濾且在真空烘箱中乾燥，得到呈白色固體狀之1-(5-環丙基-4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(75 mg，0.228 mmol，33.5%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.12(bs,1H),8.13(bs,1H),7.76(s,1H),7.16(d,J=9.8 Hz,1H),6.54(d,J=9.8 Hz,1H),5.92(s,1H),3.57(s,3H),2.85(d,J=4.7 Hz,3H),2.25(s,3H),2.02-1.93(m,1H),1.00-0.93(m,2H),0.72-0.66(m,2H)。質譜(apci)m/z=328.9(M+H)。 Step B : 1-(5-Bromo-4-(1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3 -Methylurea (250 mg, 0.681 mmol) was dissolved in 10:1 toluene: water (8 mL) and nitrogen was bubbled. In bubbling, was added cyclopropyl trifluoroborate (403 mg, 2.72 mmol), palladium two acetyl group (22.9 mg, 0.102 mmol) and K 3 PO 4 (434 mg, 2.04 mmol). Dicyclohexyl (2',6'-diisopropoxybiphenyl-2-yl)phosphine (95.3 mg, 0.204 mmol) was added and nitrogen was bubbled through for an additional 1 min. The reaction was sealed and heated to 100 ° C for 30 hours and cooled to room temperature. The reaction was diluted with EtOAc (EtOAc)EtOAc. The filtrate was concentrated and purified on EtOAc (EtOAc EtOAc) 2 O-containing solid was triturated with 25% Et DCM, the filtered and dried in a vacuum oven, to give a white solid of 1- (5-cyclopropyl-4- (1,2-dimethyl-6- sides Oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3-methylurea (75 mg, 0.228 mmol, 33.5% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.12 (bs, 1H), 8.13 (bs, 1H), 7.76 (s, 1H), 7.16 (d, J = 9.8 Hz, 1H), 6.54 (d, J = 9.8 Hz, 1H), 5.92 (s, 1H), 3.57 (s, 3H), 2.85 (d, J = 4.7 Hz, 3H), 2.25 (s, 3H), 2.02-1.93 (m, 1H), 1.00 -0.93 (m, 2H), 0.72-0.66 (m, 2H). Mass spectrum (apci) m/z = 328.9 (M+H).

遵循實例1624中之程序，亦合成以下化合物： Following the procedure in Example 1624, the following compounds were also synthesized:

實例1629Example 1629

1-(5-環丙基-4-(2,5-二甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-cyclopropyl-4-(2,5-dimethylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

步驟A：將1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.0 g，8.06 mmol)懸 浮於二噁烷(50 mL)中，且添加2 M K2CO3(12.1 ml，24.2 mmol)及環丙基三氟硼酸鉀(2.39 g，16.1 mmol)，且使氮氣鼓泡通過反應物，持續5分鐘。添加PdCl2(dppf)*DCM(0.658 g，0.806 mmol)，且加熱反應物至100℃隔夜。冷卻反應物至室溫，分配於50%鹽水與EtOAc之間，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含50%至100% EtOAc之己烷)純化，得到呈褐色固體狀之1-(5-環丙基-4-氟吡啶-2-基)-3-甲基脲(1.23 g，5.88 mmol，72.9%產率)。 Step A : 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (2.0 g, 8.06 mmol) was suspended in dioxane (50 mL) with 2 MK 2 CO 3 (12.1 ml, 24.2 mmol) and potassium cyclopropyltrifluoroborate (2.39 g, 16.1 mmol), and nitrogen was bubbled through the reaction for 5 min. PdCl 2 (dppf) * DCM (0.658 g, 0.806 mmol) was added and the reaction was heated to 100 ° C overnight. The reaction was cooled to rt EtOAc (EtOAc m. Purification on silica gel (50% to 100% EtOAc EtOAc) , 5.88 mmol, 72.9% yield).

步驟B：將1-(5-環丙基-4-氟吡啶-2-基)-3-甲基脲(50 mg，0.24 mmol)溶解於DMA(1 mL)中，且添加2,5-二甲基吡啶-3-醇(44 mg，0.36 mmol)及K2CO3(46 mg，0.33 mmol)，且加熱反應物至120℃，維持3天。冷卻反應物至室溫，分配於50%鹽水與EtOAc之間，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含4% MeOH之EtOAc)純化，得到呈褐色固體狀之1-(5-環丙基-4-(2,5-二甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(35 mg，0.11 mmol，47%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.15(m,1H),8.24(s,1H),8.09(s,1H),7.79(s,1H),7.14(s,1H),5.82(s,1H),2.82(d,J=4.7 Hz,3H),2.39(s,3H),2.33(s,3H),1.97(m,1H),0.94(m,2H),0.70(m,2H)。質譜(apci)m/z=312.9(M+H)。 Step B : Dissolve 1-(5-cyclopropyl-4-fluoropyridin-2-yl)-3-methylurea (50 mg, 0.24 mmol) in DMA (1 mL) and add 2,5- Dimethylpyridin-3-ol (44 mg, 0.36 mmol) and K 2 CO 3 (46 mg, 0.33 mmol), and the mixture was warmed to 120 ° C for 3 days. The reaction was cooled to rt EtOAc (EtOAc m. Purify on silica gel (4% MeOH in EtOAc) to afford 1-(5-cyclopropyl-4-(2,5-dimethylpyridin-3-yloxy)pyridine-2- 3-methylurea (35 mg, 0.11 mmol, 47% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.15 (m, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.79 (s, 1H), 7.14 (s, 1H), 5.82 (s) , 1H), 2.82 (d, J = 4.7 Hz, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 1.97 (m, 1H), 0.94 (m, 2H), 0.70 (m, 2H) . Mass spectrum (apci) m/z = 312.9 (M+H).

遵循實例1629中之程序，亦合成以下化合物： Following the procedure in Example 1629, the following compounds were also synthesized:

實例1633Example 1633

1-(6'-乙氧基-4-((1-乙基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-ethoxy-4-((1-ethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)-[3,3'-bipyridine] -6-yl)-3-methylurea

將1-(6'-乙氧基-4-氟-3,3'-聯吡啶-6-基)-3-甲基脲(0.060 g，0.19 mmol)、1-乙基-5-羥基吡啶-2(1H)-酮(0.027 g，0.20 mmol)及K2CO3(0.031 g，0.22 mmol)於DMA(2 mL)中之溶液在88℃下攪拌3小時。冷卻至周圍溫度後，藉由C-18逆相層析(0-70% CH3CN：水)直接純化，得到呈固體狀之1-(6'-乙氧基-4-(1-乙基-6-側氧基-1,6-二氫吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.021 g，27.6%)。H NMR(400 MHz,CD3OD)δ ppm 8.28(s,1H),8.15(s,1H),7.91(m,1H),7.78(s,1H),7.49(m,1H),6.85(m,1H),6.67-6.60(m,2H),4.35(q,J=7.4 Hz,2H), 4.02(q,J=7.2 Hz,2H),2.84(s,3H),1.44-1.31(m,6H)。質譜(apci)m/z=409.9(M+H)。 1-(6'-ethoxy-4-fluoro-3,3'-bipyridin-6-yl)-3-methylurea (0.060 g, 0.19 mmol), 1-ethyl-5-hydroxypyridine -2 (1H) - one (0.027 g, 0.20 mmol) and K 2 CO 3 in the (0.031 g, 0.22 mmol) in DMA (2 mL) was stirred at 88 ℃ 3 hours. After cooling to ambient temperature, by C-18 reverse phase chromatography (0-70% CH 3 CN: water) directly to give as a solid of 1- (6'-ethoxy-4- (1-ethyl 6-o-oxy-1,6-dihydropyridin-3-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea (0.021 g, 27.6%). H NMR (400 MHz, CD 3 OD) δ ppm 8.28 (s, 1H), 8.15 (s, 1H), 7.91 (m, 1H), 7.78 (s, 1H), 7.49 (m, 1H), 6.85 (m) , 1H), 6.67-6.60 (m, 2H), 4.35 (q, J = 7.4 Hz, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.84 (s, 3H), 1.44-1.31 (m, 6H). Mass spectrum (apci) m/z = 409.9 (M+H).

遵循實例1633中之程序，使用類似方式製備以下化合物。 Following the procedure in Example 1633, the following compounds were prepared in a similar manner.

實例1641Example 1641

1-(4-((1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(4-((1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)-5-((tetrahydro-2H-pyran-4) -yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：將1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(0.73 g，2.94 mmol)、5-羥基-1,6-二甲基吡啶-2(1H)-酮(0.430 g，3.09 mmol)及 K2CO3(0.41 g，2.94 mmol)於DMA(15 mL)中之溶液在88℃下攪拌5小時。冷卻至周圍溫度後，添加水(100 mL)。在周圍溫度下攪拌混合物30分鐘。藉由過濾收集固體，得到固體。將該固體懸浮於3：1 MeOH：DCM(40 mL)中且在周圍溫度下攪拌10分鐘。藉由過濾收集固體，用DCM(20 mL)洗滌且乾燥，得到呈固體狀之1-(5-溴-4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.30 g，27.8%)。質譜(apci)m/z=366.8(M+H)。 Step A : 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (0.73 g, 2.94 mmol), 5-hydroxy-1,6-lutidine-2 (1H ) - one (0.430 g, 3.09 mmol) and K 2 CO 3 (0.41 g, 2.94 mmol) in DMA solution (15 mL) was stirred at in the 88 ℃ 5 hours. After cooling to ambient temperature, water (100 mL) was added. The mixture was stirred at ambient temperature for 30 minutes. The solid was collected by filtration to give a solid. The solid was suspended in 3:1 MeOH: DCM (40 mL) and stirred for 10 min. The solid was collected by filtration, washed with EtOAc EtOAc (EtOAc) Hydropyridine-3-yloxy)pyridin-2-yl)-3-methylurea (0.30 g, 27.8%). Mass spectrum (apci) m/z = 366.8 (M+H).

步驟B：向1-(5-溴-4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.075 g，0.204 mmol)、Pd(OAc)2(0.0023 g，0.010 mmol)及二環己基(2',6'-二甲氧基聯苯-2-基)膦(0.0084 g，0.020 mmol)於THF(3 mL)中之溶液中添加溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(0.97 ml，0.61 mmol)。在70℃下攪拌反應混合物2小時。冷卻至周圍溫度後，添加飽和乙酸銨(5 mL)及3：1 CHCl3/IPA(15 mL)。分離有機層，用鹽水洗滌，乾燥(硫酸鈉)，過濾且在減壓下濃縮。藉由C-18逆相層析(5-60% CH3CN：水)純化殘餘物，得到呈固體狀之1-(4-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲(0.028 g，35.5%)。1H NMR(400 MHz,CD3OD)δ ppm 7.96(s,1H),7.36(d,J=9.6 Hz,1H),6.54(d,J=9.8 Hz,1H),6.36(s,1H),3.94(m,2H),3.62(s,3H),3.38(t,J=11.3 Hz,2H),2.81(s,3H),1.65(d,J=7.0 Hz,2H),2.30(s,3H),1.93(m,1H),1.61(m,2H),1.39(m,2H)。質譜(apci)m/z=386.9(M+H)。 Step B : To 1-(5-bromo-4-(1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3 -methylurea (0.075 g, 0.204 mmol), Pd(OAc) 2 (0.0023 g, 0.010 mmol) and dicyclohexyl (2',6'-dimethoxybiphenyl-2-yl)phosphine (0.0084 g) To a solution of THF (3 mL), bromo ((tetrahydro-2H-pyran-4-yl)methyl)zinc(II) (0.97 ml, 0.61 mmol). The reaction mixture was stirred at 70 ° C for 2 hours. After cooling to ambient temperature, saturated ammonium acetate (5 mL) and 3: 1 CHCl 3 / IPA ( 15 mL). The organic layer was separated, washed with brine, dried w... By C-18 reverse phase chromatography (5-60% CH 3 CN: water) to give the residue, to give as a solid of 1- (4- (1,2-dimethyl-6-oxo -1 ,6-dihydropyridin-3-yloxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)-3-methylurea (0.028 g, 35.5 %). 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.96 (s, 1H), 7.36 (d, J = 9.6 Hz, 1H), 6.54 (d, J = 9.8 Hz, 1H), 6.36 (s, 1H) , 3.94 (m, 2H), 3.62 (s, 3H), 3.38 (t, J = 11.3 Hz, 2H), 2.81 (s, 3H), 1.65 (d, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.93 (m, 1H), 1.61 (m, 2H), 1.39 (m, 2H). Mass spectrum (apci) m/z = 386.9 (M+H).

實例1642Example 1642

1-(4-(3-氯-2-氟苯氧基)-5-(3-甲基-1,2,4-噁二唑-5-基)吡啶-2-基)-3-甲基脲 1-(4-(3-Chloro-2-fluorophenoxy)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)-3-methyl Base urea

步驟A：將3-氯-2-氟苯酚(3.9 g，27 mmol)、4,6-二氯菸鹼酸甲酯(5.0 g，24 mmol)及K2CO3(4.0 g，29 mmol)溶解於DMF(70 mL)中，且在氮氣下加熱至75℃隔夜。冷卻反應物至室溫，分配於水與EtOAc之間，用水及鹽水洗滌，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含10% EtOAc之己烷)純化，得到粗6-氯-4-(3-氯-2-氟苯氧基)菸鹼酸甲酯(6.1 g，19 mmol，80%產率)。 Step A : 3-Chloro-2-fluorophenol (3.9 g, 27 mmol), 4,6-dichloronicotinic acid methyl ester (5.0 g, 24 mmol) and K 2 CO 3 (4.0 g, 29 mmol) Dissolved in DMF (70 mL) and heated to 75 ° C overnight under nitrogen. The reaction was cooled to EtOAc (EtOAc m.) Purification on silica gel (10% EtOAc in hexanes) afforded crude 6-chloro-4-(3-chloro-2-fluorophenoxy) nicotinic acid (6.1 g, 19 mmol, 80% yield ).

步驟B：將粗6-氯-4-(3-氯-2-氟苯氧基)菸鹼酸甲酯(6.1 g，19 mmol)溶解於THF(40 mL)中，且添加1 M氫氧化鈉(29 ml，29 mmol)並加熱至50℃，維持2小時。冷卻反應物，且用1 N HCl酸化至pH值為約2，用EtOAc萃取，經硫酸鈉乾燥，過濾並濃縮，得到粗6-氯-4-(3-氯-2-氟苯氧基)菸鹼酸(5.8 g，19 mmol，99%產率)。 Step B : Dissolve crude 6-chloro-4-(3-chloro-2-fluorophenoxy)nicotinic acid methyl ester (6.1 g, 19 mmol) in THF (40 mL). Sodium (29 ml, 29 mmol) and heated to 50 ° C for 2 h. The reaction was cooled and evaporated with EtOAc EtOAc EtOAc (EtOAc) Nicotinic acid (5.8 g, 19 mmol, 99% yield).

步驟C：將粗6-氯-4-(3-氯-2-氟苯氧基)菸鹼酸(250 mg，0.828 mmol)懸浮於DCM(8 mL)中，且添加三乙胺(231 μl，1.66 mmol)及氯甲酸乙酯(86.7 μl，0.910 mmol)，且在室溫下攪拌反應物1小時。添加N'-羥基乙脒(92.0 mg，1.24 mmol)，且在室溫下攪拌反應物20分鐘。將反應物傾倒至水中且攪拌。過濾所得固體，在真空烘箱中乾燥，且溶解於THF中並加熱至60℃，維持72小時。濃縮反應物且在矽膠上純化，得到5-(6-氯-4-(3-氯-2-氟苯氧基)吡啶-3-基)-3-甲基-1,2,4-噁二唑(45 mg，0.132 mmol，16.0%產率)。 Step C : Suspension of crude 6-chloro-4-(3-chloro-2-fluorophenoxy)nicotinic acid (250 mg, 0.828 mmol) in DCM (8 mL) with triethylamine (231 μl) , 1.66 mmol) and ethyl chloroformate (86.7 μl, 0.910 mmol), and the mixture was stirred at room temperature for 1 hour. N'-Hydroxyethyl hydrazine (92.0 mg, 1.24 mmol) was added and the reaction was stirred at room temperature for 20 min. The reaction was poured into water and stirred. The resulting solid was filtered, dried in a vacuum oven and dissolved in THF and warmed to 60 &lt;0&gt;C for 72 h. The reaction was concentrated and purified on silica gel to give 5-(6-chloro-4-(3-chloro-2-fluorophenoxy)pyridin-3-yl)-3-methyl-1,2,4- Diazole (45 mg, 0.132 mmol, 16.0% yield).

步驟D：將1-甲基脲(15 mg，0.20 mmol)、K3PO4(42 mg，0.20 mmol)、1,1'-聯萘-2-基二第三丁基膦(5.3 mg，0.013 mmol)及Pd2dba3 (6.1 mg，0.0066 mmol)於經脫氣之DME(1 mL)中組合，且使氮氣鼓泡通過，再持續2分鐘。密封反應物且加熱至45℃，維持1小時。添加5-(6-氯-4-(3-氯-2-氟苯氧基)吡啶-3-基)-3-甲基-1,2,4-噁二唑(45 mg，0.13 mmol)，且將反應物用氮氣淨化，密封且加熱至80℃隔夜。將反應物分配於水與EtOAc之間，用EtOAc萃取，經硫酸鈉乾燥，過濾且濃縮。在C18管柱上(含5%至95% ACN之水)純化，得到呈白色固體狀之1-(4-(3-氯-2-氟苯氧基)-5-(3-甲基-1,2,4-噁二唑-5-基)吡啶-2-基)-3-甲基脲(3.0 mg，0.0079 mmol，6.0%產率)。1H NMR(400 MHz,CD3OD)δ ppm 8.91(s,1H),7.58(s,2H),7.44(m,1H),7.27(s,1H),7.25(d,J=3.5 Hz,1H),6.63(s,1H),2.87(s,3H),2.50(s,3H)。質譜(apci)m/z=378.0(M+H)。 Step D : 1-methylurea (15 mg, 0.20 mmol), K 3 PO 4 (42 mg, 0.20 mmol), 1,1'-binaphthalen-2-yldibutylphosphine (5.3 mg, 0.013 mmol) and Pd 2 dba 3 (6.1 mg, 0.0066 mmol) were combined in degassed DME (1 mL) and nitrogen was bubbled through for a further 2 min. The reaction was sealed and heated to 45 ° C for 1 hour. Add 5-(6-chloro-4-(3-chloro-2-fluorophenoxy)pyridin-3-yl)-3-methyl-1,2,4-oxadiazole (45 mg, 0.13 mmol) The reaction was purged with nitrogen, sealed and heated to 80 ° C overnight. The reaction was partitioned between EtOAc EtOAc m. Purification on a C18 column (water containing 5% to 95% ACN) gave 1-(4-(3-chloro-2-fluorophenoxy)-5-(3-methyl- as a white solid. 1,2,4-oxadiazol-5-yl)pyridin-2-yl)-3-methylurea (3.0 mg, 0.0079 mmol, 6.0% yield). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.91 (s, 1H), 7.58 (s, 2H), 7.44 (m, 1H), 7.27 (s, 1H), 7.25 (d, J = 3.5 Hz, 1H), 6.63 (s, 1H), 2.87 (s, 3H), 2.50 (s, 3H). Mass spectrum (apci) m/z = 378.0 (M+H).

實例1643Example 1643

1-甲基-3-(5-(3-甲基-1,2,4-噁二唑-5-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)脲 1-methyl-3-(5-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(5-methylpyridin-3-yloxy)pyridine-2- Urea

步驟A：將5-甲基吡啶-3-醇(1.0 g，9.16 mmol)溶解於DMF(30 mL)中且在冰浴中冷卻。添加60%氫化鈉(0.367 g，9.16 mmol)，且攪拌反應物10分鐘。添加4,6-二氯菸鹼酸甲酯(1.89 g，9.16 mmol)，且在室溫下攪拌反應物1小時。將反應物傾倒至水(300 mL)中，且用EtOAc(×2)萃取，用鹽水洗滌，經硫酸鈉乾燥，過濾並濃縮。在矽膠上(含40%至50% EtOAc之己烷)純化，得到呈白色固體狀之6-氯-4-(5-甲基吡啶-3-基氧基)菸鹼酸甲酯(1.98 g，7.10 mmol，77.5%產率)。 Step A : 5-Methylpyridin-3-ol (1.0 g, 9.16 mmol) was dissolved in DMF (30 mL). 60% sodium hydride (0.367 g, 9.16 mmol) was added and the reaction was stirred 10 min. Methyl 4,6-dichloronicotinate (1.89 g, 9.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was poured into EtOAc (EtOAc)EtOAc. Purification on silica gel (40% to 50% EtOAc EtOAc) , 7.10 mmol, 77.5% yield).

步驟B：將1-甲基脲(0.76 g，10 mmol)及K3PO4(2.2 g，10 mmol)添加至DME(15 mL)中，且使氮氣鼓泡通過，持續5分鐘。添加Pd2dba3(0.31 g，0.34 mmol)及1,1'-聯萘-2-基二第三丁基膦(0.54 g，1.4 mmol)，且鼓泡通過反應物，再持續1分鐘，接著加熱至60℃，維持1小時。添加6-氯-4-(5-甲基吡啶-3-基氧基)菸鹼酸甲酯(1.9 g，6.8 mmol)，且用氮氣淨化反應物並加熱至80℃，維持6.5小時。冷卻反應物至室溫，分配於水與EtOAc之間，經硫酸鈉乾燥，過濾且濃縮。在矽膠上純化，得到4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)菸鹼酸甲酯(0.83 g，2.6 mmol，38%產率)。 Step B: A solution of 1-methylurea (0.76 g, 10 mmol) and K 3 PO 4 (2.2 g, 10 mmol) to DME (15 mL), and the nitrogen was bubbled through for 5 minutes. Pd 2 dba 3 (0.31 g, 0.34 mmol) and 1,1'-binaphthalen-2-yldibutylphosphonium (0.54 g, 1.4 mmol) were added and bubbled through the reaction for an additional 1 min. It was then heated to 60 ° C for 1 hour. Methyl 6-chloro-4-(5-methylpyridin-3-yloxy)nicotinate (1.9 g, 6.8 mmol) was added and the reaction was purified with nitrogen and warmed to &lt The reaction was cooled to rt EtOAc (EtOAc m. Purification on silica gel gave 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)nicotonic acid methyl ester (0.83 g, 2.6 mmol, 38% yield).

步驟C：將4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)菸鹼酸甲酯(830 mg，2.62 mmol)溶解於THF(15 mL)中，且添加1 M NaOH(2.2當量)，且加熱反應物至50℃隔夜。再添加1 M NaOH(5當量)且再加熱至50℃隔夜。用1 M HCl將反應物酸化至pH 2，用DCM(×4)萃取，經硫酸鈉乾燥，過濾且濃縮，得到4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)菸鹼酸鹽酸鹽(400 mg，1.18 mmol，45.0%產率)。 Step C : Dissolving methyl 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)nicotinate (830 mg, 2.62 mmol) in THF (15 mL) 1 M NaOH (2.2 eq.) was added and the reaction was heated to 50 ° C overnight. An additional 1 M NaOH (5 eq.) was added and heated to 50 ° C overnight. The reaction was acidified to pH 2 with EtOAc (EtOAc m. -Methylurea) Nicotine hydrochloride (400 mg, 1.18 mmol, 45.0% yield).

步驟D：將4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)菸鹼酸鹽酸鹽(50 mg，0.148 mmol)懸浮於二噁烷(1 mL)中且極度不溶，且需要音波處理5分鐘以形成精細懸浮液。添加二(1H-咪唑-1-基)甲酮(35.9 mg，0.221 mmol)，且在室溫下攪拌20分鐘。添加三乙胺(41.1 μl，0.295 mmol)，且在室溫下攪拌20分鐘。再添加三乙胺(41.1 μl，0.295 mmol)及二(1H-咪唑-1-基)甲酮(35.9 mg，0.221 mmol)，且再攪拌反應物1小時，接著添加N'-羥基乙脒(16.4 mg，0.221 mmol)且攪拌隔夜。再添加二(1H-咪唑-1-基)甲酮(35.9 mg，0.221 mmol)，且在室溫下攪拌反應物1小時。接著加熱反應物至90℃隔夜。冷卻反應物至室溫，直接加載於C18管柱上(含5%至95% ACN之水)，得到呈白色固體狀之1-甲基-3-(5-(3-甲基-1,2,4-噁二唑-5-基)-4-(5-甲基吡啶-3-基氧基)吡 啶-2-基)脲(6.0 mg，0.0176 mmol，11.9%產率)。1H NMR(400 MHz,CD3OD)δ ppm 8.90(s,1H),8.36(s,1H),8.30(s,1H),7.65-7.44(m,3H),6.61(s,1H),2.87(s,3H),2.49(s,1H),2.44(s,1H)。質譜(apci)m/z=340.9(M+H)。 Step D : Suspension of 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)nicotinate (50 mg, 0.148 mmol) in dioxane (1 It is extremely insoluble in mL) and requires sonication for 5 minutes to form a fine suspension. Bis(1H-imidazol-1-yl)methanone (35.9 mg, 0.221 mmol) was added and stirred at room temperature for 20 min. Triethylamine (41.1 μl, 0.295 mmol) was added and stirred at room temperature for 20 min. Additional triethylamine (41.1 μl, 0.295 mmol) and bis(1H-imidazol-1-yl)methanone (35.9 mg, 0.221 mmol) were added and the reaction was stirred for an additional 1 hour then N. 16.4 mg, 0.221 mmol) and stirred overnight. Further, bis(1H-imidazol-1-yl)methanone (35.9 mg, 0.221 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was then heated to 90 ° C overnight. The reaction was cooled to room temperature and applied directly to a C18 column (water containing 5% to 95% ACN) to afford 1-methyl-3-(5-(3-methyl-1) as a white solid. 2,4-oxadiazol-5-yl)-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)urea (6.0 mg, 0.0176 mmol, 11.9% yield). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.90 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.65-7.44 (m, 3H), 6.61 (s, 1H), 2.87 (s, 3H), 2.49 (s, 1H), 2.44 (s, 1H). Mass spectrum (apci) m/z = 340.9 (M+H).

實例1644Example 1644

2-(4-氟-3-((5-(1-甲基-1H-吡唑-4-基)-2-(3-甲基脲基)吡啶-4-基)氧基)苯基)乙酸 2-(4-Fluoro-3-((5-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylureido)pyridin-4-yl)oxy)phenyl Acetic acid

將2-(4-氟-3-(5-(1-甲基-1H-吡唑-4-基)-2-(3-甲基脲基)吡啶-4-基氧基)苯基)乙酸甲酯(20 mg，0.048 mmol)溶解於1：1 THF：水(1 mL)中，且添加1 N NaOH(0.1 mL)，且在室溫下攪拌隔夜。濃縮反應物以移除有機物，且用1 N HCl調整pH值直至固體沈下，且過濾並乾燥，得到2-(4-氟-3-(5-(1-甲基-1H-吡唑-4-基)-2-(3-甲基脲基)吡啶-4-基氧基)苯基)乙酸(8 mg，0.020 mmol，41%產率)。1H NMR(400 MHz,CD3OD)δ ppm 8.16(s,1H),7.83(s,1H),7.76(s,1H),7.16-7.10(m,3H),6.50(s,1H),3.84(s,3H),3.51(s,2H),2.70(s,3H)。質譜(apci)m/z=400.1(M+H)。 2-(4-Fluoro-3-(5-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylureido)pyridin-4-yloxy)phenyl) Methyl acetate (20 mg, 0.048 mmol) was dissolved in 1:1 THF: water (1 mL). The reaction was concentrated to remove the organics, and the pH was adjusted with 1 N HCl until solids were allowed to settle, and filtered and dried to give 2-(4-fluoro-3-(5-(1-methyl-1H-pyrazole-4) -yl)-2-(3-methylureido)pyridin-4-yloxy)phenyl)acetic acid (8 mg, 0.020 mmol, 41% yield). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.16 (s, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.16-7.10 (m, 3H), 6.50 (s, 1H), 3.84 (s, 3H), 3.51 (s, 2H), 2.70 (s, 3H). Mass spectrum (apci) m/z = 400.1 (M+H).

遵循實例109中之程序，亦合成以下化合物： Following the procedure in Example 109, the following compounds were also synthesized:

實例1646Example 1646

4-((6-(3-甲基脲基)-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)硫基)哌啶-1-甲酸甲酯 4-((6-(3-methylureido)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)thio)piperidin-1- Methyl formate

步驟A：將4-(6-(3-甲基脲基)-4-(6-(三氟甲基)吡啶-3-基氧基)吡啶-3-基硫基)哌啶-1-甲酸第三丁酯(190 mg，0.360 mmol)溶解於DCM(3 mL)中，且添加TFA(1 mL)，且在室溫下攪拌1小時。濃縮反應物且分配於DCM與飽和NaHCO3水溶液之間。藉由添加MeOH溶解固體。用DCM：MeOH萃取，經硫酸鈉乾燥，過濾且濃縮，得到呈白色固體狀之1-甲基-3-(5-(哌啶-4-基硫基)-4-(6-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)脲(140 mg，0.328 mmol，90.9%產率)。 Step A : 4-(6-(3-Methylureido)-4-(6-(trifluoromethyl)pyridin-3-yloxy)pyridin-3-ylthio)piperidin-1- The third butyl formate (190 mg, 0.360 mmol) was dissolved in DCM (3 mL). The reaction was concentrated and partitioned between DCM and saturated aqueous NaHCO 3. The solid was dissolved by the addition of MeOH. Extracted with EtOAc EtOAc (EtOAc m.jHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl)pyridin-3-yloxy)pyridin-2-yl)urea (140 mg, 0.328 mmol, 90.9% yield).

步驟B：將1-甲基-3-(5-(哌啶-4-基硫基)-4-(6-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)脲(45 mg，0.105 mmol)溶解於DMF(1 mL)中，且添加三乙胺(29.3 μl，0.211 mmol)及氯甲酸甲酯(8.59 μl，0.126 mmol)，且在室溫下攪拌反應物30分鐘。添加水(5 mL)且劇烈攪拌5分鐘，過濾並乾燥，得到呈白色固體狀之4-(6-(3-甲基脲基)-4-(6-(三氟甲基)吡啶-3-基氧基)吡啶-3-基硫基)哌啶-1-甲酸甲酯(43 mg，0.0886 mmol，84.1%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.15(s,1H),8.91(bs,1H),8.53(d,J=2.5 Hz,1H),8.27(s,1H),7.76(d,J=8.6 Hz,1H),7.51(dd,J=8.4,2.5 Hz,1H),6.28(s,1H),4.01(bs,2H),3.68(s,3H),3.14(m,1H),2.96(m,2H),2.79(d,J=4.7 Hz,3H),1.89(m,2H),1.51(m,2H)。質譜(apci)m/z=486.1(M+H)。 Step B : 1-methyl-3-(5-(piperidin-4-ylthio)-4-(6-(trifluoromethyl)pyridin-3-yloxy)pyridin-2-yl) The urea (45 mg, 0.105 mmol) was dissolved in DMF (1 mL) and triethylamine (29.3 μl, 0.211 mmol) and methyl chloroformate (8.59 μl, 0.126 mmol), and the mixture was stirred at room temperature 30 minutes. Water (5 mL) was added and stirred vigorously for 5 min, filtered and dried to give 4-(6-(3-methylureido)-4-(6-(trifluoromethyl)pyridine-3 as a white solid. Methyl - oxy)pyridin-3-ylthio)piperidine-1-carboxylate (43 mg, 0.0886 mmol, 84.1% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.15 (s, 1H), 8.91 (bs, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.27 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 8.4, 2.5 Hz, 1H), 6.28 (s, 1H), 4.01 (bs, 2H), 3.68 (s, 3H), 3.14 (m, 1H), 2.96 (m, 2H), 2.79 (d, J = 4.7 Hz, 3H), 1.89 (m, 2H), 1.51 (m, 2H). Mass spectrum (apci) m/z = 486.1 (M+H).

遵循實例1646中之程序，亦合成以下化合物： Following the procedure in Example 1646, the following compounds were also synthesized:

實例1649Example 1649

1-(5-((2-氯吡啶-4-基)硫基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((2-chloropyridin-4-yl)thio)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：將1-(5-溴-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(200 mg，0.593 mmol)、Xantphos(17.2 mg，0.0297 mmol)及N-乙基-N-異丙基丙-2-胺(207 μl，1.19 mmol)溶解於二噁烷(5 mL)中，且使氮氣鼓泡通過，持續5分鐘。添加3-巰基丙酸甲酯(70.6 μl，0.652 mmol)及Pd2dba3(13.6 mg，0.0148 mmol)，且將反應物傾沒於90℃油浴中隔夜。冷卻反應物至室溫，經矽藻土過濾，濃縮且在矽膠上(含0%至3%MeOH之EtOAc)純化，得到呈白色固體狀之3-(4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(188 mg，0.499 mmol， 84.2%產率)。 Step A : 1-(5-Bromo-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (200 mg, 0.593 mmol), Xantphos (17.2 mg) , 0.0297 mmol) and N-ethyl-N-isopropylpropan-2-amine (207 μl, 1.19 mmol) were dissolved in dioxane (5 mL) and nitrogen was bubbled through for 5 min. Methyl 3-mercaptopropionate (70.6 μl, 0.652 mmol) and Pd 2 dba 3 (13.6 mg, 0.0148 mmol) were added and the reaction was poured into a 90 ° C oil bath overnight. The reaction was cooled to room temperature, EtOAc (EtOAc m.) Methyl-p-oxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (188 mg, 0.499 mmol, 84.2% yield).

步驟B：將3-(4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(50 mg，0.13 mmol)溶解於THF(1 mL)中，且使氮氣鼓泡通過，持續5分鐘。添加2-甲基丙-2-醇鉀(1 M，於THF中，398 μl，0.40 mmol)，且攪拌反應物30秒。添加2-氯-4-硝基吡啶(25 mg，0.16 mmol)，且在室溫下攪拌反應物10分鐘。用飽和NH4Cl淬滅反應物，分配於EtOAc與水之間，經硫酸鈉乾燥，過濾且濃縮。在矽膠上(含1% MeOH之EtOAc)純化殘餘物，得到呈白色固體狀之1-(5-(2-氯吡啶-4-基硫基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(35 mg，0.087 mmol，66%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.15(s,1H),8.93(s,1H),8.36(s,1H),8.30(s,1H),8.18(m,2H),7.15(m,1H),6.95(m,2H),6.20(s,1H),2.81(d,J=4.5 Hz,3H),2.37(s,3H)。質譜(apci)m/z=401.7(M+H)。 Step B : Methyl 3-(4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (50 mg, 0.13 Methyl) was dissolved in THF (1 mL) and nitrogen was bubbled through for 5 min. Potassium 2-methylpropan-2-ol (1 M in THF, 398 [mu]l, 0.40 mmol) was then evaporated 2-Chloro-4-nitropyridine (25 mg, 0.16 mmol) was added and the reaction was stirred at room temperature for 10 min. With saturated NH 4 Cl was quenched reaction was partitioned between EtOAc and water, dried over sodium sulfate, filtered and concentrated. The residue was purified on EtOAc (EtOAc (EtOAc) Alkoxy)pyridin-2-yl)-3-methylurea (35 mg, 0.087 mmol, 66% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.15 (s, 1H), 8.93 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.18 (m, 2H), 7.15 (m) , 1H), 6.95 (m, 2H), 6.20 (s, 1H), 2.81 (d, J = 4.5 Hz, 3H), 2.37 (s, 3H). Mass spectrum (apci) m/z = 401.7 (M+H).

實例1650Example 1650

1-(6'-乙氧基-4-(2-(三氟甲基)吡啶-4-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(6'-ethoxy-4-(2-(trifluoromethyl)pyridin-4-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea

步驟A：將1-(4-(苄氧基)-5-溴吡啶-2-基)-3-甲基脲(2.0 g，5.95 mmol)、6-乙氧基吡啶-3-基酸(1.99 g，11.9 mmol)及CsF(2.35 g，15.5 mmol)於i-PrOH(119 ml，5.95 mmol)中之混合物用氮氣脫氣10分鐘。添加三乙胺(1.33 ml，9.52 mmol)及PdCl2(dppf)*DCM(486 mg，0.595 mmol)，將容器密封且在100℃下加熱隔夜。用EtOAc稀釋反應 混合物，經矽藻土過濾且在減壓下濃縮。在矽膠上(含30% EtOAc之己烷，繼之以含15%丙酮之二氯甲烷)純化殘餘物，得到1-(4-(苄氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲。產量811 mg(36%)。 Step A : 1-(4-(Benzyloxy)-5-bromopyridin-2-yl)-3-methylurea (2.0 g, 5.95 mmol), 6-ethoxypyridin-3-yl A mixture of the acid (1.99 g, 11.9 mmol) and CsF (2.35 g, 15.5 mmol) in i- PrOH (119 ml, 5.95 mmol) was degassed with nitrogen for 10 min. Triethylamine (1.33 ml, 9.52 mmol) and PdCl 2 (dppf)*DCM (486 mg, 0.595 mmol) were added and the vessel was sealed and heated overnight at 100 °C. The reaction mixture was diluted with EtOAc EtOAc m. The residue was purified on EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc '-Bipyridyl-6-yl)-3-methylurea. Yield 811 mg (36%).

步驟B：在密封管中，將含有1-(4-(苄氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(811 mg，2.14 mmol)及2-胺基乙硫醇鹽酸鹽(365 mg，3.21 mmol)於6 N HCl(10 mL)中之混合物在85℃下加熱32小時。將經冷卻之反應混合物緩慢添加至30% K2CO3溶液中以調整至pH 9。藉由過濾收集分離之固體，且用水洗滌並乾燥，得到1-(6'-乙氧基-4-羥基-3,3'-聯吡啶-6-基)-3-甲基脲。產量370 mg(60%)。 Step B : In a sealed tube, 1-(4-(benzyloxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3-methylurea (811 mg, 2.14 mmol) and a mixture of 2-aminoethanethiol hydrochloride (365 mg, 3.21 mmol) in 6 N HCl (10 mL). The cooled reaction mixture was slowly added to a 30% K 2 CO 3 solution to adjust to pH 9. The isolated solid was collected by filtration, washed with water and dried to give 1-(6'-ethoxy-4-hydroxy-3,3'-bipyridin-6-yl)-3-methylurea. Yield 370 mg (60%).

步驟C：在密封管中，將60% NaH於礦物油中之分散液(9 mg，0.225 mmol)於無水DMA(2 mL)中之懸浮液冷卻至0℃，添加1-(6'-乙氧基-4-羥基-3,3'-聯吡啶-6-基)-3-甲基脲(60 mg，0.187 mmol)，且在室溫下攪拌混合物10分鐘。添加4-溴-2-(三氟甲基)吡啶(64 mg，0.281 mmol)，且將容器密封並加熱至90℃隔夜。向經冷卻之混合物中添加60% NaH於礦物油中之分散液(9 mg，0.225 mmol)及4-溴-2-(三氟甲基)吡啶(50 mg，0.221 mmol)，且在100℃下再加熱混合物隔夜。將經冷卻之混合物分配於水(10 mL)與EtOAc(15 mL)之間。分離有機層，且再用EtOAc(10 mL)萃取水層。用鹽水洗滌經合併之有機萃取物，經MgSO4乾燥且在減壓下濃縮。藉由C18逆相層析(含0-65% MeCN之H2O)純化粗物質，得到1-(6'-乙氧基-4-(2-(三氟甲基)吡啶-4-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲。產量23 mg(27%)。質譜(APCI)m/z 433.8(M+H)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.41(br.s,1H),8.70(d,J=6 Hz,1H),8.35(s,1H),8.30-8.27(m,1H),7.85(dd,J=3 Hz,8.8 Hz,1H),7.72(d,J=3 Hz,1H),7.67-7.52(m,1H),7.42(dd,J=2.4 Hz,6 Hz,1H),7.24(s,1H),6.82(d,J=8.8 Hz,1H),4.29(q,J=7.2 Hz,2H),2.70(d,J=4 Hz,3H),1.30(t,J=7.2 Hz,3H)。 Step C : In a sealed tube, cool a suspension of 60% NaH in mineral oil (9 mg, 0.225 mmol) in anhydrous DMA (2 mL) to 0 ° C, add 1-(6'-B Oxy-4-hydroxy-3,3'-bipyridin-6-yl)-3-methylurea (60 mg, 0.187 mmol), and the mixture was stirred at room temperature for 10 min. 4-Bromo-2-(trifluoromethyl)pyridine (64 mg, 0.281 mmol) was added and the vessel was sealed and heated to 90 ° C overnight. To the cooled mixture was added a dispersion of 60% NaH in mineral oil (9 mg, 0.225 mmol) and 4-bromo-2-(trifluoromethyl)pyridine (50 mg, 0.221 mmol) at 100 ° C The mixture was heated again overnight. The cooled mixture was partitioned between water (10 mL)EtOAcEtOAc The organic layer was separated and EtOAc (EtOAc) , Washed with brine and dried the combined organic extracts were dried over MgSO 4 and concentrated under reduced pressure. By C18 reverse phase chromatography (0-65% MeCN containing the H 2 O) The crude material was purified to give 1- (6'-ethoxy-4- (2- (trifluoromethyl) pyridin-4-yl Oxy)-3,3'-bipyridin-6-yl)-3-methylurea. Yield 23 mg (27%). Mass Spectrum (APCI) m/z 433.8 (M+H). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.41 (br.s, 1H), 8.70 (d, J = 6 Hz, 1H), 8.35 (s, 1H), 8.30-8.27 (m, 1H) , 7.85 (dd, J = 3 Hz, 8.8 Hz, 1H), 7.72 (d, J = 3 Hz, 1H), 7.67-7.52 (m, 1H), 7.42 (dd, J = 2.4 Hz, 6 Hz, 1H ), 7.24 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.70 (d, J = 4 Hz, 3H), 1.30 (t, J =7.2 Hz, 3H).

實例1651Example 1651

6-(6'-乙氧基-6-(3-甲基脲基)-3,3'-聯吡啶-4-基氧基)-N-(2-甲氧基乙基)吡啶醯胺 6-(6'-ethoxy-6-(3-methylureido)-3,3'-bipyridin-4-yloxy)-N-(2-methoxyethyl)pyridiniumamine

步驟A：向6-氟吡啶甲酸(300 mg，2.13 mmol)於無水DMF(7 mL)中之溶液中添加HBTU(1.21 g，3.19 mmol)。向此混合物中依序添加2-甲氧基乙胺(0.207 mL，2.34 mmol)、DIEA(0.815 mL，4.68 mmol)，且在室溫下攪拌混合物隔夜。用水(10 mL)淬滅反應物且用EtOAc(3×20 mL)萃取。用鹽水洗滌經合併之有機萃取物，經MgSO4乾燥並濃縮，且在矽膠上(含35% EtOAc之己烷)純化殘餘物，得到6-氟-N-(2-甲氧基乙基)吡啶醯胺。產量375 mg(89%)。 Step A : To a solution of 6-fluoropicolinic acid (300 mg, 2.13 mmol) in anhydrous DMF (7 mL). 2-Methoxyethylamine (0.207 mL, 2.34 mmol), DIEA (0.815 mL, 4.68 mmol) was added to this mixture, and the mixture was stirred overnight at room temperature. The reaction was quenched with EtOAc (EtOAc)EtOAc. , Washed with brine and dried the combined organic extracts were dried over MgSO 4 and concentrated, and the on silica (35% EtOAc in hexanes of) the residue was purified to give 6-fluoro -N- (2- methoxyethyl) Pyridinamine. Yield 375 mg (89%).

步驟B：向密封容器中之1-(6'-乙氧基-4-羥基-3,3'-聯吡啶-6-基)-3-甲基脲(65 mg，0.203 mmol)及6-氟-N-(2-甲氧基乙基)吡啶醯胺(44.2 mg，0.223 mmol)於無水DMA(1.5 mL)中之混合物中添加K2CO3(56 mg，0.406 mmol)，將容器密封，且在80℃下加熱72小時。接著藉由C18逆相層析(含0-60% MeCN之H2O)純化混合物，得到6-(6'-乙氧基-6-(3-甲基脲基)-3,3'-聯吡啶-4-基氧基)-N-(2-甲氧基乙基)吡啶醯胺。產量6 mg(6%)。質譜(APCI)m/z 467(M+H)。1H NMR(400 MHz,CDCl3)δ ppm 9.05(br,s,1H),8.22-8.19(m,2H),8.12(s,1H),7.91(d,J=7 Hz,1H),7.83(t,J=8 Hz,1H),7.78-7.70(m,1H),7.65(dd,J=4 Hz,8 Hz,1H),7.05(d,J=8 Hz,1H),6.75-6.68(m,2H),4.34(q,J=7 Hz, 2H),3.60-3.53(m,2H),3.53-3.47(m,2H),3.35(s,3H),2.93(d,J=3 Hz,6 Hz,1H),1.38(t,J=3Hz,8 Hz,3H)。 Step B : 1-(6'-ethoxy-4-hydroxy-3,3'-bipyridin-6-yl)-3-methylurea (65 mg, 0.203 mmol) in a sealed container and 6- K 2 CO 3 (56 mg, 0.406 mmol) was added to a mixture of fluoro-N-(2-methoxyethyl)pyridiniumamine (44.2 mg, 0.223 mmol) in anhydrous DMA (1.5 mL). And heated at 80 ° C for 72 hours. The mixture is then purified by C18 reverse phase chromatography (H 2 O with 0-60% MeCN) to give 6-(6'-ethoxy-6-(3-methylureido)-3,3'- Bipyridin-4-yloxy)-N-(2-methoxyethyl)pyridiniumamine. Yield 6 mg (6%). Mass Spectrum (APCI) m/z 467 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.05 (br, s, 1H), 8.22-8.19 (m, 2H), 8.12 (s, 1H), 7.91 (d, J = 7 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.78-7.70 (m, 1H), 7.65 (dd, J=4 Hz, 8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.75-6.68 (m, 2H), 4.34 (q, J = 7 Hz, 2H), 3.60-3.53 (m, 2H), 3.53-3.47 (m, 2H), 3.35 (s, 3H), 2.93 (d, J = 3) Hz, 6 Hz, 1H), 1.38 (t, J = 3 Hz, 8 Hz, 3H).

實例1652Example 1652

3-(6'-乙氧基-6-(3-甲基脲基)-3,3'-聯吡啶-4-基氧基)-N-乙基-4-氟苯磺醯胺 3-(6'-ethoxy-6-(3-methylureido)-3,3'-bipyridin-4-yloxy)-N-ethyl-4-fluorobenzenesulfonamide

步驟A：向NaOH(106 mg，2.66 mmol)於水(2 mL)及乙醚(2 mL)中之溶液中依序添加2 M乙胺於THF中之溶液(100 mg，1.11 mL，2.22 mmol)、4-氟-3-甲氧基苯-1-磺醯氯(548 mg，2.44 mmol)，且在室溫下攪拌所得混合物18小時。用二氯甲烷(3×10 mL)萃取反應混合物，用鹽水洗滌，且經MgSO4乾燥並在減壓下濃縮，得到4-氟-3-甲氧基-N-(2-甲氧基乙基)苯磺醯胺。產量453 mg(88%)。 Step A : To a solution of NaOH (106 mg, 2.66 mmol) in water (2 mL) 4-Fluoro-3-methoxybenzene-1-sulfonium chloride (548 mg, 2.44 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction with dichloromethane (3 × 10 mL) the mixture was extracted, washed with brine, and concentrated under reduced pressure and dried over MgSO 4, to give 4-fluoro-3-methoxy -N- (2- methoxyethyl Base) benzenesulfonamide. Yield 453 mg (88%).

步驟B：將N-乙基-4-氟-3-甲氧基苯磺醯胺(453 mg，1.94 mmol)於無水二氯甲烷(16 mL)中之溶液在氮氣氛圍下冷卻至-78℃，且向此溶液中逐滴添加1 M BBr3於二氯甲烷中之溶液(6 mL，6.02 mmol)。添加完成後，在周圍溫度下攪拌混合物隔夜。在冰浴上冷卻混合物且藉由逐滴添加甲醇(6 mL)淬滅。用EtOAc稀釋所得混合物，且用水及鹽水洗滌，接著經MgSO4乾燥，且經矽膠襯墊過濾並濃縮，得到N-乙基-4-氟-3-羥基苯磺醯胺。產量403 mg(95%)。 Step B : A solution of N-ethyl-4-fluoro-3-methoxybenzenesulfonamide (453 mg, 1.94 mmol) in anhydrous dichloromethane (16 mL) 1 M BBr 3 solution in dichloromethane of (6 mL, 6.02 mmol), and to this solution was added dropwise. After the addition was completed, the mixture was stirred overnight at ambient temperature. The mixture was cooled on an ice-bath and quenched by EtOAc (EtOAc) The resulting mixture was diluted with EtOAc and washed with water and brine, then dried over MgSO 4, and filtered through silica gel pad and concentrated to give N- ethyl-4-fluoro-3-hydroxyphenyl sulfonylurea amine. Yield 403 mg (95%).

步驟C：向未密封管中之N-乙基-4-氟-3-羥基苯磺醯胺(117 mg，0.532 mmol)於無水DMA(1 mL)中之溶液中添加60% NaH於礦物油中 之分散液(23 mg，0.581 mmol)，且在室溫下攪拌混合物15分鐘。添加1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(120 mg，0.484 mmol)，密封且在90℃下加熱混合物5小時。藉由C18逆相層析(含0-65% MeCN之H2O)純化混合物，得到3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-N-乙基-4-氟苯磺醯胺。產量44 mg(21%)。 Step C : Add 60% NaH to mineral oil to a solution of N-ethyl-4-fluoro-3-hydroxybenzenesulfonamide (117 mg, 0.532 mmol) in anhydrous DMA (1 mL). The dispersion was concentrated (23 mg, 0.581 mmol) and the mixture was stirred at room temperature for 15 min. 1-(5-Bromo-4-fluoropyridin-2-yl)-3-methylurea (120 mg, 0.484 mmol) was added, sealed and the mixture was stirred at <RTIgt; The mixture was purified by C18 reverse phase chromatography (H 2 O with 0-65% MeCN) to give 3-(5-bromo-2-(3-methylureido)pyridin-4-yloxy)-N -ethyl-4-fluorobenzenesulfonamide. Yield 44 mg (21%).

步驟D：在密封管中，將3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-N-乙基-4-氟苯磺醯胺(44 mg，0.099 mmol)、6-乙氧基吡啶-3-基酸(33 mg，0.199 mmol)及CsF(39 mg，0.258 mmol)於i-PrOH(2 ml)中之混合物用氮氣脫氣10分鐘。添加三乙胺(0.0221 ml，0.159 mmol)及PdCl2(dppf)*DCM(8 mg，0.0099 mmol)，將容器密封且在100℃下加熱18小時。用EtOAc稀釋反應混合物，經矽藻土栓塞過濾並濃縮，且藉由C18逆相層析(含0-60% MeCN之H2O)純化殘餘物，得到3-(6'-乙氧基-6-(3-甲基脲基)-3,3'-聯吡啶-4-基氧基)-N-乙基-4-氟苯磺醯胺。產量35 mg(71%)。質譜(APCI)m/z 489.7(M+H)。1H NMR(400 MHz,CD3OD)δ ppm 8.34(br s,1H),8.25(s,1H),7.96(dd,J=3 Hz,8 Hz,1H),7.88-7.82(m,1H),7.82-7.79(m,1H),7.57(t,J=9 Hz,1H),6.90(d,J=9 Hz,1H),6.60(s,1H),4.37(q,J=2Hz,7 Hz,2H),2.92(q,J=8 Hz,2H),2.82(s,3H),1.40(t,J=7 Hz,3H),1.08(t,J=7 Hz,3H)。 Step D : 3-(5-Bromo-2-(3-methylureido)pyridin-4-yloxy)-N-ethyl-4-fluorobenzenesulfonamide (44 mg in a sealed tube) , 0.099 mmol), 6-ethoxypyridin-3-yl A mixture of the acid (33 mg, 0.199 mmol) and CsF (39 mg, 0.258 mmol) in i- PrOH (2 ml) was degassed with nitrogen for 10 min. Triethylamine (0.0221 ml, 0.159 mmol) and PdCl 2 (dppf)*DCM (8 mg, 0.0099 mmol) were added, and the vessel was sealed and heated at 100 ° C for 18 hours. The reaction mixture was diluted with EtOAc and filtered through diatomaceous earth and concentrated to plug, and by C18 reverse phase chromatography (0-60% MeCN containing the H 2 O) The residue was purified to give 3- (6'-ethoxy - 6-(3-Methylureido)-3,3'-bipyridin-4-yloxy)-N-ethyl-4-fluorobenzenesulfonamide. Yield 35 mg (71%). Mass Spectrum (APCI) m/z 489.7 (M+H). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.34 (br s, 1H), 8.25 (s, 1H), 7.96 (dd, J = 3 Hz, 8 Hz, 1H), 7.88-7.82 (m, 1H) ), 7.82-7.79 (m, 1H), 7.57 (t, J = 9 Hz, 1H), 6.90 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 4.37 (q, J = 2 Hz, 7 Hz, 2H), 2.92 (q, J = 8 Hz, 2H), 2.82 (s, 3H), 1.40 (t, J = 7 Hz, 3H), 1.08 (t, J = 7 Hz, 3H).

實例1653Example 1653

1-(6'-乙氧基-4-(3-(5-甲基-1H-四唑-1-基)苯氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(6'-ethoxy-4-(3-(5-methyl-1H-tetrazol-1-yl)phenoxy)-3,3'-bipyridin-6-yl)-3- Methyl urea

向3-(5-甲基-1H-四唑-1-基)苯酚(85 mg，0.482 mmol)於無水DMA(1 mL)中之溶液中添加1-(6'-乙氧基-4-氟-3,3'-聯吡啶-6-基)-3-甲基脲(70 mg，0.241 mmol)，繼而添加K2CO3(70 mg，0.506 mmol)，且在95℃下加熱混合物隔夜。藉由C18逆相層析(含0-60% MeCN之H2O)純化經冷卻之反應混合物，得到1-(6'-乙氧基-4-(3-(5-甲基-1H-四唑-1-基)苯氧基)-3,3'-聯吡啶-6-基)-3-甲基脲。產量30 mg(27%)。質譜(APCI)m/z 446.8(M+H)。1H NMR(400 MHz,CD3OD)δ ppm 8.28(d,J=3 Hz,1H),8.22(s,1H),7.91(dd,J=3 Hz,9 Hz,1H),7.70(t,J=9 Hz,1H),7.53-7.45(m,2H),7.39(dd,J=2Hz,8 Hz,1H),6.83(d,J=9 Hz,1H),6.74(s,1H),4.33(q,J=7 Hz,2H),2.84(s,3H),2.60(s,3H),1.38(t,J=7 Hz,3H)。 Add 1-(6'-ethoxy-4-) to a solution of 3-(5-methyl-1H-tetrazol-1-yl)phenol (85 mg, 0.482 mmol) in dry EtOAc (1 mL) Fluorin-3,3'-bipyridin-6-yl)-3-methylurea (70 mg, 0.241 mmol), followed by K 2 CO 3 (70 mg, 0.506 mmol), and the mixture was heated overnight at 95 ° C . The cooled reaction mixture was purified by C18 reverse phase chromatography (H 2 O with 0-60% MeCN) to afford 1-(6'-ethoxy-4-(3-(5-methyl-1H-) Tetrazol-1-yl)phenoxy)-3,3'-bipyridin-6-yl)-3-methylurea. Yield 30 mg (27%). Mass Spectrum (APCI) m/z 446.8 (M+H). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.28 (d, J = 3 Hz, 1H), 8.22 (s, 1H), 7.91 (dd, J = 3 Hz, 9 Hz, 1H), 7.70 (t , J=9 Hz, 1H), 7.53-7.45 (m, 2H), 7.39 (dd, J=2 Hz, 8 Hz, 1H), 6.83 (d, J=9 Hz, 1H), 6.74 (s, 1H) , 4.33 (q, J = 7 Hz, 2H), 2.84 (s, 3H), 2.60 (s, 3H), 1.38 (t, J = 7 Hz, 3H).

