TWI423974B - Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor - Google Patents

Description

三氮唑並吡啶和三氮唑並吡嗪化合物及其組合物和應用Triazolopyridine and triazolopyrazine compounds, compositions and uses thereof

本發明係關於醫藥領域，具體的說係關於一種c-Met抑制劑及其醫藥用途。The present invention relates to the field of medicine