遵循實例1653中之程序，使用適當起始物質製備以下化合物： Following the procedure in Example 1653, the following compounds were prepared using the appropriate starting materials:

實例1655Example 1655

1-(6'-乙氧基-4-(5-(乙基磺醯基)-2-氟苯氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(6'-ethoxy-4-(5-(ethylsulfonyl)-2-fluorophenoxy)-3,3'-bipyridin-6-yl)-3-methylurea

步驟A：將4-氟-3-甲氧基苯-1-磺醯氯(1.0 g，4.45 mmol)、碳酸氫鈉(748 mg，8.90 mmol)及亞硫酸鈉(1.12 g，8.90 mmol)於水(7 mL)中之混合物在100℃下加熱1小時。冷卻混合物至50℃且用溴化四丁基銨(144 mg，0.445 mmol)及碘乙烷(4.17 g，2.2 mL，26.71 mmol)處理，且在70℃下加熱所得混合物18小時。用水(10 mL)稀釋經冷卻之混合物且用DCM(3×15 mL)萃取。經MgSO4乾燥經合併之有機萃取物，濃縮且在矽膠上(含20-30% EtOAc之己烷)純化殘餘物，得到4-(乙基磺醯基)-1-氟-2-甲氧基苯。產量729 mg(75%)。 Step A : 4-Fluoro-3-methoxybenzene-1-sulfonium chloride (1.0 g, 4.45 mmol), sodium bicarbonate (748 mg, 8.90 mmol) and sodium sulfite (1.12 g, 8.90 mmol) in water ( The mixture in 7 mL) was heated at 100 ° C for 1 hour. The mixture was cooled to 50 ° C and treated with tetrabutylammonium bromide (144 mg, 0.445 mmol) and ethyl iodide (4.17 g, 2.2 mL, 26.71 mmol) and the mixture was warmed at 70 ° C for 18 hours. The cooled mixture was diluted with water (10 mL). Dried over MgSO 4 the organic extracts were combined, and concentrated on silica gel (20-30% EtOAc in hexanes of) the residue was purified to give 4- (ethyl sulfo acyl) -1-fluoro-2-methoxy Base benzene. Yield 729 mg (75%).

步驟B：將4-(乙基磺醯基)-1-氟-2-甲氧基苯(729 mg，3.34 mmol)於無水二氯甲烷(28 mL)中之溶液在氮氣下冷卻至-78℃，且向此溶液中逐滴添加含1 M BBr3之二氯甲烷(10.4 mL，10.4 mmol)，且在周圍溫度下攪拌混合物隔夜。在冰-水浴上冷卻混合物且藉由逐滴添加MeOH淬滅。用EtOAc(50 mL)稀釋所得混合物，且用水(3×15 mL)及鹽水(3×15 mL)洗滌，接著經MgSO4乾燥，且經二氧化矽襯墊過濾並濃縮，得到4-氟-3-羥基-N-(2-羥基乙基)苯磺醯胺。產量691 mg。 Step B : A solution of 4-(ethylsulfonyl)-1-fluoro-2-methoxybenzene (729 mg, 3.34 mmol) in anhydrous dichloromethane (28 mL) °C, and 1 M BBr 3 in dichloromethane (10.4 mL, 10.4 mmol) was added dropwise, and the mixture was stirred overnight at ambient temperature. The mixture was cooled on an ice-water bath and quenched by dropwise addition of MeOH. With EtOAc (50 mL) and the resulting mixture was diluted and washed with water (3 × 15 mL) and brine (3 × 15 mL), dried and then dried over MgSO 4, and filtered through a pad silicon dioxide and concentrated to give 4-fluoro - 3-hydroxy-N-(2-hydroxyethyl)benzenesulfonamide. Yield 691 mg.

步驟C：向5-(乙基磺醯基)-2-氟苯酚(98.8 mg，0.484 mmol)及1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(120 mg，0.484 mmol)於無水DMA(1.0 mL)中之溶液中添加K2CO3(134 mg，0.968 mmol)，且在95℃下加熱混合物隔夜。藉由C18逆相層析(含0-60% MeCN之H2O)純化混合物，得到1-(5-溴-4-(5-(乙基磺醯基)-2-氟苯氧基)吡啶-2-基)-3-甲基脲。產量80 mg(38%)。 Step C : To 5-(ethylsulfonyl)-2-fluorophenol (98.8 mg, 0.484 mmol) and 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (120) K 2 CO 3 (134 mg, 0.968 mmol) was added to a solution of EtOAc (EtOAc). The mixture was purified by C18 reverse phase chromatography (H 2 O with 0-60% MeCN) to give 1-(5-bromo-4-(5-(ethylsulfonyl)-2-fluorophenoxy) Pyridin-2-yl)-3-methylurea. Yield 80 mg (38%).

步驟D：將3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-N-乙基-4-氟苯磺醯胺(44.4 mg，0.099 mmol)、6-乙氧基吡啶-3-基酸(0.0616 g，0.369 mmol)及CsF(0.0729 g，0.480 mmol)於i-PrOH(4 ml)中之混合物用氮氣脫氣10分鐘。添加三乙胺(0.0412 ml，0.295 mmol)及PdCl2(dppf)*DCM(15 mg，0.0185 mmol)，將容器密封且在100℃下加 熱18小時。用EtOAc(10 mL)稀釋經冷卻之反應混合物，經矽藻土栓塞過濾且濃縮。藉由C18逆相層析(含0-60% MeCN之H2O)，接著藉由矽膠層析(100% EtOAc)純化殘餘物，得到1-(6'-乙氧基-4-(5-(乙基磺醯基)-2-氟苯氧基)-3,3'-聯吡啶-6-基)-3-甲基脲。產量39 mg(43%)。質譜(APCI)m/z 474.7(M+H)。1H NMR(400 MHz,CDCl3)δ ppm 8.97(br s,1H),8.58(s,1H),8.30(d,J=3 Hz,1H),8.13(s,1H),7.80-7.75(m,2H),7.69(dd,J=2Hz,7 Hz,1H),7.39(t,J=9 Hz,1H),6.80(d,J=9 Hz,1H),6.17(s,1H),4.39(q,J=7 Hz,2H),3.10(q,J=7 Hz,2H),2.83(d,J=5 Hz,3H),1.41(t,J=7 Hz,3H),1.27(t,J=8Hz,3H)。 Step D : 3-(5-Bromo-2-(3-methylureido)pyridin-4-yloxy)-N-ethyl-4-fluorobenzenesulfonamide (44.4 mg, 0.099 mmol), 6-ethoxypyridin-3-yl A mixture of the acid (0.0616 g, 0.369 mmol) and CsF (0.0729 g, 0.480 mmol) in i- PrOH (4 ml) was degassed with nitrogen for 10 min. Triethylamine (0.0412 ml, 0.295 mmol) and PdCl 2 (dppf)*DCM (15 mg, 0.015 mmol) were added and the vessel was sealed and heated at 100 ° C for 18 hours. The cooled reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. By C18 reverse phase chromatography (0-60% MeCN containing the H 2 O), followed by silica gel chromatography (100% EtOAc) The residue was purified to give 1- (6'-ethoxy-4- (5 -(Ethylsulfonyl)-2-fluorophenoxy)-3,3'-bipyridin-6-yl)-3-methylurea. Yield 39 mg (43%). Mass Spectrum (APCI) m/z 474.7 (M+H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.97 (br s, 1H), 8.58 (s, 1H), 8.30 (d, J = 3 Hz, 1H), 8.13 (s, 1H), 7.80-7. m, 2H), 7.69 (dd, J = 2 Hz, 7 Hz, 1H), 7.39 (t, J = 9 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.17 (s, 1H), 4.39 (q, J = 7 Hz, 2H), 3.10 (q, J = 7 Hz, 2H), 2.83 (d, J = 5 Hz, 3H), 1.41 (t, J = 7 Hz, 3H), 1.27 ( t, J = 8 Hz, 3H).

實例1656Example 1656

1-(6'-乙氧基-4-(1-甲基-6-側氧基-5-(三氟甲基)-1,6-二氫吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(6'-ethoxy-4-(1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yloxy)-3, 3'-bipyridyl-6-yl)-3-methylurea

步驟A：在0℃下，向5-溴-3-(三氟甲基)吡啶-2(1H)-酮(1.50 g，6.20 mmol)及K2CO3(2.14 g，15.5 mmol)於無水DMF(10 mL)中之混合物中添加碘甲烷(0.46 ml，7.44 mmol)。在0℃下攪拌混合物，且緩慢升溫至周圍溫度並在周圍溫度下攪拌隔夜。添加水(30 mL)，使得沈澱物分離，藉由過濾收集該沈澱物，用水洗滌且乾燥。濃縮濾液至乾燥，且將所獲得之固體與10% MeCN-EtOAc(100 mL)一起攪拌隔夜。經矽藻土襯墊過濾懸浮液且在減壓下濃縮。在矽膠上(50% EtOAc-己烷)純化所獲得之殘餘物，得到5-溴-1-甲基-3-(三氟甲基)吡啶-2(1H)- 酮。產量1.07 g(67%)。 Step A : To a solution of 5-bromo-3-(trifluoromethyl)pyridine-2(1H)-one (1.50 g, 6.20 mmol) and K 2 CO 3 (2.14 g, 15.5 mmol) at 0 ° C Methyl iodide (0.46 ml, 7.44 mmol) was added to a mixture of DMF (10 mL). The mixture was stirred at 0 ° C and slowly warmed to ambient temperature and stirred overnight at ambient temperature. Water (30 mL) was added to separate the precipitate, which was collected by filtration, washed with water and dried. The filtrate was concentrated to dryness and the obtained solid was stirred overnight with 10% MeCN-EtOAc (100 mL). The suspension was filtered through a pad of Celite and concentrated under reduced pressure. The residue obtained was purified on EtOAc (EtOAc:EtOAc) The yield was 1.07 g (67%).

步驟B：在-78℃下，經10分鐘，向5-溴-1-甲基-3-(三氟甲基)吡啶-2(1H)-酮(715 mg，2.79 mmol)及硼酸三異丙酯(1.26 g，1.54 mL，6.75 mmol)於甲苯-THF混合物(2：1，15 mL)中之溶液中逐滴添加含2.5 M n-BuLi之己烷(2.68 mL，6.70 mmol)。在此溫度下攪拌所得混合物2小時。添加32%過乙酸於乙酸中之溶液(1.83 g，1.62 mL，7.68 mmol)，且在-78℃下攪拌10分鐘後，使混合物升溫至0℃且攪拌1小時。冷卻混合物至-10℃，且添加亞硫酸鈉之水溶液(10 mL，8.38 mmol)，且用4：1氯仿-IPA(3×50 mL)萃取混合物。經MgSO4乾燥經合併之有機萃取物且濃縮，得到5-羥基-1-甲基-3-(三氟甲基)吡啶-2(1H)-酮。產量300 mg。 Step B : 5-Bromo-1-methyl-3-(trifluoromethyl)pyridine-2(1H)-one (715 mg, 2.79 mmol) and tribasic borate at -78 °C over 10 min. Hexane (2.68 mL, 6.70 mmol) containing 2.5 M n -BuLi was added dropwise to a solution of propyl ester (1.26 g, 1.54 mL, 6.75 mmol) in toluene-THF mixture (2:1, 15 mL). The resulting mixture was stirred at this temperature for 2 hours. A solution of 32% peracetic acid in acetic acid (1.83 g, 1.62 mL, 7.68 mmol) was added, and after stirring at -78 °C for 10 minutes, the mixture was warmed to 0 ° C and stirred for 1 hour. The mixture was cooled to -10.degree. C. and aqueous sodium sulphate (10 mL, 8.38 mmol) was added and the mixture was extracted with 4:1 chloroform-IPA (3 x 50 mL). Dried over MgSO 4 the organic extracts were combined and concentrated to give 5-hydroxy-1-methyl-3- (trifluoromethyl) pyridin -2 (1H) - one. Yield 300 mg.

步驟C：向1-(6'-乙氧基-4-氟-3,3'-聯吡啶-6-基)-3-甲基脲(70 mg，0.241 mmol)於DMA(1 mL)中之溶液中添加5-羥基-1-甲基-3-(三氟甲基)吡啶-2(1H)-酮(93 mg，0.482 mmol)及K2CO3(70 mg，0.506 mmol)，且在90℃下加熱混合物13小時。向經冷卻之反應混合物中饋入無水DMA(1 mL)、5-羥基-1-甲基-3-(三氟甲基)吡啶-2(1H)-酮(55 mg，0.285 mmol)及K2CO3(70 mg)，且在90℃下再加熱混合物18小時。向經冷卻之反應混合物中再饋入5-羥基-1-甲基-3-(三氟甲基)吡啶-2(1H)-酮(55 mg，0.285 mmol)及K2CO3(70 mg)，且在90℃下再加熱混合物18小時。藉由C18逆相層析(含0-60% MeCN之H2O)，接著藉由製備型TLC(0.5 mm二氧化矽板，用EtOAc溶離)純化經冷卻之混合物，得到1-(6'-乙氧基-4-(1-甲基-6-側氧基-5-(三氟甲基)-1,6-二氫吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲。產量7 mg(6%)。質譜(APCI)m/z 463.7(M+H)。1H NMR(400 MHz,CD3OD)δ ppm 8.27(br s,1H),8.15(s,1H),8.07(d,J=3 Hz,1H),7.97(d,J=4 Hz,1H),7.90(dd,J=3 Hz,8 Hz,1H),6.84(d,J=8 Hz,1H),6.64(s,1H),4.34(q,J=7 Hz,2H),3.6(s,3H),2.83(s,3H),1.38(t,J=7 Hz,3H)。 Step C : To 1-(6'-ethoxy-4-fluoro-3,3'-bipyridin-6-yl)-3-methylurea (70 mg, 0.241 mmol) in EtOAc (1 mL) To the solution was added 5-hydroxy-1-methyl-3-(trifluoromethyl)pyridine-2(1H)-one (93 mg, 0.482 mmol) and K 2 CO 3 (70 mg, 0.506 mmol). The mixture was heated at 90 ° C for 13 hours. Anhydrous DMA (1 mL), 5-hydroxy-1-methyl-3-(trifluoromethyl)pyridine-2(1H)-one (55 mg, 0.285 mmol) and K were fed to the cooled reaction mixture. 2 CO 3 (70 mg), and the mixture was heated at 90 ° C for an additional 18 hours. To the cooled reaction mixture was further fed 5-hydroxy-1-methyl-3-(trifluoromethyl)pyridine-2(1H)-one (55 mg, 0.285 mmol) and K 2 CO 3 (70 mg) And the mixture was heated at 90 ° C for an additional 18 hours. Purification of the cooled mixture by C18 reverse phase chromatography (H 2 O with 0-60% MeCN) followed by preparative TLC (0.5 mm cerium dioxide, eluting with EtOAc) affords 1-(6 -ethoxy-4-(1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yloxy)-3,3'-bipyridine -6-yl)-3-methylurea. Yield 7 mg (6%). Mass Spectrum (APCI) m/z 463.7 (M+H). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.27 (br s, 1H), 8.15 (s, 1H), 8.07 (d, J = 3 Hz, 1H), 7.97 (d, J = 4 Hz, 1H) ), 7.90 (dd, J = 3 Hz, 8 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 6.64 (s, 1H), 4.34 (q, J = 7 Hz, 2H), 3.6 ( s, 3H), 2.83 (s, 3H), 1.38 (t, J = 7 Hz, 3H).

實例1657Example 1657

1-(6'-乙氧基-4-((5-甲基-6-(三氟甲基)吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-ethoxy-4-((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl -3-methylurea

將1-(6'-乙氧基-4-羥基-3,3'-聯吡啶-6-基)-3-甲基脲(40 mg，0.14 mmol)及5-氟-3-甲基-2-(三氟甲基)吡啶(50 mg，0.28 mmol)溶解於DMA(0.5 mL)中，且添加K2CO3(19 mg，0.14 mmol)。加熱反應物至120℃隔夜。再添加5-氟-3-甲基-2-(三氟甲基)吡啶(50 mg，0.28 mmol)，且在120℃下再繼續加熱反應物72小時。冷卻反應物至室溫且在C18管柱上(含5%至95% ACN之水)直接純化，得到不純物質，在矽膠上(含1：1 EtOAc之己烷)純化該物質，得到呈白色固體狀之1-(6'-乙氧基-4-(5-甲基-6-(三氟甲基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(1.2 mg，0.0027 mmol，1.9%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.03(s,1H),8.55(s,1H),8.28(d,J=2.5 Hz,1H),8.27(d,J=2.3 Hz,1H),8.17(s,1H),7.72(dd,J=8.6,2.5 Hz,1H),7.30(d,J=2.0 Hz,1H),6.78(d,J=6.8 Hz,1H),6.27(s,1H),4.38(q,J=7.0 Hz,2H),2.85(d,J=4.7 Hz,3H),2.49(q,J=1.6 Hz,3H),1.41(t,J=7.0 Hz,3H)。質譜(apci)m/z=447.8(M+H)。 1-(6'-ethoxy-4-hydroxy-3,3'-bipyridin-6-yl)-3-methylurea (40 mg, 0.14 mmol) and 5-fluoro-3-methyl- 2-(Trifluoromethyl)pyridine (50 mg, 0.28 mmol) was dissolved in DMA (0.5 mL) and K 2 CO 3 (19 mg, 0.14 mmol). The reaction was heated to 120 ° C overnight. Additional 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine (50 mg, 0.28 mmol) was added and the reaction was further heated at 120 °C for a further 72 s. The reaction was cooled to room temperature and purified directly on EtOAc (EtOAc EtOAc EtOAc EtOAc) Solid 1-(6'-ethoxy-4-(5-methyl-6-(trifluoromethyl)pyridin-3-yloxy)-3,3'-bipyridin-6-yl) -3-methylurea (1.2 mg, 0.0027 mmol, 1.9% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.03 (s, 1H), 8.55 (s, 1H), 8.28 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.17(s,1H), 7.72 (dd, J = 8.6, 2.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.27 (s, 1H) ), 4.38 (q, J = 7.0 Hz, 2H), 2.85 (d, J = 4.7 Hz, 3H), 2.49 (q, J = 1.6 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 447.8 (M+H).

實例1658Example 1658

1-(4-(3-氯-2-氟苯氧基)-5-(4-羥基四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲 基脲 1-(4-(3-Chloro-2-fluorophenoxy)-5-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-A Base urea

步驟A：在室溫下，於氮氣下，向1-(5-溴-4-(3-氯-2-氟苯氧基)吡啶-2-基)-3-甲基脲(750 mg，2.00 mmol)於10 mL 4：1二噁烷：H2O中之經攪拌懸浮液中依序添加純固體形式之2-(3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼(631 mg，3.00 mmol)、純固體形式之Na2CO3(1061 mg，10.0 mmol)。將反應物用氮氣充氣10分鐘。接著添加純固體形式之PdCl2(PPh3)2(141 mg，0.200 mmol)，且使反應物升溫至80℃。攪拌隔夜後，冷卻反應混合物至室溫，用二氯甲烷稀釋至30 mL，且用1×30 mL鹽水洗滌。經MgSO4乾燥有機物，過濾，濃縮且在矽膠上(含1：1 EtOAc之己烷)純化，得到呈褐色粉末狀之1-(4-(3-氯-2-氟苯氧基)-5-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲(600 mg，77%產率)。質譜(apci)m/z=377.8(M+H)。 Step A : To 1-(5-bromo-4-(3-chloro-2-fluorophenoxy)pyridin-2-yl)-3-methylurea (750 mg, at rt under nitrogen) 2.00 mmol) sequentially added 2-(3,6-dihydro-2H-pyran-4-yl)-pure solid in a stirred suspension of 10 mL of 4:1 dioxane:H 2 O 4,4,5,5-tetramethyl-1,3,2-dioxaboron (631 mg, 3.00 mmol), Na 2 CO 3 (1061 mg, 10.0 mmol) as pure solid. The reaction was inflated with nitrogen for 10 minutes. PdCl 2 (PPh 3 ) 2 (141 mg, 0.200 mmol) was then added in pure solid form and the reaction was allowed to warm to 80 °C. After stirring overnight, the reaction mixture was cooled to room temperature, diluted with dichloromethane to 30 mL and washed with 1×30 mL brine. The organics were dried over MgSO 4, filtered, and concentrated on silica gel (with 1: 1 EtOAc in hexanes's) to give a brown powder of 1- (4- (3-chloro-2-fluorophenoxy) -5 -(3,6-Dihydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylurea (600 mg, 77% yield). Mass spectrum (apci) m/z = 377.8 (M+H).

步驟B：在0℃下，於氮氣下，由注射器向1-(4-(3-氯-2-氟苯氧基)-5-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲(65 mg，0.1720 mmol)於1 mL THF中之經攪拌溶液中逐滴添加BH3．SMe2複合物(412.9 μl，0.8258 mmol)(2 M，於THF中)。使冷卻浴緩慢融化，且在室溫下攪拌反應物隔夜。接著由注射器添加3 M NaOH(252.3 μl，0.7570 mmol)，繼而由注射器添加30% H2O2(264.5 μl，2.753 mmol)。使反應物升溫至45℃。1小時後，將反應物分配於乙酸乙酯(15 mL)與碳酸氫鈉(15 mL)之間。分離有機物，且用1×15 mL鹽水洗滌，經MgSO4乾燥，過濾並濃縮。將粗產物加載於含二氯甲烷之20 cm×20 cm×0.5 mm 製備型板(prep plate)上且用1：1乙酸乙酯：己烷溶離，得到呈透明油狀之1-(4-(3-氯-2-氟苯氧基)-5-(4-羥基四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲(6 mg，7%產率)。1H NMR(CDCl3)δ 9.16(bs,1H),8.61(bs,1H),8.19(s,1H),7.39(m,1H),7.20(m,2H),6.03(s,1H),4.02(m,2H),3.90(m,2H),2.81(d.3H),2.39(m,2)。質譜(apci)m/z=395.8(M+H)。 Step B : 1-(4-(3-chloro-2-fluorophenoxy)-5-(3,6-dihydro-2H-pyran-4-) from a syringe under nitrogen at 0 °C BH 3 was added dropwise to a stirred solution of pyridine-2-yl)-3-methylurea (65 mg, 0.1720 mmol) in 1 mL THF. SMe 2 complex (412.9 μl, 0.8258 mmol) (2 M in THF). The cooling bath was slowly melted and the reaction was stirred at room temperature overnight. 3 M NaOH (252.3 μl, 0.7570 mmol) was then added by syringe followed by 30% H 2 O 2 (264.5 μl, 2.753 mmol) by syringe. The reaction was allowed to warm to 45 °C. After 1 h, the reaction was partitioned between ethyl acetate (15 mL) and sodium hydrogen sulfate (15 mL). The organics were separated and washed 1 × 15 mL brine, dried over MgSO 4, filtered and concentrated. The crude product was loaded onto a 20 cm × 20 cm × 0.5 mm preparative plate (methylene chloride) and eluted with 1:1 ethyl acetate:hexane to afford 1-(4- (3-chloro-2-fluorophenoxy)-5-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylurea (6 mg, 7% yield) rate). 1 H NMR (CDCl 3 ) δ 9.16 (bs, 1H), 8.61 (bs, 1H), 8.19 (s, 1H), 7.39 (m, 1H), 7.20 (m, 2H), 6.03 (s, 1H), 4.02 (m, 2H), 3.90 (m, 2H), 2.81 (d.3H), 2.39 (m, 2). Mass spectrum (apci) m/z = 395.8 (M+H).

實例1659Example 1659

1-(4-(3-氯-2-氟苯氧基)-5-((3S,4S)-3,4-二羥基四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲 1-(4-(3-Chloro-2-fluorophenoxy)-5-((3S,4S)-3,4-dihydroxytetrahydro-2H-piperidin-4-yl)pyridin-2-yl -3-methylurea

步驟A：在0℃下，向AD-mix-α(700 mg，0.498 mmol)於2.5 mL tBuOH及2.5 mL水中之經攪拌懸浮液中依序添加甲烷磺醯胺(47.3 mg，0.498 mmol)、1-(4-(3-氯-2-氟苯氧基)-5-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲(188 mg，0.498 mmol)。攪拌36小時後，添加固體形式之Na2SO3(750 mg)。攪拌90分鐘後，用1：1二氯甲烷：水將反應物稀釋至50 mL。分離各層，且用1×30 mL二氯甲烷萃取水相。經MgSO4乾燥經合併之有機物，過濾且濃縮。在矽膠上(100% EtOAc)純化粗產物，繼而進行製備型TLC純化(20 cm×20 cm×0.5 mm製備型板；9：1二氯甲烷：甲醇)，得到呈白色固體狀之1-(4-(3-氯-2-氟苯氧基)-5-((3S,4S)-3,4-二羥基四氫-2H-哌喃-4-基)吡啶-2-基)-3-甲基脲(50 mg，24%產率)。H NMR(CDCl3)δ ppm 9.15(bs,1H),8.40(s,1H),8.27(bs,1H),7.36(m,1H),7.15(m,2H),5.88(s,1H),4.56(m,2H), 3.84(m,2H),3.76(m,1H),3.56(m,1H),3.34(bs,1H),2.77(d.3H),2.56(m,1H)。質譜(apci)m/z=411.7(M+H)。 Step A : Methanesulfonamide (47.3 mg, 0.498 mmol) was added sequentially to a stirred suspension of AD-mix-α (700 mg, 0.498 mmol) in 2.5 mL of tBuOH and 2.5 mL of water at 0 °C. 1-(4-(3-Chloro-2-fluorophenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-3-methylurea 188 mg, 0.498 mmol). After stirring for 36 hours, Na 2 SO 3 (750 mg) was obtained as a solid. After stirring for 90 minutes, the reaction was diluted to 50 mL with 1:1 dichloromethane: water. The layers were separated and the aqueous phase was extracted with 1×30 mL dichloromethane. Dried over MgSO 4 The organics were combined, filtered and concentrated. The crude product was purified on EtOAc (EtOAc (EtOAc) elute elute 4-(3-Chloro-2-fluorophenoxy)-5-((3S,4S)-3,4-dihydroxytetrahydro-2H-piperidin-4-yl)pyridin-2-yl)-3 -methylurea (50 mg, 24% yield). H NMR (CDCl 3 ) δ ppm 9.15 (bs, 1H), 8.40 (s, 1H), 8.27 (bs, 1H), 7.36 (m, 1H), 7.15 (m, 2H), 5.88 (s, 1H), 4.56 (m, 2H), 3.84 (m, 2H), 3.76 (m, 1H), 3.56 (m, 1H), 3.34 (bs, 1H), 2.77 (d.3H), 2.56 (m, 1H). Mass spectrum (apci) m/z = 411.7 (M+H).

實例1660Example 1660

(±)-1-(順-5-(3-羥基四氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 (±)-1-(cis-5-(3-hydroxytetrahydro-2H-piperazin-4-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl -3-methylurea

步驟A：在0℃下，於氮氣下，向1-(5-(3,6-二氫-2H-哌喃-4-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(68 mg，0.20 mmol)於2 mL二氯甲烷中之經攪拌溶液中添加純固體形式之MCPBA(460 mg，2.00 mmol)。使冷卻浴緩慢升溫至室溫。攪拌隔夜後，用二氯甲烷稀釋反應物至30 mL且用2×30 mL 2 M碳酸鈉洗滌。用2×30 mL 9：1二氯甲烷：甲醇反萃取碳酸鈉溶液。經MgSO4乾燥經合併之有機物，過濾且濃縮。在矽膠上(二氯甲烷(200 mL)、2.5/97.5甲醇/二氯甲烷(200 mL)、5/95甲醇/二氯甲烷(200 mL)及1/9甲醇/二氯甲烷(400 mL))純化粗產物，得到呈白色膜狀之5-(3,7-二氧雜雙環[4.1.0]庚-6-基)-4-((5-甲基-1-氧離子基吡啶-3-基)氧基)-2-(3-甲基脲基)吡啶1-氧化物(30 mg，39%產率)。質譜(apci)m/z=388.8(M+H)。 Step A : 1-(5-(3,6-Dihydro-2H-pyran-4-yl)-4-(5-methylpyridin-3-yloxy) at 0 ° C under N2 The pyridin-2-yl)-3-methylurea (68 mg, 0.20 mmol) was added to aq. The cooling bath was slowly warmed to room temperature. After stirring overnight, the reaction was diluted with dichloromethane to 30 mL and washed with 2×30 mL 2 M sodium carbonate. The sodium carbonate solution was back extracted with 2 x 30 mL of 9:1 dichloromethane:methanol. Dried over MgSO 4 The organics were combined, filtered and concentrated. On silica gel (dichloromethane (200 mL), 2.5/97.5 methanol/dichloromethane (200 mL), 5/95 methanol/dichloromethane (200 mL) and 1/9 methanol/dichloromethane (400 mL) The crude product was purified to give 5-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-4-((5-methyl-1-oxo-ylpyridine) as a white film. 3-yl)oxy)-2-(3-methylureido)pyridine 1-oxide (30 mg, 39% yield). Mass spectrum (apci) m/z = 388.8 (M+H).

步驟B：向5-(3,7-二氧雜雙環[4.1.0]庚-6-基)-4-(5-甲基-1-氧離子基吡啶-3-基氧基)-2-(3-甲基脲基)吡啶1-氧化物(30 mg，0.077 mmol)於2 mL甲醇中之經攪拌溶液中依序添加Et3N(269 μl，1.9 mmol)、10%鈀/碳(16 mg，0.015 mmol)。在帕爾震盪器(Parr Shaker)上使混合物經歷三次真空/氫氣淨化循環，接著在震盪下保持於50 psi氫氣下。 震盪隔夜後，經含甲醇之GF/F濾紙過濾粗反應物且由旋轉蒸發器及高真空濃縮至乾燥。將粗產物加載於含二氯甲烷之0.5 mm×20 cm×20 cm製備型板上且用9：1二氯甲烷：甲醇溶離，得到呈白色固體狀之1-(5-((3R,4S)-3-羥基四氫-2H-哌喃-4-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(5 mg，18%產率)。1H NMR(CDCl3)δ ppm 9.08(bs,1H),8.36(m,1H),8.24(d,1H),8.15(s,1H),7.44(bs,1H),7.22(m,1H),5.91(s,1H),4.15(m,1H),4.03(m,1H),3.94(m,1H),3.69(m,1H),3.59(m,1H),3.36(m,1H),2.87(d.3H),2.39(s,3H)。質譜(apci)m/z=358.9(M+H)。 Step B : to 5-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-4-(5-methyl-1-oxopyridin-3-yloxy)-2 - (3-methyl-ureido) pyridine 1-oxide (30 mg, 0.077 mmol) in 2 mL of methanol was stirred solution sequentially added Et 3 N (269 μl, 1.9 mmol), 10% Pd / C (16 mg, 0.015 mmol). The mixture was subjected to three vacuum/hydrogen purge cycles on a Parr Shaker and then maintained under 50 psi of hydrogen under shaking. After shaking overnight, the crude reaction was filtered through a methanol-containing GF/F filter paper and concentrated to dryness by rotary evaporator and high vacuum. The crude product was loaded onto a 0.5 mm × 20 cm × 20 cm preparative plate containing dichloromethane and eluted with 9:1 dichloromethane:methanol to afford 1-(5-((3R,4S) as a white solid. -3-hydroxytetrahydro-2H-piperidin-4-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (5 mg , 18% yield). 1 H NMR (CDCl 3 ) δ ppm 9.08 (bs, 1H), 8.36 (m, 1H), 8.24 (d, 1H), 8.15 (s, 1H), 7.44 (bs, 1H), 7.22 (m, 1H) , 5.91 (s, 1H), 4.15 (m, 1H), 4.03 (m, 1H), 3.94 (m, 1H), 3.69 (m, 1H), 3.59 (m, 1H), 3.36 (m, 1H), 2.87 (d.3H), 2.39 (s, 3H). Mass spectrum (apci) m/z = 358.9 (M+H).

實例1661Example 1661

1-(5-(1-(3-羥基丙基)-1H-吡唑-5-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(1-(3-hydroxypropyl)-1H-pyrazol-5-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)- 3-methylurea

步驟A：在室溫下，於氮氣下，向1-(5-溴-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(67 mg，0.20 mmol)於1 mL 4：1二噁烷：水中之經攪拌懸浮液中依序添加純固體形式之1-(3,3-二乙氧基丙基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(97 mg，0.30 mmol)、純固體形式之Na2CO3(105 mg，0.99 mmol)。將反應物用氮氣充氣5分鐘，接著添加純固體形式之PdCl2(PPh3)2(14 mg，0.020 mmol)，且加熱混合物至80℃。攪拌隔夜後，將淡紅色反應混合物冷卻至室溫，用 二氯甲烷稀釋至15 mL且用1×15 mL鹽水洗滌。分離有機物，經MgSO4乾燥，過濾，濃縮且在矽膠上(100% EtOAc)純化，得到呈黃色泡沫狀之1-(5-(1-(3,3-二乙氧基丙基)-1H-吡唑-5-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(65 mg，72%產率)。質譜(apci)m/z=454.9(M+H)。 Step A : 1-(5-Bromo-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (67 mg at room temperature under nitrogen) , 0.20 mmol) sequentially added 1-(3,3-diethoxypropyl)-5-(4,4, in pure solid form in a stirred suspension of 1 mL of 4:1 dioxane:water. 5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (97 mg, 0.30 mmol), Na 2 CO 3 (105 mg, 0.99 mmol) as a solid. The reaction was aerated with nitrogen for 5 min then PdCl 2 (PPh 3 ) 2 (14 mg, 0.020 mmol) was added as a solid solid and the mixture was heated to 80 °C. After stirring overnight, the light red reaction mixture was cooled to room temperature, diluted with dichloromethane to 15 mL and washed with 1×15 mL brine. The organics were separated, dried over MgSO 4, filtered, concentrated and purified (100% EtOAc) on silica gel to give a yellow foam of l- (5- (l- (3,3-diethoxy-propyl) -1H -pyrazol-5-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (65 mg, 72% yield). Mass spectrum (apci) m/z = 454.9 (M+H).

步驟B：在室溫下，向開口燒瓶中之1-(5-(1-(3,3-二乙氧基丙基)-1H-吡唑-5-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(61 mg，0.13 mmol)於2.6 mL乙腈中之經攪拌溶液中添加1 M HCl(750 μL)。攪拌1.5小時後，由旋轉蒸發器部分濃縮反應物，接著用20 mL二氯甲烷及20 mL 10%碳酸鈉溶液稀釋，且快速攪拌。分離各層後，用3×20 mL二氯甲烷萃取水相。經MgSO4乾燥經合併之有機物，過濾且濃縮至油狀物。將該油狀物溶解於2.6 mL甲醇中且在0℃下於氮氣下攪拌。添加純固體形式之NaBH4(25 mg，0.67 mmol)。攪拌1小時後，濃縮反應物至接近乾燥且在矽膠上(9：1乙酸乙酯：甲醇)純化，得到呈棕色油狀之1-(5-(1-(3-羥基丙基)-1H-吡唑-5-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(30 mg，58%產率)。1H NMR(CDCl3)δ ppm 9.32(bs,1H),9.02(bs,1H),8.29(d,1H),8.23(d,1H),8.03(s,1H),7.57(d,1H),7.23(m,1H),6.30(d,1H),6.26(s,1H),4.23(m,2H),3.64(m,2H),2.80(d.3H),2.36(s,3H)。質譜(apci)m/z=382.9(M+H)。 Step B : 1-(5-(1-(3,3-diethoxypropyl)-1H-pyrazol-5-yl)-4-(5-A) in an open flask at room temperature Pyridine-3-yloxy)pyridin-2-yl)-3-methylurea (61 mg, 0.13 mmol) was added 1 M HCl (750 μL) to a stirred solution in 2.6 mL EtOAc. After stirring for 1.5 hours, the reaction was partially concentrated by a rotary evaporator, then diluted with 20 mL of dichloromethane and 20 mL of 10% sodium carbonate and stirred rapidly. After separating the layers, the aqueous phase was extracted with 3 x 20 mL dichloromethane. Dried over MgSO 4 The organics were combined, filtered and concentrated to an oil. The oil was dissolved in 2.6 mL of methanol and stirred at 0 ° C under nitrogen. NaBH 4 (25 mg, 0.67 mmol) was added as a solid. After stirring for 1 hour, the reaction was concentrated to dryness eluting EtOAc (EtOAc:EtOAc) -pyrazol-5-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (30 mg, 58% yield). 1 H NMR (CDCl 3 ) δ ppm 9.32 (bs, 1H), 9.02 (bs, 1H), 8.29 (d, 1H), 8.23 (d, 1H), 8.03 (s, 1H), 7.57 (d, 1H) , 7.23 (m, 1H), 6.30 (d, 1H), 6.26 (s, 1H), 4.23 (m, 2H), 3.64 (m, 2H), 2.80 (d.3H), 2.36 (s, 3H). Mass spectrum (apci) m/z = 382.9 (M+H).

實例1662Example 1662

1-(5-環丙基-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲 1-(5-cyclopropyl-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea

將1-(5-溴-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲(75 mg，0.22 mmol)(實例1546)、環丙基酸(57 mg，0.67 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II)與二氯甲烷之複合物(PdCl2(dppf)*DCM)(18 mg，0.022 mmol)及碳酸鉀(556 μL，2 N水溶液，1.10 mmol)於1,4-二噁烷(3 mL)中之混合物用氮氣淨化且在90℃下於密封管中攪拌24小時。再添加環丙基酸(0.67 mmol)、PdCl2(dppf)*DCM(0.022 mmol)及碳酸鉀溶液(0.67 mmol)，且繼續加熱3天。將混合物分配於水(20 mL)與乙酸乙酯(20 mL)之間，且經矽藻土過濾移除鈀。將混合物萃取至乙酸乙酯(4×20 mL)中。接著乾燥(MgSO4)經合併之萃取物，過濾且在減壓下濃縮。對殘餘物進行C18逆相層析(乙腈：水5：95至1：1梯度)，得到部分純之物質(7 mg)。用乙醚濕磨此物質，得到1-(5-環丙基-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(4 mg，6%產率)。MS(apci)m/z 298.9(M+H)。1H NMR(400 MHz,DMSO-d6)δ ppm 9.01(1H,s),8.34(1H,s),8.27(1H,d,J=2.4 Hz),7.85(1H,s),7.80(1H,br,s),7.46(1H,s),6.76(1H,s),2.65(3H,d,J=4.3 Hz),2.34(3H,s),1.88-1.96(1H,m),0.84-0.90(1H,m),0.70-0.75(1H,m)。 1-(5-Bromo-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea (75 mg, 0.22 mmol) (Example 1546), ring Propyl Complex of acid (57 mg, 0.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride and methylene chloride (PdCl 2 (dppf)*DCM) (18 mg, 0.022 mmol) and a mixture of potassium carbonate (556 μL, 2 N aqueous solution, 1.10 mmol) in 1,4-dioxane (3 mL) were purified with nitrogen and stirred at 90 ° C in a sealed tube. hour. Add cyclopropyl Acid (0.67 mmol), PdCl 2 (dppf)*DCM (0.022 mmol) and potassium carbonate solution (0.67 mmol), and heating was continued for 3 days. The mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The mixture was extracted into ethyl acetate (4×20 mL). Then dried (MgSO 4) of the combined extracts were filtered and concentrated under reduced pressure. The residue was subjected to C18 reverse phase chromatography (acetonitrile: water 5:95 to 1:1 gradient) to afford partially purified material (7 mg). This material was triturated with diethyl ether to give 1-(5-cyclopropyl-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (4 mg, 6% Yield). MS (apci) m/z 298.9 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.01 (1H, s), 8.34 (1H, s), 8.27 (1H, d, J = 2.4 Hz), 7.85 (1H, s), 7.80 (1H) , br, s), 7.46 (1H, s), 6.76 (1H, s), 2.65 (3H, d, J = 4.3 Hz), 2.34 (3H, s), 1.88-1.96 (1H, m), 0.84- 0.90 (1H, m), 0.70-0.75 (1H, m).

實例1663Example 1663

1-甲基-3-(5-(1-甲基-1H-1,2,3-三唑-4-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)脲 1-methyl-3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(5-methylpyridin-3-yloxy)pyridine-2 -based urea

步驟A：向1-(5-乙炔基-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲 基脲(43 mg，0.15 mmol)於第三丁醇(1 mL)及水(1 mL)中之溶液中添加(疊氮基甲基)三甲基矽烷(20 mg，0.15 mmol)、(R)-5-((S)-1,2-二羥基乙基)-4-羥基-2-側氧基-2,5-二氫呋喃-3-醇鈉(0.015 mmol，15 μL，1.0 M溶液)及硫酸銅(II)(0.0015 mmol，1.5 μL，1.0 M溶液)。在周圍溫度下攪拌混合物24小時，接著用水(10 mL)稀釋。將混合物萃取至乙酸乙酯(4×10 mL)中，且經硫酸鈉乾燥經合併之萃取物，過濾並在減壓下濃縮，得到1-甲基-3-(4-(5-甲基吡啶-3-基氧基)-5-(1-((三甲基矽烷基)甲基)-1H-1,2,3-三唑-4-基)吡啶-2-基)脲(56 mg，89%產率)，其具有足夠純度而直接用於下一步驟。MS(apci)m/z 411.9(M+H)。 Step A : To 1-(5-ethynyl-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (43 mg, 0.15 mmol) Add (azidomethyl)trimethylnonane (20 mg, 0.15 mmol), (R)-5-((S)-1,2- to a solution of alcohol (1 mL) and water (1 mL) Dihydroxyethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-ol sodium (0.015 mmol, 15 μL, 1.0 M solution) and copper (II) sulfate (0.0015 mmol, 1.5) μL, 1.0 M solution). The mixture was stirred at ambient temperature for 24 hours and then diluted with water (10 mL). The mixture was extracted into ethyl acetate (4.times.10 mL) and dried over sodium sulfate. Pyridin-3-yloxy)-5-(1-((trimethyldecyl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)urea (56 Mg, 89% yield), which was of sufficient purity to be used directly in the next step. MS (apci) m/z 411.9 (M+H).

步驟B：向1-甲基-3-(4-(5-甲基吡啶-3-基氧基)-5-(1-((三甲基矽烷基)甲基)-1H-1,2,3-三唑-4-基)吡啶-2-基)脲(55 mg，0.13 mmol)於四氫呋喃(1 mL)中之溶液中添加氟化四正丁基銨(0.27 mmol，270 μL，2.0 M溶液)。攪拌混合物2小時，用水(10 mL)稀釋且萃取至乙酸乙酯(4×10 mL)中。經硫酸鈉乾燥經合併之萃取物，過濾且在減壓下濃縮。在矽膠上(乙酸乙酯：乙醇(20：1至10：1))純化殘餘物，得到部分純之物質(22 mg)，用乙醚濕磨該物質以移除一些殘餘起始物質。此得到呈白色固體狀之1-甲基-3-(5-(1-甲基-1H-1,2,3-三唑-4-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)脲(14 mg，31%產率)。MS(apci)m/z 339.8(M+H)。1H NMR(400 MHz,DMSO-d6)δ ppm 9.19(1H,s),8.86(1H,s),8.39-8.42(2H,br,s),8.36(1H,d,J=2.7 Hz),7.57-7.65(2H,br,m),6.96(1H,s),4.09(3H,s),2.66(3H,d,J=4.7 Hz),2.36(3H,s)。 Step B : To 1-methyl-3-(4-(5-methylpyridin-3-yloxy)-5-(1-((trimethyldecyl)methyl)-1H-1,2 Add 3-tetrabutylammonium fluoride (0.27 mmol, 270 μL, 2.0) to a solution of 3-triazol-4-yl)pyridin-2-yl)urea (55 mg, 0.13 mmol) in tetrahydrofuran (1 mL) M solution). The mixture was stirred for 2 h, diluted with water (10 mL) andEtOAcEtOAc. The combined extracts were dried with sodium sulfate, filtered and evaporated. The residue was purified on EtOAc (EtOAc:EtOAc (EtOAc:EtOAc) This gave 1-methyl-3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(5-methylpyridine-3-) as a white solid. Alkoxy)pyridin-2-yl)urea (14 mg, 31% yield). MS (apci) m/z 339.8 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, s), 8.86 (1H, s), 8.39-8.42 (2H, br, s), 8.36 (1H, d, J = 2.7 Hz), 7.57-7.65 (2H, br, m), 6.96 (1H, s), 4.09 (3H, s), 2.66 (3H, d, J = 4.7 Hz), 2.36 (3H, s).

經由實例1663步驟A中之程序，利用適當疊氮化物製備以下實例。 The following example was prepared using the appropriate azide via the procedure in Example 1663, Step A.

實例1668Example 1668

5-(4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)吡啶-3-基)噻吩-2-甲酸甲酯 Methyl 5-(4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)pyridin-3-yl)thiophene-2-carboxylate

步驟A：在5 mL二噁烷中組合5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)噻吩-2-甲酸甲酯(0.348 g，1.30 mmol)、1-(5-溴-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.250 g，0.741 mmol)及K3PO4(1.11 ml，2.22 mmol)，且將此物質用氬氣充氣10分鐘，隨後添加PdCl2(dppf)*DCM(0.0606 g，0.0741 mmol)，且繼續充氣5分鐘，隨後密封反應物且加熱至90℃，維持5小時。此後，用二氯甲烷稀釋反應物，直接加載於矽膠上(1：1丙酮：二氯甲烷w/0.1% NH4OH)，得到5-(4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基)噻吩-2-甲酸甲酯(0.200 g，0.502 mmol，67%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.00(s,1H),8.88(s,1H),8.46(s,1H),8.37(s,1H),8.33(d,J=2.1 Hz,1H),7.78(d,J=4.1 Hz,1H),7.43(d,J=3.9 Hz,1H),7.31(s,1H),6.18(s,1H),3.89(s,3H),2.82(d,J=4.7 Hz,3H),2.39(s,3H)。質譜(apci)m/z=399.1(M+H)。 Step A: Combining 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron in 5 mL of dioxane Methyl-2-thio)-2-carboxylate (0.348 g, 1.30 mmol), 1-(5-bromo-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3 - methylurea (0.250 g, 0.741 mmol) and K 3 PO 4 (1.11 ml, 2.22 mmol), and this material was then added PdCl inflated with argon 10 minutes, 2 (dppf) * DCM ( 0.0606 g, 0.0741 mmol ), and continued to inflate for 5 minutes, then the reaction was sealed and heated to 90 ° C for 5 hours. Thereafter, the reaction was diluted with dichloromethane and directly loaded onto silica gel (1:1 acetone: dichloromethane w/0.1% NH 4 OH) to give 5-(4-(5-methylpyridin-3-yloxy) Methyl-6-(3-methylureido)pyridin-3-yl)thiophene-2-carboxylate (0.200 g, 0.502 mmol, 67% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.00 (s, 1H), 8.88 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H) ), 7.78 (d, J = 4.1 Hz, 1H), 7.43 (d, J = 3.9 Hz, 1H), 7.31 (s, 1H), 6.18 (s, 1H), 3.89 (s, 3H), 2.82 (d) , J = 4.7 Hz, 3H), 2.39 (s, 3H). Mass spectrum (apci) m/z = 399.1 (M+H).

實例1669Example 1669

1-(4-(3-氯-2-氰基苯氧基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲 1-(4-(3-Chloro-2-cyanophenoxy)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridine-2- 3-methylurea

步驟A：在2 mL DMA中組合1-(5-溴-4-羥基吡啶-2-基)-3-甲基脲(0.500 g，1.63 mmol)、2-氯-6-氟苄腈(0.379 g，2.44 mmol)及K2CO3(0.449 g，3.25 mmol)，且將其加熱至90℃經週末。用水(8 mL)稀釋反應物，且經由真空過濾收集所得固體。在真空烘箱中乾燥所得固體， 接著用含5% MeOH之DCM(10 mL)濕磨且進行音波處理。經由真空過濾收集所得固體，進行分析，且發現其含有產物。沖洗液含有與初始固體相同之型態。用EtOAc萃取初始水相兩次。合併有機物，經MgSO4乾燥，過濾，且在減壓下移除。分析粗物質，且發現其主要含有胺基吡啶及起始物質(SM)芳基氟化物。合併此有機物與以上所得之沖洗液，接著在矽膠上(含10%丙酮之二氯甲烷)純化。將此物質與固體物質合併，且發現其為1-(5-溴-4-(3-氯-2-氰基苯氧基)吡啶-2-基)-3-甲基脲(0.319 g，0.502 mmol，30.9%產率)與2-(2-胺基-5-溴吡啶-4-基氧基)-6-氯苄腈(0.319 g，0.393 mmol，24.2%產率)之混合物。此物質按原樣用於下一步中。 Step A : Combine 1-(5-bromo-4-hydroxypyridin-2-yl)-3-methylurea (0.500 g, 1.63 mmol), 2-chloro-6-fluorobenzonitrile (0.379) in 2 mL DMA g, 2.44 mmol) and K 2 CO 3 (0.449 g, 3.25 mmol), and heated to 90 ° C over the weekend. The reaction was diluted with water (8 mL) and the obtained solid was collected from vacuo. The resulting solid was dried in a vacuum oven, then was then triturated with 5% MeOH in DCM (10 mL) and sonicated. The resulting solid was collected by vacuum filtration, analyzed, and found to contain product. The rinse contains the same form as the initial solid. The initial aqueous phase was extracted twice with EtOAc. The organics were combined, dried over MgSO 4, filtered, and removed under reduced pressure. The crude material was analyzed and found to contain mainly aminopyridine and starting material (SM) aryl fluoride. The organics were combined with the rinsing solution obtained above and then purified on silica gel (dichloromethane containing 10% acetone). This material was combined with solid material and found to be 1-(5-bromo-4-(3-chloro-2-cyanophenoxy)pyridin-2-yl)-3-methylurea (0.319 g, A mixture of 0.502 mmol, 30.9% yield) with 2-(2-amino-5-bromopyridin-4-yloxy)-6-chlorobenzonitrile (0.319 g, 0.393 mmol, 24.2% yield). This material was used as it is in the next step.

步驟B：在室溫下，於10 mL二氯甲烷中組合粗2-(2-胺基-5-溴吡啶-4-基氧基)-6-氯苄腈(0.309 g，0.381 mmol)、吡啶(0.0924 ml，1.14 mmol)及氯甲酸4-硝基苯酯(0.154 g，0.762 mmol)。在1小時內，再添加1當量氯甲酸酯(80 mg)及2當量吡啶(70 μL)。次日早晨，以一整份添加甲胺(0.952 ml，7.62 mmol)，且使反應在室溫下繼續進行。30分鐘後，反應完成，但繼續進行2小時。此後，在減壓下濃縮反應物，接著溶解於10 mL乙醇中，且向其中添加300 mg K2CO3，且在室溫下攪拌此物質2小時並在50℃下攪拌1小時。濃縮反應物且溶解於20 mL水及50 mL EtOAc中，且分離各層。用EtOAc萃取水層，且經MgSO4乾燥經合併之有機物，過濾且濃縮。在矽膠上(含10%丙酮之二氯甲烷)純化粗物質，得到1-(5-溴-4-(3-氯-2-氰基苯氧基)吡啶-2-基)-3-甲基脲(0.125 g，0.328 mmol，86%產率)。 Step B : Combine the crude 2-(2-amino-5-bromopyridin-4-yloxy)-6-chlorobenzonitrile (0.309 g, 0.381 mmol) in 10 mL dichloromethane. Pyridine (0.0924 ml, 1.14 mmol) and 4-nitrophenyl chloroformate (0.154 g, 0.762 mmol). An additional equivalent of chloroformate (80 mg) and 2 equivalents of pyridine (70 μL) were added over 1 hour. The next morning, methylamine (0.952 ml, 7.62 mmol) was added in one portion and the reaction was allowed to proceed at room temperature. After 30 minutes, the reaction was completed but continued for 2 hours. Thereafter, the reactant was concentrated under reduced pressure, followed by dissolution in 10 mL of ethanol, and 300 mg of K 2 CO 3 was added thereto, and the mixture was stirred at room temperature for 2 hours and at 50 ° C for 1 hour. The reaction was concentrated and dissolved in 20 mL water and 50 mL EtOAc. The aqueous layer was extracted with EtOAc, dried over MgSO 4 and over the organics were combined, filtered and concentrated. The crude material was purified on silica gel (10% aq. EtOAc) to afford 1-(5-bromo-4-(3-chloro-2-cyanophenoxy)pyridin-2-yl)-3- Base urea (0.125 g, 0.328 mmol, 86% yield).

步驟C：在2 mL二噁烷中組合1-(5-溴-4-(3-氯-2-氰基苯氧基)吡啶-2-基)-3-甲基脲(0.060 g，0.157 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1-(2,2,2-三氟乙基)-1H-吡唑(0.0603 g，0.219 mmol)、K2CO3(0.236 ml，0.472 mmol)及PdCl2(dppf)*DCM(0.0128 g，0.0157 mmol)，且將此物質用氬氣充氣15分鐘，隨後密封反應物且加熱至100℃。7小時後，冷卻反應物且用含10%丙酮之二氯甲烷稀釋，隨後將其加載於矽膠上且用含25%-40%丙酮之DCM溶離，得到1-(4-(3-氯-2-氰基苯氧基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(0.009 g，0.0190 mmol，12.1%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.16(s,1H),8.54(s,1H),8,19(s,1H),8.03(s,1H),7.75(t,J=8.4 Hz,1H),7.62(d,J=8.2 Hz,1H),7.34(s,1H),7.31(d,J=8.4 Hz,1H),7.05(s,1H),5.11(q,J=9.2 Hz,2H),2.61(d,J=4.5 Hz,3H)。質譜(apci)m/z=451.1,453.1(M+H)。 Step C : Combining 1-(5-bromo-4-(3-chloro-2-cyanophenoxy)pyridin-2-yl)-3-methylurea (0.060 g, 0.157) in 2 mL of dioxane Ment), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (0.0603 g, 0.219 mmol), K 2 CO 3 (0.236 ml, 0.472 mmol) and PdCl 2 (dppf) *DCM (0.0128 g, 0.0157 mmol), and this material was then vented with argon for 15 minutes, then the reaction was sealed and heated to 100 °C. After 7 hours, the reaction was cooled and diluted with dichloromethane containing 10% acetone, then loaded on silica gel and eluted with &lt;RTI ID=0.0&gt; 2-cyanophenoxy)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea (0.009 g, 0.0190 mmol, 12.1% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.16 (s, 1H), 8.54 (s, 1H), 8, 19 (s, 1H), 8.03 (s, 1H), 7.75 (t, J = 8.4 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 5.11 (q, J = 9.2 Hz, 2H), 2.61 (d, J = 4.5 Hz, 3H). Mass spectrum (apci) m/z = 451.1, 453.1 (M+H).

遵循實例1669中之程序，亦可合成以下化合物： Following the procedure in Example 1669, the following compounds were also synthesized:

實例1671Example 1671

1-(4-(3-氯-2-氰基苯氧基)-5-(1-(2-羥基乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲 1-(4-(3-Chloro-2-cyanophenoxy)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-3- Methyl urea

步驟A：使用實例1669中之方法，用1-(2-(第三丁基二甲基矽烷氧基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑替代4- (4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1-(2,2,2-三氟乙基)-1H-吡唑，獲得1-(5-(1-(2-(第三丁基二甲基矽烷氧基)乙基)-1H-吡唑-4-基)-4-(3-氯-2-氰基苯氧基)吡啶-2-基)-3-甲基脲(0.044 g，0.083 mmol，53%產率)。 Step A : Using the method of Example 1669, 1-(2-(t-butyldimethylammonyloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3 2-diboron -2-yl)-1H-pyrazole in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole to give 1-(5-(1-(2-(t-butyldimethyl decyloxy)) Ethyl)-1H-pyrazol-4-yl)-4-(3-chloro-2-cyanophenoxy)pyridin-2-yl)-3-methylurea (0.044 g, 0.083 mmol, 53% Yield).

步驟B：在1 mL MeOH中組合1-(5-(1-(2-(第三丁基二甲基矽烷氧基)乙基)-1H-吡唑-4-基)-4-(3-氯-2-氰基苯氧基)吡啶-2-基)-3-甲基脲(0.044 g，0.083 mmol)及濃鹽酸(0.014 ml，0.17 mmol)，且在室溫下攪拌反應物兩天，且用約100 mg固體碳酸氫鈉淬滅。用2：1二氯甲烷：丙酮稀釋反應物且過濾。在減壓下濃縮沖洗液，且用乙醚濕磨殘餘物，且經由真空過濾收集所得固體，得到1-(4-(3-氯-2-氰基苯氧基)-5-(1-(2-羥基乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(0.021 g，0.051 mmol，61%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.23(s,1H),8.55(s,1H),8.13(s,1H),7.90(s,1H),7.79(t,J=8.2 Hz,1H),7.65(d,J=8.0 Hz,1H),7.50(s,1H),7.31(d,J=8.6 Hz,1H),7.11(s,1H),5.76(s,1H),4.92(s,1H),4.15(t,J=5.6 Hz,1H),3.73(t,J=5.5 Hz,2H),2.66(d,J=4.3 Hz,3H)。質譜(apci)m/z=413.1,415.0(M+H)。 Step B : Combination of 1-(5-(1-(2-(t-butyldimethylmethyloxy)oxy)ethyl)-1H-pyrazol-4-yl)-4-(3) in 1 mL MeOH -Chloro-2-cyanophenoxy)pyridin-2-yl)-3-methylurea (0.044 g, 0.083 mmol) and concentrated hydrochloric acid (0.014 ml, 0.17 mmol). It was quenched with about 100 mg of solid sodium bicarbonate. The reaction was diluted with 2:1 dichloromethane: acetone and filtered. The rinse was concentrated under reduced pressure, and the residue was evaporated to dryness with diethyl ether, and the obtained solid was collected by vacuum filtration to give 1-(4-(3-chloro-2-cyanophenoxy)-5-(1-( 2-Hydroxyethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea (0.021 g, 0.051 mmol, 61% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.23 (s, 1H), 8.55 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.79 (t, J = 8.2 Hz , 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.11 (s, 1H), 5.76 (s, 1H), 4.92 (s, 1H), 4.15 (t, J = 5.6 Hz, 1H), 3.73 (t, J = 5.5 Hz, 2H), 2.66 (d, J = 4.3 Hz, 3H). Mass spectrum (apci) m/z = 413.1, 415.0 (M+H).

遵循實例1671中之程序，亦可合成以下化合物： Following the procedure in Example 1671, the following compounds were also synthesized:

實例1674Example 1674

4-氯-3-((2-(3-甲基脲基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)氧基)苯甲酸 4-Chloro-3-((2-(3-methylureido)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridine-4- Alkyloxybenzoic acid

步驟A：將4-氯-3-(2-(3-甲基脲基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基氧基)苯甲酸乙酯(0.070 g，0.14 mmol)溶解於1 mL THF中，隨後以一整份添加NaOH(0.28 ml，0.28 mmol)，且在室溫下攪拌此物質6小時。此後，添加HCl(0.35 ml，0.35 mmol)及5 mL水。用EtOAc(3×50 mL)萃取水相。合併有機物，經MgSO4乾燥，過濾且濃縮，得到4-氯-3-(2-(3-甲基脲基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基氧基)苯甲酸(0.054 g，0.11 mmol，80%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.10(s,1H),8.53(s,1H),8.32(s,1H),8.13(s,1H),7.93-7.90(m,1H),7.86-7.83(m,1H),7.81(d,J=1.9 Hz,1H),7.57(s,1H),6.82(s,1H),5.18(q,J=9.2 Hz,2H),2.64(d,J=4.7 Hz,3H)。質譜(apci)m/z=470.0,472.0(M+H)。 Step A : 4-Chloro-3-(2-(3-methylureido)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridine Ethyl -4-yloxy)benzoate (0.070 g, 0.14 mmol) was dissolved in 1 mL THF then NaOH (0.28 ml, 0.28 mmol) was added in one portion and the mixture was stirred at room temperature for 6 hours. . Thereafter, HCl (0.35 ml, 0.35 mmol) and 5 mL of water were added. The aqueous phase was extracted with EtOAc (3×50 mL). The organics were combined, dried over MgSO 4, filtered and concentrated to give 4-chloro-3- (2- (3-methyl-ureido) -5- (1- (2,2,2-trifluoroethyl) -1H -pyrazol-4-yl)pyridin-4-yloxy)benzoic acid (0.054 g, 0.11 mmol, 80% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.10 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.93-7.90 (m, 1H) , 7.86-7.83 (m, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.57 (s, 1H), 6.82 (s, 1H), 5.18 (q, J = 9.2 Hz, 2H), 2.64 ( d, J = 4.7 Hz, 3H). Mass spectrum (apci) m/z = 470.0, 472.0 (M+H).

遵循實例1674中之程序，亦可合成以下化合物： Following the procedure in Example 1674, the following compounds were also synthesized:

實例1679Example 1679

1-(4-(2-氯-5-(4-甲基哌嗪-1-羰基)苯氧基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲 1-(4-(2-chloro-5-(4-methylpiperazine-1-carbonyl)phenoxy)-5-(1-(2,2,2-trifluoroethyl)-1H-pyridyl Zin-4-yl)pyridin-2-yl)-3-methylurea

步驟A：在0.5 mL DMA中組合4-氯-3-(2-(3-甲基脲基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基氧基)苯甲酸(0.012 g，0.0255 mmol)、EDCI(0.00588 g，0.0307 mmol)及1-甲基哌嗪(0.00567 ml，0.0511 mmol)，且在室溫下使其繼續維持隔夜。反應未完成，因此添加1-甲基哌嗪(0.00567 ml，0.0511 mmol)及HOBT-H2O(0.00469 g，0.0307 mmol)，且加熱反應物至50℃。此後反應無變化，且經由C18逆相層析(含0-30%乙腈之水)對反應物進行層析，得到1-(4-(2-氯-5-(4-甲基哌嗪-1-羰基)苯氧基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-2-基)-3-甲基脲(0.006 g，0.0104 mmol，40.9%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.93(s,1H),8.35(s,1H),7.97(s,1H),7.95(s,1H),7.70(s,1H),7.56(d,J=8.2 Hz,1H),7.30-7.26(m,1H),7.21(d,J=1.9 Hz,1H),6.01(s,1H),4.75(q,J=8.2 Hz,2H),3.75(bs,2H),3.43(bs,2H),2.87(d,J=4.7 Hz,3H),2.45(bs,2H),2.30(s,3H),1.63(bs,2H)。質譜(apci)m/z=552.2,554.2(M+H)。 Step A : Combining 4-chloro-3-(2-(3-methylureido)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazole in 0.5 mL DMA - 4-yl)pyridin-4-yloxy)benzoic acid (0.012 g, 0.0255 mmol), EDCI (0.00588 g, 0.0307 mmol) and 1-methylpiperazine (0.00567 ml, 0.0511 mmol) at room temperature Let it continue to stay overnight. The reaction was not completed, so 1-methylpiperazine (0.00567 ml, 0.0511 mmol) and HOBT-H 2 O (0.00469 g, 0.0307 mmol) were added and the reaction was heated to 50 °C. Thereafter, the reaction was unchanged, and the reaction was chromatographed by C18 reverse phase chromatography (water containing 0-30% acetonitrile) to give 1-(4-(2-chloro-5-(4-methylpiperazine)- 1-carbonyl)phenoxy)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-3-methylurea (0.006 g, 0.0104 mmol, 40.9% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.93 (s, 1H), 8.35 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.56 (d) , J = 8.2 Hz, 1H), 7.30-7.26 (m, 1H), 7.21 (d, J = 1.9 Hz, 1H), 6.01 (s, 1H), 4.75 (q, J = 8.2 Hz, 2H), 3.75 (bs, 2H), 3.43 (bs, 2H), 2.87 (d, J = 4.7 Hz, 3H), 2.45 (bs, 2H), 2.30 (s, 3H), 1.63 (bs, 2H). Mass spectrum (apci) m/z = 552.2, 554.2 (M+H).

遵循實例1679中之程序，亦合成以下化合物： Following the procedure in Example 1679, the following compounds were also synthesized:

實例1717Example 1717

N-環戊基-4-氟-3-(2-(3-甲基脲基)-5-(四氫-2H-哌喃-4-基)吡啶-4-基氧基)苄醯胺 N-cyclopentyl-4-fluoro-3-(2-(3-methylureido)-5-(tetrahydro-2H-pyran-4-yl)pyridin-4-yloxy)benzylamine

步驟A：在室溫下，將3-(5-(3,6-二氫-2H-哌喃-4-基)-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.450 g，1.12 mmol)置於MeOH：DCM(15：1 mL)中。添加Pd/C(0.954 g，0.448 mmol)且在50 PSI下氫化24小時。接著過濾反應物，用MeOH洗滌且濃縮，得到粗產物，在矽膠上(500：7 DCM：MeOH)純化該粗產物，得到4-氟-3-(2-(3-甲基脲基)-5-(四氫-2H-哌喃-4-基)吡啶-4-基氧基)苯甲酸甲酯(0.320 g，70.8%產率)。 Step A : 3-(5-(3,6-Dihydro-2H-pyran-4-yl)-2-(3-methylureido)pyridin-4-yloxy) at room temperature Methyl 4-fluorobenzoate (0.450 g, 1.12 mmol) was taken in MeOH: DCM (15:1 mL). Pd/C (0.954 g, 0.448 mmol) was added and hydrogenated at 50 PSI for 24 hours. The reaction was then filtered, washed with EtOAc EtOAc (EtOAc m. Methyl 5-(tetrahydro-2H-piperazin-4-yl)pyridin-4-yloxy)benzoate (0.320 g, 70.8% yield).

步驟B：在室溫下，將4-氟-3-(2-(3-甲基脲基)-5-(四氫-2H-哌喃-4-基)吡啶-4-基氧基)苯甲酸甲酯(0.320 g，0.793 mmol)置於4：1 THF：水(5 mL)中。添加2 M NaOH(0.793 ml，1.59 mmol)，且在室溫下攪 拌2小時。添加1 M HCl直至pH 2，接著用4：1 DCM：IPA萃取反應物且濃縮，得到產物4-氟-3-(2-(3-甲基脲基)-5-(四氫-2H-哌喃-4-基)吡啶-4-基氧基)苯甲酸(0.30 g，97.1%產率)。 Step B : 4-Fluoro-3-(2-(3-methylureido)-5-(tetrahydro-2H-piperidin-4-yl)pyridin-4-yloxy) at room temperature Methyl benzoate (0.320 g, 0.793 mmol) was taken in 4:1 THF: water (5 mL). 2 M NaOH (0.793 ml, 1.59 mmol) was added and stirred at room temperature for 2 h. 1 M HCl was added until pH 2, then the reaction was extracted with 4:1 DCM:IPA and concentrated to give the product 4-fluoro-3-(2-(3-methylureido)-5-(tetrahydro-2H- Piperan-4-yl)pyridin-4-yloxy)benzoic acid (0.30 g, 97.1% yield).

步驟C：在室溫下，將4-氟-3-(2-(3-甲基脲基)-5-(四氫-2H-哌喃-4-基)吡啶-4-基氧基)苯甲酸(0.075 g，0.19 mmol)、環戊胺(0.018 g，0.21 mmol)、HBTU(0.080 g，0.21 mmol)及DIEA(0.10 ml，0.58 mmol)置於DMF(5 mL)中且攪拌1小時，接著傾倒至水中，且用EtOAc萃取。乾燥(MgSO4)經合併之有機部分，過濾且濃縮，得到粗產物，在矽膠上(500：15-500：20 DCM：MeOH)純化該粗產物，得到N-環戊基-4-氟-3-(2-(3-甲基脲基)-5-(四氫-2H-哌喃-4-基)吡啶-4-基氧基)苄醯胺(0.010 g，11%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 8.99(s,1H),8.38-8.36(m,1H),8.05(m,1H),7.90-7.84(m,2H),7.80-7.74(m,1H),7.58-7.53(m,1H),6.69(s,1H),4.24-4.20(m,1H),3.98-3.94(m,2H),3.48-3.42(m,2H),3.14-3.07(m,1H),2.63(d,3H,J=4Hz),1.90-1.49(m,12H)。質譜(APCI)m/z=456.8(M+H)。 Step C : 4-Fluoro-3-(2-(3-methylureido)-5-(tetrahydro-2H-piperidin-4-yl)pyridin-4-yloxy) at room temperature Benzoic acid (0.075 g, 0.19 mmol), cyclopentylamine (0.018 g, 0.21 mmol), HBTU (0.080 g, 0.21 mmol) and DIEA (0.10 ml, 0.58 mmol) in DMF (5 mL) It was then poured into water and extracted with EtOAc. Dried (MgSO 4) the organic fractions were combined, filtered and concentrated to give the crude product on silica gel (500: 15-500: 20 DCM: MeOH) The crude product was purified to give N- cyclopentyl-4-fluoro - 3-(2-(3-Methylureido)-5-(tetrahydro-2H-pyran-4-yl)pyridin-4-yloxy)benzylamine (0.010 g, 11% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 8.99 (s, 1H), 8.38-8.36 (m, 1H), 8.05 (m, 1H), 7.90-7.84 (m, 2H), 7.80-7.74 ( m,1H), 7.58-7.53 (m, 1H), 6.69 (s, 1H), 4.24-4.20 (m, 1H), 3.98-3.94 (m, 2H), 3.48-3.42 (m, 2H), 3.14 3.07 (m, 1H), 2.63 (d, 3H, J = 4 Hz), 1.90-1.49 (m, 12H). Mass Spectrum (APCI) m/z = 456.8 (M+H).

遵循實例1717中之程序，亦合成以下化合物： Following the procedure in Example 1717, the following compounds were also synthesized:

實例Instance

3-((5-環丙基-2-(3-甲基脲基)吡啶-4-基)氧基)-4-氟-N-(1-甲基-1H-吡唑-4-基)苄醯胺 3-((5-Cyclopropyl-2-(3-methylureido)pyridin-4-yl)oxy)-4-fluoro-N-(1-methyl-1H-pyrazol-4-yl Benzoylamine

步驟A：將3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.200 g，0.502 mmol)呈懸浮液形式置於10：1甲苯：水(5：0.5 mL)中且用N2脫氣。接著添加環丙基三氟硼酸鉀(0.297 g，2.01 mmol)、Pd(OAc)2(0.0169 g，0.0753 mmol)及K3PO4(0.320 g，1.51 mmol)，繼而添加二環己基(2',6'-二異丙氧基聯苯-2-基)膦(0.0703 g，0.151 mmol)。將反應物再用N2脫氣5分鐘，接著加熱至110℃，維持18小時。接著冷卻反應物至室溫，用DCM萃取，用鹽水洗滌，乾燥(MgSO4)，經矽藻土過濾且濃縮，得到粗產物，在矽膠上(500：5-500：8 DCM：MeOH)純化該粗產物，得到3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.125 g，69.3%產率)。 Step A : A solution of methyl 3-(5-bromo-2-(3-methylureido)pyridin-4-yloxy)-4-fluorobenzoate (0.200 g, 0.502 mmol) as a suspension 10: 1 toluene: water (5: 0.5 mL) was degassed and treated with N 2. Potassium cyclopropyltrifluoroborate (0.297 g, 2.01 mmol), Pd(OAc) 2 (0.0169 g, 0.0753 mmol) and K 3 PO 4 (0.320 g, 1.51 mmol) were then added followed by dicyclohexyl (2' , 6'-Diisopropoxybiphenyl-2-yl)phosphine (0.0703 g, 0.151 mmol). The reaction was then degassed N 2 for 5 min, then heated to 110 deg.] C, for 18 h. The reaction was then cooled to room temperature, extracted with DCM, washed with brine, dried (MgSO 4), filtered through diatomaceous earth and concentrated to give the crude product on silica gel (500: 5-500: 8 DCM: MeOH) was purified The crude product gave methyl 3-(5-cyclopropyl-2-(3-methylureido)pyridin-4-yloxy)-4-fluorobenzoate (0.125 g, 69.3% yield).

步驟B：將3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.125 g，0.348 mmol)置於4：1 THF：水(5 mL)中，接著添加NaOH(0.696 ml，0.696 mmol)，且在室溫下攪拌反應物1小時。接著用1 M HCl將反應物酸化至pH 2，接著用3：1 DCM：IPA萃取且濃縮，得到3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸(0.100 g，83.2%產率)。 Step B : Methyl 3-(5-cyclopropyl-2-(3-methylureido)pyridin-4-yloxy)-4-fluorobenzoate (0.125 g, 0.348 mmol). 1 THF: water (5 mL), followed by EtOAc (0.696 <RTI ID=0.0> The reaction was then acidified to pH 2 with 1 M HCl then extracted with 3:1 DCM:IPA and concentrated to give 3-(5-cyclopropyl-2-(3-methylureido)pyridin-4-yl Oxy)-4-fluorobenzoic acid (0.100 g, 83.2% yield).

步驟C：將3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸(0.050 g，0.14 mmol)、1-甲基-1H-吡唑-4-胺(0.015 g，0.16 mmol)、HBTU(0.060 g，0.16 mmol)及DIEA(0.076 ml，0.43 mmol)置於DMF(5 mL)中，且在室溫下攪拌2小時，接著傾倒至水中，且用EtOAc萃取。乾燥(MgSO4)經合併之有機部分，過濾，濃縮且在矽膠 上(500：20-500：40 DCM：MeOH)純化，得到3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟-N-(1-甲基-1H-吡唑-4-基)苄醯胺(0.006 g，9.8%產率)。1H NMR(400 MHz,CD3OD)δ ppm 8.01(s,1H),7.96-7.89(m,1H),7.88(s,1H),7.87-7.85(m,1H),7.61(s,1H),7.50-7.44(m,1H),6.40(s,1H),3.87(s,3H),2.80(s,3H),2.05-2.00(m,1H),0.99-0.94(m,2H),0.79-0.74(m,2H)。質譜(APCI)m/z=424.8(M+H)。 Step C : 3-(5-Cyclopropyl-2-(3-methylureido)pyridin-4-yloxy)-4-fluorobenzoic acid (0.050 g, 0.14 mmol), 1-methyl- 1H-Pyrazole-4-amine (0.015 g, 0.16 mmol), HBTU (0.060 g, 0.16 mmol) and DIEA (0.076 ml, 0.43 mmol) in DMF (5 mL) It was then poured into water and extracted with EtOAc. Dried (MgSO 4) the organic fractions were combined, filtered, and concentrated on silica gel (500: 20-500: 40 DCM: MeOH) to give 3- (5-cyclopropyl-2- (3-methyl-urea Pyridin-4-yloxy)-4-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzylamine (0.006 g, 9.8% yield). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.01 (s, 1H), 7.96-7.89 (m, 1H), 7.88 (s, 1H), 7.87-7.85 (m, 1H), 7.61 (s, 1H) ), 7.50-7.44 (m, 1H), 6.40 (s, 1H), 3.87 (s, 3H), 2.80 (s, 3H), 2.05-2.00 (m, 1H), 0.99-0.94 (m, 2H), 0.79-0.74 (m, 2H). Mass Spectrum (APCI) m/z = 424.8 (M+H).

遵循實例1719中之程序，亦合成以下化合物： Following the procedure in Example 1719, the following compounds were also synthesized:

實例1731Example 1731

3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟-N-(哌啶-4-基)苄醯胺二鹽酸鹽 3-(5-Cyclopropyl-2-(3-methylureido)pyridin-4-yloxy)-4-fluoro-N-(piperidin-4-yl)benzylamine dihydrochloride

在室溫下，將4-(3-((5-環丙基-2-(3-甲基脲基)吡啶-4-基)氧基)-4-氟苄醯胺基)哌啶-1-甲酸第三丁酯(0.100 g，0.190 mmol)置於DCM(5 mL)中。接著逐滴添加HCl(0.23 mL，4 M，於二噁烷中)且攪拌2小時，接著濃縮至乾燥。將所得固體溶解於MeOH(1 mL)中，接著添加Et2O(30 mL)，且過濾所得固體，用Et2O洗滌並乾燥，得到產物3-(5-環丙基-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟-N-(哌啶-4-基)苄醯胺二鹽酸鹽(0.080 g，84.3%產率)。1H NMR(400 MHz,CD3OD)δ ppm 8.65- 8.63(m,1H),8.00-7.97(m,2H),7.89(s,1H),7.57-7.52(m,1H),6.41(s,1H),4.23-4.11(m,1H),3.51-3.46(m,2H),3.18-3.10(m,2H),2.78(s,3H),2.23-2.10(m,3H),1.96-1.86(m,2H),1.14-1.10(m,2H),0.87-0.83(m,2H)。質譜(apci)m/z=428.2(M+H)。 4-(3-((5-Cyclopropyl-2-(3-methylureido)pyridin-4-yl)oxy)-4-fluorobenzylamino)piperidine- at room temperature 1-Butyl 1-carboxylate (0.100 g, 0.190 mmol) was taken in DCM (5 mL). Then HCl (0.23 mL, 4 M in dioxane) was added dropwise and stirred for 2 h then concentrated to dry. The resulting solid was dissolved in MeOH (1 mL), followed by Et 2 O (30 mL), and the resulting solid was filtered, washed with 2 O Et and dried, to give the product 3- (5-cyclopropyl-2- (3 Methylurea)pyridin-4-yloxy)-4-fluoro-N-(piperidin-4-yl)benzylguanamine dihydrochloride (0.080 g, 84.3% yield). 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.65- 8.63 (m, 1H), 8.00-7.97 (m, 2H), 7.89 (s, 1H), 7.57-7.52 (m, 1H), 6.41 (s) , 1H), 4.23-4.11 (m, 1H), 3.51-3.46 (m, 2H), 3.18-3.10 (m, 2H), 2.78 (s, 3H), 2.23-2.10 (m, 3H), 1.96-1.86 (m, 2H), 1.14-1.10 (m, 2H), 0.87-0.83 (m, 2H). Mass spectrum (apci) m/z = 428.2 (M+H).

遵循實例1731中之程序，亦合成以下化合物： Following the procedure in Example 1731, the following compounds were also synthesized:

實例1733Example 1733

4-氟-N-(1-甲基哌啶-4-基)-3-((2-(3-甲基脲基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-4-基)氧基)苄醯胺 4-fluoro-N-(1-methylpiperidin-4-yl)-3-((2-(3-methylureido)-5-((tetrahydro-2H-pyran-4-yl)) Methyl)pyridin-4-yl)oxy)benzylamine

步驟A：將3-(5-溴-2-(3-甲基脲基)吡啶-4-基氧基)-4-氟苯甲酸甲酯(0.400 g，1.00 mmol)置於密封管中之THF(3 mL)且用N2脫氣。添加Pd(OAc)2(0.0113 g，0.0502 mmol)及二環己基(2',6'-二甲氧基聯苯-2-基)膦(0.0412 g，0.100 mmol)，繼而添加溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(4.78 ml，3.01 mmol)，且加熱反應物至70℃，維持2小時。接著冷卻反應物至室溫，且傾倒至飽和NH4Cl中，且用DCM萃取。乾燥(MgSO4)有機部分，過濾，濃縮且在矽膠上(500：5-500：10)純化，得 到4-氟-3-(2-(3-甲基脲基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-4-基氧基)苯甲酸甲酯(0.300 g，71.5%產率)。 Step A : Methyl 3-(5-bromo-2-(3-methylureido)pyridin-4-yloxy)-4-fluorobenzoate (0.400 g, 1.00 mmol) was placed in a sealed tube THF (3 mL) and degassed with N. Add Pd(OAc) 2 (0.0113 g, 0.0502 mmol) and dicyclohexyl (2',6'-dimethoxybiphenyl-2-yl)phosphine (0.0412 g, 0.100 mmol) followed by bromination (( Tetrahydro-2H-piperazin-4-yl)methyl)zinc(II) (4.78 ml, 3.01 mmol), and the reaction was heated to 70 ° C for 2 h. The reaction was then cooled to room temperature and poured into saturated NH 4 Cl, and the extracted with DCM. Dried (MgSO 4) organic moiety, filtered, and concentrated on silica gel (500: 5-500: 10) to give 4-fluoro-3- (2- (3-methyl-ureido) -5 - ((four Methyl hydrogen-2H-piperazin-4-yl)methyl)pyridin-4-yloxy)benzoate (0.300 g, 71.5% yield).

步驟B：在室溫下，將4-氟-3-(2-(3-甲基脲基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-4-基氧基)苯甲酸甲酯(0.400 g，0.958 mmol)置於4：1 THF：水(5 mL)中。添加1 M NaOH(1.92 ml，1.92 mmol)，且在室溫下攪拌反應物4小時。接著添加1 M HCl直至達到pH 2，且用4：1 DCM：IPA萃取反應物，得到4-氟-3-(2-(3-甲基脲基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-4-基氧基)苯甲酸(0.220 g，56.9%產率)。 Step B : 4-Fluoro-3-(2-(3-methylureido)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridine-4- at room temperature Methyl benzoate (0.400 g, 0.958 mmol) was taken in 4:1 THF: water (5 mL). 1 M NaOH (1.92 ml, 1.92 mmol) was added and the mixture was stirred at room temperature for 4 h. Then 1 M HCl was added until pH 2 was reached, and the reaction was extracted with 4:1 DCM:IPA to give 4-fluoro-3-(2-(3-methylureido)-5-((tetrahydro-2H-) Piperazin-4-yl)methyl)pyridin-4-yloxy)benzoic acid (0.220 g, 56.9% yield).

步驟C：在室溫下，將4-氟-3-(2-(3-甲基脲基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-4-基氧基)苯甲酸(0.050 g，0.12 mmol)、1-甲基哌啶-4-胺(0.016 g，0.14 mmol)、HBTU(0.052 g，0.14 mmol)及DIEA(0.065 ml，0.37 mmol)置於DMF(5 mL)中且攪拌2小時，接著傾倒至水中，且用DCM萃取。乾燥(MgSO4)經合併之有機部分，過濾，濃縮，得到粗產物，在矽膠上(5：1 DCM：MeOH w/10 mL NH4OH/500 mL溶劑)純化該粗產物，得到4-氟-N-(1-甲基哌啶-4-基)-3-(2-(3-甲基脲基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-4-基氧基)苄醯胺(0.005 g，8.1%產率)。1H NMR(400 MHz,CD3OD)δ ppm 7.99(s,1H),7.86-7.82(m,1H),7.78-7.76(m,1H),7.44-7.39(m,1H),6.36(s,1H),3.96-3.84(m,3H),3.41-3.35(m,2H),2.95-2.89(m,2H),2.80(s,3H),2.66(d,2H,J=3Hz),2.30(s,3H),2.21-2.12(m,2H),1.96-1.92(m,3H),1.68-1.59(m,4H),1.43-1.32(m,2H)。質譜(APCI)m/z=500.2(M+H)。 Step C : 4-Fluoro-3-(2-(3-methylureido)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridine-4- Benzyl)benzoic acid (0.050 g, 0.12 mmol), 1-methylpiperidin-4-amine (0.016 g, 0.14 mmol), HBTU (0.052 g, 0.14 mmol) and DIEA (0.065 ml, 0.37 mmol) It was stirred in DMF (5 mL) for 2 h then poured into water and extracted with DCM. Dried (MgSO 4) the organic fractions were combined, filtered, and concentrated to give the crude product on silica gel (5: 1 DCM: MeOH w / 10 mL NH 4 OH / 500 mL solvent) to give the crude product was 4-fluoro -N-(1-methylpiperidin-4-yl)-3-(2-(3-methylureido)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridine 4--4-oxyl)benzylamine (0.005 g, 8.1% yield). 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.99 (s, 1H), 7.86-7.82 (m, 1H), 7.78-7.76 (m, 1H), 7.44-7.39 (m, 1H), 6.36 (s) , 1H), 3.96-3.84 (m, 3H), 3.41-3.35 (m, 2H), 2.95-2.89 (m, 2H), 2.80 (s, 3H), 2.66 (d, 2H, J = 3 Hz), 2.30 (s, 3H), 2.21-2.12 (m, 2H), 1.96-1.92 (m, 3H), 1.68-1.59 (m, 4H), 1.43-1.32 (m, 2H). Mass Spectrum (APCI) m/z = 500.2 (M+H).

實例1734Example 1734

1-(6'-(2-羥基-2-甲基丙氧基)-4-((5-甲基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-(2-hydroxy-2-methylpropoxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3'-bipyridine]-6- 3-methylurea

步驟A：在100 mL DMA中組合1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(17.5 g，70.5 mmol)、5-甲基吡啶-3-醇(9.24 g，84.7 mmol)及K2CO3(10.1 g，77.6 mmol)，且加熱至90℃，維持5天。此後，反應完成，且向其中添加水及二氯甲烷並劇烈攪拌3小時。經由真空過濾分離所得固體，且用水及二氯甲烷洗滌濾餅。在氮氣流及劇烈攪拌下乾燥含二氯甲烷之水性沖洗液。接著經由真空過濾收集所得固體，且將此等固體於含10% MeOH之EtOAc中劇烈攪拌，且經由真空過濾收集所得固體。合併兩批，得到1-(5-溴-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(18.1 g，53.7 mmol，76%產率)。 Step A : Combine 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (17.5 g, 70.5 mmol), 5-methylpyridin-3-ol (9.24) in 100 mL DMA. g, 84.7 mmol) and K 2 CO 3 (10.1 g, 77.6 mmol), and heated to 90 ° C for 5 days. Thereafter, the reaction was completed, and water and dichloromethane were added thereto and stirred vigorously for 3 hours. The resulting solid was isolated via vacuum filtration and washed with water and dichloromethane. The aqueous rinse containing dichloromethane was dried under a stream of nitrogen with vigorous stirring. The resulting solid was then collected via vacuum <RTI ID=0.0></RTI> and the solid was stirred vigorously in 10% MeOH EtOAc. The two batches were combined to give 1-(5-bromo-4-(5-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (18.1 g, 53.7 mmol, 76% yield ).

步驟B：在2 mL二噁烷中組合2-甲基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-基氧基)丙-2-醇(0.098 g，0.33 mmol)、1-(5-溴-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.075 g，0.22 mmol)及2 M碳酸鉀(0.33 ml，0.67 mmol)，且將此物質用氬氣充氣10分鐘，隨後添加PdCl2(dppf)*DCM(0.018 g，0.022 mmol)，且將反應物再充氣5分鐘，隨後將其密封且加熱至100℃隔夜。接著將反應物直接加載於矽膠上(含50%丙酮之DCM w/0.1% NH4OH)，得到1-(6'-(2-羥基-2-甲基丙氧基)-4-(5-甲基吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.042 g，0.096 mmol，43%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.06(s,1H),8.33(s,1H),8.27(m,2H),8.11(s,1H),8.08(s,1H),7.82(dd,J=8.6,1.9 Hz,1H),7.22(s,1H),6.88(d,J=8.6 Hz,1H),6.11(s,1H),4.25(s,2H),2.87(d,J=4.5 Hz,3H)2.37(s,3H),1.33(s,6H)。質譜 (apci)m/z=423.9(M+H)。 Step B : Combining 2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) in 2 mL of dioxane -2-yl)pyridin-2-yloxy)propan-2-ol (0.098 g, 0.33 mmol), 1-(5-bromo-4-(5-methylpyridin-3-yloxy)pyridine- 2-yl)-3-methylurea (0.075 g, 0.22 mmol) and 2 M potassium carbonate (0.33 ml, 0.67 mmol), and this material was inflated with argon for 10 minutes, then PdCl 2 (dppf)*DCM was added (0.018 g, 0.022 mmol), and the reaction was re-inflated for 5 minutes, then sealed and heated to 100 ° C overnight. The reaction was then loaded directly onto silica gel (DCM w/0.1% NH 4 OH containing 50% acetone) to give 1-(6'-(2-hydroxy-2-methylpropoxy)-4-(5) Methylpyridin-3-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea (0.042 g, 0.096 mmol, 43% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.06 (s, 1H), 8.33 (s, 1H), 8.27 (m, 2H), 8.11 (s, 1H), 8.08 (s, 1H), 7.82 (dd , J = 8.6, 1.9 Hz, 1H), 7.22 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.11 (s, 1H), 4.25 (s, 2H), 2.87 (d, J = 4.5 Hz, 3H) 2.37 (s, 3H), 1.33 (s, 6H). Mass spectrum (apci) m/z = 423.9 (M+H).

遵循實例1734中之程序，亦合成以下化合物： Following the procedure in Example 1734, the following compounds were also synthesized:

遵循實例148中之程序，用K2CO3替代Cs2CO3且使用適當起始物質來製備以下化合物： Following the procedure in Example 148, the following compounds were prepared using K 2 CO 3 in place of Cs 2 CO 3 and using the appropriate starting materials:

實例1773Example 1773

(S)-1-(4-(3-氯-2-氟苯氧基)-5-((3,4-二羥基丁基)硫基)吡啶-2-基)-3-甲基脲 (S)-1-(4-(3-chloro-2-fluorophenoxy)-5-((3,4-dihydroxybutyl)thio)pyridin-2-yl)-3-methylurea

步驟A：在10 mL以氮氣充氣之二噁烷中組合1-(5-溴-4-氟吡啶-2-基)-3-甲基脲(2.0 g，8.063 mmol)、N-乙基-N-異丙基丙-2-胺(2.816 ml，16.13 mmol)、Pd2(dba)3(0.3692 g，0.4031 mmol)及(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)(0.4665 g，0.8063 mmol)，且將此物質充氣10分鐘，隨後添加3-巰基丙酸甲酯(1.311 ml，12.09 mmol)，且將反應物再充氣1分鐘，密封，且加熱至70℃隔夜並加熱至80℃維持兩天。此後，用1：1 EtOAc：二氯甲烷(100 mL)稀釋反應物 且過濾。用極少量EtOAc沖洗固體，且在減壓下濃縮沖洗液。在矽膠上(含15%丙酮之二氯甲烷)純化粗物質，得到混合物。如上文所述使此物質(2.1 g)再經受反應條件(70℃)，持續6天，且分離並純化，得到3-(4-氟-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(0.870 g，2.968 mmol，36.81%產率)。 Step A : Combine 1-(5-bromo-4-fluoropyridin-2-yl)-3-methylurea (2.0 g, 8.063 mmol), N-ethyl- in 10 mL of dioxane. N-isopropylpropan-2-amine (2.816 ml, 16.13 mmol), Pd 2 (dba) 3 (0.3692 g, 0.4031 mmol) and (9,9-dimethyl-9H-dibenzopyran-4 ,5-diyl)bis(diphenylphosphine) (0.4665 g, 0.8063 mmol), and this material was inflated for 10 min, then methyl 3-mercaptopropionate (1.311 ml, 12.09 mmol) was added and the It was again inflated for 1 minute, sealed, and heated to 70 ° C overnight and heated to 80 ° C for two days. After this time the reaction was diluted with EtOAc EtOAc (EtOAc) The solid was rinsed with a very small amount of EtOAc and the rinse was concentrated under reduced pressure. The crude material was purified on silica gel (15% acetone in dichloromethane) to give a mixture. This material (2.1 g) was again subjected to the reaction conditions (70 ° C) as described above for 6 days, and isolated and purified to give 3-(4-fluoro-6-(3-methylureido)pyridine-3 Methyl-thio)propionic acid methyl ester (0.870 g, 2.968 mmol, 36.81% yield).

步驟B：在0.5 mL THF中組合3-(4-氟-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(0.1500 g，0.5221 mmol)及4-甲基苯磺酸(S)-2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙酯(0.188 g，0.626 mmol)且用氬氣充氣1分鐘，隨後添加KOtBu(1.57 ml，1.57 mmol)且繼續充氣1分鐘，隨後密封反應物，使其繼續維持於氬氣下。1.5小時後，反應完成且用二氯甲烷稀釋，且在矽膠上(含20%丙酮之二氯甲烷)直接純化，得到(S)-1-(5-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)-4-氟吡啶-2-基)-3-甲基脲(0.090 g，0.232 mmol，44.5%產率)。 Step B : Combining methyl 3-(4-fluoro-6-(3-methylureido)pyridin-3-ylthio)propanoate (0.1500 g, 0.5221 mmol) and 4-methyl in 0.5 mL THF (S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl benzenesulfonate (0.188 g, 0.626 mmol) and inflated with argon for 1 min. KOtBu (1.57 ml, 1.57 mmol) was then added and the aeration was continued for 1 minute, after which the reaction was sealed and maintained under argon. After 1.5 hours, the reaction was completed and diluted with dichloromethane and purified directly on silica gel eluting with 20% acetone to afford (S)-1-(5-(2-(2,2-dimethyl) Base-1,3-dioxol-4-yl)ethylthio)-4-fluoropyridin-2-yl)-3-methylurea (0.090 g, 0.232 mmol, 44.5% yield).

步驟C：在1.0 mL DMA中組合(S)-1-(5-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)-4-氟吡啶-2-基)-3-甲基脲(0.100 g，0.304 mmol)、3-氯-2-氟苯酚(0.0667 g，0.455 mmol)及Cs2CO3(0.143 g，0.440 mmol)，且將其密封並加熱至90℃，維持3天。此後，用5 mL水稀釋反應物，接著用EtOAc(3×75 mL)萃取。接著合併有機物，經MgSO4乾燥，過濾，且在減壓下移除。在矽膠上(含10%丙酮之二氯甲烷)純化殘餘物，得到(S)-1-(4-(3-氯-2-氟苯氧基)-5-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)吡啶-2-基)-3-甲基脲(0.088 g，0.164 mmol，54.0%產率)。 Step C : Combine (S)-1-(5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylthio)- in 1.0 mL of DMA 4-fluoropyridin-2-yl)-3-methylurea (0.100 g, 0.304 mmol), 3-chloro-2-fluorophenol (0.0667 g, 0.455 mmol) and Cs 2 CO 3 (0.143 g, 0.440 mmol) And sealed and heated to 90 ° C for 3 days. After this time the reaction was diluted with EtOAc (3×EtOAc). Next organics were combined, dried over MgSO 4, filtered, and removed under reduced pressure. The residue was purified on silica gel (dichloromethane containing 10% acetone) to afford (S)-1-(4-(3-chloro-2-fluorophenoxy)-5-(2-(2,2-) Dimethyl-1,3-dioxolan-4-yl)ethylthio)pyridin-2-yl)-3-methylurea (0.088 g, 0.164 mmol, 54.0% yield).

步驟D：在1 mL甲醇中組合(S)-1-(4-(3-氯-2-氟苯氧基)-5-(2-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)乙硫基)吡啶-2-基)-3-甲基脲(0.088 g，0.193 mmol)、H2O(0.174 ml，9.65 mmol)及HCl(0.0322 ml，0.386 mmol)，且在室溫下攪拌此物質經週末。此後，反應完成，接著向反 應物中添加NH4OH(0.0371 ml，0.483 mmol)。在劇烈攪拌下用水(5 mL)稀釋反應物，且經由真空過濾收集所得固體，得到(S)-1-(4-(3-氯-2-氟苯氧基)-5-(3,4-二羥基丁硫基)吡啶-2-基)-3-甲基脲(0.060 g，0.139 mmol，71.8%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.19(s,1H),8.19(s,1H),7.62-7.53(m,2H),7.40-7.64(m,2H),6.89(s,1H),3.56-3.49(m,1H),3.30(dd,J=10.7,5.5 Hz,1H),3.21(dd,J=10.5,5.6 Hz,1H),3.03-2.95(m,1H),2.92-2.83(m,2H),2.64(d,J=4.7 Hz,3H),1.74-1.64(m,1H),1.55-1.44(m,1H)。質譜(apci)m/z=216.1,218.0(M+H)。 Step D : Combine (S)-1-(4-(3-chloro-2-fluorophenoxy)-5-(2-(2,2-dimethyl-1,3-) in 1 mL of methanol Oxolane-4-yl)ethylthio)pyridin-2-yl)-3-methylurea (0.088 g, 0.193 mmol), H 2 O (0.174 ml, 9.65 mmol) and HCl (0.0322 ml, 0.386 mmol) and the mixture was stirred at room temperature over the weekend. Thereafter, the reaction was completed, and then NH 4 OH (0.0371 ml, 0.483 mmol) was added to the mixture. The reaction was diluted with water (5 mL) with vigorous stirring, and the obtained solid was collected by vacuum filtration to afford (S)-1-(4-(3-chloro-2-fluorophenoxy)-5- (3,4 -Dihydroxybutylthio)pyridin-2-yl)-3-methylurea (0.060 g, 0.139 mmol, 71.8% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.19 (s, 1H), 8.19 (s, 1H), 7.62-7.53 (m, 2H), 7.40-7.64 (m, 2H), 6.89 (s, 1H), 3.56-3.49 (m, 1H), 3.30 (dd, J = 10.7, 5.5 Hz, 1H), 3.21 (dd, J = 10.5, 5.6 Hz, 1H), 3.03-2.95 (m, 1H), 2.92 -2.83 (m, 2H), 2.64 (d, J = 4.7 Hz, 3H), 1.74-1.64 (m, 1H), 1.55-1.44 (m, 1H). Mass spectrum (apci) m/z = 216.1, 218.0 (M+H).

實例1774Example 1774

1-(5-((二氟甲基)硫基)-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((Difluoromethyl)thio)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：遵循實例109中之程序，用1-(5-溴-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲替代1-(5-溴-4-(喹啉-5-基氧基)吡啶-2-基)-3-甲基脲，合成3-((6-(3-甲基脲基)-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)硫基)丙酸甲酯(0.279 g，0.6482 mmol，78.50%產率)。 Step A : Following the procedure in Example 109 using 1-(5-bromo-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-3-methyl Substituting urea for 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)-3-methylurea to synthesize 3-((6-(3-methylureido)-) Methyl 4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)thio)propanoate (0.279 g, 0.6482 mmol, 78.50% yield).

步驟B：遵循實例118中之程序且用3-((6-(3-甲基脲基)-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)硫基)丙酸酯(0.150 g，0.3485 mmol)及2-溴-2,2-二氟乙酸乙酯(0.1341 ml，1.046 mmol)分別替代3-(6-(3-甲基脲基)-4-(喹啉-5-基氧基)吡啶-3-基硫基)丙酸甲酯及1-溴-3- 甲氧基丙烷，合成2,2-二氟-2-((6-(3-甲基脲基)-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)硫基)乙酸乙酯且以粗物質形式用於後續反應中。 Step B : Following the procedure in Example 118 using 3-((6-(3-methylureido)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine-3 -(yl)thio)propionate (0.150 g, 0.3485 mmol) and ethyl 2-bromo-2,2-difluoroacetate (0.1341 ml, 1.046 mmol) instead of 3-(6-(3-methylurea) Methyl 4-(quinolin-5-yloxy)pyridin-3-ylthio)propanoate and 1-bromo-3-methoxypropane to synthesize 2,2-difluoro-2-( (6-(3-Methylureido)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)thio)acetate as a crude material Used in subsequent reactions.

步驟C：將來自步驟B反應混合物之2,2-二氟-2-((6-(3-甲基脲基)-4-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)硫基)乙酸乙酯(約0.037 mg，0.08 mmol)溶解於1 mL THF中，且快速添加嗎啉(0.140 ml，1.61 mmol)，且在室溫下攪拌反應物隔夜。此後觀測到極少所要物質，但觀測到二氟-甲基硫醚。用飽和氯化銨(4 mL)淬滅反應物，接著用EtOAc(3×20 mL)萃取。合併有機物，經MgSO4乾燥，過濾，且在減壓下移除。將粗物質與類似反應所得之粗物質合併且溶解於甲醇中，且經由C18逆相層析(含10-80%乙腈之水)純化，得到1-(5-(二氟甲硫基)-4-(6-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.013 g，0.032 mmol)。1H NMR(400 MHz,CDCl3)δ ppm 9.99(s,1H),8.94(s,1H),8.58(d,J=1.9 Hz,1H),8.33(s,1H),7.78(d,J=8.6 Hz,1H),7.61(dd,J=8.4,1.8 Hz,1H),7.26(s,1H),6.80(t,J=56.6 Hz,1H),6.30(s,1H),2.72(d,J=4.7 Hz,3H)質譜(apci)m/z=394.7(M+H)。 Step C : 2,2-Difluoro-2-((6-(3-methylureido)-4-((6-(trifluoromethyl)pyridin-3-yl)))) Ethyl oxy)pyridin-3-yl)thio)acetate (about 0.037 mg, 0.08 mmol) was dissolved in 1 mL THF and morpholine (0.140 ml, 1.61 mmol) was quickly added and stirred at room temperature Things overnight. Very few substances were observed thereafter, but difluoro-methyl sulfide was observed. The reaction was quenched with EtOAc (EtOAc) The organics were combined, dried over MgSO 4, filtered, and removed under reduced pressure. The crude material was combined with a crude material obtained by a similar reaction and dissolved in methanol, and purified by C18 reverse phase chromatography (water containing 10-80% acetonitrile) to give 1-(5-(difluoromethylthio)- 4-(6-(Trifluoromethyl)pyridin-3-yloxy)pyridin-2-yl)-3-methylurea (0.013 g, 0.032 mmol). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.99 (s, 1H), 8.94 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.33 (s, 1H), 7.78 (d, J) = 8.6 Hz, 1H), 7.61 (dd, J = 8.4, 1.8 Hz, 1H), 7.26 (s, 1H), 6.80 (t, J = 56.6 Hz, 1H), 6.30 (s, 1H), 2.72 (d , J = 4.7 Hz, 3H) Mass spectrum (apci) m/z = 394.7 (M+H).

遵循實例68中之程序，亦可合成以下化合物： Following the procedure in Example 68, the following compounds were also synthesized:

實例1776Example 1776

1-(6'-乙氧基-4-(3-(羥基甲基)-5-甲基苯氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-ethoxy-4-(3-(hydroxymethyl)-5-methylphenoxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea

步驟A：遵循實例155中之程序且以1-(6'-乙氧基-4-氟-3,3'-聯吡啶-6-基)-3-甲基脲(0.150 g，0.517 mmol)為起始物，合成1-(4-(3-溴-5-(羥基甲基)苯氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.106 g，0.224 mmol，43.3%產率)。 Step A : Following the procedure in Example 155 with 1-(6'-ethoxy-4-fluoro-3,3'-bipyridin-6-yl)-3-methylurea (0.150 g, 0.517 mmol) For the starting material, 1-(4-(3-bromo-5-(hydroxymethyl)phenoxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3- Methyl urea (0.106 g, 0.224 mmol, 43.3% yield).

步驟B：在1 mL二噁烷中組合1-(4-(3-溴-5-(羥基甲基)苯氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.050 g，0.11 mmol)、甲基酸(0.019 g，0.32 mmol)及K3PO4(0.21 ml，0.42 mmol)，且將此物質用氬氣充氣5分鐘，隨後添加PdCl2(dppf)．DCM(0.0086 g，0.011 mmol)。接著將反應物再充氣2分鐘，隨後將其密封且加熱至100℃。 Step B : Combination of 1-(4-(3-bromo-5-(hydroxymethyl)phenoxy)-6'-ethoxy-3,3'-bipyridine-6- in 1 mL of dioxane 3-methylurea (0.050 g, 0.11 mmol), methyl Acid (0.019 g, 0.32 mmol) and K 3 PO 4 (0.21 ml, 0.42 mmol), and this substance inflator 5 minutes with argon, followed by addition of PdCl 2 (dppf). DCM (0.0086 g, 0.011 mmol). The reaction was then re-inflated for 2 minutes, then sealed and heated to 100 °C.

用二氯甲烷稀釋反應物，接著在矽膠上(含35%丙酮之二氯甲烷)直接純化，繼而進行C18逆相層析(含5-95%乙腈之水)，得到1-(6'-乙氧基-4-(3-(羥基甲基)-5-甲基苯氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.010 g，0.024 mmol，23%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.03(s,1H),8.28(d,J=2.2 Hz,1H),8.06(s,1H),7.91(s,1H),7.80(dd,J=8.6,2.5 Hz,1H),7.00(s,1H),6.92(s,1H),6.80-6.76(m,2H),6.15(s,1H),4.65(s,2H),4.39(q,J=7.0 Hz,2H),2.86(d,J=4.7 Hz,3H),2.33(s,3H),1.41(t,J=7.0 Hz,3H)。質譜(apci)m/z=408.9(M+H)。 The reaction was diluted with dichloromethane, then directly purified on silica gel (35% acetone in dichloromethane), followed by C18 reverse phase chromatography (5-95% acetonitrile in water) to give 1-(6'- Ethoxy-4-(3-(hydroxymethyl)-5-methylphenoxy)-3,3'-bipyridin-6-yl)-3-methylurea (0.010 g, 0.024 mmol, 23 %Yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.03 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.80 (dd, J = 8.6, 2.5 Hz, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 6.80-6.76 (m, 2H), 6.15 (s, 1H), 4.65 (s, 2H), 4.39 (q, J = 7.0 Hz, 2H), 2.86 (d, J = 4.7 Hz, 3H), 2.33 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 408.9 (M+H).

實例1777Example 1777

3-((6'-乙氧基-6-(3-甲基脲基)-[3,3'-聯吡啶]-4-基)氧基)-5-(羥基甲基)苯甲酸甲酯 3-((6'-ethoxy-6-(3-methylureido)-[3,3'-bipyridyl]-4-yl)oxy)-5-(hydroxymethyl)benzoic acid ester

步驟A：遵循實例155中之程序且以1-(6'-乙氧基-4-氟-3,3'-聯吡啶-6-基)-3-甲基脲(0.150 g，0.517 mmol)為起始物，合成1-(4-(3-溴-5-(羥基甲基)苯氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.106 g，0.224 mmol，43.3%產率)。 Step A : Following the procedure in Example 155 with 1-(6'-ethoxy-4-fluoro-3,3'-bipyridin-6-yl)-3-methylurea (0.150 g, 0.517 mmol) For the starting material, 1-(4-(3-bromo-5-(hydroxymethyl)phenoxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3- Methyl urea (0.106 g, 0.224 mmol, 43.3% yield).

步驟B：在1 mL MeOH中組合1-(4-(3-溴-5-(羥基甲基)苯氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.050 g，0.11 mmol)、Et3N(0.044 ml，0.32 mmol)及PdCl2(dppf)．DCM(0.0086 g，0.011 mmol)，且將此物質置於經抽真空並用氮氣淨化(3×)之高壓罐(bomb)中，隨後將反應物用CO(g)加壓且抽真空(3×)，且最後置於85 psi一氧化碳氣體下並加熱至100℃隔夜。次日早晨，反應物乾燥且將其溶解於二氯甲烷中，直接加載於二氧化矽上且用含35%丙酮之二氯甲烷溶離。經由C18逆相層析(含5-95%乙腈之水)進一步純化不純物質，得到3-(6'-乙氧基-6-(3-甲基脲基)-3,3'-聯吡啶-4-基氧基)-5-(羥基甲基)苯甲酸甲酯(0.015 g，0.033 mmol，31%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.96(s,1H),8.71(s,1H),8.26(d,J=2.0 Hz,1H),8.05(s,1H),7.82-7.77(m,2H),7.60(t,J=2.0 Hz,1H),7.38-7.36(m,1H),6.78(d,J=8.2 Hz,1H),6.24(s,1H),4.69(s,2H),4.39(q,J=7.0 Hz,2H),3.86(s,3H),2.77(d,J=4.7 Hz,3H),1.41(t,J=7.0 Hz,3H)。質譜(apci)m/z=452.8(M+H)。 Step B : Combination of 1-(4-(3-bromo-5-(hydroxymethyl)phenoxy)-6'-ethoxy-3,3'-bipyridin-6-yl) in 1 mL of MeOH -3-methylurea (0.050 g, 0.11 mmol), Et 3 N (0.044 ml, 0.32 mmol) and PdCl 2 (dppf). DCM (0.0086 g, 0.011 mmol), and this material was placed in a vacuum (3×) high pressure bomb (bob), then the reaction was pressurized with CO (g) and vacuumed (3× ), and finally placed under 85 psi of carbon monoxide gas and heated to 100 ° C overnight. The next morning, the reaction was dried and dissolved in dichloromethane, applied directly to cerium chloride and eluted with dichloromethane containing 35% acetone. The impurities were further purified by C18 reverse phase chromatography (5-95% acetonitrile in water) to give 3-(6'-ethoxy-6-(3-methylureido)-3,3'-bipyridine. Methyl 4-methyloxy)-5-(hydroxymethyl)benzoate (0.015 g, 0.033 mmol, 31% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.96 (s, 1H), 8.71 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.82-7.77 (m) , 2H), 7.60 (t, J = 2.0 Hz, 1H), 7.38-7.36 (m, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.24 (s, 1H), 4.69 (s, 2H) , 4.39 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 2.77 (d, J = 4.7 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 452.8 (M+H).

實例1778Example 1778

N-甲基-4-((5-甲基吡啶-3-基)氧基)-6-(3-甲基脲基)-[3,4'-聯吡啶]-2'-甲醯胺 N-methyl-4-((5-methylpyridin-3-yl)oxy)-6-(3-methylureido)-[3,4'-bipyridyl]-2'-carboxamide

步驟A：使用與實例1668相同之方法，用4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶甲酸甲酯(0.051 g，0.19 mmol)替代5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)噻吩-2-甲酸甲酯，獲得4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)-3,4'-聯吡啶-2'-甲酸甲酯(0.020 g，0.051 mmol，26%產率)。 Step A : Using the same procedure as in Example 1668, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Methyl-2-yl)picolinate (0.051 g, 0.19 mmol) in place of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Methyl-2-thio)-2-carboxylate, 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)-3,4'-bipyridine-2 '-Methylformate (0.020 g, 0.051 mmol, 26% yield).

步驟B：使用與1674實例相同之方法，用4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)-3,4'-聯吡啶-2'-甲酸甲酯(0.020 g，0.051 mmol)替代4-氯-3-(2-(3-甲基脲基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基氧基)苯甲酸乙酯，獲得4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)-3,4'-聯吡啶-2'-甲酸(0.019 g，0.050 mmol，99%產率)。 Step B : Using 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)-3,4'-bipyridine-2'- using the same procedure as the 1674 example. Methyl formate (0.020 g, 0.051 mmol) in place of 4-chloro-3-(2-(3-methylureido)-5-(1-(2,2,2-trifluoroethyl)-1H-pyridin Ethyl oxazol-4-yl)pyridin-4-yloxy)benzoate to give 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)-3,4 '-Bipyridine-2'-carboxylic acid (0.019 g, 0.050 mmol, 99% yield).

步驟C：使用與實例1679相同之方法，用4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)-3,4'-聯吡啶-2'-甲酸(0.010 g，0.026 mmol)及甲胺(0.033 ml，0.26 mmol)分別替代4-氯-3-(2-(3-甲基脲基)-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基氧基)苯甲酸及1-甲基哌嗪，獲得N-甲基-4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)-3,4'-聯吡啶-2'-甲醯胺(0.0015 g，0.0037 mmol，14%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.94(s,1H),8.58(dd,J=5.1,0.8 Hz,1H),8.43-8.42(m,1H),8.37-8.36(m,1H),8.29-8.26(m,2H),8.08-8.03(m,1H),7.66(dd,J=5.1,1.8 Hz,1H),7.46(s,1H),6.07(s,1H),4.12(q.J=7.2 Hz,1H),3.06(d,J=5.1 Hz,3H),2.91(d,J=4.7 Hz,3H),2.38(s,3H),1.26(t,J=7.2 Hz,3H)。質譜(apci)m/z=392.9(M+H)。 Step C : Using 4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)-3,4'-bipyridine-2'- using the same procedure as Example 1679. Formic acid (0.010 g, 0.026 mmol) and methylamine (0.033 ml, 0.26 mmol) were substituted for 4-chloro-3-(2-(3-methylureido)-5-(1-(2,2,2-) Trifluoroethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)benzoic acid and 1-methylpiperazine give N-methyl-4-(5-methylpyridine-3- Benzyl)-6-(3-methylureido)-3,4'-bipyridyl-2'-carboxamide (0.0015 g, 0.0037 mmol, 14% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.94 (s, 1H), 8.58 (dd, J = 5.1, 0.8 Hz, 1H), 8.43-8.42 (m, 1H), 8.37-8.36 (m, 1H) , 8.29-8.26 (m, 2H), 8.08-8.03 (m, 1H), 7.66 (dd, J = 5.1, 1.8 Hz, 1H), 7.46 (s, 1H), 6.07 (s, 1H), 4.12 (q) J = 7.2 Hz, 1H), 3.06 (d, J = 5.1 Hz, 3H), 2.91 (d, J = 4.7 Hz, 3H), 2.38 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H ). Mass spectrum (apci) m/z = 392.9 (M+H).

遵循實例1778中之程序，亦可合成以下化合物： Following the procedure in Example 1778, the following compounds were also synthesized:

實例1780Example 1780

1-(6'-乙氧基-4-((5-(2-羥基乙基)吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-ethoxy-4-((5-(2-hydroxyethyl)pyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl)-3- Methyl urea

步驟A：遵循實例155中之程序，用5-溴吡啶-3-醇(0.450 g，2.58 mmol)及1-(6'-乙氧基-4-氟-3,3'-聯吡啶-6-基)-3-甲基脲(0.500 g，1.72 mmol)分別替代喹啉-5-醇及1-(4-氟-2'-(三氟甲基)-3,4'-聯吡啶-6-基)-3-甲基脲，獲得1-(4-(5-溴吡啶-3-基氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.48 g，1.08 mmol，63%產率)。 Step A : Following the procedure in Example 155, 5-bromopyridin-3-ol (0.450 g, 2.58 mmol) and 1-(6'-ethoxy-4-fluoro-3,3'-bipyridine-6 -yl)-3-methylurea (0.500 g, 1.72 mmol) in place of quinoline-5-ol and 1-(4-fluoro-2'-(trifluoromethyl)-3,4'-bipyridine, respectively 6-yl)-3-methylurea to give 1-(4-(5-bromopyridin-3-yloxy)-6'-ethoxy-3,3'-bipyridin-6-yl)- 3-methylurea (0.48 g, 1.08 mmol, 63% yield).

步驟B：遵循實例195中之程序，用1-(4-(5-溴吡啶-3-基氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.480 g，1.08 mmol)替代1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲，獲得(Z)-1-(6'-乙氧基-4-(5-(2-乙氧基乙烯基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.340 g，0.781 mmol，72.3%產率)。 Step B : Following the procedure in Example 195, 1-(4-(5-bromopyridin-3-yloxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3 -methylurea (0.480 g, 1.08 mmol) in place of 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-3-methylurea to give (Z)- 1-(6'-ethoxy-4-(5-(2-ethoxyvinyl)pyridin-3-yloxy)-3,3'-bipyridin-6-yl)-3-methyl Urea (0.340 g, 0.781 mmol, 72.3% yield).

步驟C：遵循實例197中之程序，用(Z)-1-(6'-乙氧基-4-(5-(2-乙氧基乙烯基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.200 g，0.459 mmol)替代(Z)-1-(4-(2,6-二氟苯氧基)-5-(2-乙氧基乙烯基)吡啶-2-基)- 3-甲基脲，獲得1-(6'-乙氧基-4-(5-(2-羥基乙基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.025 g，0.061 mmol，28%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.19-9.10(m,2H),8.32-8.28(m,3H),8.07(s,1H),7.77(dd,J=8.6,2.5 Hz,1H),7.42-7.40(m,1H),6.79(d,J=8.6 Hz,1H),6.34(s,1H),4.39(q,J=7.2 Hz,2H),3.83(t,J=5.9 Hz,2H),2.82(t,J=5.9 Hz,2H),2.74(d,J=4.7 Hz,3H),1.41(t,J=7.0 Hz,3H)。質譜(apci)m/z=410.1(M+H)。 Step C : Following the procedure in Example 197, using (Z)-1-(6'-ethoxy-4-(5-(2-ethoxyvinyl)pyridin-3-yloxy)-3, 3'-bipyridyl-6-yl)-3-methylurea (0.200 g, 0.459 mmol) instead of (Z)-1-(4-(2,6-difluorophenoxy)-5-(2- Ethoxyvinyl)pyridin-2-yl)-3-methylurea to give 1-(6'-ethoxy-4-(5-(2-hydroxyethyl)pyridin-3-yloxy) -3,3'-bipyridin-6-yl)-3-methylurea (0.025 g, 0.061 mmol, 28% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.19-9.10 (m, 2H), 8.32-8.28 (m, 3H), 8.07 (s, 1H), 7.77 (dd, J = 8.6, 2.5 Hz, 1H) , 7.42-7.40 (m, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.34 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 2.74 (d, J = 4.7 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H). Mass spectrum (apci) m/z = 410.1 (M+H).

實例1781Example 1781

1-(6'-乙氧基-4-((5-(2-羥基丙基)吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(6'-ethoxy-4-((5-(2-hydroxypropyl)pyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl)-3- Methyl urea

步驟A：將(Z)-1-(6'-乙氧基-4-(5-(2-乙氧基乙烯基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.200 g，0.459 mmol)溶解於5 mL THF中，且添加HCl(0.459 ml，1.84 mmol)，且加熱反應物至80℃，維持10分鐘。此後，用飽和碳酸氫鈉(約20 mL)淬滅反應物且用EtOAc(3×50 mL)萃取。經MgSO4乾燥有機物，過濾且濃縮。粗物質經測定含有1-(6'-乙氧基-4-(5-(2-側氧基乙基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.187 g，0.229 mmol，50.0%產率)且按原樣使用。 Step A : (Z)-1-(6'-ethoxy-4-(5-(2-ethoxyvinyl)pyridin-3-yloxy)-3,3'-bipyridine-6 -Methyl 3-carbazide (0.200 g, 0.459 mmol) was dissolved in 5 mL THF and HCl (0.45. The reaction was quenched with EtOAc EtOAc (EtOAc) The organics were dried over MgSO 4, filtered and concentrated. The crude material was determined to contain 1-(6'-ethoxy-4-(5-(2-o-oxyethyl)pyridin-3-yloxy)-3,3'-bipyridin-6-yl) 3-methylurea (0.187 g, 0.229 mmol, 50.0% yield) and used as received.

步驟B：在1 mL THF中組合1-(6'-乙氧基-4-(5-(2-側氧基乙基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.100 g，0.245 mmol)，且冷卻此物質至0℃，隨後緩慢添加3 M MeMgBr(0.270 ml，0.810 mmol)。添加之後，自冰浴中移出反應物。1小時後，藉由經數分鐘 緩慢添加飽和NH4Cl淬滅反應物。接著用1 M洛瑟耳氏鹽溶液使反應物之pH值達到6-7。用EtOAc(3×50 mL)萃取水相。合併有機物，經MgSO4乾燥，過濾，且在減壓下移除。在矽膠上(含75%丙酮之二氯甲烷w/0.1% NH4OH及丙酮w/0.1% NH4OH)純化殘餘物，得到1-(6'-乙氧基-4-(5-(2-羥基丙基)吡啶-3-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲(0.010 g，0.0236 mmol，9.62%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.10(s,1H),8.88(s,1H),8.33-8.28(m,1H),8.08(s,1H),7.77(dd,J=8.6,2.5 Hz,1H),7.41-7.38(m,1H),6.79(d,J=8.6 Hz,1H),6.32(s,1H),4.39(q,J=7.0 Hz,2H),4.03-3.94(m,1H),2.75(d,J=4.7 Hz,3H),1.41(t,J=7.0 Hz,3H),1.28-1.24(m,3H)。質譜(apci)m/z=424.2(M+H)。 Step B : Combination of 1-(6'-ethoxy-4-(5-(2-o-oxyethyl)pyridin-3-yloxy)-3,3'-bipyridine in 1 mL of THF - 6-yl)-3-methylurea (0.100 g, 0.245 mmol), and this material was cooled to 0 ° C then 3 M MeMgBr (0.270 ml, 0.810 mmol) was slowly added. After the addition, the reaction was removed from the ice bath. After 1 hour, slowly over several minutes by addition of saturated NH 4 Cl The reaction was quenched. The pH of the reactants was then brought to 6-7 with a 1 M solution of Loch's salt. The aqueous phase was extracted with EtOAc (3×50 mL). The organics were combined, dried over MgSO 4, filtered, and removed under reduced pressure. The residue was purified on silica gel (yield: 75% acetone in dichloromethane w/ 0.1% NH 4 OH and acetone w/ 0.1% NH 4 OH) to give 1-(6'-ethoxy-4-(5-( 2-Hydroxypropyl)pyridin-3-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea (0.010 g, 0.0236 mmol, 9.62% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.10 (s, 1H), 8.88 (s, 1H), 8.33-8.28 (m, 1H), 8.08 (s, 1H), 7.77 (dd, J = 8.6, 2.5 Hz, 1H), 7.41-7.38 (m, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.32 (s, 1H), 4.39 (q, J = 7.0 Hz, 2H), 4.03-3.94 ( m, 1H), 2.75 (d, J = 4.7 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.28-1.24 (m, 3H). Mass spectrum (apci) m/z = 424.2 (M+H).

實例1782Example 1782

1-(5-(5-(2-羥基丙-2-基)噻吩-2-基)-4-((5-甲基吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-(5-(2-hydroxypropan-2-yl)thiophen-2-yl)-4-((5-methylpyridin-3-yl)oxy)pyridin-2-yl)-3 -methylurea

步驟A：將5-(4-(5-甲基吡啶-3-基氧基)-6-(3-甲基脲基)吡啶-3-基)噻吩-2-甲酸甲酯(0.050 g，0.13 mmol)溶解於1 mL THF中且冷卻至0℃，隨後在攪拌下緩慢添加3 M MeMgBr(0.17 ml，0.50 mmol)。1小時後，用飽和NH4Cl(2 mL)及1 M洛瑟耳氏鹽(2 mL)淬滅反應物，且用EtOAc(3×10 mL)萃取此物質。經MgSO4乾燥有機物，過濾且濃縮。經由C18逆相層析(含5-95%乙腈之水)純化殘餘物，得到1-(5-(5- (2-羥基丙-2-基)噻吩-2-基)-4-(5-甲基吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.016 g，0.040 mmol，32%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.93(s,1H),8.55(s,1H),8.35(s,1H),8.33-8.28(m,2H),7.28-7.24(m,2H),6.93(d,J=3.7 Hz,1H),6.17(s,1H),2.84(d,J=4.7 Hz,3H),2.37(s,3H),1.69(s,6H)。質譜(apci)m/z=424.2(M+H)。 Step A : methyl 5-(4-(5-methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-yl)thiophene-2-carboxylate (0.050 g, 0.13 mmol) was dissolved in 1 mL THF and cooled to 0 ° C then 3 M MeMgBr (0.17 ml, 0.50 mmol) was slowly added with stirring. After 1 hour, saturated with NH 4 Cl (2 mL) and 1 M Luose ear's salt (2 mL) The reaction was quenched and the material was extracted with EtOAc (3 × 10 mL). The organics were dried over MgSO 4, filtered and concentrated. The residue was purified via C18 reverse phase chromatography (5-95% EtOAc in water) to afford 1-(5-(5-(2-hydroxypropyl-2-yl)thiophen-2-yl)-4-(5) Methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (0.016 g, 0.040 mmol, 32% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.93 (s, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 8.33-8.28 (m, 2H), 7.28-7.24 (m, 2H) , 6.93 (d, J = 3.7 Hz, 1H), 6.17 (s, 1H), 2.84 (d, J = 4.7 Hz, 3H), 2.37 (s, 3H), 1.69 (s, 6H). Mass spectrum (apci) m/z = 424.2 (M+H).

實例1783Example 1783

1-(4-((5-(1,2-二羥基乙基)吡啶-3-基)氧基)-6'-乙氧基-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(4-((5-(1,2-dihydroxyethyl)pyridin-3-yl)oxy)-6'-ethoxy-[3,3'-bipyridyl]-6-yl) -3-methylurea

步驟A：遵循實例195中之程序，用1-(4-(5-溴吡啶-3-基氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.150 g，0.338 mmol)及三丁基(乙烯基)錫烷(0.161 g，0.506 mmol)分別替代1-(5-溴-4-(2,6-二氟苯氧基)吡啶-2-基)-3-甲基脲及(Z)-1-乙氧基-2-(三丁基錫烷基)乙烷，獲得1-(6'-乙氧基-4-((5-乙烯基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(0.050 g，0.128 mmol，37.8%產率)。 Step A : Following the procedure in Example 195, 1-(4-(5-bromopyridin-3-yloxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3 -methylurea (0.150 g, 0.338 mmol) and tributyl(vinyl)stannane (0.161 g, 0.506 mmol) instead of 1-(5-bromo-4-(2,6-difluorophenoxy) Pyridin-2-yl)-3-methylurea and (Z)-1-ethoxy-2-(tributylstannyl)ethane give 1-(6'-ethoxy-4-(5 -Vinylpyridin-3-yl)oxy)-[3,3'-bipyridyl]-6-yl)-3-methylurea (0.050 g, 0.128 mmol, 37.8% yield).

步驟B：在室溫下，於1 mL 1：1 tBuOH：水中組合1-(6'-乙氧基-4-((5-乙烯基吡啶-3-基)氧基)-[3,3'-聯吡啶]-6-基)-3-甲基脲(0.050 g，0.128 mmol)、2.5% OsO4(0.0324 ml，0.00255 mmol)及NMO(0.0224 g，0.192 mmol)，且繼續維持於氮氣下。兩小時後，再添加1份OsO4(0.0324 ml，0.00255 mmol)，且加熱反應物至45℃。加熱兩小時後，用DMA稀釋反應物，接著經由C18逆相層析(含5-95%乙腈之水)純 化，得到1-(4-(5-(1,2-二羥基乙基)吡啶-3-基氧基)-6'-乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.030 g，0.0705 mmol，55.2%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.15(s,1H),9.00(s,1H),8.28-8.22(m,3H),8.05(s,1H),7.74(dd,J=8.6,2.1 Hz,1H),7.53(s1H),6.77(d,J=8.6 Hz,1H),6.26(s,1H),5.53(s,1H),4.84(s,1H),4.74(s,1H),4.37(q,J=7.0 Hz,2H),3.69-3.63(m,1H),3.59-3.53(m,1H),2.74(d,J=4.3 Hz,3H),1.40(t,J=7.0 Hz,3H)。質譜(apci-負模式)m/z=424.1(M-H)。 Step B : Combine 1-(6'-ethoxy-4-((5-vinylpyridin-3-yl)oxy)-[3,3 in 1 mL of 1:1 tBuOH:water at room temperature '-Bipyridyl]-6-yl)-3-methylurea (0.050 g, 0.128 mmol), 2.5% OsO 4 (0.0324 ml, 0.00255 mmol) and NMO (0.0224 g, 0.192 mmol). under. After two hours, another 1 part of OsO 4 (0.0324 ml, 0.00255 mmol) was added and the reaction was heated to 45 °C. After heating for two hours, the reaction was diluted with DMA and then purified by C18 reverse phase chromatography (water containing 5-95% acetonitrile) to give 1-(4-(5-(1,2-dihydroxyethyl)pyridine. -3-yloxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3-methylurea (0.030 g, 0.0705 mmol, 55.2% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.15 (s, 1H), 9.00 (s, 1H), 8.28-8.22 (m, 3H), 8.05 (s, 1H), 7.74 (dd, J = 8.6, 2.1 Hz, 1H), 7.53 (s1H), 6.77 (d, J = 8.6 Hz, 1H), 6.26 (s, 1H), 5.53 (s, 1H), 4.84 (s, 1H), 4.74 (s, 1H) , 4.37 (q, J = 7.0 Hz, 2H), 3.69-3.63 (m, 1H), 3.59-3.53 (m, 1H), 2.74 (d, J = 4.3 Hz, 3H), 1.40 (t, J = 7.0) Hz, 3H). Mass spectrum (apci-negative mode) m/z = 424.1 (MH).

遵循實例267中之程序，亦合成以下化合物： Following the procedure in Example 267, the following compounds were also synthesized:

遵循實例411中之程序，使用類似方式製備以下化合物。 Following the procedure in Example 411, the following compounds were prepared in a similar manner.

實例1792Example 1792

1-(5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶-2-基)-3-甲基脲 1-(5-(Difluoromethylthio)-3-(1-ethyl-1H-pyrazol-5-yloxy)pyridin-2-yl)-3-methylurea

步驟A：在室溫下，將5-溴-2-氯-3-氟吡啶(4.0 g，19.0 mmol)、1-乙基-1H-吡唑-5-醇(2.13 g，19.0 mmol)、Cs2CO3(6.19 g，19.0 mmol) 於DMSO(10 mL)中攪拌48小時。添加水(100 mL)且攪拌1小時，過濾並乾燥，得到5-溴-2-氯-3-(1-乙基-1H-吡唑-5-基氧基)吡啶(3.42 g，59.5%產率)。 Step A : 5-Bromo-2-chloro-3-fluoropyridine (4.0 g, 19.0 mmol), 1-ethyl-1H-pyrazol-5-ol (2.13 g, 19.0 mmol), Cs 2 CO 3 (6.19 g, 19.0 mmol) was stirred in DMSO (10 mL) for 48 h. Water (100 mL) was added and stirred for 1 hour, filtered and dried to give 5-bromo-2-chloro-3-(1-ethyl-1H-pyrazol-5-yloxy)pyridine (3.42 g, 59.5% Yield).

步驟B：將5-溴-2-氯-3-(1-乙基-1H-吡唑-5-基氧基)吡啶(1.00 g，3.31 mmol)、3-巰基丙酸甲酯(0.368 ml，3.31 mmol)、DIEA(1.15 ml，6.61 mmol)、Xantphos(0.191 g，0.331 mmol)溶解於二噁烷(30 ml)中，且使N2鼓泡通過，持續5分鐘。添加Pd2dba3(0.151 g，0.165 mmol)，且使N2鼓泡通過，再持續5分鐘，且加熱反應物至50℃隔夜。冷卻反應物至室溫，濃縮且在矽膠上(含5%至95%丙酮之己烷)純化，得到3-(6-氯-5-(1-乙基-1H-吡唑-5-基氧基)吡啶-3-基硫基)丙酸甲酯(970 mg，85.8%產率)。 Step B : 5-Bromo-2-chloro-3-(1-ethyl-1H-pyrazol-5-yloxy)pyridine (1.00 g, 3.31 mmol), methyl 3-mercaptopropionate (0.368 ml , 3.31 mmol), DIEA (1.15 ml, 6.61 mmol), Xantphos (0.191 g, 0.331 mmol) was dissolved in dioxane (30 ml), and the N 2 was bubbled through so that, for 5 minutes. Pd 2 dba 3 (0.151 g, 0.165 mmol) was added and N 2 was bubbled through for a further 5 min and the reaction was heated to 50 ° C overnight. The reaction was cooled to room temperature, concentrated and purified on silica gel eluting with 5% to 95% hexanes to afford 3-(6-chloro-5-(1-ethyl-1H-pyrazol-5-yl) Methyl oxy)pyridin-3-ylthio)propanoate (970 mg, 85.8% yield).

步驟C：將3-(6-氯-5-(1-乙基-1H-吡唑-5-基氧基)吡啶-3-基硫基)丙酸甲酯(0.247 g，0.7226 mmol)溶解於THF(5 mL)中，且使N2鼓泡通過，持續5分鐘。添加1 M KOtBu(2.168 ml，2.168 mmol)且攪拌5分鐘，接著添加2-溴-2,2-二氟乙酸乙酯(0.1019 ml，0.7949 mmol)且攪拌1小時。將反應物分配於水與EtOAc之間，經硫酸鈉乾燥，過濾且濃縮，得到粗2-氯-5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶(0.2209 g，100%產率)。 Step C : Dissolving methyl 3-(6-chloro-5-(1-ethyl-1H-pyrazol-5-yloxy)pyridin-3-ylthio)propanoate (0.247 g, 0.7226 mmol) in THF (5 mL), and that the N 2 was bubbled through for 5 minutes. 1 M KOtBu (2.168 ml, 2.168 mmol) was added and stirred for 5 min then ethyl 2-bromo-2,2-difluoroacetate (0.1019 ml, 0.7949 mmol) was added and stirred for 1 hour. The reaction was partitioned between EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - oxy)pyridine (0.2209 g, 100% yield).

步驟D：將2-氯-5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶(0.2209 g，0.7226 mmol)溶解於DMSO(1 mL)中，且添加(4-甲氧基苯基)甲胺(0.1888 ml，1.445 mmol)，且加熱至120℃，維持72小時。冷卻反應物至室溫且在矽膠上(含5%至95% EtOAc之己烷)直接純化，得到5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)-N-(4-甲氧基苄基)吡啶-2-胺(0.0591 g，20.1%產率)。 Step D : Dissolving 2-chloro-5-(difluoromethylthio)-3-(1-ethyl-1H-pyrazol-5-yloxy)pyridine (0.2209 g, 0.7226 mmol) in DMSO (1) (mL), and (4-methoxyphenyl)methanamine (0.1888 ml, 1.445 mmol) was added and heated to 120 ° C for 72 h. The reaction was cooled to rt and directly purified on EtOAc (EtOAc EtOAc EtOAc EtOAc -Noxy)-N-(4-methoxybenzyl)pyridin-2-amine (0.0591 g, 20.1% yield).

步驟E：將5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)-N-(4-甲氧基苄基)吡啶-2-胺(0.0591 g，0.145 mmol)溶解於純TFA中，且加熱 至50℃，維持2小時。濃縮反應物，溶解於飽和NaHCO3水溶液中，用DCM萃取，經Na2SO4乾燥，過濾且濃縮，得到呈褐色固體狀之5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶-2-胺(0.0464 g，112%產率)。 Step E : 5-(Difluoromethylthio)-3-(1-ethyl-1H-pyrazol-5-yloxy)-N-(4-methoxybenzyl)pyridin-2-amine (0.0591 g, 0.145 mmol) was dissolved in neat TFA and heated to 50 ° C for 2 h. , The reaction was concentrated to dryness, dissolved in saturated NaHCO 3 solution and extracted with DCM over Na 2 SO 4, filtered and concentrated to give a brown solid of 5- (difluoromethyl methylthio) -3- (1-ethyl -1H-pyrazol-5-yloxy)pyridin-2-amine (0.0464 g, 112% yield).

步驟F：將5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶-2-胺(0.0464 g，0.162 mmol)溶解於DCM(1 mL)中，且添加吡啶(0.0393 ml，0.486 mmol)。添加氯甲酸4-硝基苯酯(0.0686 g，0.340 mmol)，且在室溫下攪拌隔夜。添加含33%甲胺之EtOH(0.0813 ml，0.648 mmol)，在室溫下攪拌。40分鐘後，用水淬滅反應物且用DCM萃取。經Na2SO4乾燥有機物且濃縮至黃色固體。在矽膠上(含5%至95%丙酮之己烷)純化該物質，繼而進行C18層析(含5%至95% ACN之水)，得到1-(5-(二氟甲硫基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶-2-基)-3-甲基脲(13.1 mg，23.5%產率)。質譜(apci)m/z=344.0(M+H)。 Step F : Dissolving 5-(difluoromethylthio)-3-(1-ethyl-1H-pyrazol-5-yloxy)pyridin-2-amine (0.0464 g, 0.162 mmol) in DCM (1) In mL), pyridine (0.0393 ml, 0.486 mmol) was added. 4-Nitrophenyl chloroformate (0.0686 g, 0.340 mmol) was added and stirred at rt overnight. Add EtOH (0.0813 ml, 0.648 mmol) containing 33% methylamine and stir at room temperature. After 40 minutes, the reaction was quenched with EtOAc EtOAc. Over Na 2 SO 4 organics were dried and concentrated to a yellow solid. This material was purified on silica gel (hexane containing 5% to 95% acetone), followed by C18 chromatography (water containing 5% to 95% ACN) to give 1-(5-(difluoromethylthio)- 3-(1-Ethyl-1H-pyrazol-5-yloxy)pyridin-2-yl)-3-methylurea (13.1 mg, 23.5% yield). Mass spectrum (apci) m/z = 344.0 (M+H).

實例1793Example 1793

1-(5-((1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-6'-乙氧基-[3,3'-聯吡啶]-6-基)-3-甲基脲 1-(5-((1,4-Dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)-6'-ethoxy-[3,3'- Bipyridyl]-6-yl)-3-methylurea

步驟A：將5-羥基-1,4-二甲基吡啶-2(1H)-酮(0.13 g，0.95 mmol)、5-溴-3-氟-2-氰基吡啶(0.19 g，0.95 mmol)及Cs2CO3(0.68 g，2.08 mmol)於NMP(3 mL)中之溶液在周圍溫度下攪拌4小時。添加水(10 mL)及EtOAc(20 mL)。分離有機層，用鹽水洗滌，乾燥(硫酸鈉)，過濾且在減壓下濃縮。藉由C-18逆相急驟層析(0-85% CH3CN/ 水)純化所獲得之殘餘物，得到呈油狀之5-溴-3-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-2-氰基吡啶(0.059 g，19.5%)。質譜(apci)m/z=320.0(M+H)。 Step A : 5-Hydroxy-1,4-dimethylpyridine-2(1H)-one (0.13 g, 0.95 mmol), 5-bromo-3-fluoro-2-cyanopyridine (0.19 g, 0.95 mmol The solution of Cs 2 CO 3 (0.68 g, 2.08 mmol) in NMP (3 mL) was stirred at ambient temperature for 4 hr. Water (10 mL) and EtOAc (20 mL) were added. The organic layer was separated, washed with brine, dried w... By C-18 reverse phase flash chromatography (0-85% CH 3 CN / water) purification of the obtained residue to give an oil of 5-bromo-3- (1,4-dimethyl-6- The pendant oxy-1,6-dihydropyridin-3-yloxy)-2-cyanopyridine (0.059 g, 19.5%). Mass spectrum (apci) m/z = 320.0 (M+H).

步驟B：將5-溴-3-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-2-氰基吡啶(0.059 g，0.1843 mmol)於濃鹽酸(0.90 ml，29.49 mmol)中之溶液在周圍溫度下攪拌20小時。用飽和碳酸氫鈉將其淬滅至pH值為約8且用4：1 CHCl3：IPA(20 mL)萃取。分離有機層，乾燥(硫酸鈉)，過濾且在減壓下濃縮，得到呈固體狀之5-溴-3-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶醯胺(0.062 g，99.5%)。質譜(apci)m/z=340.0(M+H)。 Step B : 5-Bromo-3-(1,4-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)-2-cyanopyridine (0.059 g, 0.1843) A solution of mmol in concentrated hydrochloric acid (0.90 ml, 29.49 mmol) was stirred at ambient temperature for 20 hours. With saturated sodium bicarbonate quenched to a pH of about 8 and extracted with 4: IPA (20 mL) and extracted: 1 CHCl 3. The organic layer was separated, dried (Na2SO4), filtered and evaporatedEtOAcjjjjjjjj Pyridin-3-yloxy)pyridiniumamine (0.062 g, 99.5%). Mass spectrum (apci) m/z = 340.0 (M+H).

步驟C：向5-溴-3-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶醯胺(0.062 g，0.183 mmol)及40%甲胺(0.08 ml，0.92 mmol)之水溶液於1：1 ACN：H2O(10 mL)中之溶液中添加[雙(三氟乙醯氧基)碘]苯(0.083 g，0.19 mmol)。在周圍溫度下攪拌混合物1小時。添加5：1 DCM：IPA(20 mL)。分離有機層，用鹽水洗滌，乾燥(硫酸鈉)，過濾且在減壓下濃縮。藉由C-18逆相急驟層析(0-85% CH3CN：水梯度)純化所獲得之殘餘物，得到1-(5-溴-3-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.052 g，77.2%)。質譜(apci)m/z=367.0(M+H)。 Step C : to 5-bromo-3-(1,4-dimethyl-6-oxooxy-1,6-dihydropyridin-3-yloxy)pyridiniumamine (0.062 g, 0.183 mmol) Add [bis(trifluoroethyloxy)iodo]benzene (0.083 g, 0.19 mmol) to a solution of 40% methylamine (0.08 mL, 0.92 mmol) in 1:1 ACN:H 2 O (10 mL) ). The mixture was stirred at ambient temperature for 1 hour. Add 5:1 DCM: IPA (20 mL). The organic layer was separated, washed with brine, dried w... By C-18 reverse phase flash chromatography (0-85% CH 3 CN: water gradient) the residue obtained was purified to give 1- (5-bromo-3- (1,4-dimethyl-6- The pendant oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3-methylurea (0.052 g, 77.2%). Mass spectrum (apci) m/z = 367.0 (M+H).

步驟D：將1-(5-溴-3-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.025 g，0.0681 mmol)、6-乙氧基吡啶-3-基酸(0.0227 g，0.136 mmol)、PdCl2(dppf)*DCM(0.00556 g，0.00681 mmol)、三乙胺(0.0152 ml，0.109 mmol)及氟化銫(0.0269 g，0.177 mmol)於IPA(2 mL)中之溶液在100℃(浴)下攪拌1小時。冷卻至周圍溫度後，藉由C-18逆相急驟層析(0-85% CH3CN：水梯度)直接純化，得到呈固體狀之1-(5-(1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-6'- 乙氧基-3,3'-聯吡啶-6-基)-3-甲基脲(0.024 g，86.1%)。1H NMR(400 MHz,CDCl3)δ ppm 9.21(s,1H),8.21(s,1H),8.04(s,1H),7.59(m,1H),7.48(s,1H),7.17(m,1H),6.96(s,1H),6.79(m,1H),6.51(s,1H),4.38(q,J=7.0 Hz,2H),3.53(s,3H),3.02(d,J=4.3 Hz,3H),2.03(s,3H),1.41(t,J=6.5 Hz,3H)。質譜(apci)m/z=410.2(M+H)。 Step D : 1-(5-Bromo-3-(1,4-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3 -methylurea (0.025 g, 0.0681 mmol), 6-ethoxypyridin-3-yl Acid (0.0227 g, 0.136 mmol), PdCl 2 (dppf)*DCM (0.00556 g, 0.00681 mmol), triethylamine (0.0152 ml, 0.109 mmol) and cesium fluoride (0.0269 g, 0.177 mmol) in IPA (2 mL) The solution in the solution was stirred at 100 ° C (bath) for 1 hour. After cooling to ambient temperature, by C-18 reverse phase flash chromatography (0-85% CH 3 CN: water gradient) directly to give as a solid of l- (5- (1,4-dimethyl - 6-Sideoxy-1,6-dihydropyridin-3-yloxy)-6'-ethoxy-3,3'-bipyridin-6-yl)-3-methylurea (0.024 g, 86.1%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.21 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.59 (m, 1H), 7.48 (s, 1H), 7.17 (m) , 1H), 6.96 (s, 1H), 6.79 (m, 1H), 6.51 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 3.53 (s, 3H), 3.02 (d, J = 4.3 Hz, 3H), 2.03 (s, 3H), 1.41 (t, J = 6.5 Hz, 3H). Mass spectrum (apci) m/z = 410.2 (M+H).

遵循實例1793中之程序，使用類似方式製備以下化合物。 Following the procedure in Example 1793, the following compounds were prepared in a similar manner.

實例1801Example 1801

1-(3-((1,4-二甲基-6-側氧基-1,6-二氫吡啶-3-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1,4-Dimethyl-6-o-oxy-1,6-dihydropyridin-3-yl)oxy)-5-((tetrahydro-2H-pyran-4) -yl)methyl)pyridin-2-yl)-3-methylurea

向1-(5-溴-3-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(0.050 g，0.14 mmol)、Pd(OAc)2(0.0015 g，0.0068 mmol)及二環己基(2',6'-二甲氧基聯苯-2-基)膦(0.0056 g，0.014 mmol)於THF(3 mL)中之溶液中添加溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(0.65 ml，0.41 mmol)。在70℃下攪拌反應混合物2小時。冷卻至周圍溫度後，添加飽和乙酸銨(5 mL)及乙酸乙酯(10 mL)。分離有機層， 用鹽水洗滌，乾燥(硫酸鈉)，過濾且濃縮。藉由C-18逆相急驟層析(0-85% CH3CN：水梯度)純化殘餘物，得到呈固體狀之1-(3-(1,2-二甲基-6-側氧基-1,6-二氫吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲(0.024 g，45.6%)。1H NMR(400 MHz,CDCl3)δ ppm 9.20(s,1H),7.75(s,1H),7.37(s,1H),7.12(s,1H),6.65(s,1H),6.51(s,1H),3.92(d,2H),3.52(s,3H),3.31(t,2H),2.99(s,3H),2.42(d,2H),2.00(s,3H),1.60-0.70(m,5H)。質譜(apci)m/z=387.2(M+H)。 To 1-(5-bromo-3-(1,2-dimethyl-6-o-oxy-1,6-dihydropyridin-3-yloxy)pyridin-2-yl)-3-methyl Urea (0.050 g, 0.14 mmol), Pd(OAc) 2 (0.0015 g, 0.0068 mmol) and dicyclohexyl (2',6'-dimethoxybiphenyl-2-yl)phosphine (0.0056 g, 0.014 mmol) To a solution in THF (3 mL) was added ((tetrahydro-2H-pyran-4-yl)methyl)zinc(II) (0.65 ml, 0.41 mmol). The reaction mixture was stirred at 70 ° C for 2 hours. After cooling to ambient temperature, saturated ammonium acetate (5 mL) and ethyl acetate (10 mL). The organic layer was separated, washed with brine, dried w... By C-18 reverse phase flash chromatography (0-85% CH 3 CN: water gradient) the residue was purified to give as a solid of 1- (3- (1,2-dimethyl-6-oxo -1,6-dihydropyridin-3-yloxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)-3-methylurea (0.024 g , 45.6%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.20 (s, 1H), 7.75 (s, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 6.65 (s, 1H), 6. , 1H), 3.92 (d, 2H), 3.52 (s, 3H), 3.31 (t, 2H), 2.99 (s, 3H), 2.42 (d, 2H), 2.00 (s, 3H), 1.60-0.70 ( m, 5H). Mass spectrum (apci) m/z = 387.2 (M+H).

遵循實例1801中之程序，使用類似方式製備以下化合物。 Following the procedure in Example 1801, the following compounds were prepared in a similar manner.

實例1806Example 1806

1-(6'-乙氧基-5-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)-3,3'-聯吡啶- 6-基)-3-甲基脲 1-(6'-ethoxy-5-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yloxy)-3,3'-bipyridine- 6-yl)-3-methylurea

步驟A：將3-甲基-3H-咪唑并[4,5-b]吡啶-6-醇(327 mg，2.19 mmol)、5-溴-3-硝基-2-氰基吡啶(500 mg，2.19 mmol)及Cs2CO3(786 mg，2.19 mmol)於無水DMSO(3 mL)中之混合物在室溫下攪拌2小時。用飽和NH4Cl溶液處理混合物，接著傾倒至水(20 mL)中。藉由過濾收集所形成之沈澱物，且用水洗滌並在真空下乾燥，得到5-溴-3-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)-2-氰基吡啶。產量156 mg(21%)。 Step A : 3-methyl-3H-imidazo[4,5-b]pyridine-6-ol (327 mg, 2.19 mmol), 5-bromo-3-nitro-2-cyanopyridine (500 mg A mixture of 2.19 mmol) and Cs 2 CO 3 (786 mg, 2.19 mmol) in anhydrous EtOAc (3 mL) Cl mixture was treated with a solution of saturated NH 4, then poured into water (20 mL) of. The precipitate formed was collected by filtration, washed with water and dried under vacuum to give 5-bromo-3-(3-methyl-3H-imidazo[4,5-b]pyridine-6-yloxy. )-2-cyanopyridine. Yield 156 mg (21%).

步驟B：向100 mL圓底燒瓶中饋入5-溴-3-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)-2-氰基吡啶(156 mg，0.473 mmol)，且在冰-乙醇浴中冷卻至-10℃。將冷卻至-10℃之濃鹽酸(2 mL)緩慢添加至固體中，且使混合物維持於周圍溫度下隔夜。向混合物中添加冰且緩慢添加30% NaOH水溶液，同時使混合物溫度保持低於20℃以將混合物之pH值調整至12。接著用EtOAc萃取混合物，用飽和NaHCO3溶液及鹽水洗滌，接著經MgSO4乾燥，且在減壓下蒸發，得到5-溴-3-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)吡啶醯胺。產量134 mg(82%)。 Step B : To a 100 mL round bottom flask was fed 5-bromo-3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yloxy)-2-cyanopyridine ( 156 mg, 0.473 mmol) and cooled to -10 °C in an ice-ethanol bath. Concentrated hydrochloric acid (2 mL) cooled to -10 °C was slowly added to the solid and mixture was maintained at ambient temperature overnight. Ice was added to the mixture and a 30% aqueous NaOH solution was slowly added while maintaining the temperature of the mixture below 20 °C to adjust the pH of the mixture to 12. Then, the mixture was extracted with EtOAc followed by drying with saturated NaHCO 3 solution was washed with brine and MgSO 4, and evaporated under reduced pressure to give 5-bromo-3- (3-methyl -3H- imidazo [4,5- b] Pyridine-6-yloxy)pyridiniumamine. Yield 134 mg (82%).

步驟C：向5-溴-3-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)吡啶醯胺(130 mg，0.373 mmol)於MeCN：H2O混合物(1：1，5 mL)中之溶液中添加40%甲胺之水溶液(0.161 mL，1.87 mmol)。以一整份添加[雙(三氟乙醯氧基)碘]苯(174 mg，0.392 mmol)，且在周圍溫度下攪拌所得混合物1小時。接著將混合物分配於飽和NaHCO3溶液(5 mL)與 EtOAc(10 mL)之間。分離各層，且用鹽水洗滌有機層，接著經MgSO4乾燥並濃縮。藉由C18逆相層析(含10-55% MeCN之H2O)純化殘餘物，得到1-(5-溴-3-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)吡啶-2-基)-3-甲基脲。產量107 mg(76%)。 Step C : To 5-bromo-3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yloxy)pyridiniumamine (130 mg, 0.373 mmol) in MeCN:H 2 A 40% aqueous solution of methylamine (0.161 mL, 1.87 mmol) was added to a solution of a mixture of EtOAc (1:1, 5 mL). [Bis(trifluoroacetoxy)iodo]benzene (174 mg, 0.392 mmol) was added in one portion, and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then partitioned between (10 mL) saturated NaHCO 3 solution (5 mL) and EtOAc. The layers were separated, and the organic layer was washed with brine, then dried over MgSO 4 and concentrated. By C18 reverse phase chromatography (10-55% MeCN containing the H 2 O) and the residue was purified to afford l- (5-bromo-3- (3-methyl -3H- imidazo [4,5-b] Pyridine-6-yloxy)pyridin-2-yl)-3-methylurea. Yield 107 mg (76%).

步驟D：在密封管中，將1-(5-溴-3-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)吡啶-2-基)-3-甲基脲(30 mg，0.08 mmol)、6-乙氧基吡啶-3-基酸(27 mg，0.159 mmol)及CsF(31 mg，0.207 mmol)於i-PrOH(2 ml)中之混合物用N2脫氣10分鐘。添加三乙胺(0.02 ml，0.127 mmol)及PdCl2(dppf)*DCM(7 mg，0.008 mmol)，將容器密封且在100℃下加熱18小時。用EtOAc(10 mL)稀釋經冷卻之反應混合物，經矽藻土栓塞過濾且再用EtOAc洗滌，且濃縮經合併之濾液。藉由C18逆相層析(含15-55% MeCN之H2O)純化殘餘物，得到1-(6'-乙氧基-5-(3-甲基-3H-咪唑并[4,5-b]吡啶-6-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲。產量21 mg(63%)。質譜(APCI)m/z=420(M+H)。1H-NMR(400 MHz,CDCl3)δ 9.29(br s,1H),8.18(d,J=3 Hz,1H),8.03(d,J=3 Hz,1H),7.92(s,1H),7.63(s,1H),7.55(dd,J=2 Hz,8 Hz,1H),7.50(d,J=3 Hz,1H),7.42(d,J=2 Hz,1H),7.09(dd,J=2.8 Hz,8.8 Hz,1H),6.71(d,J=9 Hz,1H),4.34(q,J=8 Hz,2H),3.89(s,3H),3.02(d,J=7 Hz,3H),1.38(t,J=8 Hz,3H)。 Step D : 1-(5-Bromo-3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yloxy)pyridin-2-yl)- in a sealed tube 3-methylurea (30 mg, 0.08 mmol), 6-ethoxypyridin-3-yl Mixture (2 ml) of the acid (27 mg, 0.159 mmol) and CsF (31 mg, 0.207 mmol) in i -PrOH was degassed with N 2 for 10 min. Triethylamine (0.02 ml, 0.127 mmol) and PdCl 2 (dppf)*DCM (7 mg, 0.008 mmol) were added, and the vessel was sealed and heated at 100 ° C for 18 hours. The cooled reaction mixture was diluted with EtOAc (EtOAc)EtOAc. By C18 reverse phase chromatography (15-55% MeCN containing the H 2 O) The residue was purified to give 1- (6'-ethoxy-5- (3-methyl -3H- imidazo [4,5 -b]pyridine-6-yloxy)-3,3'-bipyridin-6-yl)-3-methylurea. Yield 21 mg (63%). Mass Spectrum (APCI) m/z = 420 (M+H). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.29 (br s, 1H), 8.18 (d, J = 3 Hz, 1H), 8.03 (d, J = 3 Hz, 1H), 7.92 (s, 1H) , 7.63 (s, 1H), 7.55 (dd, J = 2 Hz, 8 Hz, 1H), 7.50 (d, J = 3 Hz, 1H), 7.42 (d, J = 2 Hz, 1H), 7.09 (dd , J=2.8 Hz, 8.8 Hz, 1H), 6.71 (d, J=9 Hz, 1H), 4.34 (q, J=8 Hz, 2H), 3.89 (s, 3H), 3.02 (d, J=7) Hz, 3H), 1.38 (t, J = 8 Hz, 3H).

遵循實例1806中之程序，使用適當起始物質製備以下化合物： Following the procedure in Example 1806, the following compounds were prepared using the appropriate starting materials:

實例1808Example 1808

1-甲基-3-(3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)脲 1-methyl-3-(3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)-5-((tetrahydro-2H-pyran-4) -yl)methyl)pyridin-2-yl)urea

步驟A：根據實例1806步驟A及B製備5-溴-3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)吡啶醯胺，得到5-溴-3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)吡啶醯胺。產量416 mg(50%)。 Step A : Preparation of 5-bromo-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)pyridiniumamine according to Example 1806, Steps A and B, affording 5- Bromo-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)pyridiniumamine. Yield 416 mg (50%).

步驟B：在密封管中，將5-溴-3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)吡啶醯胺(276 mg，0.793 mmol)於無水THF(20 mL)中之溶液用N2脫氣10分鐘。添加S-Phos(33 mg，0.079 mmol)及Pd(OAc)2(9 mg，0.04 mmol)，繼而添加溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)於THF中之溶液(0.63 M，3.79 mL，2.38 mmol)。將容器密封且在70℃下加熱2小時。冷卻反應混合物至室溫，用飽和NH4Cl溶液淬滅且用EtOAc(3×20 mL)萃取。用鹽水洗滌經合併之萃取物，且經MgSO4乾燥並濃縮。 Step B : 5-Bromo-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)pyridiniumamine (276 mg, 0.793 mmol) in a sealed tube ) in dry THF (20 mL) of the solution was degassed with N 2 for 10 min. Add S-Phos (33 mg, 0.079 mmol) and Pd(OAc) 2 (9 mg, 0.04 mmol) followed by bromination ((tetrahydro-2H-piperidin-4-yl)methyl)zinc (II) A solution in THF (0.63 M, 3.79 mL, 2.38 mmol). The vessel was sealed and heated at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated NH 4 Cl solution, and (3 × 20 mL) and extracted with EtOAc. The combined extracts were washed with brine and dried over MgSO 4

步驟C：向3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶醯胺(291 mg，0.792 mmol)於MeCN：H2O混合物(1：1，10 mL)中之粗混合物溶液中添加40%甲胺之水溶液(0.341 mL，3.96 mmol)，繼而添加[雙(三氟乙醯氧基)碘]苯(369 mg，0.0.832 mmol)，且在周圍溫度下攪拌混合物3小時。接著將混合物分配於飽和NaHCO3溶液(15 mL)與EtOAc(30 mL)之間。分離各層，且用鹽水洗滌有機層，接著經MgSO4乾燥並濃縮。在矽膠上(二氯甲烷，繼之 以含50% EtOAc之己烷)純化殘餘物，得到1-甲基-3-(3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)脲。產量67 mg(21%)。質譜(APCI)m/z=397(M+H)。1H-NMR(400 MHz,CDCl3)δ ppm 9.25(br s,1H),8.59(dd,J=1.6 Hz,6 Hz,1H),7.90(dd,J=1.6 Hz,6 Hz,1H),7.79(d,J=1.6 Hz,1H),7.43(s,1H),7.33(d,J=1.6 Hz,1H),7.11(dd,J=4 Hz,8 Hz,1H),4.05(s,3H),3.94(d,J=4 Hz,1H),3.91(d,J=4 Hz,1H),3.29(td,J=2 Hz,11 Hz,2H),2.99(d,J=5 Hz,3H),2.46(d,J=7 Hz,2H),1.53(d,J=12 Hz,2H),1.40-1.20(m,3H)。 Step C : To 3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)-5-((tetrahydro-2H-pyran-4-yl)- Add a 40% aqueous solution of methylamine (0.341 mL, 3.96 mmol) to a solution of the crude mixture of pyridine amide (291 mg, 0.792 mmol) in a mixture of MeCN:H 2 O (1:1, 10 mL). [Bis(trifluoroacetoxy)iodo]benzene (369 mg, 0.0.832 mmol), and the mixture was stirred at ambient temperature for 3 hours. The mixture was then partitioned between saturated NaHCO 3 solution and EtOAc (30 mL) (15 mL ). The layers were separated, and the organic layer was washed with brine, then dried over MgSO 4 and concentrated. The residue was purified on EtOAc (EtOAc (EtOAc:EtOAc) b] Pyridin-3-yloxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)urea. Yield 67 mg (21%). Mass Spectrum (APCI) m/z = 397 (M+H). 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 9.25 (br s, 1H), 8.59 (dd, J = 1.6 Hz, 6 Hz, 1H), 7.90 (dd, J = 1.6 Hz, 6 Hz, 1H) , 7.79 (d, J = 1.6 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.11 (dd, J = 4 Hz, 8 Hz, 1H), 4.05 (s) , 3H), 3.94 (d, J = 4 Hz, 1H), 3.91 (d, J = 4 Hz, 1H), 3.29 (td, J = 2 Hz, 11 Hz, 2H), 2.99 (d, J = 5) Hz, 3H), 2.46 (d, J = 7 Hz, 2H), 1.53 (d, J = 12 Hz, 2H), 1.40-1.20 (m, 3H).

實例1809Example 1809

1-(6'-乙氧基-5-(1-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-3,3'-聯吡啶-6-基)-3-甲基脲 1-(6'-ethoxy-5-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3,3' -bipyridyl-6-yl)-3-methylurea

步驟A：向5-溴-3-硝基-2-氰基吡啶(4.0 g，17.5 mmol)及1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-醇(WO2007103308)(4.70 g，18.4 mmol)於DMF(20 mL)中之溶液中依序添加水(3 mL)、K2CO3(3.64 g，26.3 mmol)，且在室溫下攪拌混合物隔夜。將混合物傾倒至水(200 mL)中且攪拌1小時，接著過濾，且用水洗滌固體並乾燥。在矽膠上(100%二氯甲烷)純化粗固體，得到5-溴-3-(1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-2-氰基吡啶。產量3.25 g(43%)。 Step A : to 5-bromo-3-nitro-2-cyanopyridine (4.0 g, 17.5 mmol) and 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b] Pyridin-4-ol (WO2007103308) (4.70 g, 18.4 mmol) in water (3 mL), K 2 CO 3 (3.64 g, 26.3 mmol) in DMF (20 mL) The mixture was stirred overnight. The mixture was poured into water (200 mL) and stirred for 1 hour then filtered and the solid was washed with water and dried. The crude solid was purified on silica gel (100% dichloromethane) to afford 5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-4- Alkoxy)-2-cyanopyridine. The yield was 3.25 g (43%).

步驟B：將5-溴-3-(1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-2-氰基吡啶(3.25 g，7.45 mmol)於TFA(10 ml)中之溶液在90℃下加熱隔夜。用二氯甲烷(50 mL)稀釋混合物且在減壓下濃縮。將殘餘物分配於EtOAc與飽和NaHCO3溶液之間且攪拌30分鐘。分離固體並藉由過濾收集，且依序用EtOAc、水洗滌。分離濾液，且用鹽水洗滌有機層，且經MgSO4乾燥並濃縮。用含5%甲醇之EtOAc濕磨固體殘餘物，得到3-(1H-吡唑并[3,4-b]吡啶-4-基氧基)-5-溴-2-氰基吡啶。產量1.75 g(74%)。 Step B : 5-Bromo-3-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-cyanopyridine ( 3.25 g, 7.45 mmol) of the solution in TFA (10 ml) was heated at 90 ° C overnight. The mixture was diluted with dichloromethane (50 mL) and concentrated. The residue was stirred for 30 min and partitioned between EtOAc and saturated NaHCO 3 solution. The solid was separated and collected by filtration and washed sequentially with EtOAcEtOAc. The filtrate was separated, and the organic layer was washed with brine, and dried over MgSO 4 and concentrated. The solid residue was triturated with EtOAc (EtOAc EtOAc) The yield was 1.75 g (74%).

步驟C：向3-(1H-吡唑并[3,4-b]吡啶-4-基氧基)-5-溴-2-氰基吡啶(500 mg，1.58 mmol)於無水DMF(6 mL)中之溶液中添加K2CO3(1.09 g，7.91 mmol)及1-溴-2-甲氧基乙烷(660 mg，4.75 mmol)，且在60℃下加熱混合物5小時。將經冷卻之混合物分配於水(15 mL)與EtOAc(30 mL)之間，且分離各層。用鹽水洗滌有機層，且經MgSO4乾燥並濃縮。在矽膠上(含50% EtOAc之己烷)純化殘餘物，得到5-溴-3-(1-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-2-氰基吡啶。產量357 mg(60%產率)。 Step C : To 3-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-5-bromo-2-cyanopyridine (500 mg, 1.58 mmol) in dry DMF (6 mL K 2 CO 3 (1.09 g, 7.91 mmol) and 1-bromo-2-methoxyethane (660 mg, 4.75 mmol) were added to the solution, and the mixture was heated at 60 ° C for 5 hr. The cooled mixture was partitioned between water (15 mL) and EtOAc (30 mL). The organic layer was washed with brine and dried MgSO 4 The residue was purified on EtOAc (EtOAc EtOAc EtOAc) 4-yloxy)-2-cyanopyridine. Yield 357 mg (60% yield).

步驟D：將5-溴-3-(1-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-2-氰基吡啶(168 mg，0.449 mmol)、6-乙氧基吡啶-3-基酸(150 mg，0.898 mmol)及CsF(177 mg，1.17 mmol)於i-PrOH(9 ml)中之混合物用N2脫氣10分鐘。添加三乙胺(0.100 ml，0.718 mmol)及PdCl2(dppf)．DCM(37 mg，0.045 mmol)，將容器密封且在100℃下加熱18小時。用EtOAc(20 mL)稀釋經冷卻之混合物，經矽藻土栓塞過濾且濃縮。藉由C18逆相層析(含15-80% MeCN之H2O)純化殘餘物，得到6'-乙氧基-5-(1-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-3,3'-聯吡啶-6-甲腈。產量134 mg(72%)。 Step D : 5-Bromo-3-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-cyanopyridine ( 168 mg, 0.449 mmol), 6-ethoxypyridin-3-yl Mixture (9 ml) of the acid (150 mg, 0.898 mmol) and CsF (177 mg, 1.17 mmol) in i -PrOH was degassed with N 2 for 10 min. Add triethylamine (0.100 ml, 0.718 mmol) and PdCl 2 (dppf). DCM (37 mg, 0.045 mmol), was sealed and heated at 100 ° C for 18 h. The cooled mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. By C18 reverse phase chromatography (15-80% MeCN containing the H 2 O) The residue was purified to give 6'-ethoxy-5- (l- (2-methoxyethyl) lH-pyrazole And [3,4-b]pyridin-4-yloxy)-3,3'-bipyridyl-6-carbonitrile. Yield 134 mg (72%).

步驟E：向在冰浴上冷卻之6'-乙氧基-5-(1-(2-甲氧基乙基)-1H-吡 唑并[3,4-b]吡啶-4-基氧基)-3,3'-聯吡啶-6-甲腈(134 mg，0.322 mmol)於DMSO(3 mL)中之溶液中添加K2CO3(45 mg，0.322 mmol)，繼而添加30% H2O2之水溶液(1.2 mL，3.22 mmol)。接著使混合物升溫至周圍溫度且攪拌48小時。用水(15 mL)稀釋反應混合物且攪拌20分鐘，接著過濾。用水洗滌固體且乾燥，得到6'-乙氧基-5-(1-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-3,3'-聯吡啶-6-甲醯胺。產量114 mg(82%)。 Step E : 6'-ethoxy-5-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy which was cooled on an ice bath Add K 2 CO 3 (45 mg, 0.322 mmol) to a solution of -3,3'-bipyridyl-6-carbonitrile (134 mg, 0.322 mmol) in DMSO (3 mL), followed by 30% H 2 O 2 in water (1.2 mL, 3.22 mmol). The mixture was then allowed to warm to ambient temperature and stirred for 48 hours. The reaction mixture was diluted with water (15 mL) and stirred for 20 min then filtered. The solid was washed with water and dried to give 6'-ethoxy-5-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)- 3,3'-bipyridyl-6-formamide. Yield 114 mg (82%).

步驟F：向6'-乙氧基-5-(1-(2-甲氧基乙基)-1H-吡唑并[3,4-b]吡啶-4-基氧基)-3,3'-聯吡啶-6-甲醯胺(110 mg，0.253 mmol)及40%甲胺之水溶液(0.109 mL，1.27 mmol)於MeCN：H2O(1：1，3 mL)中之溶液中添加[雙(三氟乙醯氧基)碘]苯(123 mg，0.279 mmol)，且在周圍溫度下攪拌混合物1小時。接著將混合物分配於飽和NaHCO3溶液(5 mL)與EtOAc(10 mL)之間。分離各層，且用鹽水洗滌有機相，接著經MgSO4乾燥並濃縮。在矽膠上(二氯甲烷，繼之以EtOAc)純化殘餘物，得到1-(5-溴-3-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)吡啶-2-基)-3-甲基脲。產量111 mg(93%)。質譜(APCI)m/z 464(M+H)。1H-NMR(400 MHz,CDCl3)δ ppm 9.19(br s,1H),8.42(d,J=5 Hz,1H),8.30(d,J=2 Hz,1H),8.28-8.26(m,1H),7.80(s,1H),7.65(dd,J=2.6 Hz,6 Hz,1H),7.52(d,J=2 Hz,1H),7.32(br,s,1H),6.79(dd,J=2 Hz,7.6 Hz,1H),6.55(d,J=5.4 Hz,1H),4.72(t,J=5.6 Hz,2H),4.38(q,J=7.2 Hz,2H),3.90(t,J=5.6 Hz,2H),3.34(s,3H),2.99(d,J=5 Hz,3H),1.40(t,J=7 Hz,3H)。 Step F : to 6'-ethoxy-5-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3,3 Add a solution of '-bipyridyl-6-formamide (110 mg, 0.253 mmol) and 40% methylamine (0.109 mL, 1.27 mmol) in MeCN:H 2 O (1:1,3 mL) [Bis(trifluoroacetoxy)iodo]benzene (123 mg, 0.279 mmol), and the mixture was stirred at ambient temperature for 1 hour. The mixture was then partitioned between (10 mL) saturated NaHCO 3 solution (5 mL) and EtOAc. The layers were separated, and the organic phase was washed with brine, then dried over MgSO 4 and concentrated. The residue was purified on EtOAc (EtOAc (EtOAcEtOAcEtOAc) Oxy)pyridin-2-yl)-3-methylurea. Yield 111 mg (93%). Mass Spectrum (APCI) m/z 464 (M+H). 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 9.19 (br s, 1H), 8.42 (d, J = 5 Hz, 1H), 8.30 (d, J = 2 Hz, 1H), 8.28-8.26 (m) , 1H), 7.80 (s, 1H), 7.65 (dd, J = 2.6 Hz, 6 Hz, 1H), 7.52 (d, J = 2 Hz, 1H), 7.32 (br, s, 1H), 6.79 (dd , J=2 Hz, 7.6 Hz, 1H), 6.55 (d, J=5.4 Hz, 1H), 4.72 (t, J=5.6 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 3.90 ( t, J = 5.6 Hz, 2H), 3.34 (s, 3H), 2.99 (d, J = 5 Hz, 3H), 1.40 (t, J = 7 Hz, 3H).

遵循實例1809中之程序，使用適當起始物質製備以下化合物： Following the procedure in Example 1809, the following compounds were prepared using the appropriate starting materials:

實例1811Example 1811

1-(5-溴-3-((3-環丙基-1-甲基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-bromo-3-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)oxy)pyridin-2-yl)-3-methylurea

步驟A：在室溫下，將5-溴-3-氟-2-氰基吡啶(1.0 g，4.98 mmol)及3-環丙基-1-甲基-1H-吡唑-5-醇(0.722 g，5.22 mmol)置於NMP(10 mL)中。添加K2CO3(1.38 g，9.95 mmol)，且在室溫下攪拌反應物2小時，接著傾倒至水中且用EtOAc萃取。乾燥(MgSO4)有機部分，過濾且濃縮，得到粗產物，在矽膠上(500：3-500：4 DCM：MeOH)純化該粗產物，得到5-溴-3-(3-環丙基-1-甲基-1H-吡唑-5-基氧基)-2-氰基吡啶(1.4 g，88.2%產率)。 Step A : 5-Bromo-3-fluoro-2-cyanopyridine (1.0 g, 4.98 mmol) and 3-cyclopropyl-1-methyl-1H-pyrazol-5-ol (at room temperature) 0.722 g, 5.22 mmol) was taken in NMP (10 mL). K 2 CO 3 (1.38 g, 9.95 mmol) was added and the~~~~~~~~ Dried (MgSO 4) organic portion was filtered and concentrated to give the crude product on silica gel (500: 3-500: 4 DCM: MeOH) The crude product was purified to give 5-bromo-3- (3-cyclopropyl - 1-Methyl-1H-pyrazol-5-yloxy)-2-cyanopyridine (1.4 g, 88.2% yield).

步驟B：將5-溴-3-(3-環丙基-1-甲基-1H-吡唑-5-基氧基)-2-氰基吡啶(1.9 g，5.95 mmol)冷卻至0℃，接著緩慢添加0℃濃鹽酸溶液(6.51 g，179 mmol)，且加熱反應物至50℃，維持12小時，接著冷卻至室溫。添加30% NaOH直至達到pH 10，接著用DCM萃取，濃縮且在矽膠上(500：10 DCM：MeOH)純化，得到5-溴-3-(3-環丙基-1-甲基-1H-吡 唑-5-基氧基)吡啶醯胺(1.6 g，79.7%產率)。 Step B : Cool 5-bromo-3-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yloxy)-2-cyanopyridine (1.9 g, 5.95 mmol) to 0 ° C Then, a 0 ° C concentrated hydrochloric acid solution (6.51 g, 179 mmol) was slowly added, and the reaction was heated to 50 ° C for 12 hours, then cooled to room temperature. Add 30% NaOH until pH 10 is reached, then extract with DCM, concentrate and purify on silica gel (500:10 DCM:MeOH) to give 5-bromo-3-(3-cyclopropyl-1-methyl-1H- Pyrazol-5-yloxy)pyridiniumamine (1.6 g, 79.7% yield).

步驟C：將5-溴-3-(3-環丙基-1-甲基-1H-吡唑-5-基氧基)吡啶醯胺(0.700 g，2.08 mmol)置於1：1 ACN：水(20 mL)中。接著添加40%甲胺水溶液(0.896 ml，10.4 mmol)，繼而添加雙[(三氟乙醯氧基)碘]苯(0.937 g，2.18 mmol)。在室溫下攪拌反應物2小時，傾倒至飽和碳酸氫鈉中且用EtOAc萃取。乾燥(MgSO4)有機部分，過濾，濃縮且在矽膠上(500：5 DCM：MeOH)純化，得到1-(5-溴-3-(3-環丙基-1-甲基-1H-吡唑-5-基氧基)吡啶-2-基)-3-甲基脲(0.50 g，65.8%)。1H NMR(400 MHz,CDCl3)δ ppm 8.88(s,1H),8.02-8.01(m,1H),7.33(s,1H),7.29-7.27(m,1H),5.45-5.43(m,1H),3.64-3.62(s,3H),2.99-2.96(m,3H),1.90-1.81(m,1H),0.94-0.89(m,2H),0.74-0.70(m,2H)。質譜(apci)m/z=366.0(M+H)。 Step C : 5-Bromo-3-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yloxy)pyridiniumamine (0.700 g, 2.08 mmol) was taken in 1:1 ACN: In water (20 mL). A 40% aqueous solution of methylamine (0.896 ml, 10.4 mmol) was then added followed by bis[(trifluoroethyloxy)iodo]benzene (0.937 g, 2.18 mmol). The reaction was stirred at rt EtOAc (EtOAc) Dried (MgSO 4) organic moiety, filtered, and concentrated on silica gel (500: 5 DCM: MeOH) to give l- (5-bromo-3- (3-cyclopropyl-l-methyl -1H- pyrazol Zyrid-5-yloxy)pyridin-2-yl)-3-methylurea (0.50 g, 65.8%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.88 (s, 1H), 8.02-8.01 (m, 1H), 7.33 (s, 1H), 7.29-7.27 (m, 1H), 5.45-5.43 (m, 1H), 3.64-3.62 (s, 3H), 2.99-2.96 (m, 3H), 1.90-1.81 (m, 1H), 0.94-0.89 (m, 2H), 0.74-0.70 (m, 2H). Mass spectrum (apci) m/z = 366.0 (M+H).

遵循實例1811中之程序，亦合成以下化合物： Following the procedure in Example 1811, the following compounds were also synthesized:

實例1813Example 1813

1-(3-((1-異丙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1-isopropyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl -3-methylurea

步驟A：將5-溴-3-氟-2-氰基吡啶(0.5 g，2.49 mmol)及1-異丙基-1H-吡唑-5-醇(0.330 g，2.61 mmol)及微粉化K2CO3(0.688 g，4.98 mmol)置於NMP(6mL)中，且在室溫下攪拌2小時。傾倒至水中，且用DCM萃取。乾燥(MgSO4)經合併之有機部分，過濾且濃縮，得到粗產物，在矽膠上(500：3 DCM：MeOH)純化該粗產物，得到5-溴-3-(1-異丙基-1H-吡唑-5-基氧基)-2-氰基吡啶(0.66 g，86.4%產率)。 Step A : 5-Bromo-3-fluoro-2-cyanopyridine (0.5 g, 2.49 mmol) and 1-isopropyl-1H-pyrazol-5-ol (0.330 g, 2.61 mmol) and micronized K 2 CO 3 (0.688 g, 4.98 mmol) was taken in NMP (6 mL) and stirred at room temperature for 2 hr. Pour into water and extract with DCM. Dried (MgSO 4) the organic fractions were combined, filtered and concentrated to give the crude product on silica gel (500: 3 DCM: MeOH) The crude product was purified to give 5-bromo-3- (l-isopropyl--1H -pyrazol-5-yloxy)-2-cyanopyridine (0.66 g, 86.4% yield).

步驟B：在室溫下，將5-溴-3-(1-異丙基-1H-吡唑-5-基氧基)-2-氰基吡啶(0.66 g，2.1 mmol)置於MeOH中。接著添加含KOH(0.36 g，6.4 mmol)之3 mL水，繼而逐滴添加30% H2O2(0.097 g，0.86 mmol)。接著加熱反應物至65℃，維持3小時，冷卻至室溫，濃縮，且用EtOAc萃取，用水洗滌並濃縮。在矽膠上(500：5-500：8-500：10 DCM：MeOH)純化殘餘物，得到5-溴-3-(1-異丙基-1H-吡唑-5-基氧基)吡啶醯胺(0.25 g，36%產率)。 Step B : 5-Bromo-3-(1-isopropyl-1H-pyrazol-5-yloxy)-2-cyanopyridine (0.66 g, 2.1 mmol) was taken in MeOH. . Containing 3 mL of water was added followed by KOH (0.36 g, 6.4 mmol), the subsequently added dropwise 30% H 2 O 2 (0.097 g, 0.86 mmol). The reaction was then heated to 65.degree. C. for 3 h, cooled to EtOAc. The residue was purified on silica gel (500:5-500:8-500:10 DCM:MeOH) to afford 5-bromo-3-(1-isopropyl-1H-pyrazol-5-yloxy)pyridinium Amine (0.25 g, 36% yield).

步驟C：將5-溴-3-(1-異丙基-1H-吡唑-5-基氧基)吡啶醯胺(0.250 g，0.769 mmol)置於密封管中之THF(3 mL)中且使N2鼓泡通過。添加Pd(OAc)2(0.00863 g，0.0384 mmol)及二環己基(2',6'-二甲氧基聯苯-2-基)膦(0.0316 g，0.0769 mmol)，繼而添加溴化((四氫-2H-哌喃-4-基)甲基)鋅(II)(3.66 ml，2.31 mmol)，且加熱反應物至70℃，維持2小時，冷卻至室溫，且傾倒至飽和NH4Cl中，且用DCM萃取。乾燥(MgSO4)有機部分，過濾且濃縮，得到粗產物，在矽膠上(500：10-500：20 DCM：MeOH)純化該粗產物，得到3-(1-異丙基-1H-吡唑-5-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶醯胺(0.200 g，75.5%產率)。 Step C : 5-Bromo-3-(1-isopropyl-1H-pyrazol-5-yloxy)pyridiniumamine (0.250 g, 0.769 mmol) was placed in THF (3 mL) And N 2 was bubbled through. Add Pd(OAc) 2 (0.00863 g, 0.0384 mmol) and dicyclohexyl (2',6'-dimethoxybiphenyl-2-yl)phosphine (0.0316 g, 0.0769 mmol) followed by bromination (( -2H- tetrahydro-pyran-4-yl) methyl) zinc (II) (3.66 ml, 2.31 mmol), and the reaction was heated to 70 ℃, for 2 hours, cooled to room temperature and poured into saturated NH 4 Cl, and extracted with DCM. Dried (MgSO 4) organic portion was filtered and concentrated to give the crude product on silica gel (500: 10-500: 20 DCM: MeOH) The crude product was purified to give 3- (1-isopropyl--1H- pyrazole 5-5-yloxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridiniumamine (0.200 g, 75.5% yield).

步驟D：將3-(1-異丙基-1H-吡唑-5-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶醯胺(0.200 g，0.581 mmol)置於1：1 ACN：水(6mL)中。接著添加甲胺(0.250 ml，2.90 mmol)，繼而添加雙[(三氟乙醯氧基)碘]苯(0.262 g，0.610 mmol)。在室溫下攪拌反應物2小時，傾倒至飽和 碳酸氫鈉中，且用EtOAc萃取。乾燥(MgSO4)有機部分，過濾且濃縮，得到粗產物，在矽膠上(500：5 DCM：MeOH)純化該粗產物，得到1-(3-(1-異丙基-1H-吡唑-5-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲(0.040 g，18.4%產率)。1H NMR(400 MHz,CDCl3)δ ppm 7.89(d,1H J=2Hz),7.46(d,1H,J=2H),7.18(d,1H,J=2H),5.75(d,1H,J=2Hz),4.60(七重峰，1H,J=7Hz),3.91-3.87(m,2H),3.36-3.30(m,2H),2.91(s,3H),2.50(d,2H,J=7Hz),1.73-1.66(m,1H),1.53-1.49(m,2H),1.44(d,6H,J=7Hz),1.32-1.21(m,2H)。質譜(apci)m/z=373.9(M+H)。 Step D : 3-(1-Isopropyl-1H-pyrazol-5-yloxy)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridiniumamine (0.200 g , 0.581 mmol) in 1:1 ACN: water (6 mL). Methylamine (0.250 ml, 2.90 mmol) was then added followed by bis[(trifluoroethyloxy)iodo]benzene (0.262 g, 0.610 mmol). The reaction was stirred at rt EtOAc (EtOAc) Dried (MgSO 4) organic portion was filtered and concentrated to give the crude product on silica gel (500: 5 DCM: MeOH) The crude product was purified to give 1- (3- (1-isopropyl--1H- pyrazol - 5-yloxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)-3-methylurea (0.040 g, 18.4% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.89 (d, 1H J = 2 Hz), 7.46 (d, 1H, J = 2H), 7.18 (d, 1H, J = 2H), 5.75 (d, 1H, J = 2 Hz), 4.60 (seven peaks, 1H, J = 7 Hz), 3.91-3.87 (m, 2H), 3.36-3.30 (m, 2H), 2.91 (s, 3H), 2.50 (d, 2H, J = 7 Hz), 1.73-1.66 (m, 1H), 1.53-1.49 (m, 2H), 1.44 (d, 6H, J = 7 Hz), 1.32-1.21 (m, 2H). Mass spectrum (apci) m/z = 373.9 (M+H).

遵循實例1813中之程序，亦合成以下化合物： Following the procedure in Example 1813, the following compounds were also synthesized:

遵循實例449中之程序，亦合成以下化合物： Following the procedure in Example 449, the following compounds were also synthesized:

遵循實例316中之程序，亦合成以下化合物： Following the procedure in Example 316, the following compounds were also synthesized:

實例1822 1-甲基-3-(5-((四氫-2H-哌喃-4-基)硫基)-3-((2-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)脲 Example 1822 1-Methyl-3-(5-((tetrahydro-2H-piperidin-4-yl)thio)-3-((2-(trifluoromethyl)pyridin-3-yl)oxy) Pyridin-2-yl)urea

步驟A：在氮氣氛圍下將2-(三氟甲基)吡啶-3-基酸(5.00 g，26.19 mmol)溶解於DCM(100 mL)中，且在室溫下添加30% H2O2(11.25 ml，130.9 mmol)並攪拌隔夜。過濾固體且乾燥，得到2-(三氟甲基)吡啶-3-醇(4.112 g，96.3%產率)。 Step A : 2-(Trifluoromethyl)pyridin-3-yl under nitrogen atmosphere Acid (5.00 g, 26.19 mmol) was dissolved in DCM (100 mL), was added at room temperature and 30% H 2 O 2 (11.25 ml, 130.9 mmol) and stirred overnight. The solid was filtered and dried to give 2-(trifluoromethyl)pyridin-3-ol (4.112 g, 96.3% yield).

步驟B：將5-溴-3-氟-2-氰基吡啶(740 mg，3.682 mmol)、2-(三氟甲基)吡啶-3-醇(600.5 mg，3.682 mmol)及K2CO3(1018 mg，7.363 mmol)置於NMP(10 mL)中，且在室溫下攪拌3小時。添加水，且過濾固體並用水洗滌，得到5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)-2-氰基吡啶(1.107 g，87.4%產率)。 Step B : 5-Bromo-3-fluoro-2-cyanopyridine (740 mg, 3.682 mmol), 2-(trifluoromethyl)pyridin-3-ol (600.5 mg, 3.682 mmol) and K 2 CO 3 (1018 mg, 7.363 mmol) was taken in NMP (10 mL) and stirred at room temperature for 3 hr. Water was added, and the solid was filtered and washed with water to give 5-bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)-2-cyanopyridine (1.107 g, 87.4% yield).

步驟C：將5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)-2-氰基吡啶(193 mg，0.561 mmol)及四氫-2H-哌喃-4-硫醇(133 mg，1.12 mmol)置於DMF(5 mL)中且冷卻至0℃。緩慢添加60% NaH(27.6 mg，1.15 mmol)且升溫至室溫。攪拌反應物2小時，接著傾倒於50 mL水上，且用EtOAc(2×50 mL)萃取混合物。乾燥有機層，過濾，濃縮且藉由逆相層析(C18，含5-90% ACN之水)純化，得到5-(四氫-2H-哌喃-4-基硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)-2-氰基吡啶(171 mg，0.448 mmol，79.9%產率)。 Step C : 5-Bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)-2-cyanopyridine (193 mg, 0.561 mmol) and tetrahydro-2H-pyran-4 - Mercaptan (133 mg, 1.12 mmol) was taken in DMF (5 mL) and cooled to 0. 60% NaH (27.6 mg, 1.15 mmol) was added slowly and allowed to warm to room temperature. The reaction was stirred for 2 h then poured over 50 mL water and EtOAc (2 &lt The organic layer was dried, filtered, concentrated and purified by reverse phase chromatography (cjjjjjjjjjj 2-(Trifluoromethyl)pyridin-3-yloxy)-2-cyanopyridine (171 mg, 0.448 mmol, 79.9% yield).

步驟D：在室溫下，將5-(四氫-2H-哌喃-4-基硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)-2-氰基吡啶(171 mg，0.448 mmol)置於濃鹽酸(2 mL)中且攪拌18小時。 Step D : 5-(tetrahydro-2H-piperidin-4-ylthio)-3-(2-(trifluoromethyl)pyridin-3-yloxy)-2-cyanide at room temperature The pyridine (171 mg, 0.448 mmol) was taken in concentrated hydrochloric acid (2 mL) and stirred for 18 h.

逐滴添加6 N NaOH以使pH值達到7-8。用DCM萃取混合物。濃縮有機層且在矽膠上(EtOAc)純化所得殘餘物，得到5-(四氫-2H-哌喃-4-基硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶醯胺(90 mg，0.225 mmol，50.3%產率)。 6 N NaOH was added dropwise to bring the pH to 7-8. The mixture was extracted with DCM. The organic layer was concentrated and purified EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjj Oxy)pyridiniumamine (90 mg, 0.225 mmol, 50.3% yield).

步驟E：將5-(四氫-2H-哌喃-4-基硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶醯胺(35 mg，0.0876 mmol)置於1：1 ACN：水(5 mL)中。接著添加40%甲胺水溶液(37.8 μl，0.438 mmol)，繼而添加雙[(三氟乙醯氧基)碘]苯(39.6 mg，0.0920 mmol)。在室溫下攪拌反應物2小時，傾倒至飽和碳酸氫鈉中，且用EtOAc萃取。分離有機層，經硫酸鈉乾燥，過濾，濃縮且藉由逆相層析(C18，含5-65% ACN之水)純化，得到1-甲基-3-(5-(四氫-2H-哌喃-4-基硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)脲(26.3 mg，70.0%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.04(m,1H),8.60(m,1H),8.09(m,1H),7.57(m,1H),7.38(m,2H),7.05(m,1H),3.94(m,2H),3.36(m,2H),3.00(m,4H),1.80(m,2H),1.59(m,2H)。質譜(apci)m/z=428.7(M+H)。 Step E : 5-(Tetrahydro-2H-piperidin-4-ylthio)-3-(2-(trifluoromethyl)pyridin-3-yloxy)pyridiniumamine (35 mg, 0.0876 mmol) ) placed in 1:1 ACN: water (5 mL). A 40% aqueous solution of methylamine (37.8 μl, 0.438 mmol) was then added followed by bis[(trifluoroethyloxy)iodo]benzene (39.6 mg, 0.0920 mmol). The reaction was stirred at rt EtOAc (EtOAc) The organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified with EtOAc EtOAc Piperazin-4-ylthio)-3-(2-(trifluoromethyl)pyridin-3-yloxy)pyridin-2-yl)urea (26.3 mg, 70.0% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.04 (m, 1H), 8.60 (m, 1H), 8.09 (m, 1H), 7.57 (m, 1H), 7.38 (m, 2H), 7.05 (m) , 1H), 3.94 (m, 2H), 3.36 (m, 2H), 3.00 (m, 4H), 1.80 (m, 2H), 1.59 (m, 2H). Mass spectrum (apci) m/z = 428.7 (M+H).

實例1823Example 1823

1-甲基-3-(5-(吡啶-2-基硫基)-3-((2-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)脲 1-methyl-3-(5-(pyridin-2-ylthio)-3-((2-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)urea

根據實例1822步驟C-E製備，5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)-2-氰基吡啶(0.607 g，1.76 mmol)及吡啶-2(1H)-硫酮(0.304 g，2.73 mmol)及NaH(0.0656 g，2.73 mmol)得到1-甲基-3-(5-(吡啶-2-基硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)脲(205 mg，65.4%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 8.90(m,2H),8.49(m,1H),8.36(m,1H),8.25(d,J=2.0 Hz,1H),7.75-7.61(m,4H),7.15(dd,J=4.9,0.8 Hz,1H),7.09(m,1H),2.80(d,J=4.7 Hz,3H)。質譜(apci)m/z=422.1(M+H)。 5-Bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)-2-cyanopyridine (0.607 g, 1.76 mmol) and pyridine-2 (1H). -thione (0.304 g, 2.73 mmol) and NaH (0.0656 g, 2.73 mmol) afford 1-methyl-3-(5-(pyridin-2-ylthio)-3-(2-(trifluoromethyl) Pyridin-3-yloxy)pyridin-2-yl)urea (205 mg, 65.4% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 8.90 (m, 2H), 8.49 (m, 1H), 8.36 (m, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.75-7.61 (m, 4H), 7.15 (dd, J = 4.9, 0.8 Hz, 1H), 7.09 (m, 1H), 2.80 (d, J = 4.7 Hz, 3H). Mass spectrum (apci) m/z = 422.1 (M + H).

實例1824Example 1824

1-(5-((3-羥基-3-甲基丁基)硫基)-3-((2-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲 1-(5-((3-Hydroxy-3-methylbutyl)thio)-3-((2-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)- 3-methylurea

步驟A：在室溫下，將5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)-2-氰基吡啶(1.462 g，4.249 mmol)置於濃鹽酸(2 mL)中且攪拌48小時。添加6 N NaOH以使pH值達到7-8。過濾固體且用水洗滌，接著乾燥，得到5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶醯胺(1.406 g，3.883 mmol，91.4%產率)。 Step A : 5-Bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)-2-cyanopyridine (1.462 g, 4.249 mmol) was taken in concentrated hydrochloric acid 2 mL) and stirred for 48 hours. 6 N NaOH was added to bring the pH to 7-8. The solid was filtered and washed with water then dried to give &lt;RTIgt;5-bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)pyridinamine (1.406 g, 3.83 mmol, 91.4% yield).

步驟B：根據實例1822步驟E製備1-(5-溴-3-((2-(三氟甲基)吡啶-3-基)氧基)吡啶-2-基)-3-甲基脲。5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶醯胺(1.406 g，3.883 mmol)、40%甲胺水溶液(1.675 ml，19.41 mmol)及雙[(三氟乙醯氧基)碘]苯(1.753 g，4.077 mmol)得到1-(5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(1.120 g，73.7%產率)。 Step B : 1-(5-Bromo-3-((2-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-3-methylurea was prepared according to Step 18 of Example 1822. 5-bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)pyridiniumamine (1.406 g, 3.883 mmol), 40% aqueous methylamine solution (1.675 ml, 19.41 mmol) and bis[( Trifluoroacetoxy)iodo]benzene (1.753 g, 4.077 mmol) gave 1-(5-bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)pyridin-2-yl) 3-methylurea (1.120 g, 73.7% yield).

步驟C：將1-(5-溴-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)-3- 甲基脲(744 mg，1.902 mmol)、3-巰基丙酸甲酯(309.2 μl，2.853 mmol)、Xantphos(110.1 mg，0.1902 mmol)、DIEA(662.6 μl，3.804 mmol)於二噁烷中脫氣5分鐘。添加Pd2dba3(87.09 mg，0.09511 mmol)，再脫氣5分鐘，且在80℃下加熱18小時。冷卻反應物且添加水。用EtOAc(2×50 mL)萃取混合物，接著乾燥，過濾且濃縮，得到粗3-(6-(3-甲基脲基)-5-(2-(三氟甲基)吡啶-3-基氧基)吡啶-3-基硫基)丙酸甲酯，其按原樣使用。 Step C : 1-(5-Bromo-3-(2-(trifluoromethyl)pyridin-3-yloxy)pyridin-2-yl)-3-methylurea (744 mg, 1.902 mmol), Methyl 3-mercaptopropionate (309.2 μl, 2.853 mmol), Xantphos (110.1 mg, 0.1902 mmol), DIEA (662.6 μl, 3.804 mmol) was degassed in dioxane for 5 min. Pd 2 dba 3 (87.09 mg, 0.09511 mmol) was added, degassed for a further 5 minutes, and heated at 80 ° C for 18 hours. The reaction was cooled and water was added. The mixture was extracted with EtOAc (2×50 mL) then dried, filtered and concentrated to give crude 3-(6-(3-methylureido)-5-(2-(trifluoromethyl)pyridin-3-yl Methyl oxy)pyridin-3-ylthio)propionate, which was used as it is.

步驟D：將3-(6-(3-甲基脲基)-5-(2-(三氟甲基)吡啶-3-基氧基)吡啶-3-基硫基)丙酸甲酯(225 mg，0.523 mmol)置於THF(5 mL)中且冷卻至-78℃。添加溴化甲基鎂(1867 μl，2.61 mmol)，且在室溫下攪拌反應物3小時。添加含10% DCM之MeOH，且過濾固體。濃縮濾液且在矽膠上(100% EtOAc)純化所得殘餘物，得到1-(5-3-羥基-3-甲基丁硫基)-3-(2-(三氟甲基)吡啶-3-基氧基)吡啶-2-基)-3-甲基脲(43 mg，0.0999 mmol，19.1%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.02(m,1H),8.58(d,J=4.5 Hz,1H),8.04(d,J=1.8 Hz,1H),8.55(dd,J=8.8,4.5 Hz,1H),7.35(m,2H),7.03(d,J=1.8 Hz,1H),2.99(d,J=4.5 Hz,3H),2.87(m,2H),1.69(m,2H),1.20(s,6H)。質譜(apci)m/z=430.8(M+H)。 Step D : methyl 3-(6-(3-methylureido)-5-(2-(trifluoromethyl)pyridin-3-yloxy)pyridin-3-ylthio)propanoate ( 225 mg, 0.523 mmol) was taken in THF (5 mL) and cooled to -78. Methylmagnesium bromide (1867 μl, 2.61 mmol) was added and the reaction was stirred at room temperature for 3 h. MeOH containing 10% DCM was added and the solid was filtered. The filtrate was concentrated and the residue obtained was purified eluted eluted elut elut elut Alkoxy)pyridin-2-yl)-3-methylurea (43 mg, 0.0999 mmol, 19.1% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.02 (m, 1H), 8.58 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 8.55 (dd, J = 8.8 , 4.5 Hz, 1H), 7.35 (m, 2H), 7.03 (d, J = 1.8 Hz, 1H), 2.99 (d, J = 4.5 Hz, 3H), 2.87 (m, 2H), 1.69 (m, 2H) ), 1.20 (s, 6H). Mass spectrum (apci) m/z = 430.8 (M+H).

實例1825Example 1825

1-(3-((5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)oxy)-5-((tetrahydro-2H-pyran)- 4-yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：在壓力容器中，將2-氯-5-氟菸鹼酸(3.50 g，19.94 mmol)、K2CO3(4.133 g，29.91 mmol)、甲肼(6.681 ml，127.6 mmol)及氧化銅(II)(0.03172 g，0.3988 mmol)置於苯中。使反應物脫氣10分鐘，密封，且加熱至110℃，維持18小時。冷卻反應物至室溫。添加水及EtOAc。分離水層，且用1 M HCl使pH值達到約5-6。過濾固體且用水洗滌，乾燥後得到5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-醇(1.074 g，6.426 mmol，32.2%產率)。 Step A : 2-Chloro-5-fluoronicotinic acid (3.50 g, 19.94 mmol), K 2 CO 3 (4.133 g, 29.91 mmol), formazan (6.681 ml, 127.6 mmol) and oxidized in a pressure vessel Copper (II) (0.03172 g, 0.3988 mmol) was placed in benzene. The reaction was degassed for 10 minutes, sealed and heated to 110 ° C for 18 hours. The reaction was cooled to room temperature. Water and EtOAc were added. The aqueous layer was separated and the pH was brought to about 5-6 with 1 M HCl. The solid was filtered and washed with water and dried to give &lt;RTI ID=0.0&gt;&gt;&gt;

步驟B：根據實例1822步驟B製備5-溴-3-(5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-2-氰基吡啶，5-溴-3-氟-2-氰基吡啶(.550 g，2.74 mmol)、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-醇(0.480 g，2.87 mmol)及K2CO3(0.756 g，5.47 mmol)得到(887 mg，93.1%產率)。 Step B : Preparation of 5-bromo-3-(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)-2-cyano group according to Example 1822 Step B Pyridine, 5-bromo-3-fluoro-2-cyanopyridine (.550 g, 2.74 mmol), 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-ol (0.480 g, 2.87 mmol) and K 2 CO 3 (0.756 g, 5.47 mmol) afforded (887 mg, 93.1% yield).

步驟C：將5-溴-3-(5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-2-氰基吡啶(450 mg，1.29 mmol)置於DMSO(2 mL)中且冷卻至0℃。添加K2CO3(35.7 mg，0.259 mmol)及30% H2O2水溶液(2.0 ml，1.29 mmol)。在室溫下攪拌反應物24小時。再添加DMSO(5 mL)，且再添加1當量K2CO3(176 mg，1.29 mmol)。攪拌反應物4小時。添加水，且過濾固體，用水洗滌並乾燥，得到5-溴-3-(5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)吡啶醯胺(411 mg，1.12 mmol，86.8%產率)。 Step C : 5-Bromo-3-(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)-2-cyanopyridine (450 mg, 1.29 mmol) was placed in DMSO (2 mL) and cooled to 0 °C. K 2 CO 3 (35.7 mg, 0.259 mmol) and 30% aqueous H 2 O 2 (2.0 mL, 1.29 mmol). The reaction was stirred at room temperature for 24 hours. Additional DMSO (5 mL) was added and 1 equivalent of K 2 CO 3 (176 mg, 1.29 mmol) was then added. The reaction was stirred for 4 hours. Water was added and the solid was filtered, washed with water and dried to give 5-bromo-3-(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)pyridine Guanidine (411 mg, 1.12 mmol, 86.8% yield).

步驟D：根據實例1822步驟E製備1-(3-(5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲，3-(5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶醯胺(158 mg，0.410 mmol)、40%甲胺水溶液(177 μl，2.05 mmol)及雙[(三氟乙醯氧基)碘]苯(185 mg，0.430 mmol)得到(42 mg，24.7%產率)。1H NMR(400 MHz,d6-DMSO)δ ppm 9.02(m,1H),8.67(m,2H),8.08(dd,J=8.4,2.7 Hz,1H),7.90(m,1H),7.57(m,1H),3.92(s,3H),3.79(m,3H),3.20(t,J=10.4 Hz,2H),2.78(d,J=4.7 Hz,3H),2.45(d,J=7.0 Hz,2H),1.65(m,1H),1.45(m,2H),1.16(m,2H)。質譜(apci)m/z=415.2(M+H)。 Step D : Preparation of 1-(3-(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yloxy)-5-(4 Hydrogen-2H-piperazin-4-yl)methyl)pyridin-2-yl)-3-methylurea, 3-(5-fluoro-1-methyl-1H-pyrazolo[3,4-b Pyridin-3-yloxy)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyridiniumamine (158 mg, 0.410 mmol), 40% aqueous methylamine solution (177 μl, 2.05 Methyl) and bis[(trifluoroacetoxy)iodo]benzene (185 mg, 0.430 mmol) afforded (42 mg, 24.7% yield). 1 H NMR (400 MHz, d 6 -DMSO) δ ppm 9.02 (m, 1H), 8.67 (m, 2H), 8.08 (dd, J = 8.4, 2.7 Hz, 1H), 7.90 (m, 1H), 7.57 (m, 1H), 3.92 (s, 3H), 3.79 (m, 3H), 3.20 (t, J = 10.4 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H), 2.45 (d, J = 7.0 Hz, 2H), 1.65 (m, 1H), 1.45 (m, 2H), 1.16 (m, 2H). Mass spectrum (apci) m/z = 415.2 (M+H).

實例1826Example 1826

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((2R,4R)-2-(羥基甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((2R,4R)-2-(hydroxymethyl)tetrahydro-2H-pyran- 4-yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：將2-側氧基乙酸乙酯(7.089 ml，34.82 mmol)及(E)-(4-甲氧基丁-1,3-二烯-2-基氧基)三甲基矽烷(6.00 g，34.82 mmol)於甲苯(50 ml)中之溶液置於氮氣下。添加氯化鋅(II)(34.82 ml，17.41 mmol)，且在周圍溫度下攪拌反應物18小時。在真空中濃縮混合物，用乙酸乙酯(100 ml)稀釋，且用1 N鹽酸(20 ml)、飽和碳酸氫鈉(20 ml)及鹽水(20 ml)洗滌。乾燥(Na2SO4)有機層，過濾，且在真空中蒸發溶劑。藉由矽膠層析，使用乙酸乙酯/己烷混合物(30-50%)作為溶離劑純化殘餘物，得到4-側氧基-3,4-二氫-2H-哌喃-2-甲酸乙酯(1.687 g，7.931 mmol，22.8%產率)。 Step A : 2-ethyl oxyacetate (7.089 ml, 34.82 mmol) and (E)-(4-methoxybutyl-1,3-dien-2-yloxy)trimethylnonane ( A solution of 6.00 g, 34.82 mmol) in toluene (50 ml) was placed under nitrogen. Zinc(II) chloride (34.82 ml, 17.41 mmol) was added and the reaction was stirred at ambient temperature for 18 h. The mixture was concentrated in EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was dried (Na 2 SO 4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate / hexanes mixture (30-50%) as eluting solvent to afford 4- </RTI><RTIgt; Ester (1.687 g, 7.931 mmol, 22.8% yield).

步驟B：將4-側氧基-3,4-二氫-2H-哌喃-2-甲酸乙酯(10.0 g，58.77 mmol)及10% Pd/C(3.127 g，2.938 mmol)溶解於EtOH(50 mL)中，且置於氫氣球壓力下18小時。經矽藻土過濾反應物且濃縮濾液。藉由矽膠(含30-40% EtOAc之己烷)純化所得殘餘物，得到4-側氧基四氫-2H-哌喃-2-甲酸乙酯(2.358 g，13.70 mmol，23.3%產率)。 Step B : Ethyl 4-oxo-3,4-dihydro-2H-pentan-2-carboxylate (10.0 g, 58.77 mmol) and 10% Pd/C (3.127 g, 2.938 mmol) were dissolved in EtOH (50 mL) and placed under hydrogen balloon pressure for 18 hours. The reaction was filtered through celite and concentrated. The residue was purified by EtOAc (EtOAc EtOAc) .

步驟C：將溴化甲基三苯基鏻(5.248 g，14.69 mmol)置於THF(2 mL)中。添加KHMDS(14.69 ml，14.69 mmol)，且在室溫下攪拌30分鐘。冷卻溶液至0℃。添加4-側氧基四氫-2H-哌喃-2-甲酸乙酯(2.108 g，12.24 mmol)於THF(20 mL)中之溶液，且在室溫下攪拌反應物1小時。添加水，且用乙醚萃取混合物兩次。接著乾燥萃取物，過濾且濃縮。使物質溶於1：1戊烷：乙醚(100 mL)中。濾除固體且濃縮濾液，得到粗4-亞甲基四氫-2H-哌喃-2-甲酸乙酯，其按原樣用於下一步驟中。 Step C : Methyltriphenylphosphonium bromide (5.248 g, 14.69 mmol) was taken in THF (2 mL). KHMDS (14.69 ml, 14.69 mmol) was added and stirred at room temperature for 30 min. The solution was cooled to 0 °C. A solution of 4-sided oxytetrahydro-2H-pentan-2-carboxylic acid ethyl ester (2.108 g, 12.24 mmol) in THF (20 mL). Water was added and the mixture was extracted twice with diethyl ether. The extract was then dried, filtered and concentrated. The material was dissolved in 1:1 pentane: diethyl ether (100 mL). The solid was filtered off and the filtrate was concentrated to give crude ethyl <RTI ID=0.0>#</RTI><RTIgt;

步驟D：將粗4-亞甲基四氫-2H-哌喃-2-甲酸乙酯(2.17 g，12.7 mmol)置於乙醚(10 mL)中。添加LAH(19.1 ml，19.1 mmol)，且攪拌反應物15分鐘。冷卻反應物，且緩慢添加水。用DCM(2×50 mL)萃取反應物。乾燥有機層，過濾且濃縮。在矽膠上(含40% EtOAc之己烷)純化所得殘餘物，得到(4-亞甲基四氫-2H-哌喃-2-基)甲醇(0.800 g，6.24 mmol，49.0%產率)。 Step D : Crude ethyl 4-methylenetetrahydro-2H-pyran-2-carboxylate (2.17 g, 12.7 mmol) was taken in diethyl ether (10 mL). LAH (19.1 ml, 19.1 mmol) was added and the reaction was stirred 15 min. The reaction was cooled and water was added slowly. The reaction was extracted with DCM (2×50 mL). The organic layer was dried, filtered and concentrated. The residue was purified on EtOAc (EtOAc EtOAc)

步驟E：將(4-亞甲基四氫-2H-哌喃-2-基)甲醇(800 mg，6.242 mmol)置於DMF(10 mL)中，繼而逐滴添加含咪唑(509.9 mg，7.490 mmol)及TBDMS-Cl(987.8 mg，6.554 mmol)之DMF(5 mL)。攪拌反應物24小時。添加乙醚，且濾除固體。接著用水及鹽水洗滌乙醚，接著乾燥，過濾且濃縮。在矽膠上(含10% EtOAc之己烷)純化所得殘餘物，得到第三丁基二甲基((4-亞甲基四氫-2H-哌喃-2-基)甲氧基)矽烷(1.292 g，5.329 mmol，85.4%產率)。 Step E : (4-Methylenetetrahydro-2H-piperidin-2-yl)methanol (800 mg, 6.422 mmol) was taken in DMF (10 mL) Methyl) and TBDMS-Cl (987.8 mg, 6.554 mmol) in DMF (5 mL). The reaction was stirred for 24 hours. Ether was added and the solid was filtered off. The ether was then washed with water and brine, then dried, filtered and concentrated. The resulting residue was purified on EtOAc (EtOAc EtOAc EtOAc) 1.292 g, 5.329 mmol, 85.4% yield).

步驟F：將第三丁基二甲基((4-亞甲基四氫-2H-哌喃-2-基)甲氧基)矽烷(909.8 mg，3.753 mmol)及9-BBN(13646 μl，6.823 mmol)溶解於THF(1 mL)中，加熱至至回流，維持3小時。冷卻反應物，且添加0.5 ml水。將此溶液添加至含有5-溴-3-(1-乙基-1H-吡唑-5-基氧基)-2-氰基吡啶(1000 mg，3.412 mmol)、K2CO3(1414 mg，10.23 mmol)及PdCl2(dppf)*DCM(278.6 mg，0.3412 mmol)於經脫氣DMF(10 mL)及水(1.0 mL)中之燒瓶中。將混合物脫氣10分鐘，接著加熱至80℃，維持5小時。冷卻反應物，且添加水。用EtOAc(50 mL×2)萃取混合物。乾燥有機層，過濾且濃縮。在矽膠上(含30-40% EtOAc之己烷)純化所 得殘餘物，得到5-((2-((第三丁基二甲基矽烷氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-(1-乙基-1H-吡唑-5-基氧基)-2-氰基吡啶(1.144 g，2.505 mmol，73.43%產率)。 Step F : tert-butyldimethyl((4-methylenetetrahydro-2H-piperidin-2-yl)methoxy)decane (909.8 mg, 3.753 mmol) and 9-BBN (13646 μl, 6.823 mmol) was dissolved in THF (1 mL) and heated to reflux for 3 h. The reaction was cooled and 0.5 ml water was added. This solution was added to 5-bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)-2-cyanopyridine (1000 mg, 3.412 mmol), K 2 CO 3 (1414 mg) , 10.23 mmol) and PdCl 2 (dppf) * DCM (278.6 mg, 0.3412 mmol) in a flask of degassed DMF (10 mL) and water (1.0 mL). The mixture was degassed for 10 minutes and then heated to 80 ° C for 5 hours. The reaction was cooled and water was added. The mixture was extracted with EtOAc (50 mL×2). The organic layer was dried, filtered and concentrated. The resulting residue was purified on EtOAc (EtOAc EtOAc EtOAc) 4-yl)methyl)-3-(1-ethyl-1H-pyrazol-5-yloxy)-2-cyanopyridine (1.144 g, 2.505 mmol, 73.43% yield).

步驟G：根據實例1825步驟C製備5-((2-(((第三丁基二甲基矽烷基)氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶醯胺，5-((2-((第三丁基二甲基矽烷氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-(1-乙基-1H-吡唑-5-基氧基)-2-氰基吡啶(740 mg，1.62 mmol)、K2CO3(336 mg，2.43 mmol)及30% H2O2水溶液(0.5 ml，1.62 mmol)得到5-((2-((第三丁基二甲基矽烷氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶醯胺(604 mg，1.27 mmol，78.5%產率)。 Step G : Preparation of 5-((2-(((tert-butyldimethylmethyl)alkyl)oxy)methyl)tetrahydro-2H-pyran-4-yl)methyl)- 3-((1-Ethyl-1H-pyrazol-5-yl)oxy)pyridiniumamine, 5-((2-((t-butyldimethyl)alkyl))tetrahydro- 2H-Pylan-4-yl)methyl)-3-(1-ethyl-1H-pyrazol-5-yloxy)-2-cyanopyridine (740 mg, 1.62 mmol), K 2 CO 3 (336 mg, 2.43 mmol) and 30% aqueous H 2 O 2 (0.5 ml, 1.62 mmol) afforded 5- ((2-((t-butyl dimethyl </RTI> Piperazin-4-yl)methyl)-3-(1-ethyl-1H-pyrazol-5-yloxy)pyridiniumamine (604 mg, 1.27 mmol, 78.5% yield).

步驟H：根據實例1822步驟E製備1-(5-((2-(((第三丁基二甲基矽烷基)氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲。5-((2-((第三丁基二甲基矽烷氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶醯胺(628 mg，1.32 mmol)、甲胺(571 μl，6.62 mmol)及雙[(三氟乙醯氧基)碘]苯(626 mg，1.46 mmol)得到1-(5-((2-(((第三丁基二甲基矽烷基)氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-((1-乙基-1H-吡唑-5-基)氧基)吡啶-2-基)-3-甲基脲(470 mg，0.933 mmol，70.5%產率)。 Step H : Preparation of 1-(5-((2-((t-butyldimethyl)alkyl)oxy)methyl)tetrahydro-2H-pyran-4-yl) 3-((1-Ethyl-1H-pyrazol-5-yl)oxy)pyridin-2-yl)-3-methylurea. 5-((2-((t-butyldimethyl)alkyl)methyl)tetrahydro-2H-piperidin-4-yl)methyl)-3-(1-ethyl-1H-pyrazole -5-yloxy)pyridiniumamine (628 mg, 1.32 mmol), methylamine (571 μl, 6.62 mmol) and bis[(trifluoroethyloxy)iodo]benzene (626 mg, 1.46 mmol) gave 1 -(5-((2-((t-butyldimethyl)alkyl)oxy)methyl)tetrahydro-2H-pyran-4-yl)methyl)-3-((1-B) Base-1H-pyrazol-5-yl)oxy)pyridin-2-yl)-3-methylurea (470 mg, 0.933 mmol, 70.5% yield).

步驟I：將1-(5-((2-((第三丁基二甲基矽烷氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-(1-乙基-1H-吡唑-5-基氧基)吡啶-2-基)-3-甲基脲(650 mg，1.16 mmol)置於DCM(5 mL)及MeOH(1 mL)中。添加含4 N HCl之二噁烷(3 mL)且攪拌反應物15分鐘。濃縮反應物。添加飽和碳酸氫鈉，且用含10% MeOH之DCM(3×50 mL)萃取混合物。濃縮有機層，且藉由矽膠(含1.5-4.5% MeOH之DCM)純化所得殘餘物，得到呈4：1反式與順式之混合物形式的1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(羥基 甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲(401 mg，1.03 mmol，88.7%產率)。 Step I : 1-(5-((2-((tert-butyldimethyl)alkyl)oxy)methyl)tetrahydro-2H-pyran-4-yl)methyl)-3-(1- Ethyl-1H-pyrazol-5-yloxy)pyridin-2-yl)-3-methylurea (650 mg, 1.16 mmol) was taken in DCM (5 mL) Dioxane (3 mL) containing 4 N HCl was added and the mixture was stirred 15 min. Concentrate the reactants. Saturated sodium bicarbonate was added and the mixture was extracted with DCM (3.times.50 mL) containing 10% MeOH. The organic layer was concentrated, and the obtained residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Pyrazol-5-yloxy)-5-((2-(hydroxymethyl)tetrahydro-2H-piperidin-4-yl)methyl)pyridin-2-yl)-3-methylurea (401 Mg, 1.03 mmol, 88.7% yield).

步驟J：使用Chiral Tech IA管柱(4.6 mm×250 mm，5 μ)，用20%乙醇：80%己烷以1 mL/min之流動速率溶離，解析1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(羥基甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲之混合物(401 mg，1.03 mmol)，得到標題化合物(84.0 mg，21.0%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.16(m,1H),7.76(m,1H),7.46(d,J=2.0 Hz,1H),7.28(s,1H),6.96(d,J=2.0 Hz,1H),5.67(d,J=2.2 Hz,1H),4.05(m,3H),3.57(m,1H),3.49(m,1H),3.88(m,2H),2.98(d,J=4.7 Hz,3H),2.44(m,2H),1.95(m,1H),1.68(m,1H),1.50(m,2H),1.42(t,J=7.2 Hz,3H),1.25(m,1H),1.02(m,1H)。質譜(apci)m/z=390.2(M+H)。 Step J : Dissolve 1-(3-(1-ethyl) using a Chiral Tech IA column (4.6 mm × 250 mm, 5 μ) with 20% ethanol: 80% hexane at a flow rate of 1 mL/min. -1H-pyrazol-5-yloxy)-5-((2-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)-3-methyl A mixture of urea (401 mg, 1.03 mmol) gave 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.16 (m, 1H), 7.76 (m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 6.96 (d, J =2.0 Hz,1H), 5.67 (d, J = 2.2 Hz, 1H), 4.05 (m, 3H), 3.57 (m, 1H), 3.49 (m, 1H), 3.88 (m, 2H), 2.98 (d) , J = 4.7 Hz, 3H), 2.44 (m, 2H), 1.95 (m, 1H), 1.68 (m, 1H), 1.50 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.25 (m, 1H), 1.02 (m, 1H). Mass spectrum (apci) m/z = 390.2 (M+H).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1830Example 1830

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((2R,4R)-2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((2R,4R)-2-(methoxymethyl)tetrahydro-2H-piperidyl Butan-4-yl)methyl)pyridin-2-yl)-3-methylurea

步驟A：將5-((2-((第三丁基二甲基矽烷氧基)甲基)四氫-2H-哌喃-4-基)甲基)-3-(1-乙基-1H-吡唑-5-基氧基)-2-氰基吡啶(468 mg，1.02 mmol)置於DCM(5 mL)及4 N HCl(2 mL)中，且攪拌反應物30分鐘。用飽和碳酸氫鈉緩慢淬滅反應物。接著用含10% MeOH之DCM(3×30 mL)萃取混合物。濃縮有機層，得到粗3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(羥基甲基)四氫-2H-哌喃-4-基)甲基)-2-氰基吡啶，其按原樣用於下一反應中。 Step A : 5-((2-((t-butyldimethyl)alkyl)oxy)methyltetrahydro-2H-pyran-4-yl)methyl)-3-(1-ethyl- 1H-Pyrazol-5-yloxy)-2-cyanopyridine (468 mg, 1.02 mmol) was taken in DCM (5 mL) and 4 N HCl (2 mL). The reaction was slowly quenched with saturated sodium bicarbonate. The mixture was then extracted with 10% MeOH in DCM (3×30 mL). The organic layer was concentrated to give crude 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-((2-(hydroxymethyl)tetrahydro-2H-pyran-4-yl). Base-2-cyanopyridine, which was used as such in the next reaction.

步驟B：將3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(羥基甲基)四氫-2H-哌喃-4-基)甲基)-2-氰基吡啶(351 mg，1.03 mmol)置於THF(5 mL)中且冷卻至0℃。添加60% NaH(61.5 mg，1.54 mmol)，且攪拌反應物10分鐘。添加MeI(192 μl，3.08 mmol)，且在室溫下攪拌反應物30分鐘。緩慢添加水，且用DCM萃取物質。濃縮有機層且在矽膠上(EtOAc)純化所得殘餘物，得到3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)-2-氰基吡啶(276 mg，0.774 mmol，75.5%產率)。 Step B : 3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-((2-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl) 2-cyanopyridine (351 mg, 1.03 mmol) was taken in THF (5 mL) and cooled to 0. 60% NaH (61.5 mg, 1.54 mmol) was added and the reaction was stirred 10 min. MeI (192 μl, 3.08 mmol) was added and the reaction was stirred at room temperature for 30 min. Water was added slowly and the material was extracted with DCM. The organic layer was concentrated and the obtained residue was purified eluted elut elut Hydrogen-2H-piperazin-4-yl)methyl)-2-cyanopyridine (276 mg, 0.774 mmol, 75.5% yield).

步驟C：根據實例1825步驟C製備3-((1-乙基-1H-吡唑-5-基)氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶醯胺，3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)-2-氰基吡啶(274 mg，0.769 mmol)、K2CO3(159 mg，1.15 mmol)及30% H2O2水溶液(0.5 ml，0.769 mmol)得到3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(甲 氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶醯胺(200 mg，0.534 mmol，69.5%產率)。 Step C : Preparation of 3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((2-(methoxymethyl)tetrahydro-2H-喃-4-yl)methyl)pyridinium, 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-((2-(methoxymethyl)tetrahydro-2H -piperazin-4-yl)methyl)-2-cyanopyridine (274 mg, 0.769 mmol), K 2 CO 3 (159 mg, 1.15 mmol), and 30% aqueous H 2 O 2 (0.5 ml, 0.769 mmol To give 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-((2-(methoxymethyl)tetrahydro-2H-pyran-4-yl)methyl) Pyridinamine (200 mg, 0.534 mmol, 69.5% yield).

步驟D：根據實例1822步驟E製備1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲，3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶醯胺(200 mg，0.534 mmol)、甲胺(230 μl，2.67 mmol)及雙[(三氟乙醯氧基)碘]苯(253 mg，0.588 mmol)得到1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲(146 mg，67.7%產率)。 Step D : Preparation of 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((2-(methoxymethyl)tetrahydro)- 2H-piperazin-4-yl)methyl)pyridin-2-yl)-3-methylurea, 3-(1-ethyl-1H-pyrazole-5-yloxy)-5-(2 -(Methoxymethyl)tetrahydro-2H-pyran-4-yl)methyl)pyridiniumamine (200 mg, 0.534 mmol), methylamine (230 μl, 2.67 mmol) and bis[(trifluoroethyl)醯oxy)iodo]benzene (253 mg, 0.588 mmol) gave 1-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-((2-(methoxymethyl) Tetrahydro-2H-piperazin-4-yl)methyl)pyridin-2-yl)-3-methylurea (146 mg, 67.7% yield).

步驟E：使用Chiral Tech OD-H管柱(4.6 mm×250 mm，5 μ)，用15%乙醇：85%己烷以1 mL/min之流動速率溶離，解析1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-((2-(甲氧基甲基)四氫-2H-哌喃-4-基)甲基)吡啶-2-基)-3-甲基脲之混合物(146 mg)，得到標題化合物(56.6 mg，38.8%產率)。1H NMR(400 MHz,CDCl3)δ ppm 9.17(m,1H),7.76(m,1H),7.45(d,J=2.2 Hz,1H),7.27(m,1H),6.96(d,J=2.0 Hz,1H),5.67(d,J=2.2 Hz,1H),4.05(m,3H),3.45-3.30(m,7H),2.99(d,J=4.7 Hz,3H),2.44(m,2H),1.66(m,1H),1.50(m,2H),1.42(t,J=7.2 Hz,3H),1.26(m,1H),1.03(m,1H)。質譜(apci)m/z=404.2(M+H)。 Step E : Dissolve 1-(3-(1-) using a Chiral Tech OD-H column (4.6 mm × 250 mm, 5 μ) with 15% ethanol: 85% hexane at a flow rate of 1 mL/min. Ethyl-1H-pyrazol-5-yloxy)-5-((2-(methoxymethyl)tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-yl)- A mixture of 3-methylurea (146 mg) gave the title compound (56.6 mg, 38.8% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.17 (m, 1H), 7.76 (m, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.27 (m, 1H), 6.96 (d, J =2.0 Hz,1H), 5.67 (d, J = 2.2 Hz, 1H), 4.05 (m, 3H), 3.45-3.30 (m, 7H), 2.99 (d, J = 4.7 Hz, 3H), 2.44 (m) , 2H), 1.66 (m, 1H), 1.50 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.26 (m, 1H), 1.03 (m, 1H). Mass spectrum (apci) m/z = 404.2 (M+H).

自上述製備亦獲得以下化合物： The following compounds were also obtained from the above preparation:

實例1834Example 1834

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((哌啶-4-基(吡啶-2-基)甲基)硫基)吡啶-2-基)-3-甲基脲 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((piperidin-4-yl(pyridin-2-yl)methyl)thio)pyridine- 2-yl)-3-methylurea

步驟A：將2-溴吡啶(2.149 ml，22.03 mmol)置於THF(25 mL)中且冷卻至-78℃。緩慢添加丁基鋰(8.812 ml，22.03 mmol)且攪拌5分鐘。將4-(甲氧基(甲基)胺甲醯基)哌啶-1-甲酸第三丁酯(5.00 g，18.36 mmol)溶解於THF(3 mL)中，且緩慢添加至上述溶液中並在-78℃下攪拌30分鐘。添加氯化銨，且用DCM萃取混合物。濃縮有機層，且藉由矽膠(含80-100% EtOAc之己烷)純化所得殘餘物，得到4-甲基吡啶醯基哌啶-1-甲酸第三丁酯(3.677 g，12.66 mmol，69.0%產率)。 Step A : 2-Bromopyridine (2.149 ml, 22.03 mmol) was taken in THF (25 mL) and cooled to -78. Butyllithium (8.812 ml, 22.03 mmol) was added slowly and stirred for 5 minutes. 3-(Methoxy(methyl)aminemethionyl)piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 18.36 mmol) was dissolved in THF (3 mL) and slowly added to the above solution Stir at -78 ° C for 30 minutes. Ammonium chloride was added and the mixture was extracted with DCM. The organic layer was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj %Yield).

步驟B：將4-甲基吡啶醯基哌啶-1-甲酸第三丁酯(1.00 g，3.44 mmol)置於MeOH(20 mL)中，且逐份添加NaBH4直至反應完成。接著添加水，且用DCM萃取混合物。濃縮有機層，得到粗4-(羥基(吡啶-2- 基)甲基)哌啶-1-甲酸第三丁酯，其按原樣用於下一反應中。 Step B: 4-methylpyridin-acyl piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.44 mmol) placed in MeOH (20 mL), and the NaBH 4 was added portionwise until the reaction was complete. Water was then added and the mixture was extracted with DCM. The organic layer was concentrated to give crude 4-(hydroxy(pyridin-2-yl)methyl)piperidine-1-carboxylic acid as the butyl ester, which was used in the next reaction.

步驟C：將4-(羥基(吡啶-2-基)甲基)哌啶-1-甲酸第三丁酯(1.01 g，3.45 mmol)及Et3N(1.44 ml，10.4 mmol)置於DCM中且冷卻至0℃。添加MsCl(0.334 ml，4.32 mmol)，且在室溫下攪拌3小時，添加水且用DCM萃取。乾燥有機層，過濾且濃縮。在矽膠上(含50-60% EtOAc之己烷)純化所得殘餘物，得到4-((甲基磺醯基氧基)(吡啶-2-基)甲基)哌啶-1-甲酸第三丁酯(1.07 g，2.89 mmol，83.6%產率)。 Step C: 4- (hydroxy (pyridin-2-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (1.01 g, 3.45 mmol) and Et 3 N (1.44 ml, 10.4 mmol) was placed in DCM And cooled to 0 ° C. MsCl (0.334 ml, 4.32 mmol) was added and stirred at room temperature for 3 hr. The organic layer was dried, filtered and concentrated. The resulting residue was purified on EtOAc (EtOAc EtOAc EtOAc) Butyl ester (1.07 g, 2.89 mmol, 83.6% yield).

步驟D：根據實例350，使用3-(5-(1-乙基-1H-吡唑-5-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)丙酸甲酯(500 mg，1.32 mmol)、2-甲基丙-2-醇鉀(3953 μl，3.95 mmol)、4-((甲基磺醯基氧基)(吡啶-2-基)甲基)哌啶-1-甲酸第三丁酯(732 mg，1.98 mmol)製備4-(((5-((1-乙基-1H-吡唑-5-基)氧基)-6-(3-甲基脲基)吡啶-3-基)硫基)(吡啶-2-基)甲基)哌啶-1-甲酸第三丁酯，得到4-((5-(1-乙基-1H-吡唑-5-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)(吡啶-2-基)甲基)哌啶-1-甲酸第三丁酯(194 mg，0.342 mmol，25.9%產率)。 Step D : According to Example 350, 3-(5-(1-ethyl-1H-pyrazol-5-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propyl Methyl ester (500 mg, 1.32 mmol), potassium 2-methylpropan-2-ol (3953 μl, 3.95 mmol), 4-((methylsulfonyloxy)(pyridin-2-yl)methyl Preparation of 4-((5-((1-ethyl-1H-pyrazol-5-yl)oxy)-6-(3) by piperidine-1-carboxylic acid tert-butyl ester (732 mg, 1.98 mmol) -Methylurea)pyridin-3-yl)thio)(pyridin-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester to give 4-((5-(1-ethyl-1H) -pyrazol-5-yloxy)-6-(3-methylureido)pyridin-3-ylthio)(pyridin-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester ( 194 mg, 0.342 mmol, 25.9% yield).

步驟E：將4-((5-(1-乙基-1H-吡唑-5-基氧基)-6-(3-甲基脲基)吡啶-3-基硫基)(吡啶-2-基)甲基)哌啶-1-甲酸第三丁酯(194 mg，0.342 mmol)置於DCM(5 ml)及TFA(2 mL)中，且在室溫下攪拌2小時。濃縮反應物，且使所得殘餘物溶於DCM及飽和碳酸氫鈉中。分離有機層且濃縮。藉由逆相(含0-55% ACN之水)純化粗物質，得到1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-(哌啶-4-基(吡啶-2-基)甲硫基)吡啶-2-基)-3-甲基脲(54 mg，0.115 mmol，33.8%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.99(m,1H),8.45(m,1H),7.83(d,J=1.8 Hz,1H),7.55(m,1H),7.44(d,J=2.0 Hz,1H),7.10(m,2H),6.89(d,J=1.8 Hz,1H),5.53(d,J=2.0 Hz,1H),3.94(m,3H),3.14(m,1H),3.03(m,1H),2.96(d,J=4.7 Hz,3H),2.65(m,1H),2.54(m,1H),2.27(m,1H),2.07(m,1H),1.36 (m,5H),1.22(m,1H)。質譜(apci)m/z=467.9(M+H)。 Step E : 4-((5-(1-Ethyl-1H-pyrazol-5-yloxy)-6-(3-methylureido)pyridin-3-ylthio)(pyridine-2) -Methyl)piperidine-1-carboxylic acid tert-butyl ester (194 mg, 0.342 mmol) was taken in DCM (5 ml) The reaction was concentrated and the residue obtained was taken eluted eluted elut The organic layer was separated and concentrated. The crude material was purified by reverse phase (water containing 0-55% ACN) to give 1-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(piperidin-4- (Pyridine-2-yl)methylthio)pyridin-2-yl)-3-methylurea (54 mg, 0.115 mmol, 33.8% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.99 (m, 1H), 8.45 (m, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.55 (m, 1H), 7.44 (d, J =2.0 Hz, 1H), 7.10 (m, 2H), 6.89 (d, J = 1.8 Hz, 1H), 5.53 (d, J = 2.0 Hz, 1H), 3.94 (m, 3H), 3.14 (m, 1H) ), 3.03 (m, 1H), 2.96 (d, J = 4.7 Hz, 3H), 2.65 (m, 1H), 2.54 (m, 1H), 2.27 (m, 1H), 2.07 (m, 1H), 1.36 (m, 5H), 1.22 (m, 1H). Mass spectrum (apci) m/z = 467.9 (M+H).

實例1835Example 1835

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((1-(2-羥基乙基)哌啶-4-基)(吡啶-2-基)甲基)硫基)吡啶-2-基)-3-甲基脲 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(((1-(2-hydroxyethyl))piperidin-4-yl)(pyridine-2 -yl)methyl)thio)pyridin-2-yl)-3-methylurea

將1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-(哌啶-4-基(吡啶-2-基)甲硫基)吡啶-2-基)-3-甲基脲(25 mg，0.0535 mmol)、2-羥基乙醛(4.82 mg，0.0802 mmol)及NaBH(OAc)3(45.3 mg，0.214 mmol)置於DCE(50 mL)中，且在室溫下攪拌1小時。添加水且用DCM萃取。乾燥有機層，過濾且濃縮。藉由逆相層析(0-25% ACN：水)純化所得殘餘物，得到1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-((1-(2-羥基乙基)哌啶-4-基)(吡啶-2-基)甲硫基)吡啶-2-基)-3-甲基脲(4.0 mg，15%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.99(m,1H),8.45(m,1H),7.83(d,J=1.8 Hz,1H),7.75(dt,J=7.8,2.0 Hz,1H),7.42(d,J=2.0 Hz,1H),7.28(m,1H),7.10(m,2H),6.89(d,J=2.0 Hz,1H),5.53(d,J=2.0 Hz,1H),3.94(m,4H),3.58(m,2H),3.00(m,1H),2.95(d,J=4.7 Hz,3H),2.84(m,1H),2.50(m,2H),2.22(m,2H),2.10(m,1H),2.00(m,2H),1.48(m,1H),1.38(t,J=7.2 Hz,3H),1.32(m,2H)。質譜(apci)m/z=511.9(M+H)。 1-(3-(1-Ethyl-1H-pyrazol-5-yloxy)-5-(piperidin-4-yl(pyridin-2-yl)methylthio)pyridin-2-yl) -3-methylurea (25 mg, 0.0535 mmol), 2-hydroxyacetaldehyde (4.82 mg, 0.0802 mmol) and NaBH(OAc) 3 (45.3 mg, 0.214 mmol) in DCE (50 mL) Stir at room temperature for 1 hour. Water was added and extracted with DCM. The organic layer was dried, filtered and concentrated. The obtained residue was purified by reverse phase chromatography (0-25% ACN: water) to give 1-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-((1- (2-Hydroxyethyl)piperidin-4-yl)(pyridin-2-yl)methylthio)pyridin-2-yl)-3-methylurea (4.0 mg, 15% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.99 (m, 1H), 8.45 (m, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.75 (dt, J = 7.8, 2.0 Hz, 1H) ), 7.42 (d, J = 2.0 Hz, 1H), 7.28 (m, 1H), 7.10 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 5.53 (d, J = 2.0 Hz, 1H) ), 3.94 (m, 4H), 3.58 (m, 2H), 3.00 (m, 1H), 2.95 (d, J = 4.7 Hz, 3H), 2.84 (m, 1H), 2.50 (m, 2H), 2.22 (m, 2H), 2.10 (m, 1H), 2.00 (m, 2H), 1.48 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.32 (m, 2H). Mass spectrum (apci) m/z = 511.9 (M+H).

實例1836Example 1836

1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((1-甲基哌啶-4-基)(吡啶-2-基)甲基)硫基)吡啶-2-基)-3-甲基脲 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(((1-methylpiperidin-4-yl)(pyridin-2-yl)methyl) Thio)pyridin-2-yl)-3-methylurea

根據實例1835製備1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((1-甲基哌啶-4-基)(吡啶-2-基)甲基)硫基)吡啶-2-基)-3-甲基脲，1-(3-(1-乙基-1H-吡唑-5-基氧基)-5-(哌啶-4-基(吡啶-2-基)甲硫基)吡啶-2-基)-3-甲基脲(25 mg，0.0535 mmol)、三聚甲醛(3.21 mg，0.107 mmol)及NaBH(OAc)3得到1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(((1-甲基哌啶-4-基)(吡啶-2-基)甲基)硫基)吡啶-2-基)-3-甲基脲(7.1 mg，12.7%產率)。1H NMR(400 MHz,CDCl3)δ ppm 8.99(m,1H),8.45(m,1H),7.83(d,J=1.8 Hz,1H),7.54(m,1H),7.42(d,J=2.0 Hz,1H),7.10(m,2H),6.89(d,J=1.8 Hz,1H),5.52(d,J=2.0 Hz,1H),3.96(q,J=7.2 Hz,2H),3.90(d,J=9.2 Hz,1H),2.95(m,4H),2.77(m,1H),2.25(s,3H),2.20(m,1H),1.95(m,3H),1.85(m,1H),1.50(m,1H),1,35(m,5H)。質譜(apci)m/z=481.9(M+H)。 Preparation of 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(((1-methylpiperidin-4-yl)(pyridine-2-) according to Example 1835 Methyl)thio)pyridin-2-yl)-3-methylurea, 1-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(piperidine- 4-yl(pyridin-2-yl)methylthio)pyridin-2-yl)-3-methylurea (25 mg, 0.0535 mmol), trioxane (3.21 mg, 0.107 mmol) and NaBH (OAc) 3 1-(3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-(((1-methylpiperidin-4-yl)(pyridin-2-yl)methyl) Base thio)pyridin-2-yl)-3-methylurea (7.1 mg, 12.7% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.99 (m, 1H), 8.45 (m, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.54 (m, 1H), 7.42 (d, J =2.0 Hz, 1H), 7.10 (m, 2H), 6.89 (d, J = 1.8 Hz, 1H), 5.52 (d, J = 2.0 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 9.2 Hz, 1H), 2.95 (m, 4H), 2.77 (m, 1H), 2.25 (s, 3H), 2.20 (m, 1H), 1.95 (m, 3H), 1.85 (m) , 1H), 1.50 (m, 1H), 1, 35 (m, 5H). Mass spectrum (apci) m/z = 481.9 (M+H).

實例1837Example 1837

1-乙基-3-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)脲 1-ethyl-3-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridine -2-yl)urea

向3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶醯胺(74 mg，0.22 mmol)及68重量%乙胺之水溶液(0.1 mL，1.20 mmol)於1：1乙腈(2 mL)：水(2 mL)中之溶液中添加[雙(三氟乙醯氧基)碘]苯(102 mg，0.24 mmol)。在23℃下攪拌混合物且用TLC及LC-MS監測。1.5小時後，將飽和碳酸氫鈉水溶液添加至混合物中。用乙酸乙酯萃取三次後，彙集有機物，接著用鹽水洗滌一次。經無水硫酸鈉乾燥，過濾並在減壓下濃縮後，用4.2 mL DMF(含10-50%乙腈(預混有0.1% TFA)之水(含0.1% TFA))稀釋殘餘物。合併含有所要產物之溶離份，接著在減壓下濃縮。將殘餘物溶解於二氯甲烷中，接著用飽和碳酸氫鈉水溶液洗滌兩次且用鹽水洗滌一次。經無水硫酸鎂乾燥，過濾並濃縮後，將灰白色固體鑑別為1-乙基-3-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-((四氫-2H-哌喃-4-基)甲基)吡啶-2-基)脲(44 mg，0.12 mmol，52.4%產率)。1H NMR(400 MHz,DMSO-d6)δ ppm 9.03(1H,t,J=4.9 Hz),8.68(1H,s),7.88(1H,d,J=1.8 Hz),7.36(1H,d,J=2.0 Hz),7.28(1H,d,J=1.8 Hz),5.63(1H,d,J=2.0 Hz),4.06(2H,q,J=7.2 Hz),3.79(2H,dd,J=11.2,2.8 Hz),3.15-3.30(4H,m),2.45(2H,d,J=7.2 Hz),1.64(1H,ttt,J=11.2,11.2,7.4,7.4,3.7,3.7 Hz),1.38-1.48(2H,m),1.30(3H,t,J=7.2 Hz),1.09-1.21(5H,m)。質譜(正模式)m/e：374.2(M+H)+。 3-((1-Ethyl-1H-pyrazol-5-yl)oxy)-5-((tetrahydro-2H-piperidin-4-yl)methyl)pyridiniumamine (74 mg, 0.22 Add [bis(trifluoroethyloxy)iodo]benzene to a solution of a solution of 68% by weight of ethylamine (0.1 mL, 1.20 mmol) in 1:1 acetonitrile (2 mL): water (2 mL) (102 mg, 0.24 mmol). The mixture was stirred at 23 ° C and monitored by TLC and LC-MS. After 1.5 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture. After extracting three times with ethyl acetate, the organics were combined and washed once with brine. After drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure, the residue was diluted with &lt;RTI ID=0.0&gt;0&gt; The fractions containing the desired product were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane then washed twice with saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, filtered and concentrated, the white solid was identified as 1-ethyl-3-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5- (( Tetrahydro-2H-piperazin-4-yl)methyl)pyridin-2-yl)urea (44 mg, 0.12 mmol, 52.4% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.03 (1H, t, J = 4.9 Hz), 8.68 (1H, s), 7.78 (1H, d, J = 1.8 Hz), 7.36 (1H, d , J = 2.0 Hz), 7.28 (1H, d, J = 1.8 Hz), 5.63 (1H, d, J = 2.0 Hz), 4.06 (2H, q, J = 7.2 Hz), 3.79 (2H, dd, J =11.2, 2.8 Hz), 3.15-3.30 (4H, m), 2.45 (2H, d, J = 7.2 Hz), 1.64 (1H, ttt, J = 11.2, 11.2, 7.4, 7.4, 3.7, 3.7 Hz), 1.38-1.48 (2H, m), 1.30 (3H, t, J = 7.2 Hz), 1.09-1.21 (5H, m). Mass spectrum (positive mode) m/e: 374.2 (M+H) + .

活體外葡糖激酶活化分析 In vitro glucokinase activation assay

GKA活化分析GKA activation analysis

在葡糖激酶活化分析中在葡萄糖之生理相關濃度(5 mM)下評估本發明之葡糖激酶活化劑之活體外功效。藉由在含有NAD+及葡萄糖6-磷酸去氫酶之偶合分析系統中監測340 nm下之吸光度增加來估算葡糖激酶活性。在30℃下使用恆溫控制之吸光度板讀取器(Spectramax 340PC,Molecular Devices Corp.)及透明的96孔平底聚苯乙烯板(Costar 3695,Corning)進行分析。各50 μL分析混合物含有10 mM K+MOPS(pH 7.2)、2 mM MgCl2、50 mM KCl、0.01% Triton X-100、2% DMSO、1 mM DTT、1 mM ATP、1 mM NAD+、5 mM葡萄糖、5 U/mL葡萄糖6-磷酸去氫酶、約5 nM重組人類葡糖激酶及不同濃度之測試化合物。測試化合物之濃度在3倍稀釋系列之10個點上變化，且通常在50 μM高劑量至約2.5 nM低劑量之範圍內。以動力學方式經5分鐘之時段(10秒/週期)監測340 nm下之吸光度，且自與原始數據線性擬合之斜率來估算速率。藉由計算在整個給藥範圍內達成之最大斜率與不存在測試化合物之情況下所獲得之斜率平均值的比率來評估由測試化合物活化之程度(本文中定義為活性比)。結果提供於表1中。據發現活性比高於1.2之任何化合物視為較佳。 The in vitro efficacy of the glucokinase activator of the invention was evaluated in a glucokinase activation assay at a physiologically relevant concentration of glucose (5 mM). Glucokinase activity was estimated by monitoring the increase in absorbance at 340 nm in a coupling analysis system containing NAD + and glucose 6-phosphate dehydrogenase. Analysis was performed at 30 ° C using a thermostatically controlled absorbance plate reader (Spectramax 340PC, Molecular Devices Corp.) and a clear 96-well flat-bottom polystyrene plate (Costar 3695, Corning). Each 50 μL assay mixture contains 10 mM K + MOPS (pH 7.2), 2 mM MgCl 2 , 50 mM KCl, 0.01% Triton X-100, 2% DMSO, 1 mM DTT, 1 mM ATP, 1 mM NAD + , 5 mM glucose, 5 U/mL glucose 6-phosphate dehydrogenase, approximately 5 nM recombinant human glucokinase, and varying concentrations of test compound. The concentration of the test compound varied from 10 points in the 3-fold dilution series and typically ranged from a high dose of 50 μM to a low dose of about 2.5 nM. The absorbance at 340 nm was monitored kinetically over a period of 5 minutes (10 seconds/cycle) and the rate was estimated from the slope of the linear fit to the raw data. The extent of activation by the test compound (defined herein as activity ratio) was evaluated by calculating the ratio of the maximum slope achieved over the entire dosing range to the average of the slopes obtained in the absence of the test compound. The results are provided in Table 1. Any compound having an activity ratio higher than 1.2 was found to be preferred.

β值分析Beta value analysis

在葡糖激酶活化分析中評估本發明之葡糖激酶活化劑之活體外功效，其中葡萄糖與測試化合物在單一96孔分析板中並行地變化。使機械模型與所得分析數據擬合以確定活化程度。在此分析中，藉由在含有NAD+及葡萄糖6-磷酸去氫酶之偶合分析系統中監測340 nm下之吸光度增加來估算葡糖激酶活性。在30℃下使用恆溫控制之吸光度板讀取器(Spectramax 340PC,Molecular Devices Corp.)及透明的96孔平底聚苯乙烯板(Costar 3695,Corning)進行分析。各50 μL分析混合物含有10 mM K+MOPS(pH 7.2)、2 mM MgCl2、50 mM KCl、0.01% Triton X-100、2% DMSO、1 mM DTT、1 mM ATP、1 mM NAD+、5 U/mL葡萄糖6-磷酸去氫酶、約5 nM重組人類葡糖激酶及不同濃度之葡萄糖及測試化合物。葡萄糖之濃度在2倍稀釋系列之10個點上變化，使用80 mM最高劑量。測試化合物在適於特定化合物之不規則稀釋系列之8個點上變化。以動力學方式經5分鐘之時段(10秒/週期)監測340 nm下之吸光度，且自與原始數據線性擬合之斜率來估算速率。使以下機械模型與原始斜率擬合以確定活化程度： The in vitro efficacy of the glucokinase activators of the invention was evaluated in a glucokinase activation assay in which glucose and test compounds were varied in parallel in a single 96-well assay plate. The mechanical model is fitted to the resulting analytical data to determine the degree of activation. In this assay, glucokinase activity was estimated by monitoring the increase in absorbance at 340 nm in a coupled assay system containing NAD + and glucose 6-phosphate dehydrogenase. Analysis was performed at 30 ° C using a thermostatically controlled absorbance plate reader (Spectramax 340PC, Molecular Devices Corp.) and a clear 96-well flat-bottom polystyrene plate (Costar 3695, Corning). Each 50 μL assay mixture contains 10 mM K + MOPS (pH 7.2), 2 mM MgCl 2 , 50 mM KCl, 0.01% Triton X-100, 2% DMSO, 1 mM DTT, 1 mM ATP, 1 mM NAD + , 5 U/mL glucose 6-phosphate dehydrogenase, approximately 5 nM recombinant human glucokinase, and varying concentrations of glucose and test compounds. The concentration of glucose was varied at 10 points in the 2-fold dilution series using the highest dose of 80 mM. Test compounds vary at 8 points that are suitable for the irregular dilution series of a particular compound. The absorbance at 340 nm was monitored kinetically over a period of 5 minutes (10 seconds/cycle) and the rate was estimated from the slope of the linear fit to the raw data. The following mechanical model is fitted to the original slope to determine the degree of activation:

在此模型中，v為速度(原始斜率)，[S]為葡萄糖濃度，[A]為測試化合物濃度，Vm為最大速度，h為希爾係數(Hill Coefficient)，KS為不存在測試化合物之情況下葡萄糖之解離常數，KA為不存在葡萄糖之情況下測試化合物之解離常數，α為當葡萄糖被結合時KA變化之因數，β為存在測試化合物之情況下Vm變化之因數，且γ為存在測試化合物之情況下h變化之因數。自參數β評估由測試化合物活化之程度，使得據發現β值高於0.2之任何化合物較佳。 In this model, v is the velocity (original slope), [S] is the glucose concentration, [A] is the concentration of the test compound, V m is the maximum velocity, h is the Hill Coefficient, and K S is the absence test. The dissociation constant of glucose in the case of the compound, K A is the dissociation constant of the test compound in the absence of glucose, α is the factor of the change in K A when glucose is bound, and β is the factor of the change in V m in the presence of the test compound. And γ is a factor of h change in the presence of the test compound. The degree of activation by the test compound is evaluated from the parameter β such that any compound having a beta value above 0.2 is preferred.

本發明化合物可於含有習知醫藥學上可接受之載劑、佐劑及媒 劑之單位劑量調配物中經口、非經腸、藉由吸入型噴霧、經直腸或局部投與。 The compounds of the present invention may contain conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The unit dosage formulation of the agent is administered orally, parenterally, by inhalation spray, rectally or topically.

對本文中之疾病及病症之治療欲亦包括預防性投與本發明化合物或其醫藥鹽或任一者之醫藥組合物至據信需要預防性處理之個體(亦即動物，較佳為哺乳動物，最佳為人類)。 The treatment of the diseases and conditions herein also includes the prophylactic administration of a compound of the present invention or a pharmaceutical salt thereof or a pharmaceutical composition of any of them to an individual (ie, an animal, preferably a mammal) believed to require prophylactic treatment. , the best for humans).

使用此等化合物、用本發明化合物及/或本發明組合物治療疾病、癌症及/或高血糖症之給藥方案係基於多種因素，包括疾病之類型、患者之年齡、體重、性別、醫學病狀、病狀之嚴重性、投藥途徑及所採用之特定化合物。因此，給藥方案可廣泛變化，但常規上可使用標準方法來確定。每天每公斤體重約0.01 mg至30 mg、較佳約0.1 mg/kg至10 mg/kg、更佳約0.25 mg/kg至1 mg/kg數量級之劑量適用於本文所揭示之所用使用方法。 The dosage regimen for the treatment of disease, cancer and/or hyperglycemia using such compounds, with the compounds of the invention and/or compositions of the invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient The severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen can vary widely, but can be routinely determined using standard methods. Doses of from about 0.01 mg to 30 mg, preferably from about 0.1 mg/kg to 10 mg/kg, more preferably from about 0.25 mg/kg to 1 mg/kg per kilogram of body weight per day are suitable for use in the methods disclosed herein.

本發明之醫藥活性化合物可根據習知藥學方法加工以產生用於投與患者(包括人類及其他哺乳動物)之醫學藥劑。 The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce a pharmaceutical agent for administration to a patient, including humans and other mammals.

對於經口投藥，醫藥組合物可呈例如膠囊、錠劑、懸浮液或液體形式。醫藥組合物較佳製成含有特定量之活性成分的劑量單位形式。舉例而言，此等劑量單位可含有約1至2000 mg、較佳約1至100 mg、更佳約5至500 mg之量的活性成分。適用於人類或其他哺乳動物之日劑量視患者病狀及其他因素而定可廣泛變化，但再一次地可使用常規方法確定。 For oral administration, the pharmaceutical compositions may be in the form of, for example, capsules, lozenges, suspensions or liquids. The pharmaceutical compositions are preferably in the form of dosage units containing a particular amount of active ingredient. For example, such dosage units can contain the active ingredient in an amount of from about 1 to 2000 mg, preferably from about 1 to 100 mg, more preferably from about 5 to 500 mg. The daily dosage for humans or other mammals can vary widely depending on the condition of the patient and other factors, but can be determined again using conventional methods.

活性成分亦可藉由以具有適合載劑(包括生理食鹽水、右旋糖或水)之組合物形式注射來投與。每日非經腸給藥方案將為每公斤總體重約0.1 mg至約30 mg，較佳為約0.1 mg/kg至約10 mg/kg，且更佳為0.25 mg/kg至1 mg/kg。 The active ingredient can also be administered by injection as a composition with a suitable carrier, including physiological saline, dextrose or water. The daily parenteral dosage regimen will be from about 0.1 mg to about 30 mg, preferably from about 0.1 mg/kg to about 10 mg/kg, and more preferably from 0.25 mg/kg to 1 mg/kg, per kg. .

諸如無菌可注射水性或油性懸浮液之可注射製劑可根據已知方法，使用適合分散劑或濕潤劑及懸浮劑來調配。無菌可注射製劑亦可 為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液，例如於1,3-丁二醇中之溶液。可採用之可接受媒劑及溶劑有水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。另外，無菌不揮發性油常規用作溶劑或懸浮介質。為此目的，可採用任何溫和的不揮發性油，包括合成單酸甘油酯或二酸甘油酯。另外，諸如油酸之脂肪酸可用於製備可注射劑。 Injectable preparations such as a sterile injectable aqueous or oily suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also A sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any bland fixed oil may be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

用於經直腸投與藥物之栓劑可藉由將藥物與適合之非刺激性賦形劑(諸如可可脂及聚乙二醇)混合來製備，該賦形劑在常溫下為固體但在直腸溫度下為液體且因此將於直腸中熔融並釋放藥物。 A suppository for rectal administration of a drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which is solid at ambient temperature but at rectal temperature The lower is liquid and therefore will melt in the rectum and release the drug.

本發明化合物之活性成分的適合局部劑量為0.1 mg至150 mg，每天投與1至4次，較佳1或2次。對於局部投藥，活性成分可佔調配物之0.001%至10% w/w，例如1重量%至2重量%，儘管其可佔調配物之多達10% w/w，但較佳不超過5% w/w，且更佳為0.1%至1%。 A suitable topical dose of the active ingredient of the compound of the invention is from 0.1 mg to 150 mg, administered one to four times a day, preferably one or two times. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w of the formulation, for example from 1% to 2% by weight, although it may comprise up to 10% w/w of the formulation, preferably no more than 5 % w/w, and more preferably 0.1% to 1%.

適於局部投與之調配物包括適於穿透皮膚之液體或半液體製劑(例如搽劑、洗劑、軟膏、乳膏或糊劑)及適於投與眼睛、耳朵或鼻子之滴劑。 Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (such as elixirs, lotions, ointments, creams or pastes) and drops suitable for administration to the eye, ear or nose.

對於投藥，本發明化合物通常與一或多種適於指定投藥途徑之佐劑組合。化合物可與乳糖、蔗糖、澱粉粉末、烷酸之纖維素酯、硬脂酸、滑石、硬脂酸鎂、氧化鎂、磷酸及硫酸之鈉鹽及鈣鹽、阿拉伯膠、明膠、海藻酸鈉、聚乙烯吡咯啶及/或聚乙烯醇混合，且製錠或囊封以供習知投藥。或者，本發明化合物可溶解於生理食鹽水、水、聚乙二醇、丙二醇、乙醇、玉米油、花生油、棉籽油、芝麻油、黃蓍膠及/或多種緩衝劑中。其他佐劑及投藥模式在醫藥技術中為熟知的。載劑或稀釋劑可包括延時物質，諸如單獨或與蠟一起之單硬脂酸甘油酯或二硬脂酸甘油酯，或此項技術中熟知之其他物質。 For administration, the compounds of the invention are typically combined with one or more adjuvants appropriate to the intended route of administration. The compound can be combined with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium sulfate and calcium salt, gum arabic, gelatin, sodium alginate, Polyvinylpyrrolidine and/or polyvinyl alcohol are mixed and tableted or encapsulated for conventional administration. Alternatively, the compounds of the invention may be dissolved in physiological saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical arts. The carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, or other materials well known in the art.

醫藥組合物可製成固體形式(包括顆粒、散劑或栓劑)或液體形式 (例如溶液、懸浮液或乳液)。可對醫藥組合物進行諸如殺菌之習知醫藥操作，及/或醫藥組合物可含有習知佐劑，諸如防腐劑、穩定劑、濕潤劑、乳化劑、緩衝劑等。 Pharmaceutical compositions can be prepared in solid form (including granules, powders or suppositories) or in liquid form (eg solution, suspension or emulsion). The pharmaceutical composition may be subjected to conventional medical procedures such as sterilization, and/or the pharmaceutical composition may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, buffers and the like.

供經口投與之固體劑型可包括膠囊、錠劑、丸劑、散劑及顆粒。在該等固體劑型中，活性化合物可與至少一種惰性稀釋劑(諸如蔗糖、乳糖或澱粉)混合。如在常規實踐中，該等劑型亦可包含除惰性稀釋劑以外之其他物質，例如潤滑劑，諸如硬脂酸鎂。在膠囊、錠劑及丸劑之狀況下，該等劑型亦可包含緩衝劑。另外，可用腸溶包衣製備錠劑及丸劑。 Solid dosage forms for oral administration can include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, in conventional practice, materials other than inert diluents, such as a lubricant such as magnesium stearate. In the case of capsules, lozenges and pills, such dosage forms may also contain buffering agents. Alternatively, tablets and pills can be prepared with enteric coatings.

供經口投與之液體劑型可包括醫藥學上可接受之乳液、溶液、懸浮液、糖漿及酏劑，其含有此項技術中常用之惰性稀釋劑，諸如水。該等組合物亦可包含佐劑，諸如濕潤劑、甜味劑、調味劑及芳香劑。 Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water conventional in the art. The compositions may also contain adjuvants such as wetting agents, sweetening, flavoring, and perfuming agents.

本發明化合物可具有一或多個不對稱碳原子，且因此能夠以光學異構體形式以及其外消旋或非外消旋混合物形式存在。光學異構體可藉由根據習知製程，例如藉由形成非對映異構體鹽、藉由用光學活性酸或鹼處理來解析外消旋混合物而獲得。適當酸之實例為酒石酸、二乙醯基酒石酸、二苄醯基酒石酸、二甲苯醯基酒石酸及樟腦磺酸，且藉由結晶分離非對映異構體之混合物，繼而自此等鹽釋放光學活性鹼。一種用於分離光學異構體之不同製程涉及使用對掌性層析管柱，其經最佳選擇以使對映異構體之分離達到最大。另一可用方法涉及藉由使本發明化合物與呈活化形式之光學純酸或光學純之異氰酸酯反應來合成共價非對映異構體分子。所合成之非對映異構體可由習知方式(諸如層析、蒸餾、結晶或昇華)分離，且進行水解以釋放出對映異構純之化合物。本發明之光學活性化合物可同樣藉由使用光學活性起始物質而獲得。此等異構體可呈游離酸、游離鹼、酯或鹽之形式。 The compounds of the invention may have one or more asymmetric carbon atoms and are therefore capable of being present in optical isomer form as well as in the form of their racemic or non-racemic mixtures. Optical isomers can be obtained by resolution of the racemic mixture according to conventional procedures, for example by formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of suitable acids are tartaric acid, diethyl tartaric acid, dibenzyl tartaric acid, xylyl tartaric acid and camphor sulfonic acid, and the mixture of diastereomers is separated by crystallization, followed by release of the optical from these salts. Active base. A different process for separating optical isomers involves the use of a pair of palm chromatography columns that are optimally selected to maximize separation of the enantiomers. Another useful method involves the synthesis of covalent diastereomeric molecules by reacting a compound of the invention with an optically pure acid or optically pure isocyanate in an activated form. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and subjected to hydrolysis to liberate the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

同樣地，本發明化合物可以異構體形式存在，亦即具有相同分子式但原子相對於彼此以不同方式排列之化合物。詳言之，本發明化合物之伸烷基取代基通常且較佳如針對此等基團中每一者之定義所指示自左至右排列及插入分子中。然而，在某些狀況下，熟習此項技術者應瞭解，有可能製備此等取代基之位向相對於分子中之其他原子顛倒的本發明化合物。亦即，待插入之取代基可與上文所述相同，但其以顛倒之位向插入分子中。熟習此項技術者應瞭解，本發明化合物之此等異構形式應視為涵蓋於本發明之範疇內。 Likewise, the compounds of the invention may exist in isomeric forms, i.e., compounds having the same molecular formula but arranged in different ways relative to one another. In particular, the alkyl-alkyl substituents of the compounds of the invention are typically and preferably arranged from left to right and inserted into the molecule as indicated for the definition of each of such groups. However, in certain instances, those skilled in the art will appreciate that it is possible to prepare the compounds of the invention in such a position that the substituents are reversed relative to other atoms in the molecule. That is, the substituent to be inserted may be the same as described above, but it is inserted into the molecule in an inverted position. Those skilled in the art will recognize that such isomeric forms of the compounds of the invention are considered to be within the scope of the invention.

本發明化合物可以衍生自無機酸或有機酸之鹽形式使用。鹽包括(但不限於)以下：乙酸鹽、己二酸鹽、海藻酸鹽、檸檬酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡糖酸鹽、環戊烷丙酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、葡糖庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、反丁烯二酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙烷磺酸鹽、乳酸鹽、順丁烯二酸鹽、甲烷磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、2-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、丁二酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽、甲磺酸鹽及十一烷酸鹽。又，鹼性含氮基團可經以下試劑四級銨化：諸如低碳烷基鹵化物，諸如甲基、乙基、丙基及丁基之氯化物、溴化物及碘化物；硫酸二烷酯，如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯及硫酸二戊酯；長鏈鹵化物，諸如癸基、十二烷基、十四烷基及十八烷基之氯化物、溴化物及碘化物；芳烷基鹵化物，如苄基及苯乙基之溴化物；及其他試劑。藉此獲得水溶性或油溶性或分散性產物。 The compounds of the invention may be derived from the form of a salt of a mineral or organic acid. Salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, camphor Acid salt, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethane sulfonate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methane sulfonate , nicotinic acid salt, 2-naphthalene sulfonate, oxalate, pamoate, pectate, persulfate, 2-phenylpropionate, picrate, pivalate, C Acid salts, succinates, tartrates, thiocyanates, tosylates, methanesulfonates and undecanoates. Further, the basic nitrogen-containing group can be quaternized by a reagent such as a lower alkyl halide such as a chloride, a bromide or an iodide of a methyl group, an ethyl group, a propyl group and a butyl group; Esters such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides such as the chlorides of decyl, dodecyl, tetradecyl and octadecyl, Bromide and iodide; aralkyl halides such as benzyl and phenethyl bromide; and other reagents. Thereby a water-soluble or oil-soluble or dispersible product is obtained.

可用於形成醫藥學上可接受之酸加成鹽之酸的實例包括無機酸，諸如鹽酸、硫酸及磷酸；及有機酸，諸如草酸、順丁烯二酸、丁二酸及檸檬酸。其他實例包括與鹼金屬或鹼土金屬(諸如鈉、鉀、鈣 或鎂)形成之鹽或與有機鹼形成之鹽。 Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include alkali metal or alkaline earth metals (such as sodium, potassium, calcium) Or a salt formed by magnesium or a salt formed with an organic base.

本發明之範疇內亦涵蓋羧酸或含羥基基團之醫藥學上可接受之酯，包括本發明化合物之代謝不穩定酯或前藥形式。代謝不穩定酯為可引起例如血液含量增加且延長化合物之相應非酯化形式之功效的酯。前藥形式為投與時不為分子之活性形式但在一些活體內活動或生物轉化(諸如代謝，例如酶促或水解裂解)後變得具有治療活性的形式。關於涉及酯之前藥的一般論述，參見Svensson及Tunek Drug Metabolism Reviews 165(1988)及Bundgaard Design of Prodrugs,Elsevier(1985)。經遮蔽之羧酸酯陰離子之實例包括多種酯，諸如烷基(例如甲基、乙基)、環烷基(例如環己基)、芳烷基(例如苄基、對甲氧基苄基)及烷基羰氧基烷基(例如特戊醯氧基甲基)。已將胺遮蔽為經芳基羰氧基甲基取代之衍生物，其係由酯酶活體內裂解，釋放游離藥物及甲醛(Bungaard J.Med.Chem.2503(1989))。又，含有酸性NH基團之藥物(諸如咪唑、醯亞胺、吲哚及其類似物)已經N-醯氧基甲基遮蔽(Bundgaard Design of Prodrugs,Elsevier(1985))。已將羥基遮蔽為酯及醚。EP 039,051(Sloan及Little,4/11/81)揭示曼尼希鹼異羥肟酸前藥、其製備及用途。本發明化合物之酯可包括例如甲酯、乙酯、丙酯及丁酯，以及在酸性部分與含羥基部分之間形成的其他適合酯。代謝不穩定酯可包括例如甲氧基甲基、乙氧基甲基、異丙氧基甲基、α-甲氧基乙基，諸如α-((C1-C4)烷氧基)乙基之基團，例如甲氧基乙基、乙氧基乙基、丙氧基乙基、異丙氧基乙基等；2-側氧基-1,3-二氧雜環戊烯-4-基甲基，諸如5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基甲基等；C1-C3烷硫基甲基，例如甲硫基甲基、乙硫基甲基、異丙硫基甲基等；醯氧基甲基，例如特戊醯氧基甲基、α-乙醯氧基甲基等；乙氧基羰基-1-甲基；或α-醯氧基-α-經取代甲基，例如α-乙醯氧基乙基。 Also included within the scope of the invention are carboxylic acid or pharmaceutically acceptable esters containing hydroxyl groups, including metabolically labile ester or prodrug forms of the compounds of the invention. Metabolically labile esters are esters that can cause, for example, an increase in blood levels and extend the efficacy of the corresponding non-esterified form of the compound. Prodrug forms are those which, when administered, are not active forms of the molecule but become therapeutically active after some in vivo activity or biotransformation, such as metabolism, such as enzymatic or hydrolytic cleavage. For a general discussion of prodrug-related drugs, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of blocked carboxylate anions include various esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and Alkylcarbonyloxyalkyl (e.g., p-pentyloxymethyl). The amine has been masked as an arylcarbonyloxymethyl substituted derivative which is cleaved in vivo by the esterase to release free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Further, drugs containing acidic NH groups such as imidazole, quinone imine, guanidine and the like have been masked by N-decyloxymethyl (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxyl groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich base hydroxamic acid prodrugs, their preparation and use. Esters of the compounds of the invention may include, for example, methyl, ethyl, propyl and butyl esters, as well as other suitable esters formed between the acidic moiety and the hydroxyl-containing moiety. Metabolically labile esters may include, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl, methoxyethyl alpha], such as α - ((C 1 -C 4 ) alkoxy) ethyl a group such as methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, etc.; 2-sided oxy-1,3-dioxol-4 -ylmethyl, such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, etc.; C 1 -C 3 alkylthiomethyl, such as methylthio Methyl, ethylthiomethyl, isopropylthiomethyl, etc.; oxiranylmethyl, such as pentylmethoxymethyl, α-ethenyloxymethyl, etc.; ethoxycarbonyl-1-methyl Or an α-methoxy-α-substituted methyl group, such as α-ethyloxyethyl.

此外，本發明化合物可以結晶固體形式存在，其可自常用溶劑 (諸如乙醇、N,N-二甲基甲醯胺、水或其類似物)中結晶。因此，本發明化合物之結晶形式可以母化合物或其醫藥學上可接受之鹽的多晶型物、溶劑合物及/或水合物形式存在。所有該等形式同樣應視為處於本發明之範疇內。 Furthermore, the compounds of the invention may exist in crystalline solid form, which may be derived from conventional solvents Crystallization in (such as ethanol, N,N-dimethylformamide, water or the like). Thus, the crystalline form of the compound of the invention may exist as a polymorph, solvate and/or hydrate of the parent compound or a pharmaceutically acceptable salt thereof. All such forms are also considered to be within the scope of the invention.

儘管本發明化合物可以單獨活性醫藥劑形式投與，但其亦可與一或多種本發明化合物或其他藥劑組合使用。當以組合形式投與時，治療劑可調配成同時或在不同時間給藥之各別組合物，或治療劑可以單一組合物形式給藥。 While the compounds of the invention may be administered as a separate active pharmaceutical agent, they may also be employed in combination with one or more compounds of the invention or other agents. When administered in combination, the therapeutic agents can be formulated as separate compositions for administration at the same time or at different times, or the therapeutic agents can be administered as a single composition.

前述內容僅說明本發明且不欲將本發明限於所揭示之化合物。熟習此項技術者顯而易見之變更及變化欲在隨附申請專利範圍所定義之本發明範疇及性質內。 The foregoing merely illustrates the invention and is not intended to limit the invention to the disclosed compounds. Variations and modifications apparent to those skilled in the art are intended to be within the scope and nature of the invention as defined by the appended claims.

根據前述描述，熟習此項技術者可容易地確定本發明之基本特徵，且可在不脫離其精神及範疇下作出本發明之各種變化及修改以使其適於各種用法及狀況。 The various features and modifications of the invention are apparent to those skilled in the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Claims (49)

一種式Ia化合物， 其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基(oxo)或鹵基之取代基取代；R2為H、烷基或鹵基；R3為H、鹵基、烷氧基羰基、胺基羰基、氰基、氰基烷基、烷基羰基、雜環基羰基、烷基胺基羰基、烯基、炔基、羥基烯基、烷氧基烷氧基烷基、芳氧基烯基、烷氧基羰基烷基、烷基磺醯基烷基、烷基磺醯基烯基、烷基磺醯基炔基、雜環基炔基、雜環基羰基烷基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、鹵烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷 基或雜環基羰基烷基；其中R4中之環未經取代或經1-3個獨立地選自以下之取代基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環基環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、-NRR'、烷基-NRR'或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；G為C-Q或N；L為O、S、CH2或CH2O；Q為H或-L-R5；且P為H或-L-R6； 其限制條件為：(i)當Q為H時，則P為-L-R6，或(ii)當Q為-L-R5時，則P為H；(iii)當G為N時，則P為-L-R6；其他限制條件為，當R3為H，R1為甲基，R2為H，L為O，且P為H時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，R1為甲基，R2為H，L為O，且P為H時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，R1為甲基，R2為H，L為O，且P為H時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當R3為H，R1為甲基，L為O，P為H，且R5為5-喹啉基時，R2不為鹵基；其他限制條件為，當R3為溴，R1為甲基，L為O，P為H，且R5 為5-喹啉基時，R2不為氯；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，R2為H，R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且G為CH時，R1不為苯基或第三丁基；其他限制條件為，當R2為H，R3為2-吡啶硫基，P為2-乙基-3-吡啶氧基，且G為CH時，R1不為4-甲基-2-咪唑基甲基；其他限制條件為，當R1為甲基，R2為H，G為N，且P為2-甲基-3-吡啶氧基時，R3不為4-甲基苯基或2,4-二甲基苯基或1,2-二羥基-2-苯基乙基；及其醫藥學上可接受之鹽。 a compound of formula Ia, Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or one or two independently selected from hydroxy, alkoxy, alkyl, oxo or halogen Substituted by a substituent; R 2 is H, alkyl or halo; R 3 is H, halo, alkoxycarbonyl, aminocarbonyl, cyano, cyanoalkyl, alkylcarbonyl, heterocyclylcarbonyl , alkylaminocarbonyl, alkenyl, alkynyl, hydroxyalkenyl, alkoxyalkoxyalkyl, aryloxyalkenyl, alkoxycarbonylalkyl, alkylsulfonylalkyl, alkyl sulfonate Merylalkenyl, alkylsulfonylalkynyl, heterocyclylalkynyl, heterocyclylcarbonylalkyl, alkoxyalkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or - S(O)n; n is 0, 1 or 2; R 4 is alkyl, hydroxyalkyl, haloalkyl, alkoxy Alkyl, alkoxyalkenyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, aromatic An alkyl, aralkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclylalkyl or heterocyclylcarbonylalkyl group; wherein the ring in R 4 is not Substituted or substituted with 1-3 substituents independently selected from the group consisting of H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, decyl, alkylsulfonyl, a heterocyclic group, a sulfo group acyl, alkyl sulfonic acyl group, a cyano group, an alkoxycarbonyl group, a carboxyl group, an amino group, RR'N- alkyl, alkoxyalkyl, hydroxyalkyl, or R a R b NC(=O), wherein R a is alkyl and R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a and R b are taken together with nitrogen Unsubstituted or alkyl-substituted heterocyclyl ring; R 5 is aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclyl, wherein R 5 is unsubstituted or via 1-3 Substituted independently of the substituents selected from alkyl, alkoxy, hydroxy, halo, halo Group, a cyano group, an alkoxycarbonyl group, a carboxyl group, acyl, cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, oxo, -NRR ', an alkyl group -NRR' or R a R b NC(=O), wherein R a is alkyl and R b is alkoxyalkyl or aminoalkyl; wherein R and R' are H, alkyl, aryl, heterocyclyl, heterocycloalkane Or a cycloalkyl group, wherein the heterocyclylalkyl, cycloalkyl and heterocyclyl rings are unsubstituted or are independently selected from the group consisting of alkyl, alkoxy, hydroxy, halo, halo Substituted with a substituent of a cyano group or a carboxy group; or R' and R may form a heterocyclic group together with N; R 6 is an aryl group, an aralkyl group, a heterocyclic group, a heterocyclic alkyl group or a cycloalkyl group, wherein Each of the foregoing rings is unsubstituted or substituted with from 1 to 4 substituents independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclyl. Carbonyl, cyano, cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; G is CQ or N; L is O, S, CH 2 or CH 2 O; Q is H or -LR 5; and P is H or -LR 6; with the proviso that: (i) when Q is H, P is -LR 6, or (ii) when Q is -LR 5, then P is H; (iii) when G is N, then P is -LR 6; additional proviso that when R 3 is H, R 1 is a methyl group, R 2 is H, L is O, and when P is H, then R 5 is not [1,2,4]triazolo[4,3-a]pyridine-8-yl, 1- Methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6-yl, 2-sided oxy -1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxooxy-1 ,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl- 2-sided oxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinoline-6 -yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are, when R 3 is Br, R 1 is a methyl group, R 2 is H, L is O, and when P is H, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1 , 2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-Difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl-1-yloxy -1,2-dihydro-isoquinolin-6-yl; other restrictions are that when R 3 is 1-methyl-1H-pyrazol-4-yl, R 1 is methyl and R 2 is H, When L is O and P is H, then R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazole-5- a group, R 1 is a methyl group, R 2 is H, L is O, and when P is H, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinoline-6 -yl,5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl; other restrictions are: when R 3 is H, R 1 is methyl, L is O, P is H, and R 5 is 5-quinolyl, R 2 is not a halogen group; other restrictions are: when R 3 is bromine, R 1 is methyl, L is O, P is H, and R 5 is 5-quinolyl, R 2 is not chlorine; The restriction is that when L is O, R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridyl, and R 2 is H. R 3 is 2-pyridylthio, bromo, methoxyethoxy or trifluoromethyl, and when G is CH, R 1 is not phenyl or tert-butyl; other restrictions are when R 2 is H, R 3 is 2-pyridyl group, P is 2-ethyl-3-pyridinyl Group, and when G is CH, R 1 is not methyl-2-imidazolyl-methyl; other restrictions that, when R 1 is methyl, R 2 is H, G is N, and P is 2 When methyl-3-pyridinyloxy, R 3 is not 4-methylphenyl or 2,4-dimethylphenyl or 1,2-dihydroxy-2-phenylethyl; and its medicinal Acceptable salt. 如請求項1之化合物，其中R1為H、C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy alkoxy-C 1-6 alkyl, C 6-10 aryl, C 6 a -10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group -C 1-6 alkyl group, wherein the aryl or heterocyclic ring is unsubstituted or Or two substituents independently selected from C1-6 alkyl, hydroxy, pendant or halogen; and pharmaceutically acceptable salts thereof. 如請求項1之化合物，其中R1為H、甲基、乙基、丙基、異丙基、第三丁基、烯丙基、三氟乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、胺基乙基、苯基、苯基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、4-甲基咪唑基甲基、咪唑基甲基、1-甲基-咪唑基甲基、1,5-二甲基吡唑基甲基、2-甲基噻唑基甲基、5-甲基-異噁唑基甲基、嗎啉-4-基乙基、嗎啉-4-基甲基、四氫哌喃乙基或四氫呋喃基乙基；及其醫藥學上可接受之 鹽。 The compound of claim 1, wherein R 1 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, allyl, trifluoroethyl, methoxy, methoxyethyl, Hydroxyethyl, hydroxypropyl, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, aminoethyl, phenyl, phenylethyl, 2-hydroxybenzene Methyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, pyridylmethyl, 6-methyl-2-oxooxy-1,2-di Hydropyridylmethyl, 4-methylimidazolylmethyl, imidazolylmethyl, 1-methyl-imidazolylmethyl, 1,5-dimethylpyrazolylmethyl, 2-methylthiazolyl , 5-methyl-isoxazolylmethyl, morpholin-4-ylethyl, morpholin-4-ylmethyl, tetrahydropyranylethyl or tetrahydrofuranylethyl; and pharmaceutically acceptable Accept the salt. 如請求項1之化合物，其中R1為2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、4-甲基咪唑-2-基甲基、咪唑-5-基甲基、1-甲基咪唑-5-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑-5-基甲基、5-甲基異噁唑-3-基、6-甲基-2-側氧基-1,2-二氫吡啶-3-基甲基或嗎啉-4-基乙基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 1 is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-methylimidazol-2-ylmethyl, imidazole-5-yl , 1-methylimidazolium-5-ylmethyl, 1,5-dimethylpyrazol-4-ylmethyl, 2-methylthiazol-5-ylmethyl, 5-methylisoxazole- 3-Based, 6-methyl-2-oxooxy-1,2-dihydropyridin-3-ylmethyl or morpholin-4-ylethyl; and pharmaceutically acceptable salts thereof. 如請求項1之化合物，其中R1為甲基、乙基或羥基乙基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 1 is methyl, ethyl or hydroxyethyl; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R2為H、甲基、氯或氟；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 2 is H, methyl, chloro or fluoro; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R2為H；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 2 is H; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R3為-S(O)nR4，且n為0、1或2；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is -S(O) n R 4 and n is 0, 1 or 2; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R3為-SR4；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is -SR 4 ; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C3-6環烷基-C1-6烷基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基或C1-6羥基烷基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 membered heterocyclic group, C 6- 10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 1-6 alkyl, 5-10 membered heterocyclyl-C 1 a -6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 4 is unsubstituted or via 1-3 Substituents independently selected from the group consisting of C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 Alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclic, amine, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkane Or a C 1-6 hydroxyalkyl group; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2- Dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanylmethoxy , methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutyl Thio group, carboxyethylthio group, (methylaminocarbonyl)methylthio group, (dimethylaminocarbonyl)methylthio group, (3-hydroxy-3-methylbutyl)thio group, (2-hydroxyl group) -2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1 -T-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(four Hydrogen-2H-piperazin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylsulfide Base, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridine sulfur , 2-chloro-4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1 -hydroxyvinylpiperidin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-A (carbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, ( 1-isopropylcarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylsulfide , 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl) Piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl Thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H -piperidin-4-ylthio; and pharmaceutically acceptable salts thereof. 如請求項1之化合物，其中R3為甲氧基丙基亞磺醯基、甲氧基丙基磺醯基、1-(第三丁氧基羰基)哌啶-4-基亞磺醯基、2-吡啶基亞 磺醯基、1-(第三丁氧基羰基)哌啶-4-基磺醯基或2-吡啶基磺醯基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is methoxypropylsulfinyl, methoxypropylsulfonyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfinyl , 2-pyridylsulfinyl, 1-(t-butoxycarbonyl)piperidin-4-ylsulfonyl or 2-pyridylsulfonyl; and pharmaceutically acceptable salts thereof. 如請求項1之化合物，其中R3為-OR4；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is -OR 4 ; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基或3-氧雜環丁烷基甲氧基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2- Dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy or 3-oxetanylmethoxy Base; and its pharmaceutically acceptable salts. 如請求項1之化合物，其中R3為H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或 RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is H, halo, cyano, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkane Carbocarbonyl, 4-10 membered heterocyclylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 -hydroxyalkyl, C 2-6 hydroxyalkenyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy --C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2- 6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 2-6 alkenyl, C 1-6 alkylsulfonyl- C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic, C 6-10 aryl-C 1-6 alkane , C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 ring Alkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl or 4-10 Heterocyclic carbonyl -C 1-6 alkyl; wherein R 3 is of the aryl group, cycloalkyl, cycloalkenyl or heterocyclyl ring unsubstituted or substituted by 1-3 substituents independently selected from the substituents: C 1 -6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy Carbonyl group, carboxyl group, 5- to 10-membered heterocyclic group, amino group, C 1-6 aminoalkyl group, C 1-6 alkoxy-C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 1- 6 haloalkoxy, RR'NC 1-6 alkyl-, aminosulfonyl, C 1-6 alkylaminosulfonyl, cyano or R a R b NC(=O), wherein R a Is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 aminoalkyl, or a 5- or 6-membered heterocyclic ring wherein R a and R b together with nitrogen form an unsubstituted or C 1-6 alkyl group; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯 基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基- N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基、1,4-二氧雜螺[4.5]癸-7-烯-7-基，3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯 基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基， 1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡 啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶- 5-基、吡嗪-2-基、噠嗪-4-基，3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2- Methyl butyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2- Hydroxy-2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1,2 -dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl , 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxymethyl Oxymethyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, propylene -2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy -2-methylpropenyl, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxy Vinyl, 2-hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxy B Aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonylmethyl , ethoxycarbonylpropyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, carboxyl Ethyl, carboxypropyl, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxyl -2-methylpropoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyn-1-yl , cyclopentylmethyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonylpropyl , methylsulfonyl butyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1 -phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinylmethyl , 1-piperidinylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-yl , 4-methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1,1- Dioxy ionylthiomorpholinyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3- Methyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran-3 -ylmethyl, 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl) Propyl, 1,3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]heptane- 1-ylmethyl, 2-oxa-6-azaspiro[3.3] -6-ylmethyl, 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy-cyclopentyl 1,1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1-(methoxycyclopentyl) Bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2-sided oxy Cyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl)-cyclobutane , 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxymethylcyclopentane Base, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3-sided oxy-cyclopentyl, 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl, cycloheptyl , cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentene 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-oxo-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-en-1-yl , cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4-hydroxyl Methyl-cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl) ring Hexenyl, 4-(3-fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl) ring Hexenyl, cycloheptenyl, 1,4-dioxaspiro[4.5]dec-7-ene-7-yl, 3-hydroxy-3-oxetanyl, 2-tetrahydro-furanyl , 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl-2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3- Tetrahydro-furanyl, 2-oxopyryrrolidin-1-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5,5 -tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxytetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran-3 -yl, tetrahydropyran-2-yl, 3,6-dihydropyran-4-yl, 3,6-dihydropentan-5-yl 5,6-Dihydro-2H-piperidin-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-dimethyl-3,6-dihydro-2H-peri喃-4-yl, 2,2-dimethyl-3,6-dihydro-2H-piperidin-4-yl, 3,4-2H-dihydropyran-4-yl, 1,4-di Oxaspiro[4.5]pyridin-7-en-8-yl, 1,1-di-oxy-isothiazolidin-2-yl, 1,1-dioxyindolyltetrahydro-2H-thiopyran 4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,3,6-tetrahydropyridine- 4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxycarbonyl)-1,2,3,6-tetrahydro Pyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1-(di) Methylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-tri Fluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonyl Phenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonate Mercaptoaminophenyl, 3-methylamine Sulfophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6-methoxyphenyl, 4- Cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(dimethylaminocarbonyl)phenyl, 4-(Dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl, 4-ethylaminocarbonylbenzene , 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N-methylaminocarbonyl)phenyl , 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-phenyl, 3-(N-methoxy Benzyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethylaminocarbonylbenzene , 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethylaminocarbonylbenzene , 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl-phenyl, 1 ,2 -dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-ylcarbonyl)phenyl, 3 -(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl, 3-(4- Morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methoxyphenyl, 2 -fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonylphenyl, 4-methyl Oxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3-difluoromethoxybenzene , 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxy Phenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazole 1,1,5,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2,2, 2-trifluoroethyl]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxy Methyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-cyclobutyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyridyl Azyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxy Ethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl 5-pyrazolyl, 3-methylaminocarbonyl-pyrazol-5-yl, 3-dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyridyl Zyrid-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2-methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazole-4-yl, 1-methyl -Triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxypropyl-triazin-4-yl, 1-hydroxybutyl-triazin-4-yl, 2- Cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophen-5-yl, 2-(N-methoxyethyl-N- Methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophen-5-yl, 2-(2-hydroxy-2-methylethyl)thiazide -5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2 -methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5- Pyridyl, 2-difluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2-methyl Oxy-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy 4-pyridyl, 2-methoxy-5-pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy-4 -pyridyl, 5-fluoro-2-hydroxyethoxy-4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy 5-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-(1 1,1,1-Trifluoroethoxy)-5-pyridyl, 2-cyclopropylmethoxy-5 -pyridyl, 2-(methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl, 2 -fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano- 5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5-pyridine , 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2- Sideoxy-1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxo- 1,2-dihydropyridin-5-yl, 1-isopropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy-1, 2-Dihydropyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2-di Hydropyridin-4-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl, 3 -Methylaminocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl-5- Pyridyl, 2-methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonylamino Ethylaminocarbonyl-5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethylamino Carbonyl-5-pyridyl, 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4-pyridyl 4-fluoro-2-methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl, 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2 -cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethoxy -5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl-4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylaminocarbonyl Pyrimidine-5-yl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, 5-benzofuranyl, 5-fluorenyl, 2-oxo-dihydro-5 - mercapto, 6-fluorenyl, 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6-fluorene Mercapto, imidazo[1,2-a]pyridin-3-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridine-6-yl, 1, 1-di-oxo-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-8-yl, benzoxazole-5-yl , benzoxazole-6-yl, 1,1-di-oxy-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine-8-yl, 4-methyl-5-oxooxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazole-5 -yl, 2-ethylbenzoxazol-5-yl, 2-isopropylbenzoxazol-5-yl, 2-sided oxy-2(3H)-benzo[d]oxazole-5 -yl,benzothiazol-5-yl, benzothiazole-6-yl, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5- Carbazolyl, 1-methyl-6-oxazolyl, 2-methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4-yl 1,5-Dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2-methyl- 3-sided oxy-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2 -methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b ][ 1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzo[d] [1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxathiazol-5-yl,[1,2,4]triazolo [4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2,4] Zoxao[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl; and its medicine A salt that is acceptable for learning. 如請求項1之化合物，其中R3為H或溴；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 3 is H or bromine; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中G為CH；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CH; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中G為C-Q；Q為H；P為-L-R6；且R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CQ; Q is H; P is -LR 6 ; and R 6 is 5-membered nitrogen-containing heterocyclic group, 5-membered oxygen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 6 members of an oxygen-containing heterocyclic group, a phenyl group, a benzyl group, a 9-membered bicyclic nitrogen-containing heterocyclic group, a 10-membered bicyclic oxygen-containing heterocyclic group or a 10-membered bicyclic nitrogen-containing heterocyclic group, wherein R 6 is unsubstituted or passed through a Or a plurality of substituents independently selected from the group consisting of C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl , carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [4-6 member nitrogen-containing heterocyclic group] carbonyl optionally substituted; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中G為C-Q；Q為H；P為-L-R6；且R6為四氫呋喃基、四氫哌喃基、3,4-二氫-2H-哌喃并[3,2-c]吡啶基、烷基、哌啶基、吡啶基、吡唑基、苯基、喹啉基、1,2-二氫喹啉基、吡咯啶基、苄基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基或嘧啶基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CQ; Q is H; P is -LR 6 ; and R 6 is tetrahydrofuranyl, tetrahydropyranyl, 3,4-dihydro-2H-pyrano[3, 2-c]pyridyl, Alkyl, piperidinyl, pyridyl, pyrazolyl, phenyl, quinolyl, 1,2-dihydroquinolyl, pyrrolidinyl, benzyl, 5,6,7,8-tetrahydroquinoline , quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H-pyrazolo[ 3,4-b]pyridyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-a]pyridinyl or pyrimidinyl, wherein R 6 is unsubstituted or one or more Substituted independently of the following substituents: methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, ethoxycarbonyl, tert-butoxycarbonyl, carboxy, N-(A -N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof. 如請求項1之化合物，其中G為C-Q；Q為H；P為-L-R6；且R6為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基， 2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-經基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基 苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯 苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯基， 5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CQ; Q is H; P is -LR 6 ; and R 6 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl , 1-Boc-piperidin-4-yl, hexahydrofuro[2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-dimethyl 3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-ethyl- 3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-isopropyl 5-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-tramethylmethyl-3-pyridyl, 3-hydroxymethyl -5-pyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxypropane 5-ylpyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoro Methyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3-pyridine , 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5-pyridyl , 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2-cyano 5--5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5-methyl- 3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine-5-yl, 1,3-dimethyl-2-oxo Pyridin-5-yl, 1-methyl-2-oxopurin-5-yl, 2-methyl-6-oxopurin-4-yl, 1-ethyl-2-oxopyridine -5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl-6-oxiranylpyridin-5-yl, 1-iso C -2-Sideoxypyridin-5-yl, 1,2-dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-oxopyridine- 4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylaminocarbonyl) -6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl, 4 -chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidin-5-yl , 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazin-5-yl, 2-dimethylaminocarbonyl-pyridyl Pyrazin-5-yl, pyridazin-3-yl, 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazole , 1-ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazole , 1-methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazol-2-yl, Phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3 -difluorophenyl, 2 ,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3-dichloro Phenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-three Fluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylaminosulfonate Mercapto-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5-methoxy Phenylcarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2-ethyl Phenyl, 2-methyl-5-carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro- 5-aminocarbonylphenyl, 2-cyanophenyl, 4-cyanophenyl 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4- Chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3,6 -dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro-2 -Cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl] Phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl-5- [N-(Methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2- Methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl Phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl)benzene , 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl )) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclobutyl) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl , 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-( (2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro-5- ((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-((1- Methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-(( 1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5- ((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1 -Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro- 5-(1-Ethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2 -fluoro-5-(4-morpholinyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholine) Ethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl -1-tetrazolyl)phenyl, 3-(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolinyl, 6-quinolinyl, 7-quinoline Lolinyl, 8-quinolyl, 5-chloro-6-quinolyl, 7-chloro-4-quinolyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8- Tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxalin-5-yl, 1-sided oxy-isoindol-4-yl, 1-sided oxy-isoporphyrin- 6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-carbazole-5-yl, 1,3- Dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1 , 2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-sided oxy-1,2-di Hydroquinolin-6-yl, 4-oxo-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5, 7-difluoro -1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxooxy-4-trifluoromethyl-1,2-dihydroquinolin-6- ,5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinoline ,6-isoquinolyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl -1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl- 1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazole [3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H- Imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl, 3-methylisoxazole[5,4- b]pyridin-4-yl,[1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H-pyridyl Zoxao[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中L為O；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein L is O; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中G為C-Q；Q為-L-R5；P為H；且R5為5員雜環基、6員雜環基、苯基、苯基-C1-6烷基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基烷基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CQ; Q is -LR 5 ; P is H; and R 5 is a 5-membered heterocyclic group, a 6-membered heterocyclic group, a phenyl group, a phenyl-C 1-6 alkyl group. a 9-membered nitrogen-containing heterocyclic group or a 10 membered nitrogen-containing heterocyclic group wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, and halogen Base, pendant oxy, hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxyalkyl-C 1-6 alkane Aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic group] a carbonyl group; and a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中G為C-Q；Q為-L-R5；P為H；且R5為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R5未經取代或經一或多個獨立地選自以下之取代基取代：氟、氯、氰基、甲氧基、三氟甲基、乙氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基、側氧基、甲基、乙基或丁氧基羰基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CQ; Q is -LR 5 ; P is H; and R 5 is pyridinyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl, or Hydrofurop[2,3-b]furanyl, 2,5-di-oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolinyl, 1,2 -dihydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4 ,3-a]pyridyl, isoquinolyl, 1H-pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a Pyridyl, isoxazolo[5,4-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydro-3H -pyrazolo[3,4-b]pyridinyl, 3,4-dihydro-2H-piperido[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, cyano, methoxy, trifluoromethyl, ethoxycarbonyl, carboxy , N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl)-N-(methylaminoethyl) An aminocarbonyl group, (1-methylpyrazin-4-yl)carbonyl, pendant oxy, methyl, ethyl or butoxycarbonyl; and pharmaceutically acceptable salts thereof. 如請求項1之化合物，其中G為C-Q；Q為-L-R5；P為H；且R5為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4- 基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰 基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4- 氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基) 苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 The compound of claim 1, wherein G is CQ; Q is -LR 5 ; P is H; and R 5 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl , 1-Boc-piperidin-4-yl, hexahydrofuro[2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl-5-pyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-dimethyl 3-pyridyl, 2,4-dimethyl-5-pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-ethyl- 3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-isopropyl 5-5-pyridyl, 3-(1-methylvinyl)-5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl- 5-pyridyl, 3-(2-hydroxyethyl)-5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxypropyl -5-pyridyl, -(1,2-dihydroxyethyl)-5-pyridyl, 2-trifluoromethyl-3-pyridyl 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoro Methyl-6-pyridyl, 3-trifluoromethyl-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3-pyridine , 2-methoxy-5-pyridyl, 3-methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5-pyridyl , 2-methoxy-6-ethyl-5-pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2-cyano 5--5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5-methyl- 3-pyridyl, 2-bromo-3-methyl-5-pyridyl, 1,4-dimethyl-2-oxopyridine-5-yl, 1,3-dimethyl-2-oxo Pyridin-5-yl, 1-methyl-2-oxopurin-5-yl, 2-methyl-6-oxopurin-4-yl, 1-ethyl-2-oxopyridine -5-yl, 4-ethyl-1-methyl-2-oxoylpyridin-5-yl, 1-ethyl-2-methyl-6-oxiranylpyridin-5-yl, 1-iso C -2-Sideoxypyridin-5-yl, 1,2-dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-oxopyridine- 4-yl, 2-(4-morpholinylmethyl)-3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylaminocarbonyl) -6-pyridyl, 3-(3-methoxyphenyl)-5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl, 4 -chloro-5-methyl-pyrimidin-6-yl, 2,4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidin-5-yl , 4-fluoropyrimidin-2-yl, 4-trifluoromethyl-pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazin-5-yl, 2-dimethylaminocarbonyl-pyridyl Pyrazin-5-yl, pyridazin-3-yl, 1,3,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazole , 1-ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazole , 1-methyl-3-dimethylaminocarbonyl-5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazol-2-yl, Phenyl, 2,6-difluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3 -difluorophenyl, 2 ,6-difluoro-3-methoxyphenyl, 2,4-difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3-dichloro Phenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-three Fluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 4-methoxyphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylaminosulfonate Mercapto-2-fluorophenyl, 2-fluoro-5-methylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5-methoxy Phenylcarbonylphenyl, 2-fluoro-5-methoxycarbonylmethylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2-ethyl Phenyl, 2-methyl-5-carboxyphenyl, 2-chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro- 5-aminocarbonylphenyl, 2-cyanophenyl, 4-cyanophenyl 2-cyano-3-methylphenyl, 2-cyano-5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4- Chloro-2-cyanophenyl, 2-chloro-4-cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3,6 -dichlorophenyl, 2-cyano-3,6-difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro-2 -Cyano-6-fluorophenyl, 2-cyano-6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl] Phenyl, 5-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl-5- [N-(Methyl)-N-(methoxyethyl)aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2- Methyl-5-[N-(methyl)-N-(methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl Phenyl, 2,6-difluoro-3-((isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl)benzene , 2-fluoro-3-((ethylamino)carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl )) Aminocarbonyl)phenyl, 2-fluoro-5-(cyclobutyl ))aminocarbonyl)phenyl, 2-fluoro-5-(cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl)benzene , 2-fluoro-5-((methoxypropyl))aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5- ((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro-5 -((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-((1) -methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-( (1-methylpyrazol-5-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5 -((pyridin-2-ylmethyl)aminocarbonyl)phenyl, 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-( 1-Boc-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro -5-(1-ethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-morpholinyl))aminocarbonyl)phenyl, 2-fluoro-5-((4-morpholine) Ethyl)aminocarbonyl)phenyl, 2-chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl -1-tetrazolyl)phenyl, 3-(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolyl, 6-quinolinyl, 7-quinoline Lolinyl, 8-quinolyl, 5-chloro-6-quinolyl, 7-chloro-4-quinolyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8- Tetrahydroquinolin-5-yl, 4-quinazolinyl, quinoxalin-5-yl, 1-sided oxy-isoindol-4-yl, 1-sided oxy-isoporphyrin- 6-yl, 3-methyl-1H-indazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-carbazole-5-yl, 1,3- Dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1 , 2-dihydroquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-sided oxy-1,2-di Hydroquinolin-6-yl, 4-oxo-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5, 7-two -1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxooxy -1,2-dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxooxy-4-trifluoromethyl-1,2-dihydroquinolin-6- ,5,7-difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinoline ,6-isoquinolyl, 5-isoquinolinyl, 4-isoquinolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl -1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl- 1H-pyrazolo[3,4-b]pyridin-3-yl, 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazole [3,4-d]pyrimidin-4-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H- Imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl, 3-methylisoxazole[5,4- b]pyridin-4-yl,[1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H-pyridyl Zoxao[3,4-b]pyridin-3-yl, 6-methyl-3,4-dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof. 一種式IIc及式IId化合物， 其中：R1為H、烷基、烯基、鹵烷基、烷氧基、羥基烷基、胺基烷基、烷氧基烷基、羥基烷氧基烷基、烷氧基羰基胺基烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基，其中環烷基、環烷基烷基、芳基、芳烷基、雜環基或雜環基烷基中之該環烷基、芳基或雜環基環未經取代或經一或兩個獨立地選自羥基、烷氧基、烷基、側氧基或鹵基之取代基取代；R3為H、鹵基、烷氧基羰基、胺基羰基、氰基、氰基烷基、烷基羰基、雜環基羰基、烷基胺基羰基、烯基、炔基、羥基烯基、烷氧基烷氧基烷基、芳氧基烯基、烷氧基羰基烷基、烷基磺醯基烷基、烷基磺醯基烯基、烷基磺醯基炔基、雜環基炔基、雜環基羰基烷基、烷氧基炔基、羥基炔基或-XR4；X為一鍵、-O-或-S(O)n；n為0、1或2；R4為烷基、羥基烷基、鹵烷基、烷氧基烷基、烷氧基烯基、烷氧基羰基烷基、羧基烷基、胺基羰基烷基、烷基胺基羰基烷基、芳基、環烷基、環烯基、雜環基、芳烷基、芳烯基、芳基炔基、環烷基烷基、環烷基烯基、環烷基炔基、雜環基烷基或雜環基羰基烷基；其中R4中之環經1-3個獨立地選自以下之取代 基取代：H、烷基、鹵基、鹵烷基、羥基、烷氧基、鹵烷氧基、醯基、烷基磺醯基、雜環基、胺基磺醯基、烷基胺基磺醯基、氰基、烷氧基羰基、羧基、胺基、RR'N-C1-6烷基、烷氧基烷基、羥基烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷基、烷氧基烷基、胺基烷基或烷基胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經烷基取代之雜環；R5為芳基、芳烷基、雜環基烷基、環烷基或雜環基，其中R5未經取代或經1-3個獨立地選自以下之取代基取代：烷基、烷氧基、羥基、鹵基、鹵烷基、氰基、烷氧基羰基、羧基、醯基、環烷基、雜環基、羥基烷基、烷氧基烷基、側氧基、RR'N-、RR'N-C1-6烷基或RaRbNC(=O)，其中Ra為烷基且Rb為烷氧基烷基或胺基烷基；其中R及R'獨立地為H、烷基、芳基、雜環基、雜環基烷基或環烷基，其中該等雜環基烷基、環烷基及雜環基環未經取代或經1-3個獨立地選自烷基、烷氧基、羥基、鹵基、鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成雜環基；R6為芳基、芳烷基、雜環基、雜環基烷基或環烷基，其中各前述環未經取代或經1-4個獨立地選自以下之取代基取代：烷基、鹵基、鹵烷基、烷氧基、烷氧基羰基、羧基、胺基羰基、雜環基羰基、氰基、環烷基、雜環基、羥基烷基、烷氧基烷基、NR'R'、CH2NRR'、側氧基或醯基；L為O、S、CH2或CH2O；Q為-L-R5；且P為-L-R6；其限制條件為，當R3為H，R1為甲基，且L為O時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6- 基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，L為O，且R1為甲基時，則R5不為5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，L為O，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，L為O，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；其他限制條件為，當L為O，R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基，且R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基，L為O，且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基；及其醫藥學上可接受之鹽。 a compound of formula IIc and formula IId, Wherein: R 1 is H, alkyl, alkenyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxycarbonylaminoalkane Or a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group or a heterocyclic alkyl group, wherein a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclic group Or the cycloalkyl, aryl or heterocyclyl ring in the heterocyclylalkyl group is unsubstituted or substituted by one or two independently selected from hydroxy, alkoxy, alkyl, pendant or halo groups. Substituent; R 3 is H, halo, alkoxycarbonyl, aminocarbonyl, cyano, cyanoalkyl, alkylcarbonyl, heterocyclylcarbonyl, alkylaminocarbonyl, alkenyl, alkynyl, hydroxy Alkenyl, alkoxyalkoxyalkyl, aryloxyalkenyl, alkoxycarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, alkylsulfonylalkynyl, hetero Cycloalkynyl, heterocyclylcarbonylalkyl, alkoxyalkynyl, hydroxyalkynyl or -XR 4 ; X is a bond, -O- or -S(O)n; n is 0, 1 or 2; R 4 is alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxyalkenyl, alkoxy Carbocarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, aralkenyl, arylalkynyl a cycloalkylalkyl group, a cycloalkylalkenyl group, a cycloalkylalkynyl group, a heterocyclylalkyl group or a heterocyclic carbonylalkyl group; wherein the ring in R 4 is independently substituted with from 1 to 3 Substituent: H, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, fluorenyl, alkylsulfonyl, heterocyclyl, aminosulfonyl, alkylaminosulfonate Anthracenyl, cyano, alkoxycarbonyl, carboxy, amine, RR'NC 1-6 alkyl, alkoxyalkyl, hydroxyalkyl or R a R b NC(=O), wherein R a is an alkane And R b is alkyl, alkoxyalkyl, aminoalkyl or alkylaminoalkyl, or wherein R a and R b together with nitrogen form an unsubstituted or alkyl substituted heterocycle; 5 is an aryl, aralkyl, heterocyclylalkyl, cycloalkyl or heterocyclic group wherein R 5 is unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy Base, hydroxy, halo, haloalkyl, cyano, alkoxycarbonyl, carboxyl, fluorenyl Cycloalkyl, heterocyclyl, hydroxyalkyl, alkoxyalkyl, oxo, RR'N-, RR'NC 1-6 alkyl, or R a R b NC (= O ), wherein R a is Alkyl and R b is alkoxyalkyl or aminoalkyl; wherein R and R' are independently H, alkyl, aryl, heterocyclyl, heterocyclylalkyl or cycloalkyl, wherein a heterocyclylalkyl, cycloalkyl and heterocyclyl ring unsubstituted or substituted with from 1 to 3 substituents independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, cyano or carboxy Substituting; or R' and R may form a heterocyclic group together with N; R 6 is an aryl group, an aralkyl group, a heterocyclic group, a heterocyclic alkyl group or a cycloalkyl group, wherein each of the aforementioned rings is unsubstituted or subjected to 1 - 4 substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, alkoxycarbonyl, carboxy, aminocarbonyl, heterocyclylcarbonyl, cyano, cycloalkyl, Heterocyclyl, hydroxyalkyl, alkoxyalkyl, NR'R', CH 2 NRR', pendant oxy or fluorenyl; L is O, S, CH 2 or CH 2 O; Q is -LR 5 ; And P is -LR 6 ; the restriction is that when R 3 is H, R 1 is methyl, and L is O, then R 5 is not [1,2,4]triazole [4,3-a Pyridine -8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6- Base, 2-sided oxy-1,2-dihydroquinolin-6-yl, 4-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-methyl- 1-tertiaryoxy-1,2-dihydro-isoquinolin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5- Chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 1-methyl-1H-indazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are When R 3 is Br, L is O, and R 1 is a methyl group, then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxooxy-1,2 -dihydroquinolin-6-yl, 5,7-difluoro-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5, 7-Difluoro-4-ethyl-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 2-methyl-1-yloxy-1,2-di Hydrogen-isoquinolin-6-yl; other restrictions: when R 3 is 1-methyl-1H-pyrazol-4-yl, L is O, and R 1 is methyl, then R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazole-5-yl, L is O, and when R 1 is a methyl group, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4 - dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl ; other restrictions: when L is O, R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridyl, and R 3 When it is 2-pyridylthio, bromo, methoxyethoxy or trifluoromethyl, R 1 is not phenyl or tert-butyl; other restrictions are, when R 3 is 2-pyridylthio, L When O is, and R 6 is 2-ethyl-3-pyridyl, R 1 is not 4-methyl-2-imidazolylmethyl; and a pharmaceutically acceptable salt thereof. 一種式IIIa化合物， 其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺 基、胺基磺醯基、C1-6烷基胺基磺醯基、氰基、羧基、RR'N-C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)-，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5-6員雜環；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-16員雜環基、氰基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、C1-6烷基-NRR'、胺基磺醯基、C1-6烷基胺基磺醯基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基，其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之 取代基取代；或R'及R可與N一起形成5-10員雜環基；且其中R6為5員含氮雜環基、5員含氧雜環基、6員含氮雜環基、6員含氧雜環基、苯基、苄基、9員雙環含氮雜環基、10員雙環含氧雜環基或10員雙環含氮雜環基，其中R6未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為2-吡啶硫基、溴、甲氧基乙氧基或三氟甲基，且R6為2-乙基-3-吡啶基、2-甲基-3-吡啶基或2,6-二甲基-3-吡啶基時，R1不為苯基或第三丁基；其他限制條件為，當R3為2-吡啶硫基且R6為2-乙基-3-吡啶基時，R1不為4-甲基-2-咪唑基甲基；及其醫藥學上可接受之鹽。 a compound of formula IIIa, Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 alkyl, 5-10 membered heterocyclic or 5-10 membered heterocyclyl-C 1-6 alkyl, wherein the aryl or hetero The cycloalkyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant oxy or halo; wherein R 3 is -XR 4 , H, halo, cyanide , C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkenyl, C 2-6 Alkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy- C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl -C 1-6 alkyl, C 1-6 alkylamino -C 1-6 alkyl group, C 1-6 alkylsulfonyl group -C 1-6 alkyl, C 1-6 alkylsulfonyl group -C 2-6 alkenyl group, C 1-6 alkyl sulfo Mercapto-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1 -6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3 -6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkynyl or a 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 is unsubstituted or independently selected from 1 to 3 Substituted by the following substituents: C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, aminosulfonyl, C 1-6 alkylaminosulfonyl, Cyano, carboxyl, RR'NC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl or R a R b NC(=O)-, wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl Or a C 1-6 alkyl-C 1-6 aminoalkyl group, or a 5-6 member heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein X Is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1 -6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl , C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 naphthenic , C 5-6 cycloalkenyl, 5-10 membered heterocyclic group, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 Aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2 -6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein the aryl, cycloalkyl, ring in R 4 The alkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 Alkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carboxyl, 5-16 membered heterocyclyl, cyano, amino, C 1-6 aminoalkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 alkyl-NRR', aminosulfonyl, C 1-6 alkylaminosulfonyl or R a R b NC(=O), wherein R a is C 1- 6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 amine An alkyl group, or a 5- or 6-membered heterocyclic ring wherein R a and R b together with a nitrogen form an unsubstituted or C 1-6 alkyl group; wherein R and R' are independently H, C 1-6 alkane a phenyl group, a 5-10 membered heterocyclic group, a 5-10 membered heterocyclyl-C 1-6 alkyl group or a C 3-6 cycloalkyl group, wherein the heterocyclic group is a C 1-6 alkyl group, Phenyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl ring are unsubstituted or 1-3 independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo Substituted with a substituent of a C 1-6 haloalkyl group, a cyano group or a carboxy group; or R' and R together with N form a 5-10 membered heterocyclic group; and wherein R 6 is a 5-membered nitrogen-containing heterocyclic group, 5-membered oxygen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group, 6-membered oxygen-containing heterocyclic group, phenyl group, benzyl group, 9-membered bicyclic nitrogen-containing heterocyclic group, 10 membered bicyclic oxygen-containing heterocyclic group or 10 members double a cyclic nitrogen-containing heterocyclic group wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, halo, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1-6 alkylaminocarbonyl, C 1- 6 alkylamino-C 1-6 alkylaminocarbonyl or [optionally substituted 4-6 member nitrogen-containing heterocyclic]carbonyl; the limitation is that when R 3 is 2-pyridylthio, bromine , methoxyethoxy or trifluoromethyl, and when R 6 is 2-ethyl-3-pyridyl, 2-methyl-3-pyridyl or 2,6-dimethyl-3-pyridinyl R 1 is not a phenyl group or a tert-butyl group; other restrictions are that when R 3 is 2-pyridylthio group and R 6 is 2-ethyl-3-pyridyl group, R 1 is not 4-methyl group 2-imidazolylmethyl; and pharmaceutically acceptable salts thereof. 如請求項27之化合物，其中R1為甲基、乙基、丙基、烯丙基、第三丁基、三氟-乙基、甲氧基、甲氧基乙基、羥基乙基、羥基丙基、2,3-二羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、BOC-胺基乙基、胺基乙基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、苯乙基、嗎啉-4-基乙基、2-吡啶基甲基、3-吡啶基甲基、4-吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑-5-基甲基、1-甲基-咪唑-4-基甲基、1-甲基-咪唑-5-基甲基、4-甲基-咪唑-2-基甲基、5-甲基-咪唑-2-基甲基、1,5-二甲基吡唑-4-基甲基、2-甲基噻唑基-5-甲基、5-甲基-異噁唑-3-基甲基或苯基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 1 is methyl, ethyl, propyl, allyl, tert-butyl, trifluoro-ethyl, methoxy, methoxyethyl, hydroxyethyl, hydroxy Propyl, 2,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxyethoxyethyl, BOC-aminoethyl, aminoethyl, 2-hydroxyphenylmethyl, 3- Hydroxyphenylmethyl, 4-hydroxy-phenylmethyl, 4-fluorophenylmethyl, phenethyl, morpholin-4-ylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 6-methyl-2-oxo-1,2-dihydropyridylmethyl, imidazo-5-ylmethyl, 1-methyl-imidazol-4-ylmethyl, 1-methyl-imidazol-5-ylmethyl, 4-methyl-imidazol-2-ylmethyl, 5-methyl-imidazol-2-ylmethyl, 1,5-dimethylpyrazole-4 a methyl group, a 2-methylthiazolyl-5-methyl group, a 5-methyl-isoxazol-3-ylmethyl group or a phenyl group; and a pharmaceutically acceptable salt thereof. 如請求項27之化合物，其中R1為甲基或乙基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 1 is methyl or ethyl; and a pharmaceutically acceptable salt thereof. 如請求項27之化合物，其中R3為-SR4；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 3 is -SR 4 ; and a pharmaceutically acceptable salt thereof. 如請求項27之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2- Dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanylmethoxy , methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutyl Thio group, carboxyethylthio group, (methylaminocarbonyl)methylthio group, (dimethylaminocarbonyl)methylthio group, (3-hydroxy-3-methylbutyl)thio group, (2-hydroxyl group) -2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1 -T-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(four Hydrogen-2H-piperazin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylsulfide Base, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridine sulfur , 2-chloro-4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1 -hydroxyvinylpiperidin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-A (carbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, ( 1-isopropylcarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylsulfide , 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl) Piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl Thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H -piperidin-4-ylthio; and pharmaceutically acceptable salts thereof. 如請求項27之化合物，其中R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄 基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己 烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基、1,4-二氧雜螺[4.5]癸-7-烯-7-基，3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基 苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)-4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑 基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙 氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基，3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6- 基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-唑啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2- Methyl butyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2- Hydroxy-2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1,2 -dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl , 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxymethyl Oxymethyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, propylene -2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy -2-methylpropenyl, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxy Vinyl, 2-hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxy B Aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonylmethyl , ethoxycarbonylpropyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, carboxyl Ethyl, carboxypropyl, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxyl -2-methylpropoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyn-1-yl , cyclopentylmethyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonylpropyl , methylsulfonyl butyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1 -phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinylmethyl , 1-piperidinylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-yl , 4-methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1,1- Dioxy ionylthiomorpholinyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3- Methyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran-3 -ylmethyl, 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl) Propyl, 1,3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]heptane- 1-ylmethyl, 2-oxa-6-azaspiro[3.3] Hept-6-ylmethyl, 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy-cyclopentyl Methyl, 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1-(methoxycyclopentyl) Bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2-sided oxygen Cyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl)-cyclo Butyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxymethyl ring Pentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3-sided oxy-cyclopentyl , 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl, cycloheptane Base, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentene 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-oxo-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-en-1-yl , cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4-hydroxyl Methyl-cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl) ring Hexenyl, 4-(3-fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl) ring Hexenyl, cycloheptenyl, 1,4-dioxaspiro[4.5]dec-7-ene-7-yl, 3-hydroxy-3-oxetanyl, 2-tetrahydro-furanyl , 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl-2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3- Tetrahydro-furanyl, 2-oxopyryrrolidin-1-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5,5 -tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxytetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran-3 -yl, tetrahydropyran-2-yl, 3,6-dihydropyran-4-yl, 3,6-dihydropentan-5-yl 5,6-Dihydro-2H-piperidin-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-dimethyl-3,6-dihydro-2H-peri喃-4-yl, 2,2-dimethyl-3,6-dihydro-2H-piperidin-4-yl, 3,4-2H-dihydropyran-4-yl, 1,4-di Oxaspiro[4.5]pyridin-7-en-8-yl, 1,1-di-oxy-isothiazolidin-2-yl, 1,1-dioxyindolyltetrahydro-2H-thiopyran 4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,3,6-tetrahydropyridine- 4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxycarbonyl)-1,2,3,6-tetrahydro Pyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1-(di) Methylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-tri Fluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonyl Phenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonate Mercaptoaminophenyl, 3-methylamine Sulfophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6-methoxyphenyl, 4- Cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(dimethylaminocarbonyl)phenyl, 4-(Dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl, 4-ethylaminocarbonylbenzene , 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N-methylaminocarbonyl)phenyl , 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-phenyl, 3-(N-methoxy Benzyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethylaminocarbonylbenzene , 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethylaminocarbonylbenzene , 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl-phenyl, 1 ,2 -dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-ylcarbonyl)phenyl, 3 -(3-hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl, 3-(4- Morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methoxyphenyl, 2 -fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonylphenyl, 4-methyl Oxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3-difluoromethoxybenzene , 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxy Phenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazole 1,1,5,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2,2, 2-trifluoroethyl]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxy Methyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-cyclobutyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyridyl Azyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxy Ethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl 5-pyrazolyl, 3-methylaminocarbonyl-pyrazol-5-yl, 3-dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyridyl Zyrid-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2-methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazole-4-yl, 1-methyl -Triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxypropyl-triazin-4-yl, 1-hydroxybutyl-triazin-4-yl, 2- Cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophen-5-yl, 2-(N-methoxyethyl-N- Methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophen-5-yl, 2-(2-hydroxy-2-methylethyl)thiophene -5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2 -methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5- Pyridyl, 2-difluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2-methyl Oxy-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy 4-pyridyl, 2-methoxy-5-pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy-4 -pyridyl, 5-fluoro-2-hydroxyethoxy-4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy 5-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-(1 , 1,1-trifluoroethoxy)-5-pyridyl, 2-cyclopropylmethoxy-5- Pyridyl, 2-(methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl, 2- Fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano-5 -pyridyl, 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5-pyridyl , 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2-side Oxy-1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxooxy-1 , 2-dihydropyridin-5-yl, 1-isopropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy-1,2 -dihydropyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2-dihydro Pyridin-4-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl, 3- Methylaminocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl-5-pyridyl Pyridyl, 2-methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonylamino Ethylaminocarbonyl-5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethylamino Carbonyl-5-pyridyl, 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4-pyridyl 4-fluoro-2-methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl, 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2 -cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethoxy -5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl-4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylaminocarbonyl Pyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-oxo-dihydro-5 - mercapto, 6-fluorenyl, 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6-fluorene , imidazo[1,2-a]pyridin-3-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridin-6-yl, 1,1 -di-oxo-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-8-yl, benzoxazole-5-yl, Benzooxazole-6-yl, 1,1-di-oxy-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine-8-yl, 4 -methyl-5-oxooxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazole-5- Base, 2-ethylbenzoxazol-5-yl, 2-isopropylbenzoxazol-5-yl, 2-sided oxy-2(3H)-benzo[d]oxazole-5- , benzothiazol-5-yl, benzothiazole-6-yl, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5-indole Azyl, 1-methyl-6-carbazolyl, 2-methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4-yl, 1,5-Dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2-methyl-3 - pendant oxy-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2- Methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b] [1 , 4] thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzo[d][ 1,3] oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxathiazol-5-yl,[1,2,4]triazolo[ 4,3-a]pyridin-5-yl,[1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2,4]triazole And [4,3-a]pyridin-6-yl, 6-oxazolinyl, 7-quinolyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl; and its medicine A salt that is acceptable for learning. 如請求項27之化合物，其中R6為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四 氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基；其中R6未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、第三丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 6 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, 2, 5-tertiary oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolyl, 1,2-dihydroquinolinyl, 5,6,7,8- Tetrahydroquinolyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H- Pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazole[5,4-b] Pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridinyl, 3 ,4-dihydro-2H-piperacino[2,3-b]pyridinyl or An alkyl or pyrimidinyl group; wherein R 6 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, Ethoxycarbonyl, tert-butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-( Methyl)-N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof. 如請求項27之化合物，其中R6為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶 基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧 基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰 基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2-氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉 基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 The compound of claim 27, wherein R 6 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl, 1-Boc-piperidin-4-yl, hexahydrofuran And [2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl- 3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl- 5-pyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl-5 Pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methylvinyl -5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl)- 5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-dihydroxyethyl) 5-)pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 2- Trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoromethyl-6-pyridyl, 3-trifluoromethyl 5-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridyl, 3 -methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl-5- Pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3-methyl- 5-pyridyl, 1,4-dimethyl-2-oxopurin-5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl-2- Sideoxypyridin-5-yl, 2-methyl-6-oxooxypyridin-4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1-methyl -2-Sideoxypyridin-5-yl, 1-ethyl-2-methyl-6-oxoxypyridin-5-yl, 1-isopropyl-2-indolylpyridin-5-yl, 1,2- Methyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinylmethyl)-3 -pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methoxyphenyl) -5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidin-6-yl, 2,4 - dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl- Pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl, pyridazin-3-yl, 1,3, 5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1-ethyl-4-bromo-5-pyrazolyl, 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1-methyl-3-dimethylaminocarbonyl-5 -pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazol-2-yl, phenyl, 2,6-difluorophenyl, 2-fluorophenyl , 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methoxy Phenyl group, 2, 4 -difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro- 4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyl Ethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylsulfonylbenzene , 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro-5-methyl Carbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro- 5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonylmethyl Phenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl, 2-chloro -5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2-cyanophenyl, 4- Cyanophenyl, 2-cyano-3-methylphenyl, 2-cyano 5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4- Cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3,6- Difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2-cyano- 6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[(isopropyl) Aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methoxy B Aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N- (Methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3-(( Isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl)phenyl, 2-fluoro-3-((ethylamino) Carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl))aminocarbonyl)phenyl, 2-fluoro-5- (cyclobutyl))aminocarbonyl)phenyl, 2-fluoro-5-( Amyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxypropyl)) Aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)phenyl, 2-chloro 5-(-(1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl)aminocarbonyl)benzene , 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)aminocarbonyl)phenyl , 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl))aminocarbonyl)benzene , 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl-piperidin-4-yl)) Aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-morpholinyl)aminocarbonyl Phenyl, 2-fluoro-5-((4-morpholinoethyl)aminocarbonyl)phenyl, 2- -5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl, 3-( 2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolyl, 6-quinolyl, 7-quinolinyl, 8-quinolinyl, 5-chloro- 6-quinolyl, 7-chloro-4-quinolyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquinoline- 5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4-quinazole Lolinyl, quinoxaline-5-yl, 1-sided oxy-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl-1H-carbazole 4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-indazol-4-yl, [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4-methyl Keto-2-oxo-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1 ,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-oxooxy-1,2-dihydroquinolin-6-yl, 4-sided oxy -dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl- 2-sided oxy-1,2-di Hydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxo-1,2-dihydroquinolin-6-yl, 5,7-difluoro -1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2 - pendant oxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 4-isoquine Lolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1 -ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 5- Fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo[1,2- a] Pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl- 3H-imidazo[4,5-b]pyridin-6-yl, 3-methylisoxazo[5,4-b]pyridin-4-yl,[1,2,4]triazolo[4 ,3-a]pyridine-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-methyl- 3,4-Dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof. 一種式IVa化合物， 其中R1為C1-6烷基、C2-6烯基、C1-6鹵烷基、C1-6烷氧基、C1-6羥基烷基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基-C1-6烷氧基-C1-6烷基、C1-6烷氧基羰基胺基-C1-6烷基、C6-10芳基、C6-10芳基-C1-6烷基、5-10員雜環基或5-10員雜環基-C1-6烷基，其中該芳基或雜環基環未經取代或經一或兩個獨立地選自C1-6烷基、羥基、側氧基或鹵基之取代基取代；其中R3為-X-R4、H、鹵基、氰基、C1-6鹵烷基、C1-6氰基烷基、C1-6烷氧基羰基、C1-6烷基羰基、4-10員雜環基羰基、胺基羰基、C1-6烷基胺基羰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6羥基烷基、C2-6羥基烯基、C2-6羥基炔基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基-C2-6炔基、C6-10芳氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、 C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C1-6烷基磺醯基-C1-6烷基、C1-6烷基磺醯基-C2-6烯基、C1-6烷基磺醯基-C2-6炔基、C6-10芳基、C3-6環烷基、C5-6環烯基、4-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、雜環基-C1-6烷基、雜環基-C2-6炔基或4-10員雜環基羰基-C1-6烷基；其中R3中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6醯基、C1-6烷基磺醯基、C1-6烷氧基羰基、羧基、5-10員雜環基、胺基、C1-6胺基烷基、C1-6烷氧基-C1-6烷基、C1-6羥基烷基、C1-6鹵烷氧基、RR'N-C1-6烷基-、胺基磺醯基、C1-6烷基胺基磺醯基、氰基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；其中R及R'獨立地為H、C1-6烷基、苯基、5-10員雜環基、5-10員雜環基-C1-6烷基或C3-6環烷基，其中該等雜環基-C1-6烷基、苯基、C3-6環烷基及5-10員雜環基環未經取代或經1-3個獨立地選自C1-6烷基、C1-6烷氧基、羥基、鹵基、C1-6鹵烷基、氰基或羧基之取代基取代；或R'及R可與N一起形成5-10員雜環基；其中X為S或O；其中R4為C1-6烷基、C1-6羥基烷基、C1-6鹵烷基、C1-6烷氧基-C1-6烷基、C1-6烷氧基-C2-6烯基、C1-6烷氧基羰基-C1-6烷基、C1-6羧基烷基、胺基羰基-C1-6烷基、C1-6烷基胺基羰基-C1-6烷基、C6-10芳基、C3-6環烷基、C5-6環烯基、5-10員雜環基、C6-10芳基-C1-6烷基、C6-10芳基-C2-6烯基、C6-10芳基-C2-6炔基、C3-6環烷 基-C1-6烷基、C3-6環烷基-C2-6烯基、C3-6環烷基-C2-6炔基、5-10員雜環基-C1-6烷基或5-10員雜環基羰基-C1-6烷基；其中R4中之該芳基、環烷基、環烯基或雜環基環未經取代或經1-3個獨立地選自以下之取代基取代：C1-6烷基、鹵基、C1-6鹵烷基、羥基、C1-6烷氧基、C1-6鹵烷氧基、C1-6醯基、C1-6烷基磺醯基、胺基磺醯基、C1-6烷基胺基磺醯基、C1-6烷氧基羰基、羧基、氰基、5-16員雜環基、胺基、RR'N-C1-6烷基-、C1-6烷氧基-C1-6烷基、C1-6羥基烷基或RaRbNC(=O)，其中Ra為C1-6烷基且Rb為C1-6烷基、C1-6烷氧基-C1-6烷基、C1-6胺基烷基或C1-6烷基-C1-6胺基烷基，或其中Ra及Rb與氮一起形成未經取代或經C1-6烷基取代之5或6員雜環；且其中R5為5員含氮雜環基、6員含氮雜環基、苯基、9員含氮雜環基或10員含氮雜環基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：C1-6烷基、氰基、鹵基、側氧基、羥基、C1-6烷氧基、C1-6鹵烷基、C1-6烷氧基羰基、羧基、C1-6烷氧基-C1-6烷基胺基羰基、C1-6烷基胺基羰基、C1-6烷基胺基-C1-6烷基胺基羰基或[視情況經取代之4-6員含氮雜環基]羰基；其限制條件為，當R3為H，R1為甲基時，則R5不為[1,2,4]三唑[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、異喹啉-5-基、異喹啉-6-基、喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、1-甲基-1H-吲唑-5-基或3-甲基-3H-咪唑并[4,5-b]吡啶-6-基；其他限制條件為，當R3為Br，且R1為甲基時，則R5不為5,7-二 氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基或2-甲基-1-側氧基-1,2-二氫-異喹啉-6-基；其他限制條件為，當R3為1-甲基-1H-吡唑-4-基，且R1為甲基時，則R5不為1-乙基-1H-吡唑-5-基；其他限制條件為，當R3為1-甲基-1H-吡唑-5-基，且R1為甲基時，則R5不為2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基或1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基；及其醫藥學上可接受之鹽。 a compound of formula IVa, Wherein R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxy-C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxycarbonylamino-C 1 a -6 alkyl group, a C 6-10 aryl group, a C 6-10 aryl-C 1-6 alkyl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic group-C 1-6 alkyl group, wherein The aryl or heterocyclyl ring is unsubstituted or substituted with one or two substituents independently selected from C 1-6 alkyl, hydroxy, pendant or halo; wherein R 3 is -XR 4 , H , halo, cyano, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, 4-10 membered heterocyclylcarbonyl, Aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkenyl , C 2-6 hydroxyalkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl, C 1- 6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxy-C 2-6 alkynyl, C 6-10 aryloxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl -C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkyl Aminocarbonyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 2-6 alkenyl, C 1-6 alkane Sulfosyl-C 2-6 alkynyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 4-10 membered heterocyclic, C 6-10 aryl - C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3-6 cycloalkyl-C 2-6 alkynyl, heterocyclyl-C 1-6 alkyl, heterocyclyl-C 2-6 alkyne Or a 4-10 membered heterocyclylcarbonyl-C 1-6 alkyl group; wherein the aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring in R 3 is unsubstituted or 1-3 independently Substituted by a substituent selected from C 1-6 alkyl, halo, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 fluorenyl, C 1-6 alkyl sulfonate Mercapto, C 1-6 alkoxycarbonyl, carboxyl, 5-10 membered heterocyclic, amine, C 1-6 aminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, RR 'NC 1-6 alkyl-, aminosulfonyl, C 1-6 alkylaminosulfonyl, cyano or R a R b NC (= O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl C 1-6 aminoalkyl or C 1-6 alkyl -C 1-6 form an unsubstituted or substituted C 1-6 alkyl group with the 5-alkyl, or wherein R a and R b together with the nitrogen Or a 6-membered heterocyclic ring; wherein R and R' are independently H, C 1-6 alkyl, phenyl, 5-10 membered heterocyclic, 5-10 membered heterocyclyl-C 1-6 alkyl or C a 3-6 cycloalkyl group, wherein the heterocyclic group -C 1-6 alkyl group, phenyl group, C 3-6 cycloalkyl group and 5-10 membered heterocyclic ring are unsubstituted or 1-3 independent Substituted with a substituent selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo, C 1-6 haloalkyl, cyano or carboxy; or R' and R may form together with N a 5-10 membered heterocyclic group; wherein X is S or O; wherein R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy- C 1-6 alkyl, C 1-6 alkoxy-C 2-6 alkenyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, C 1-6 carboxyalkyl, aminocarbonyl- C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, 5-10 Heterocyclyl, C 6-10 aryl-C 1-6 alkyl, C 6-10 aryl-C 2-6 alkenyl, C 6-10 aryl-C 2-6 alkynyl, C 3- 6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 2-6 alkenyl, C 3 -6 cycloalkyl-C 2-6 alkynyl, 5-10 membered heterocyclyl-C 1-6 alkyl or 5-10 membered heterocyclylcarbonyl-C 1-6 alkyl; wherein R 4 The aryl, cycloalkyl, cycloalkenyl or heterocyclyl ring is unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6 alkyl, halo, C1-6 halo Base, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 fluorenyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkyl Aminosulfonyl, C 1-6 alkoxycarbonyl, carboxyl, cyano, 5-16 membered heterocyclic, amine, RR'NC 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 hydroxyalkyl or R a R b NC(=O), wherein R a is C 1-6 alkyl and R b is C 1-6 alkyl, C 1-6 alkane Oxy-C 1-6 alkyl, C 1-6 aminoalkyl or C 1-6 alkyl-C 1-6 aminoalkyl, or wherein R a and R b together with nitrogen form unsubstituted or a 5- or 6-membered heterocyclic ring substituted with a C 1-6 alkyl group; and wherein R 5 is a 5-membered nitrogen-containing heterocyclic group, a 6-membered nitrogen-containing heterocyclic group, a phenyl group, a 9-membered nitrogen-containing heterocyclic group or 10 members. a nitrogen-containing heterocyclic group wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from C 1-6 alkyl, cyano, halo, pendant oxy , hydroxy, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, C 1 a -6 alkylaminocarbonyl group, a C 1-6 alkylamino group-C 1-6 alkylaminocarbonyl group or a [substituted 4-6 member nitrogen-containing heterocyclic group]carbonyl group; When R 3 is H and R 1 is methyl, then R 5 is not [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy -1,2-dihydroquinolin-6-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinoline-6-yl, 2-oxo-1,2-dihydroquinoline Porphyrin-6-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 2-methyl-1-oxo-1,2-dihydro-isoquine Porphyrin-6-yl, 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1, 2-Dihydroquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 1-methyl- 1H-carbazol-5-yl or 3-methyl-3H-imidazo[4,5-b]pyridine-6-yl; other restrictions are when R 3 is Br and R 1 is methyl Then R 5 is not 5,7-difluoro-1,3,4-trimethyl-2-oxo-1,2-dihydroquinolin-6-yl, 5,7-difluoro-1- Methyl-2-oxo-4-trifluoromethyl-1,2-dihydro Polin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl or 2-methyl-1-side Oxy-1,2-dihydro-isoquinolin-6-yl; other restrictions are when R 3 is 1-methyl-1H-pyrazol-4-yl and R 1 is methyl R 5 is not 1-ethyl-1H-pyrazol-5-yl; other restrictions are, when R 3 is 1-methyl-1H-pyrazol-5-yl, and R 1 is methyl, then R 5 is not 2-methyl-1-oxooxy-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl-2-oxo- 1,2-Dihydroquinolin-6-yl or 1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl; and pharmaceutically acceptable salts thereof. 如請求項35之化合物，其中R1為甲基、乙基、丙基、異丙基、第三丁基、烯丙基、三氟乙基、甲氧基乙基、羥基乙基、羥基丙基、1,2-二羥基丙基、羥基乙氧基乙基、胺基乙基、苯基、2-羥基苯基甲基、3-羥基苯基甲基、4-羥基-苯基甲基、4-氟苯基甲基、嗎啉-4-基乙基、吡啶基甲基、6-甲基-2-側氧基-1,2-二氫吡啶基甲基、咪唑基甲基、1-甲基-咪唑基甲基、2-甲基噻唑基甲基或5-甲基-異噁唑基甲基；及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 1 is methyl, ethyl, propyl, isopropyl, tert-butyl, allyl, trifluoroethyl, methoxyethyl, hydroxyethyl, hydroxypropyl 1,1,2-dihydroxypropyl, hydroxyethoxyethyl, aminoethyl, phenyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxy-phenylmethyl , 4-fluorophenylmethyl, morpholin-4-ylethyl, pyridylmethyl, 6-methyl-2-oxooxy-1,2-dihydropyridylmethyl, imidazolylmethyl, 1-methyl-imidazolylmethyl, 2-methylthiazolylmethyl or 5-methyl-isoxazolylmethyl; and pharmaceutically acceptable salts thereof. 如請求項35之化合物，其中R1為甲基或乙基；及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 1 is methyl or ethyl; and a pharmaceutically acceptable salt thereof. 如請求項35之化合物，其中R3為-SR4；及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 3 is -SR 4 ; and a pharmaceutically acceptable salt thereof. 如請求項35之化合物，其中R3為甲氧基丙氧基、2-(甲氧基)丙氧基、羥基乙氧基、羥基丙氧基、2-羥基丙氧基、1,2-二羥基丙氧基、1-羥基-2-甲基丙氧基、2-羥基丁氧基、苯氧基、2-甲基-3-吡啶氧基、3-氧雜環丁烷基甲氧基、甲氧基羰基甲硫基、甲氧基羰 基乙硫基、甲氧基丙硫基、4-甲氧基丁-2-基硫基、羥基丙硫基、3,4-二羥基丁硫基、羧基乙硫基、(甲基胺基羰基)甲硫基、(二甲基胺基羰基)甲硫基、(3-羥基-3-甲基丁基)硫基、(2-羥基-2-甲基丁基)硫基、二氟甲硫基、(4-甲基哌嗪-1-基)-羰基甲硫基、(嗎啉-4-基)羰基甲硫基、(1-第三丁氧基羰基哌啶-4-基)甲硫基、(4-哌啶基)甲硫基、(四氫-2H-哌喃-4-基)甲硫基、1-(四氫-2H-哌喃-4-基)乙硫基、(5-甲基-2-噁二唑基)甲硫基、2-吡啶基甲硫基、3,4-二羥基環戊基硫基、4-羥基環己基硫基、環戊烯基硫基、苯硫基、苄硫基、2-吡啶硫基、2-氯-4-吡啶硫基、(4-哌啶基-2-吡啶基)甲硫基、(1-甲基哌啶-4-基-2-吡啶基)甲硫基、(1-羥基乙烯基哌啶-4-基-2-吡啶基)甲硫基、(4-哌啶基)硫基、(1-異丙基)哌啶-4-基硫基、(1-甲基羰基)哌啶-4-基硫基、1-(第三丁氧基羰基)哌啶-4-基硫基、(1-甲基磺醯基)哌啶-4-基硫基、(1-異丙基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、1-(甲氧基乙基羰基)哌啶-4-基硫基、1-(二甲基胺基羰基)哌啶-4-基硫基、1-(甲氧基羰基)哌啶-4-基硫基、(1-(5-氯嘧啶-2-基)哌啶-4-基)硫基、(1-(2-嘧啶基)哌啶-4-基)硫基、(1-(5-氯吡嗪-2-基)哌啶-4-基)硫基、1-(第三丁氧基羰基)吡咯啶-3-基硫基、3-甲基異噁唑并[5,4-b]吡啶-4-基硫基或四氫-2H-哌喃-4-基硫基；及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 3 is methoxypropoxy, 2-(methoxy)propoxy, hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, 1,2- Dihydroxypropoxy, 1-hydroxy-2-methylpropoxy, 2-hydroxybutoxy, phenoxy, 2-methyl-3-pyridyloxy, 3-oxetanylmethoxy , methoxycarbonylmethylthio, methoxycarbonylethylthio, methoxypropylthio, 4-methoxybut-2-ylthio, hydroxypropylthio, 3,4-dihydroxybutyl Thio group, carboxyethylthio group, (methylaminocarbonyl)methylthio group, (dimethylaminocarbonyl)methylthio group, (3-hydroxy-3-methylbutyl)thio group, (2-hydroxyl group) -2-methylbutyl)thio, difluoromethylthio, (4-methylpiperazin-1-yl)-carbonylmethylthio, (morpholin-4-yl)carbonylmethylthio, (1 -T-butoxycarbonylpiperidin-4-yl)methylthio, (4-piperidyl)methylthio, (tetrahydro-2H-piperidin-4-yl)methylthio, 1-(four Hydrogen-2H-piperazin-4-yl)ethylthio, (5-methyl-2-oxadiazolyl)methylthio, 2-pyridylmethylthio, 3,4-dihydroxycyclopentylsulfide Base, 4-hydroxycyclohexylthio, cyclopentenylthio, phenylthio, benzylthio, 2-pyridine sulfur , 2-chloro-4-pyridylthio, (4-piperidinyl-2-pyridyl)methylthio, (1-methylpiperidin-4-yl-2-pyridyl)methylthio, (1 -hydroxyvinylpiperidin-4-yl-2-pyridyl)methylthio, (4-piperidinyl)thio, (1-isopropyl)piperidin-4-ylthio, (1-A (carbonyl)piperidin-4-ylthio, 1-(t-butoxycarbonyl)piperidin-4-ylthio, (1-methylsulfonyl)piperidin-4-ylthio, ( 1-isopropylcarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, 1-(methoxyethylcarbonyl)piperidin-4-ylsulfide , 1-(dimethylaminocarbonyl)piperidin-4-ylthio, 1-(methoxycarbonyl)piperidin-4-ylthio, (1-(5-chloropyrimidin-2-yl) Piperidin-4-yl)thio, (1-(2-pyrimidinyl)piperidin-4-yl)thio, (1-(5-chloropyrazin-2-yl)piperidin-4-yl Thio, 1-(t-butoxycarbonyl)pyrrolidin-3-ylthio, 3-methylisoxazo[5,4-b]pyridin-4-ylthio or tetrahydro-2H -piperidin-4-ylthio; and pharmaceutically acceptable salts thereof. 如請求項35之化合物，其中R3為H、溴、氰基、甲基、乙基、丙基、異丙基、2-甲基丙基、2,2-二甲基丙基、2-甲基丁基、三氟甲基、3,3,3-三氟丙基、氟甲基、氟丙基、羥基甲基、羥基乙基、1-羥基-2-甲基乙基、2-羥基-2-甲基乙基、羥基丙基、2-羥基丙基、1-羥基丙-2-基、1,2-二羥基丙基、羥基丁基、2-羥基丁基、1,2-二羥基丁基、2-羥基-2-甲基丁基、2,2-(二羥基甲基)丁 基、1-羥基乙氧基-2-溴乙基、2-(羥基乙氧基)乙基、2-(羥基乙氧基)丙基、(甲氧基甲基)乙基、1-甲氧基乙氧基-2-溴乙基、2-羥基-2-甲基戊基、2-羥基-2-甲基己基、1,2-二羥基戊基、(四氫哌喃-4-基)-羥基甲基、2-氟-2-甲基丁基、甲氧基甲氧基甲基、甲氧基甲基、甲氧基丙基、甲氧基丁基、4,5-二甲氧基戊基、甲氧基戊基、乙氧基乙烯基、乙烯基、丙烯-2-基、丙烯-1-基、丙-1-烯-2-基、3-羥基丙-1-烯-2-基、1-羥基-2-甲基丙烯基、丁烯基、3,3-二甲基丁烯-1-基、甲氧基丙烯-1-基、羥基丙烯基、苄氧基丙烯基、2-乙氧基乙烯基、2-羥基甲基丙烯基、乙氧基乙基、乙氧基羰基、甲基羰基、(4-四氫-哌喃基)羰基、N-甲基-N-(甲氧基乙基)胺基羰基、N-甲基-N-(二甲基胺基乙基)-胺基羰基、第三丁氧基羰基甲基、1-羥基-1-第三丁氧基羰基甲基、乙氧基羰基丙基、乙氧基羰基乙基、甲基胺基羰基甲基、甲基胺基羰基乙基、二甲基胺基羰基乙基、二甲基胺基羰基丙基、羧基乙基、羧基丙基、氰基乙基、氰基丙基、4,5-二羥基戊基、羥基丁炔基、羥基丙炔基、乙炔基、2-環丙基乙烯基、2-羥基-2-甲基丙氧基丙炔基、1-(1-羥基環戊基)乙炔基、3-甲基-3-氧雜環丁烷基乙炔基、甲氧基戊炔-1-基、亞環戊基甲基、2-乙氧基乙烯基、乙烯基、甲基磺醯基丙烯基、甲基磺醯基丁烯基、甲基磺醯基丙基、甲基磺醯基丁基、苯基乙基、苄基、苯基丙基、3-氯苯基甲基、1,2-二羥基-2-苯基乙基、苯基乙烯基、1-苯基乙烯基、苯基乙炔基、吡啶-2-基甲基、2-氯吡啶-5-基甲基、2-乙氧基-5-吡啶基乙炔基、4-哌啶基甲基、1-哌啶基甲基、4-甲基哌嗪-1-基甲基、4-BOC-哌嗪-1-基甲基、4-甲基磺醯基-哌嗪-1-基甲基、4-甲基羰基-哌嗪-1-基甲基、嗎啉-4-基甲基、3-嗎啉-4-基甲基、硫代嗎啉基甲基、(1,1-二氧離子基硫代嗎啉基)甲基、3-甲基-3-氧雜 環丁烷基乙基、(四氫-呋喃-2-基)甲基、(四氫-呋喃-3-基)甲基、四氫哌喃-4-基甲基、四氫哌喃-3-基甲基、四氫哌喃-4-基乙基、2-羥基甲基-四氫哌喃-3-基甲基、2-甲氧基甲基-四氫哌喃-3-基甲基、3-(2,2-二甲基-1,3-二氧雜環戊烷-4-基)丙基、1,3-二氧雜環戊烷-4-丙基、四氫-2H-硫代哌喃-4-基甲基、6-氧雜-1-氮雜螺[3.3]庚-1-基甲基、2-氧雜-6-氮雜螺[3.3]庚-6-基甲基、3-苄氧基-環丁基甲基、3-羥基環丁基甲基、3-羥基-3-甲基-環丁基甲基、1,1-二側氧基-環戊基甲基、1,1-二側氧基-環戊基丙基、1-(羥基環戊基)甲基、1-(甲氧基環戊基)甲基、1-(甲氧基環戊基)溴甲基、環己基甲基、環己基乙基、環丙基、1-第三丁氧基羰基-1-環丙基、環丁基、2-羥基環丁基、2-側氧基環丁基、3-羥基環丁基、3-苄氧基環丁基、3-苄氧基-1-羥基環丁基、3-(2-羥基-2-甲基乙基)-環丁基、3-羥基甲基-環丁基、3-乙氧基羰基-1-羥基-環丁基、環戊基、3-羥基甲基環戊基、3,3-二羥基甲基環戊基、4-羥基甲基環戊基、4-羥基環戊基、3-羥基-3-甲基環戊基、2-側氧基-環戊基、3-側氧基-環戊基、2-(N-乙基-N-甲基胺基羰基)環戊基、環己基、4-羥基環己基、3-羥基環己基、3-羥基-3-甲基-環己基、環庚基、環戊烯基、3-羥基-環戊烯基、4-羥基甲基-4-甲基-環戊烯基、4,4-雙(羥基甲基)環戊-2-烯-1-基、3-側氧基-環戊烯基、3-(羥基甲基)環戊-1-烯-1-基、環己烯基、4,4-二甲基-環己烯基、4-第三丁基-環己烯基、4-羥基環己烯基、5-羥基環己烯基、4-羥基甲基-環己烯基、4-(2-羥基-2-甲基乙基)環己烯基、4-羧基環己烯基、4-(氮雜環丁烷-1-基羰基)環己烯基、4-(3-氟-氮雜環丁烷-1-基羰基)環己烯基、4-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)環己烯基、環庚烯基、1,4-二氧雜螺[4.5]癸-7-烯-7-基，3-羥基-3-氧雜環丁烷基、2-四氫-呋喃基、2-甲基-2-四氫-呋喃 基、2-羥基甲基-2-四氫-呋喃基、2,2-二甲基-2,5-二氫呋喃-3-基、3-四氫-呋喃基、2-側氧基吡咯啶-1-基、四氫哌喃-4-基、2,2-二甲基四氫哌喃-4-基、2,2,5,5-四甲基-2,5-二氫呋喃-3-基、4-羥基四氫哌喃-4-基、3,4-二羥基四氫哌喃-4-基、四氫哌喃-3-基、四氫哌喃-2-基、3,6-二氫哌喃-4-基、3,6-二氫哌喃-5-基、5,6-二氫-2H-哌喃-3-基、3,4-二氫-2H-哌喃-6-基、6,6-二甲基-3,6-二氫-2H-哌喃-4-基、2,2-二甲基-3,6-二氫-2H-哌喃-4-基、3,4-2H-二氫哌喃-4-基、1,4-二氧雜螺[4.5]癸-7-烯-8-基、1,1-二側氧基-異噻唑啶-2-基、1,1-二氧離子基四氫-2H-硫代哌喃-4-基、1-第三丁氧基羰基-1,2,3,6-四氫吡啶-4-基、1-甲基磺醯基-1,2,3,6-四氫吡啶-4-基、1-(二甲基胺基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲氧基羰基)-1,2,3,6-四氫吡啶-4-基、1-(甲基羰基)-1,2,3,6-四氫吡啶-4-基、1-第三丁氧基羰基-哌啶-4-基、1-(二甲基胺基羰基)-哌啶-4-基，苯基、4-氯苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-甲氧基-3-三氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、4-甲基磺醯基苯基、3-乙基磺醯基苯基、4-甲基磺醯基胺基苯基、3-甲基磺醯基胺基苯基、3-甲基胺基磺醯基苯基、3-氰基苯基、4-氰基苯基、3-羧基苯基、3-羧基-4-羥基苯基、3-羧基-6-甲氧基苯基、4-氰基-3-甲氧基苯基、3-氰基-4-甲氧基苯基、3-(二甲基胺基羰基)苯基、2-(二甲基胺基羰基)苯基、4-(二甲基胺基羰基)苯基、3-乙基胺基羰基苯基、3-(N-乙基-N-甲基胺基羰基)苯基、4-乙基胺基羰基苯基、4-(N-乙基-N-甲基胺基羰基)苯基、3-異丙基胺基羰基苯基、3-(N-丁基-N-甲基胺基羰基)苯基、3-(N-丙基-N-甲基胺基羰基)苯基、3-(1,2-二羥基丙基胺基羰基)- 4-羥基-苯基、3-(N-甲氧基乙基-N-甲基胺基羰基)苯基、4-(N-羥基乙基-N-甲基胺基羰基)苯基、5-甲氧基-3-二甲基胺基羰基苯基、2-甲氧基-4-二甲基胺基羰基苯基、6-甲氧基-3-二甲基胺基羰基苯基、3-甲氧基-5-乙基胺基羰基苯基、1-羥基-2-甲基丙-2-基-胺基羰基苯基、羥基乙基胺基羰基-苯基、2-羥基-2-甲基丙基胺基羰基-苯基、1,2-二羥基丙基胺基羰基-苯基、3-(1-氮雜環丁烷基羰基)苯基、3-(3-氟-氮雜環丁烷-1-基羰基)苯基、3-(3-羥基-氮雜環丁烷-1-基羰基)苯基、3-(3-甲基磺醯基-氮雜環丁烷-1-基羰基)苯基、3-(4-嗎啉基羰基)苯基、3-(1-吡咯啶基羰基)苯基、4-甲氧基苯基、3-甲氧基苯基、3-氟-6-甲氧基苯基、2-氟-5-甲氧基苯基、2-甲氧基-4-甲基胺基磺醯基苯基、2-甲氧基-4-乙基胺基磺醯基苯基、4-甲氧基-3-甲基胺基磺醯基苯基、3-甲氧基-5-甲氧基羰基苯基、3-羧基-2-甲氧基苯基、3-二氟甲氧基苯基、3-二氟甲基苯基、3-二氟甲基-4-氟苯基、2-甲氧基苯基、2,4-二甲氧基苯基、3,4-二甲氧基苯基、5-苯并二氧雜環戊烯基，1-甲基-3-吡唑基、1-甲基-4-吡唑基、1,5-二甲基-4-吡唑基、1,3,5-三甲基-4-吡唑基、3-甲基-4-吡唑基、3-三氟-乙基-4-吡唑基、1-[2,2,2-三氟乙基]-4-吡唑基、1-羧基甲基-4-吡唑基、1-乙氧基羰基甲基-4-吡唑基、3-環丁基-4-吡唑基、1-環丁基-4-吡唑基、1-(4-嗎啉基)羰基甲基-4-吡唑基、1-(4-嗎啉基)乙基-4-吡唑基、1-羥基乙基-4-吡唑基、1-羥基乙基-5-吡唑基、1-甲氧基乙基-4-吡唑基、5-吡唑基、1-甲基-5-吡唑基、1,3-二甲基-5-吡唑基、1-甲基-3-三氟甲基-5-吡唑基、3-甲基胺基羰基-吡唑-5-基、3-二甲基胺基羰基-吡唑-5-基、3-甲基磺醯基胺基-吡唑-5-基、2-甲基磺醯基胺基-吡唑-4-基、2-甲氧基羰基-吡唑-4-基、2,4-二甲基-5-噻唑基、2-(2-羥基-2-甲基乙基)-噻唑-5-基、1-甲基-5-咪唑 基、3,5-二甲基-異噁唑-4-基、1-甲基-三嗪-4-基、1-異丙基-三嗪-4-基、1-羥基丙基-三嗪-4-基、1-羥基丁基-三嗪-4-基、2-氰基-3-甲基-噻吩-5-基、2-甲氧基羰基-噻吩-5-基、2-羧基-噻吩-5-基、2-(N-甲氧基乙基-N-甲基胺基羰基)噻吩-5-基、2-(N-乙基-N-甲基-胺基羰基)噻吩-5-基、2-(2-羥基-2-甲基乙基)噻吩-5-基、3-甲基-1,2,4-噁二唑-5-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-5-吡啶基、2-甲基-4-吡啶基、2-甲基-3-吡啶基、3-甲基-5-吡啶基、3-三氟甲基-5-吡啶基、2-三氟甲基-5-吡啶基、2-二氟甲基-5-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-3-吡啶基、2-甲氧基-3-吡啶基、4-甲氧基-3-吡啶基、2-甲氧基-4-吡啶基、2-(3-氧雜環丁烷基)甲氧基-4-吡啶基、5-氟-2-甲氧基-4-吡啶基、3-氟-4-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、3-甲氧基-4-吡啶基、2-乙氧基-4-吡啶基、2-甲氧基-5-吡啶基、2-羥基甲氧基-5-吡啶基、2-羥基乙氧基-5-吡啶基、2-羥基乙氧基-4-吡啶基、5-氟-2-羥基乙氧基-4-吡啶基、2-甲氧基乙氧基-5-吡啶基、2-羥基甲基-5-吡啶基、3-甲氧基-5-吡啶基、2-乙氧基-5-吡啶基、2-異丙氧基-5-吡啶基、2-羥基-2-甲基丙氧基-5-吡啶基、2-(1,1,1-三氟乙氧基)-5-吡啶基、2-環丙基甲氧基-5-吡啶基、2-(甲基磺醯基丙氧基)-5-吡啶基、2-乙氧基丙氧基-4-吡啶基、2-二氟甲氧基-5-吡啶基、2-氟-4-吡啶基、2-氯-4-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、2-氰基-4-吡啶基、2-氰基-5-吡啶基、2-甲氧基-3-氰基-5-吡啶基、2-氰基-6-甲基-4-吡啶基、2-甲氧基-6-甲基-5-吡啶基、3-氰基-5-吡啶基、3-氰基-4-吡啶基、2-甲基磺醯基-5-吡啶基、3-甲基磺醯基-5-吡啶基、2-側氧基-1,2-二氫吡啶-3-基、1-甲基-2-側氧基-1,2-二氫吡啶-5-基、1-乙基-2-側氧基-1,2-二氫吡啶-5-基、1-異丙基-2- 側氧基-1,2-二氫吡啶-5-基、1-羥基乙基-2-側氧基-1,2-二氫吡啶-5-基、1-羥基丙基-2-側氧基-1,2-二氫吡啶-5-基、1-甲基-2-側氧基-1,2-二氫吡啶-4-基、2-羥基吡啶-4-基、2-羥基吡啶-5-基、2-胺基羰基-4-吡啶基、2-甲基胺基羰基-4-吡啶基、3-甲基胺基羰基-5-吡啶基、2-異丙基胺基羰基-4-吡啶基、3-二乙基胺基羰基-5-吡啶基、2-甲基磺醯基乙基胺基羰基-4-吡啶基、2-甲基磺醯基胺基乙基胺基羰基-4-吡啶基、3-甲基磺醯基胺基乙基胺基羰基-5-吡啶基、2-甲基磺醯基胺基乙氧基-5-吡啶基、2-羥基乙基胺基羰基-4-吡啶基、2-羥基乙基胺基羰基-5-吡啶基、3-羥基乙基胺基羰基-4-吡啶基、2-羥基丁基胺基羰基-4-吡啶基、2-甲氧基乙基胺基羰基-4-吡啶基、4-氟-2-甲基胺基羰基胺基-5-吡啶基、2-(1-咪唑基)吡啶-4-基、5-嘧啶基、2-胺基-5-嘧啶基、2-氰基-5-嘧啶基、2-甲氧基-5-嘧啶基、2-乙氧基-5-嘧啶基、2-異丙氧基-5-嘧啶基、2-三氟乙氧基-5-嘧啶基、4-三氟甲基-6-嘧啶基、2-三氟乙基-4-嘧啶基、2-三氟乙基-5-嘧啶基、2-二甲基胺基羰基嘧啶-5-基、吡嗪-2-基、噠嗪-4-基，3-苯并噻吩基、5-苯并呋喃基、5-吲哚基、2-側氧基-二氫-5-吲哚基、6-吲哚基、2-側氧基-二氫-6-吲哚基、1-甲基-2-側氧基-二氫-6-吲哚基、咪唑并[1,2-a]吡啶-3-基、咪唑并[1,5-a]吡啶-6-基、咪唑并[1,2-a]吡啶-6-基、1,1-二側氧基-2-甲基-3,4-二氫-2H-苯并[b][1,4,5]噁噻氮呯-8-基、苯并噁唑-5-基、苯并噁唑-6-基、1,1-二側氧基-3,4-二氫-2H-[1,4]噁硫呯并[2,3-b]吡啶-8-基、4-甲基-5-側氧基-3,4-二氫苯并[f][1,4]噁氮呯-5(2H)-7-基、2-甲基苯并噁唑-5-基、2-乙基苯并噁唑-5-基、2-異丙基苯并噁唑-5-基、2-側氧基-2(3H)-苯并[d]噁唑-5-基、苯并噻唑-5-基、苯并噻唑-6-基、2-甲基苯并噻唑-5-基、1-甲基-5-苯并咪唑基、1-甲基-5-吲 唑基、1-甲基-6-吲唑基、2-甲基-2H-吲唑-4-基、7-氮雜吲哚-6-基、7-氮雜吲哚-4-基、1,5-二甲基-2,3-二氫-1H-吡咯并[2,3-b]吡啶-5-基、3-苯并異噁唑-5-基、2-甲基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基-6-甲氧基-3-側氧基-苯并[d]異噁唑-5-基、2-甲基噁唑并[5,4-b]吡啶-5-基、1,1-二側氧基-4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噻嗪-7-基、2-側氧基-1H-咪唑并[4,5-b]吡啶-2(3H)-6-基、3-側氧基-苯并[d][1,3]氧硫唑-5-基、3,3-二側氧基-苯并[d][1,3]氧硫唑-5-基、[1,2,4]三唑并[4,3-a]吡啶-5-基、[1,2,4]三唑并[4,3-a]吡啶-6-基、3-羥基甲基-[1,2,4]三唑并[4,3-a]吡啶-6-基、6-喹啉基、7-喹啉基、7-異喹啉基、1,5-啶-3-基、1H-吡唑并[3,4-b]吡啶-4-基或3-甲基-1H-吡唑并[3,4-b]吡啶-4-基；及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 3 is H, bromo, cyano, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 2- Methyl butyl, trifluoromethyl, 3,3,3-trifluoropropyl, fluoromethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-methylethyl, 2- Hydroxy-2-methylethyl, hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropyl, hydroxybutyl, 2-hydroxybutyl, 1,2 -dihydroxybutyl, 2-hydroxy-2-methylbutyl, 2,2-(dihydroxymethyl)butyl, 1-hydroxyethoxy-2-bromoethyl, 2-(hydroxyethoxy) Ethyl, 2-(hydroxyethoxy)propyl, (methoxymethyl)ethyl, 1-methoxyethoxy-2-bromoethyl, 2-hydroxy-2-methylpentyl , 2-hydroxy-2-methylhexyl, 1,2-dihydroxypentyl, (tetrahydropyran-4-yl)-hydroxymethyl, 2-fluoro-2-methylbutyl, methoxymethyl Oxymethyl, methoxymethyl, methoxypropyl, methoxybutyl, 4,5-dimethoxypentyl, methoxypentyl, ethoxyvinyl, vinyl, propylene -2-yl, propen-1-yl, prop-1-en-2-yl, 3-hydroxyprop-1-en-2-yl, 1-hydroxy -2-methylpropenyl, butenyl, 3,3-dimethylbuten-1-yl, methoxypropen-1-yl, hydroxypropenyl, benzyloxypropenyl, 2-ethoxy Vinyl, 2-hydroxymethylpropenyl, ethoxyethyl, ethoxycarbonyl, methylcarbonyl, (4-tetrahydro-piperidyl)carbonyl, N-methyl-N-(methoxy B Aminocarbonyl, N-methyl-N-(dimethylaminoethyl)-aminocarbonyl, tert-butoxycarbonylmethyl, 1-hydroxy-1-t-butoxycarbonylmethyl , ethoxycarbonylpropyl, ethoxycarbonylethyl, methylaminocarbonylmethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, dimethylaminocarbonylpropyl, carboxyl Ethyl, carboxypropyl, cyanoethyl, cyanopropyl, 4,5-dihydroxypentyl, hydroxybutynyl, hydroxypropynyl, ethynyl, 2-cyclopropylvinyl, 2-hydroxyl -2-methylpropoxypropynyl, 1-(1-hydroxycyclopentyl)ethynyl, 3-methyl-3-oxetanylethynyl, methoxypentyn-1-yl , cyclopentylmethyl, 2-ethoxyvinyl, vinyl, methylsulfonylpropenyl, methylsulfonylbutenyl, methylsulfonylpropyl , methylsulfonyl butyl, phenylethyl, benzyl, phenylpropyl, 3-chlorophenylmethyl, 1,2-dihydroxy-2-phenylethyl, phenylvinyl, 1 -phenylvinyl, phenylethynyl, pyridin-2-ylmethyl, 2-chloropyridin-5-ylmethyl, 2-ethoxy-5-pyridylethynyl, 4-piperidinylmethyl , 1-piperidinylmethyl, 4-methylpiperazin-1-ylmethyl, 4-BOC-piperazin-1-ylmethyl, 4-methylsulfonyl-piperazin-1-yl , 4-methylcarbonyl-piperazin-1-ylmethyl, morpholin-4-ylmethyl, 3-morpholin-4-ylmethyl, thiomorpholinylmethyl, (1,1- Dioxy ionylthiomorpholinyl)methyl, 3-methyl-3-oxetanylethyl, (tetrahydro-furan-2-yl)methyl, (tetrahydro-furan-3- Methyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-3-ylmethyl, tetrahydropyran-4-ylethyl, 2-hydroxymethyl-tetrahydropyran-3 -ylmethyl, 2-methoxymethyl-tetrahydropyran-3-ylmethyl, 3-(2,2-dimethyl-1,3-dioxolan-4-yl) Propyl, 1,3-dioxolane-4-propyl, tetrahydro-2H-thiopiperazin-4-ylmethyl, 6-oxa-1-azaspiro[3.3]heptane- 1-ylmethyl, 2-oxa-6-azaspiro[3.3] Hept-6-ylmethyl, 3-benzyloxy-cyclobutylmethyl, 3-hydroxycyclobutylmethyl, 3-hydroxy-3-methyl-cyclobutylmethyl, 1,1-di-oxy-cyclopentyl Methyl, 1,1-di-oxy-cyclopentylpropyl, 1-(hydroxycyclopentyl)methyl, 1-(methoxycyclopentyl)methyl, 1-(methoxycyclopentyl) Bromomethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyl, 1-tert-butoxycarbonyl-1-cyclopropyl, cyclobutyl, 2-hydroxycyclobutyl, 2-sided oxygen Cyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-benzyloxy-1-hydroxycyclobutyl, 3-(2-hydroxy-2-methylethyl)-cyclo Butyl, 3-hydroxymethyl-cyclobutyl, 3-ethoxycarbonyl-1-hydroxy-cyclobutyl, cyclopentyl, 3-hydroxymethylcyclopentyl, 3,3-dihydroxymethyl ring Pentyl, 4-hydroxymethylcyclopentyl, 4-hydroxycyclopentyl, 3-hydroxy-3-methylcyclopentyl, 2-sided oxy-cyclopentyl, 3-sided oxy-cyclopentyl , 2-(N-ethyl-N-methylaminocarbonyl)cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, 3-hydroxy-3-methyl-cyclohexyl, cycloheptane Base, cyclopentenyl, 3-hydroxy-cyclopentenyl, 4-hydroxymethyl-4-methyl-cyclopentene 4,4-bis(hydroxymethyl)cyclopent-2-en-1-yl, 3-oxo-cyclopentenyl, 3-(hydroxymethyl)cyclopent-1-en-1-yl , cyclohexenyl, 4,4-dimethyl-cyclohexenyl, 4-tert-butyl-cyclohexenyl, 4-hydroxycyclohexenyl, 5-hydroxycyclohexenyl, 4-hydroxyl Methyl-cyclohexenyl, 4-(2-hydroxy-2-methylethyl)cyclohexenyl, 4-carboxycyclohexenyl, 4-(azetidin-1-ylcarbonyl) ring Hexenyl, 4-(3-fluoro-azetidin-1-ylcarbonyl)cyclohexenyl, 4-(3-methylsulfonyl-azetidin-1-ylcarbonyl) ring Hexenyl, cycloheptenyl, 1,4-dioxaspiro[4.5]dec-7-ene-7-yl, 3-hydroxy-3-oxetanyl, 2-tetrahydro-furanyl , 2-methyl-2-tetrahydro-furanyl, 2-hydroxymethyl-2-tetrahydro-furanyl, 2,2-dimethyl-2,5-dihydrofuran-3-yl, 3- Tetrahydro-furanyl, 2-oxopyryrrolidin-1-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 2,2,5,5 -tetramethyl-2,5-dihydrofuran-3-yl, 4-hydroxytetrahydropyran-4-yl, 3,4-dihydroxytetrahydropyran-4-yl, tetrahydropyran-3 -yl, tetrahydropyran-2-yl, 3,6-dihydropyran-4-yl, 3,6-dihydropentan-5-yl 5,6-Dihydro-2H-piperidin-3-yl, 3,4-dihydro-2H-pyran-6-yl, 6,6-dimethyl-3,6-dihydro-2H-peri喃-4-yl, 2,2-dimethyl-3,6-dihydro-2H-piperidin-4-yl, 3,4-2H-dihydropyran-4-yl, 1,4-di Oxaspiro[4.5]pyridin-7-en-8-yl, 1,1-di-oxy-isothiazolidin-2-yl, 1,1-dioxyindolyltetrahydro-2H-thiopyran 4-yl, 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylsulfonyl-1,2,3,6-tetrahydropyridine- 4-yl, 1-(dimethylaminocarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-(methoxycarbonyl)-1,2,3,6-tetrahydro Pyridin-4-yl, 1-(methylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl, 1-tert-butoxycarbonyl-piperidin-4-yl, 1-(di) Methylaminocarbonyl)-piperidin-4-yl, phenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-tri Fluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxy-3-trifluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methylsulfonyl Phenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-ethylsulfonylphenyl, 4-methylsulfonylaminophenyl, 3-methylsulfonate Mercaptoaminophenyl, 3-methylamine Sulfophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl, 3-carboxy-6-methoxyphenyl, 4- Cyano-3-methoxyphenyl, 3-cyano-4-methoxyphenyl, 3-(dimethylaminocarbonyl)phenyl, 2-(dimethylaminocarbonyl)phenyl, 4-(Dimethylaminocarbonyl)phenyl, 3-ethylaminocarbonylphenyl, 3-(N-ethyl-N-methylaminocarbonyl)phenyl, 4-ethylaminocarbonylbenzene , 4-(N-ethyl-N-methylaminocarbonyl)phenyl, 3-isopropylaminocarbonylphenyl, 3-(N-butyl-N-methylaminocarbonyl)phenyl , 3-(N-propyl-N-methylaminocarbonyl)phenyl, 3-(1,2-dihydroxypropylaminocarbonyl)-4-hydroxy-phenyl, 3-(N-methoxy Benzyl-N-methylaminocarbonyl)phenyl, 4-(N-hydroxyethyl-N-methylaminocarbonyl)phenyl, 5-methoxy-3-dimethylaminocarbonylbenzene , 2-methoxy-4-dimethylaminocarbonylphenyl, 6-methoxy-3-dimethylaminocarbonylphenyl, 3-methoxy-5-ethylaminocarbonylbenzene , 1-hydroxy-2-methylpropan-2-yl-aminocarbonylphenyl, hydroxyethylaminocarbonyl-phenyl, 2-hydroxy-2-methylpropylaminocarbonyl-phenyl, 1 , 2-dihydroxypropylaminocarbonyl-phenyl, 3-(1-azetidinylcarbonyl)phenyl, 3-(3-fluoro-azetidin-1-ylcarbonyl)phenyl, 3-(3-Hydroxy-azetidin-1-ylcarbonyl)phenyl, 3-(3-methylsulfonyl-azetidin-1-ylcarbonyl)phenyl, 3-(4 -morpholinylcarbonyl)phenyl, 3-(1-pyrrolidinylcarbonyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluoro-6-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-methoxy-4-methylaminosulfonylphenyl, 2-methoxy-4-ethylaminosulfonylphenyl, 4- Methoxy-3-methylaminosulfonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 3-carboxy-2-methoxyphenyl, 3-difluoromethoxy Phenyl, 3-difluoromethylphenyl, 3-difluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethyl Oxyphenyl, 5-benzodioxolyl, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, 1,5-dimethyl-4-pyridyl Azyl, 1,3,5-trimethyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 3-trifluoro-ethyl-4-pyrazolyl, 1-[2,2 , 2-trifluoroethyl]-4-pyrazolyl, 1-carboxymethyl-4-pyrazolyl, 1-ethoxy Methyl-4-pyrazolyl, 3-cyclobutyl-4-pyrazolyl, 1-cyclobutyl-4-pyrazolyl, 1-(4-morpholinyl)carbonylmethyl-4-pyridyl Azyl, 1-(4-morpholinyl)ethyl-4-pyrazolyl, 1-hydroxyethyl-4-pyrazolyl, 1-hydroxyethyl-5-pyrazolyl, 1-methoxy Ethyl-4-pyrazolyl, 5-pyrazolyl, 1-methyl-5-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1-methyl-3-trifluoromethyl 5-pyrazolyl, 3-methylaminocarbonyl-pyrazol-5-yl, 3-dimethylaminocarbonyl-pyrazol-5-yl, 3-methylsulfonylamino-pyridyl Zyrid-5-yl, 2-methylsulfonylamino-pyrazol-4-yl, 2-methoxycarbonyl-pyrazol-4-yl, 2,4-dimethyl-5-thiazolyl, 2-(2-hydroxy-2-methylethyl)-thiazol-5-yl, 1-methyl-5-imidazolyl, 3,5-dimethyl-isoxazole-4-yl, 1-methyl -Triazin-4-yl, 1-isopropyl-triazin-4-yl, 1-hydroxypropyl-triazin-4-yl, 1-hydroxybutyl-triazin-4-yl, 2- Cyano-3-methyl-thiophen-5-yl, 2-methoxycarbonyl-thiophen-5-yl, 2-carboxy-thiophen-5-yl, 2-(N-methoxyethyl-N- Methylaminocarbonyl)thiophen-5-yl, 2-(N-ethyl-N-methyl-aminocarbonyl)thiophen-5-yl, 2-(2-hydroxy-2-methylethyl)thiazide -5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-5-pyridyl, 2 -methyl-4-pyridyl, 2-methyl-3-pyridyl, 3-methyl-5-pyridyl, 3-trifluoromethyl-5-pyridyl, 2-trifluoromethyl-5- Pyridyl, 2-difluoromethyl-5-pyridyl, 2-trifluoromethyl-4-pyridyl, 2-trifluoromethyl-3-pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 2-(3-oxetanyl)methoxy-4-pyridyl, 5-fluoro-2-methyl Oxy-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 3-methoxy-4-pyridyl, 2-ethoxy 4-pyridyl, 2-methoxy-5-pyridyl, 2-hydroxymethoxy-5-pyridyl, 2-hydroxyethoxy-5-pyridyl, 2-hydroxyethoxy-4 -pyridyl, 5-fluoro-2-hydroxyethoxy-4-pyridyl, 2-methoxyethoxy-5-pyridyl, 2-hydroxymethyl-5-pyridyl, 3-methoxy 5-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-hydroxy-2-methylpropoxy-5-pyridyl, 2-(1 1,1,1-Trifluoroethoxy)-5-pyridyl, 2-cyclopropylmethoxy-5 -pyridyl, 2-(methylsulfonylpropoxy)-5-pyridyl, 2-ethoxypropoxy-4-pyridyl, 2-difluoromethoxy-5-pyridyl, 2 -fluoro-4-pyridyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 2-cyano-4-pyridyl, 2-cyano- 5-pyridyl, 2-methoxy-3-cyano-5-pyridyl, 2-cyano-6-methyl-4-pyridyl, 2-methoxy-6-methyl-5-pyridine , 3-cyano-5-pyridyl, 3-cyano-4-pyridyl, 2-methylsulfonyl-5-pyridyl, 3-methylsulfonyl-5-pyridyl, 2- Sideoxy-1,2-dihydropyridin-3-yl, 1-methyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-ethyl-2-oxo- 1,2-dihydropyridin-5-yl, 1-isopropyl-2-yloxy-1,2-dihydropyridin-5-yl, 1-hydroxyethyl-2-oxooxy-1, 2-Dihydropyridin-5-yl, 1-hydroxypropyl-2-oxooxy-1,2-dihydropyridin-5-yl, 1-methyl-2-oxooxy-1,2-di Hydropyridin-4-yl, 2-hydroxypyridin-4-yl, 2-hydroxypyridin-5-yl, 2-aminocarbonyl-4-pyridyl, 2-methylaminocarbonyl-4-pyridyl, 3 -Methylaminocarbonyl-5-pyridyl, 2-isopropylaminocarbonyl-4-pyridyl, 3-diethylaminocarbonyl-5- Pyridyl, 2-methylsulfonylethylaminocarbonyl-4-pyridyl, 2-methylsulfonylaminoethylaminocarbonyl-4-pyridyl, 3-methylsulfonylamino Ethylaminocarbonyl-5-pyridyl, 2-methylsulfonylaminoethoxy-5-pyridyl, 2-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxyethylamino Carbonyl-5-pyridyl, 3-hydroxyethylaminocarbonyl-4-pyridyl, 2-hydroxybutylaminocarbonyl-4-pyridyl, 2-methoxyethylaminocarbonyl-4-pyridyl 4-fluoro-2-methylaminocarbonylamino-5-pyridyl, 2-(1-imidazolyl)pyridin-4-yl, 5-pyrimidinyl, 2-amino-5-pyrimidinyl, 2 -cyano-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-trifluoroethoxy -5-pyrimidinyl, 4-trifluoromethyl-6-pyrimidinyl, 2-trifluoroethyl-4-pyrimidinyl, 2-trifluoroethyl-5-pyrimidinyl, 2-dimethylaminocarbonyl Pyrimidin-5-yl, pyrazin-2-yl, pyridazin-4-yl, 3-benzothienyl, 5-benzofuranyl, 5-indenyl, 2-oxo-dihydro-5 - mercapto, 6-fluorenyl, 2-sided oxy-dihydro-6-fluorenyl, 1-methyl-2-oxo-dihydro-6-fluorene Mercapto, imidazo[1,2-a]pyridin-3-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,2-a]pyridine-6-yl, 1, 1-di-oxo-2-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-8-yl, benzoxazole-5-yl , benzoxazole-6-yl, 1,1-di-oxy-3,4-dihydro-2H-[1,4]oxathio-[2,3-b]pyridine-8-yl, 4-methyl-5-oxooxy-3,4-dihydrobenzo[f][1,4]oxazin-5(2H)-7-yl, 2-methylbenzoxazole-5 -yl, 2-ethylbenzoxazol-5-yl, 2-isopropylbenzoxazol-5-yl, 2-sided oxy-2(3H)-benzo[d]oxazole-5 -yl,benzothiazol-5-yl, benzothiazole-6-yl, 2-methylbenzothiazol-5-yl, 1-methyl-5-benzimidazolyl, 1-methyl-5- Carbazolyl, 1-methyl-6-oxazolyl, 2-methyl-2H-indazol-4-yl, 7-azaindole-6-yl, 7-azaindole-4-yl 1,5-Dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-benzisoxazole-5-yl, 2-methyl- 3-sided oxy-benzo[d]isoxazole-5-yl, 2-methyl-6-methoxy-3-oxirane-benzo[d]isoxazole-5-yl, 2 -methyloxazolo[5,4-b]pyridin-5-yl, 1,1-di-oxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b ][ 1,4]thiazin-7-yl, 2-oxo-1H-imidazo[4,5-b]pyridine-2(3H)-6-yl, 3-sided oxy-benzo[d] [1,3]oxazol-5-yl, 3,3-di-oxy-benzo[d][1,3]oxathiazol-5-yl,[1,2,4]triazolo [4,3-a]pyridin-5-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-hydroxymethyl-[1,2,4] Zoxao[4,3-a]pyridin-6-yl, 6-quinolyl, 7-quinolinyl, 7-isoquinolinyl, 1,5- Pyridin-3-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl or 3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl; and its medicine A salt that is acceptable for learning. 如請求項35之化合物，其中R5為吡啶基、吡唑基、苯基、苄基、四氫哌喃基、哌啶基、六氫呋喃并[2,3-b]呋喃基、2,5-二側氧基-吡咯啶基、吡嗪基、噠嗪基、四唑基、喹唑啉基、喹啉基、1,2-二氫喹啉基、5,6,7,8-四氫喹啉基、喹喏啉基、1H-吲唑基、2H-吲唑基、[1,2,4]三唑并[4,3-a]吡啶基、異喹啉基、1H-吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、3H-咪唑并[4,5-a]吡啶基、異噁唑并[5,4-b]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、4,5,6,7-四氫-3H-吡唑并[3,4-b]吡啶基、3,4-二氫-2H-哌喃并[2,3-b]吡啶基或烷基或嘧啶基，其中R5未經取代或經一或多個獨立地選自以下之取代基取代：甲基、乙基、氰基、氯、氟、甲氧基、三氟甲基、乙氧基羰基、丁氧基羰基、羧基、N-(甲基)-N-(甲氧基乙基)胺基羰基、(N,N-二甲基)胺基羰基、N-(甲基)-N-(甲基胺基乙基)胺基羰基、(1-甲基吡嗪-4-基)羰基或側氧基； 及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 5 is pyridyl, pyrazolyl, phenyl, benzyl, tetrahydropyranyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, 2, 5-tertiary oxy-pyrrolidinyl, pyrazinyl, pyridazinyl, tetrazolyl, quinazolinyl, quinolyl, 1,2-dihydroquinolinyl, 5,6,7,8- Tetrahydroquinolyl, quinoxalinyl, 1H-carbazolyl, 2H-carbazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoquinolinyl, 1H- Pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, 3H-imidazo[4,5-a]pyridyl, isoxazole[5,4-b] Pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, 4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridinyl, 3 ,4-dihydro-2H-piperacino[2,3-b]pyridinyl or An alkyl or pyrimidinyl group, wherein R 5 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, cyano, chloro, fluoro, methoxy, trifluoromethyl, Ethoxycarbonyl, butoxycarbonyl, carboxyl, N-(methyl)-N-(methoxyethyl)aminocarbonyl, (N,N-dimethyl)aminocarbonyl, N-(methyl -N-(methylaminoethyl)aminocarbonyl, (1-methylpyrazin-4-yl)carbonyl or pendant oxy; and pharmaceutically acceptable salts thereof. 如請求項35之化合物，其中R5為苄基、四氫哌喃-4-基、3-氟-四氫哌喃-4-基、1-Boc-哌啶-4-基、六氫呋喃并[2,3-b]呋喃-3-基、2,5-二側氧基-吡咯啶-1-基，2-吡啶基、3-吡啶基、4-吡啶基、2-甲基-3-吡啶基、2-甲基-4-吡啶基、2-甲基-5-吡啶基、2-甲基-6-吡啶基、3-甲基-4-吡啶基、3-甲基-5-吡啶基、4-甲基-3-吡啶基、2,6-二甲基-3-吡啶基、2,4-二甲基-3-吡啶基、2,4-二甲基-5-吡啶基、2,3-二甲基-5-吡啶基、2,5-二甲基-3-吡啶基、2-乙基-3-吡啶基、3-乙基-5-吡啶基、2-乙基-6-甲基-3-吡啶基、3-乙基-6-甲基-5-吡啶基、3-異丙基-5-吡啶基、3-(1-甲基乙烯基)-5-吡啶基、3-環丙基-5-吡啶基、2-羥基甲基-3-吡啶基、3-羥基甲基-5-吡啶基、3-(2-羥基乙基)-5-吡啶基、2-(1-羥基-1-甲基乙基)-3-甲基-5-吡啶基、2-羥基丙基-5-吡啶基、-(1,2-二羥基乙基)-5-吡啶基、2-三氟甲基-3-吡啶基、2-三氟甲基-4-吡啶基、2-三氟甲基-5-吡啶基、3-甲基-2-三氟甲基-5-吡啶基、4-甲基-3-三氟甲基-6-吡啶基、3-三氟甲基-5-吡啶基、3-三氟甲基-5-氟-6-吡啶基、4-三氟甲基-2-氯-3-吡啶基、2-甲氧基-5-吡啶基、3-甲氧基-5-吡啶基、3-乙氧基-5-吡啶基、2-甲氧基-4-甲基-5-吡啶基、2-甲氧基-6-乙基-5-吡啶基、2-氰基-3-吡啶基、3-氰基-4-吡啶基、3-氰基-5-吡啶基、2-氰基-5-三氟甲基-3-吡啶基、2-氯-3-吡啶基、2-氯-5-吡啶基、3-氯-5-吡啶基、4-氯-3-吡啶基、3-氯-4-氰基-5-吡啶基、2-氟-5-吡啶基、3-氟-5-吡啶基、4-氟-3-吡啶基、2-氯-5-甲基-3-吡啶基、2-溴-3-甲基-5-吡啶基、1,4-二甲基-2-側氧基吡啶-5-基、1,3-二甲基-2-側氧基吡啶-5-基、1-甲基-2-側氧基吡啶-5-基、2-甲基-6-側氧基吡啶-4-基、1-乙基-2-側氧基吡啶-5-基、4-乙基-1-甲基-2-側氧基吡啶-5-基、 1-乙基-2-甲基-6-側氧基吡啶-5-基、1-異丙基-2-側氧基吡啶-5-基、1,2-二甲基-6-側氧基吡啶-3-基、1-甲基-2-三氟甲基-6-側氧基吡啶-4-基、2-(4-嗎啉基甲基)-3-吡啶基、2-(第三丁基胺基羰基)-4-吡啶基、2-(甲氧基乙基胺基羰基)-6-吡啶基、3-(3-甲氧基苯基)-5-吡啶基、3-(3-氟-5-甲氧基苯基)-5-吡啶基，5-嘧啶基、4-氯-5-甲基-嘧啶-6-基、2,4-二甲基-嘧啶-6-基、2-氰基嘧啶-5-基、2-三氟甲基-嘧啶-5-基、4-氟嘧啶-2-基、4-三氟甲基-嘧啶-5-基、2-氮雜環丁烷基羰基-吡嗪-5-基、2-二甲基胺基羰基-吡嗪-5-基、噠嗪-3-基，1,3,5-三甲基-4-吡唑基、1-乙基-5-吡唑基、1-異丙基-5-吡唑基、1-乙基-4-溴-5-吡唑基、1-乙基-4-甲基-5-吡唑基、1-乙基-3-甲氧基甲基-5-吡唑基、1-甲基-3-二甲基胺基羰基-5-吡唑基、1-甲基-3-環丙基-5-吡唑基、1-乙基四唑-2-基，苯基、2,6-二氟苯基、2-氟苯基、2,4-二氟苯基、2,4,6-三氟苯基、2,5-二氟苯基、2,3-二氟苯基、2,6-二氟-3-甲氧基苯基、2,4-二氟-3-甲氧基苯基、3-氯苯基、2,6-二氯苯基、2,3-二氯苯基、3-氯-2-氟苯基、3-氯-4-氟苯基、2-氯-6-氟苯基、3-氯-6-氟苯基、2-氟-5-三氟甲基苯基、3-羥基甲基苯基、3-羥基乙基苯基、3-羥基甲基-5-甲基苯基、3-甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2-甲基磺醯基苯基、3-甲基磺醯基苯基、2-氟-5-乙基磺醯基苯基、5-乙基胺基磺醯基-2-氟苯基、2-氟-5-甲基羰基苯基、3-甲氧基羰基苯基、3-羧基苯基、2-甲基-5-乙氧基羰基苯基、2-氯-5-乙氧基羰基苯基、2-氟-5-甲氧基羰基苯基、3-甲基-5-甲氧基羰基苯基、3-甲氧基-5-甲氧基羰基苯基、2-氟-5-甲氧基羰基甲基苯基、2-氟-5-羧基甲基苯基、2,6-二氟-3-甲基苯基、2-乙基苯基、2-甲基-5-羧基苯基、2-氯-5-羧基苯基、2-氟-5-羧基 苯基、2-氯-5-胺基羰基苯基、2-氟-5-胺基羰基苯基、2-氰基苯基、4-氰基苯基、2-氰基-3-甲基苯基、2-氰基-5-甲基苯基、4-氰基-3-甲基苯基、2-氰基-3-乙基苯基、4-氯-2-氰基苯基、2-氯-4-氰基苯基、3-氯-2-氰基苯基、3-氯-6-氰基苯基、2-氰基-3,6-二氯苯基、2-氰基-3,6-二氟苯基、4-氰基-2,6-二氟苯基、2-氰基-6-氟苯基、3-氯-2-氰基-6-氟苯基、2-氰基-6-三氟甲基苯基、2-氰基-5-三氟甲基苯基、3-[(異丙基)胺基羰基]苯基、5-甲基-3-[(異丙基)胺基羰基]苯基、4-甲基-3-[(異丙基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲氧基乙基)胺基羰基]苯基、2-甲基-5-[(N,N-二甲基)胺基羰基]苯基、2-甲基-5-[N-(甲基)-N-(甲基胺基乙基)胺基羰基]苯基、2-甲基-5-(1-甲基吡嗪-4-基)羰基)苯基、2,6-二氟-3-((異丙基)胺基羰基)苯基、2-氟-3-((N-異丙基-N-甲基胺基)羰基)苯基、2-氟-3-((乙基胺基)羰基)苯基、-氟-3-((氟乙基胺基)羰基)苯基、2-氟-5-(環丙基甲基))胺基羰基)苯基、2-氟-5-(環丁基))胺基羰基)苯基、2-氟-5-(環戊基))胺基羰基)苯基、2-氟-5-(四氫哌喃-4-基))胺基羰基)苯基、2-氟-5-((甲氧基丙基))胺基羰基)苯基、2-氟-5-((2-甲基)胺基羰基)苯基、2-氟-5-((2-甲氧基丙基)胺基羰基)苯基、2-氟-5-((1-甲氧基-1-甲基乙基)胺基羰基)苯基、2-氯-5-((1-吡咯啶基)羰基)苯基、2-氯-5-((1,3-二甲基吡嗪-4-基)羰基)苯基、2-氟-5-((1-甲基吡唑-3-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-5-基)胺基羰基)苯基、2-氟-5-((1-甲基吡唑-4-基)胺基羰基)苯基、2-氟-5-((吡啶-2-基甲基)胺基羰基)苯基、2-氟-5-(3-氟哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-Boc-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-氟乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-乙基-哌啶-4-基))胺基羰基)苯基、2-氟-5-(1-甲基哌啶-4-基))胺基羰基)苯基、2- 氟-5-(4-嗎啉基))胺基羰基)苯基、2-氟-5-((4-嗎啉基乙基)胺基羰基)苯基、2-氯-5-(甲氧基乙基)胺基羰基)苯基、3-(2-苯并咪唑基)苯基、3-(2-甲基-1-四唑基)苯基、3-(2-甲基-1,2,4-噁二唑-3-基)苯基，5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、5-氯-6-喹啉基、7-氯-4-喹啉基、8-氯-6-喹啉基、2-甲基-4-喹啉基、5,6,7,8-四氫喹啉-5-基、1,2,3,4-四氫喹啉-5-基、6,6-二甲基-5,6,7,8-四氫喹啉-5-基、4-喹唑啉基、喹喏啉-5-基、1-側氧基-異吲哚啉-4-基、1-側氧基-異吲哚啉-6-基、3-甲基-1H-吲唑-4-基、2-甲基-2H-吲唑-4-基、1-甲基-1H-吲唑-5-基、1,3-二甲基-1H-吲唑-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-2-側氧基-1,2-二氫喹啉-6-基、4-甲基-2-側氧基-1,2-二氫喹啉-6-基、5-氯-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、2-側氧基-1,2-二氫喹啉-6-基、4-側氧基-二氫喹啉-1-基、2-甲基-1-側氧基-1,2-二氫異喹啉-6-基、5,7-二氟-1,4-二甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1,3,4-三甲基-2-側氧基-1,2-二氫喹啉-6-基、5,7-二氟-1-甲基-2-側氧基-4-三氟甲基-1,2-二氫喹啉-6-基、5,7-二氟-4-乙基-1-甲基-2-側氧基-1,2-二氫喹啉-6-基、8-異喹啉基、7-異喹啉基、6-異喹啉基、5-異喹啉基、4-異喹啉基、1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-3-基、1-乙基-1H-吡唑并[3,4-b]吡啶-4-基、1-甲氧基乙基-1H-吡唑并[3,4-b]吡啶-3-基、5-氟-1-甲基-1H-吡唑并[3,4-b]吡啶-3-基、1H-吡唑并[3,4-d]嘧啶-4-基、咪唑并[1,2-a]吡啶-7-基、咪唑并[1,2-a]吡啶-6-基、3-甲基-3H-咪唑并[4,5-b]吡啶-5-基、3-甲基-3H-咪唑并[4,5-b]吡啶-6-基、3-甲基異噁唑并[5,4-b]吡啶-4-基、[1,2,4]三唑并[4,3-a]吡啶-8-基、1-甲基-4,5,6,7-四氫-3H-吡 唑并[3,4-b]吡啶-3-基、6-甲基-3,4-二氫-2H-哌喃并[2,3-b]吡啶-5-基或5-烷基；及其醫藥學上可接受之鹽。 The compound of claim 35, wherein R 5 is benzyl, tetrahydropyran-4-yl, 3-fluoro-tetrahydropyran-4-yl, 1-Boc-piperidin-4-yl, hexahydrofuran And [2,3-b]furan-3-yl, 2,5-di-oxy-pyrrolidin-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl- 3-pyridyl, 2-methyl-4-pyridyl, 2-methyl-5-pyridyl, 2-methyl-6-pyridyl, 3-methyl-4-pyridyl, 3-methyl- 5-pyridyl, 4-methyl-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,4-dimethyl-3-pyridyl, 2,4-dimethyl-5 Pyridyl, 2,3-dimethyl-5-pyridyl, 2,5-dimethyl-3-pyridyl, 2-ethyl-3-pyridyl, 3-ethyl-5-pyridyl, 2-ethyl-6-methyl-3-pyridyl, 3-ethyl-6-methyl-5-pyridyl, 3-isopropyl-5-pyridyl, 3-(1-methylvinyl -5-pyridyl, 3-cyclopropyl-5-pyridyl, 2-hydroxymethyl-3-pyridyl, 3-hydroxymethyl-5-pyridyl, 3-(2-hydroxyethyl)- 5-pyridyl, 2-(1-hydroxy-1-methylethyl)-3-methyl-5-pyridyl, 2-hydroxypropyl-5-pyridyl, -(1,2-dihydroxyethyl) 5-)pyridyl, 2-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 2- Trifluoromethyl-5-pyridyl, 3-methyl-2-trifluoromethyl-5-pyridyl, 4-methyl-3-trifluoromethyl-6-pyridyl, 3-trifluoromethyl 5-5-pyridyl, 3-trifluoromethyl-5-fluoro-6-pyridyl, 4-trifluoromethyl-2-chloro-3-pyridyl, 2-methoxy-5-pyridyl, 3 -methoxy-5-pyridyl, 3-ethoxy-5-pyridyl, 2-methoxy-4-methyl-5-pyridyl, 2-methoxy-6-ethyl-5- Pyridyl, 2-cyano-3-pyridyl, 3-cyano-4-pyridyl, 3-cyano-5-pyridyl, 2-cyano-5-trifluoromethyl-3-pyridyl, 2-chloro-3-pyridyl, 2-chloro-5-pyridyl, 3-chloro-5-pyridyl, 4-chloro-3-pyridyl, 3-chloro-4-cyano-5-pyridyl, 2-fluoro-5-pyridyl, 3-fluoro-5-pyridyl, 4-fluoro-3-pyridyl, 2-chloro-5-methyl-3-pyridyl, 2-bromo-3-methyl- 5-pyridyl, 1,4-dimethyl-2-oxopurin-5-yl, 1,3-dimethyl-2-oxopurin-5-yl, 1-methyl-2- Sideoxypyridin-5-yl, 2-methyl-6-oxooxypyridin-4-yl, 1-ethyl-2-oxoylpyridin-5-yl, 4-ethyl-1-methyl -2-Sideoxypyridin-5-yl, 1-ethyl-2-methyl-6-oxoxypyridin-5-yl, 1-isopropyl-2-indolylpyridin-5-yl, 1,2- Dimethyl-6-oxooxypyridin-3-yl, 1-methyl-2-trifluoromethyl-6-oxoxypyridin-4-yl, 2-(4-morpholinylmethyl)- 3-pyridyl, 2-(t-butylaminocarbonyl)-4-pyridyl, 2-(methoxyethylaminocarbonyl)-6-pyridyl, 3-(3-methoxyphenyl -5-pyridyl, 3-(3-fluoro-5-methoxyphenyl)-5-pyridyl, 5-pyrimidinyl, 4-chloro-5-methyl-pyrimidin-6-yl, 2, 4-dimethyl-pyrimidin-6-yl, 2-cyanopyrimidin-5-yl, 2-trifluoromethyl-pyrimidin-5-yl, 4-fluoropyrimidin-2-yl, 4-trifluoromethyl -pyrimidin-5-yl, 2-azetidinylcarbonyl-pyrazin-5-yl, 2-dimethylaminocarbonyl-pyrazin-5-yl, pyridazin-3-yl, 1,3 ,5-trimethyl-4-pyrazolyl, 1-ethyl-5-pyrazolyl, 1-isopropyl-5-pyrazolyl, 1-ethyl-4-bromo-5-pyrazolyl , 1-ethyl-4-methyl-5-pyrazolyl, 1-ethyl-3-methoxymethyl-5-pyrazolyl, 1-methyl-3-dimethylaminocarbonyl- 5-pyrazolyl, 1-methyl-3-cyclopropyl-5-pyrazolyl, 1-ethyltetrazol-2-yl, phenyl, 2,6-difluorophenyl, 2-fluorobenzene Base, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluoro-3-methyl Oxyphenyl, 2, 4-Difluoro-3-methoxyphenyl, 3-chlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-chloro 4-fluorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-6-fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3- Hydroxyethylphenyl, 3-hydroxymethyl-5-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylsulfonyl Phenyl, 3-methylsulfonylphenyl, 2-fluoro-5-ethylsulfonylphenyl, 5-ethylaminosulfonyl-2-fluorophenyl, 2-fluoro-5-methyl Phenylcarbonylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 2-methyl-5-ethoxycarbonylphenyl, 2-chloro-5-ethoxycarbonylphenyl, 2-fluoro -5-methoxycarbonylphenyl, 3-methyl-5-methoxycarbonylphenyl, 3-methoxy-5-methoxycarbonylphenyl, 2-fluoro-5-methoxycarbonyl Phenylphenyl, 2-fluoro-5-carboxymethylphenyl, 2,6-difluoro-3-methylphenyl, 2-ethylphenyl, 2-methyl-5-carboxyphenyl, 2- Chloro-5-carboxyphenyl, 2-fluoro-5-carboxyphenyl, 2-chloro-5-aminocarbonylphenyl, 2-fluoro-5-aminocarbonylphenyl, 2-cyanophenyl, 4 -cyanophenyl, 2-cyano-3-methylphenyl, 2- 5-methylphenyl, 4-cyano-3-methylphenyl, 2-cyano-3-ethylphenyl, 4-chloro-2-cyanophenyl, 2-chloro-4- Cyanophenyl, 3-chloro-2-cyanophenyl, 3-chloro-6-cyanophenyl, 2-cyano-3,6-dichlorophenyl, 2-cyano-3,6- Difluorophenyl, 4-cyano-2,6-difluorophenyl, 2-cyano-6-fluorophenyl, 3-chloro-2-cyano-6-fluorophenyl, 2-cyano- 6-trifluoromethylphenyl, 2-cyano-5-trifluoromethylphenyl, 3-[(isopropyl)aminocarbonyl]phenyl, 5-methyl-3-[(isopropyl) Aminocarbonyl]phenyl, 4-methyl-3-[(isopropyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N-(methoxy B Aminocarbonyl]phenyl, 2-methyl-5-[(N,N-dimethyl)aminocarbonyl]phenyl, 2-methyl-5-[N-(methyl)-N- (Methylaminoethyl)aminocarbonyl]phenyl, 2-methyl-5-(1-methylpyrazin-4-yl)carbonyl)phenyl, 2,6-difluoro-3-(( Isopropyl)aminocarbonyl)phenyl, 2-fluoro-3-((N-isopropyl-N-methylamino)carbonyl)phenyl, 2-fluoro-3-((ethylamino) Carbonyl)phenyl, -fluoro-3-((fluoroethylamino)carbonyl)phenyl, 2-fluoro-5-(cyclopropylmethyl))aminocarbonyl)phenyl, 2-fluoro-5- (cyclobutyl))aminocarbonyl)phenyl, 2-fluoro-5-( Cyclopentyl))aminocarbonyl)phenyl, 2-fluoro-5-(tetrahydropyran-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-((methoxypropyl) Aminocarbonyl)phenyl, 2-fluoro-5-((2-methyl)aminocarbonyl)phenyl, 2-fluoro-5-((2-methoxypropyl)aminocarbonyl)phenyl , 2-fluoro-5-((1-methoxy-1-methylethyl)aminocarbonyl)phenyl, 2-chloro-5-((1-pyrrolidinyl)carbonyl)phenyl, 2- Chloro-5-((1,3-dimethylpyrazin-4-yl)carbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-3-yl)aminocarbonyl)phenyl 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((1-methylpyrazol-5-yl)aminocarbonyl) Phenyl, 2-fluoro-5-((1-methylpyrazol-4-yl)aminocarbonyl)phenyl, 2-fluoro-5-((pyridin-2-ylmethyl)aminocarbonyl)benzene , 2-fluoro-5-(3-fluoropiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-Boc-piperidin-4-yl))aminocarbonyl) Phenyl, 2-fluoro-5-(1-fluoroethyl-piperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(1-ethyl-piperidin-4-yl) Aminocarbonyl)phenyl, 2-fluoro-5-(1-methylpiperidin-4-yl))aminocarbonyl)phenyl, 2-fluoro-5-(4-morpholinyl)amino Carbonyl)phenyl, 2-fluoro-5-((4-morpholinylethyl)aminocarbonyl)phenyl, 2 -chloro-5-(methoxyethyl)aminocarbonyl)phenyl, 3-(2-benzimidazolyl)phenyl, 3-(2-methyl-1-tetrazolyl)phenyl, 3 -(2-methyl-1,2,4-oxadiazol-3-yl)phenyl, 5-quinolyl, 6-quinolyl, 7-quinolinyl, 8-quinolinyl, 5- Chloro-6-quinolinyl, 7-chloro-4-quinolyl, 8-chloro-6-quinolinyl, 2-methyl-4-quinolinyl, 5,6,7,8-tetrahydroquin Porphyrin-5-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 6,6-dimethyl-5,6,7,8-tetrahydroquinolin-5-yl, 4- Quinazolinyl, quinoxalin-5-yl, 1-o-oxo-isoindol-4-yl, 1-sided oxy-isoindoline-6-yl, 3-methyl-1H- Oxazol-4-yl, 2-methyl-2H-indazol-4-yl, 1-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-carbazole-4- , [1,2,4]triazolo[4,3-a]pyridin-8-yl, 1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 4 -Methyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 5-chloro-1-methyl-2-oxooxy-1,2-dihydroquinolin-6-yl , 1,4-dimethyl-2-oxooxy-1,2-dihydroquinolin-6-yl, 2-sided oxy-1,2-dihydroquinolin-6-yl, 4-side Oxy-dihydroquinolin-1-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl, 5,7-difluoro-1,4-dimethyl Keto-2-oxy-1,2- Hydroquinolin-6-yl, 5,7-difluoro-1,3,4-trimethyl-2-oxo-1,2-dihydroquinolin-6-yl, 5,7-difluoro -1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-yl, 5,7-difluoro-4-ethyl-1-methyl-2 - pendant oxy-1,2-dihydroquinolin-6-yl, 8-isoquinolinyl, 7-isoquinolyl, 6-isoquinolinyl, 5-isoquinolinyl, 4-isoquine Lolinyl, 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1-ethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1 -ethyl-1H-pyrazolo[3,4-b]pyridin-4-yl, 1-methoxyethyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 5- Fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl, imidazo[1,2- a] Pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl- 3H-imidazo[4,5-b]pyridin-6-yl, 3-methylisoxazo[5,4-b]pyridin-4-yl,[1,2,4]triazolo[4 ,3-a]pyridine-8-yl, 1-methyl-4,5,6,7-tetrahydro-3H-pyrazolo[3,4-b]pyridin-3-yl, 6-methyl- 3,4-Dihydro-2H-piperazino[2,3-b]pyridin-5-yl or 5- An alkyl group; and a pharmaceutically acceptable salt thereof. 一種化合物，其係選自由以下組成之群：1-(3-(1-乙基-1H-吡唑-5-基)氧基)-(5-(3-羥基-3-甲基環丁基)-2-吡啶基)-3-甲基脲；1-(6'-(2-羥基-2-甲基丙氧基)-4-((5-甲基-3-吡啶基)氧基)-3,3'-聯吡啶-6-基)-3-甲基脲；1-(4-((5-甲氧基-3-吡啶基)氧基)-5-((3R)-四氫-2H-哌喃-3-基)-2-吡啶基)-3-甲基脲；1-(5-環丙基-4-((1,2-二甲基-6-側氧基-1,6-二氫-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(順-3-羥基環丁基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((1,2-二甲基-6-側氧基-1,6-二氫-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲氧基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(5,6-二氫-2H-哌喃-3-基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；1-(5-(2-羥基乙基)-4-((5-甲基-3-吡啶基)氧基)-2-吡啶基)-3-甲基脲；或1-(3-((1-乙基-1H-吡唑-5-基)氧基)-5-(四氫-2H-哌喃-4-基甲基)-2-吡啶基)-3-甲基脲；或其醫藥學上可接受之鹽。 A compound selected from the group consisting of 1-(3-(1-ethyl-1H-pyrazol-5-yl)oxy)-(5-(3-hydroxy-3-methylcyclobutane) 2-(2-pyridyl)-3-methylurea; 1-(6'-(2-hydroxy-2-methylpropoxy)-4-((5-methyl-3-pyridyl)oxy) -3,3'-bipyridyl-6-yl)-3-methylurea; 1-(4-((5-methoxy-3-pyridyl)oxy)-5-((3R) -tetrahydro-2H-piperidin-3-yl)-2-pyridyl)-3-methylurea; 1-(5-cyclopropyl-4-((1,2-dimethyl-6-side) Oxy-1,6-dihydro-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; 1-(5-(cis-3-hydroxycyclobutyl)-4-( (5-methyl-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; 1-(5-(5,6-dihydro-2H-pyran-3-yl)- 4-((5-methyl-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; 1-(5-(5,6-dihydro-2H-pyran-3- 4-((1,2-dimethyl-6-o-oxy-1,6-dihydro-3-pyridyl)oxy)-2-pyridyl)-3-methylurea; -(5-(5,6-dihydro-2H-pyran-3-yl)-4-((5-methoxy-3-pyridyl)oxy)-2-pyridyl)-3-methyl Base urea; 1-(5-(5,6-dihydro-2H-piperid-3-yl)-4-((5-methyl-3-pyridyl)oxy)-2-pyridyl)- 3-methylurea; 1-(5-(2-hydroxyethyl)-4-((5-methyl-3-pyridyl)) Oxy)-2-pyridyl)-3-methylurea; or 1-(3-((1-ethyl-1H-pyrazol-5-yl)oxy)-5-(tetrahydro-2H- Piperazin-4-ylmethyl)-2-pyridyl)-3-methylurea; or a pharmaceutically acceptable salt thereof. 如請求項1至43中任一項之式Ia化合物，或其醫藥學上可接受之鹽，其係用於療法中。 A compound of formula Ia , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 43 for use in therapy. 如請求項1至43中任一項之式Ia化合物，或其醫藥學上可接受之鹽，其係用於治療由葡糖激酶活性程度不足介導或可藉由活化葡糖激酶而治療之疾病或病症。 A compound of formula Ia , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 43 for use in the treatment of a condition mediated by insufficient glucokinase activity or by activation of glucokinase A disease or condition. 如請求項45之化合物，其中該疾病或病症為糖尿病。 The compound of claim 45, wherein the disease or condition is diabetes. 一種醫藥組合物，其包含如請求項1至43中任一項之式Ia化合物，或其醫藥學上可接受之鹽，及醫藥學上可接受之稀釋劑或載劑。 A pharmaceutical composition comprising a compound of formula Ia according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 一種如請求項1至43中任一項之式Ia化合物，或其醫藥學上可接受之鹽之用途，其係用於製造用以治療由葡糖激酶活性程度不足介導或可藉由活化葡糖激酶而治療之疾病或病症的藥物。 A use of a compound of the formula Ia according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an insufficient degree of glucokinase activity or by activation A drug that treats a disease or condition with glucokinase. 如請求項48之用途，其中該疾病或病症為糖尿病。 The use of claim 48, wherein the disease or condition is diabetes.
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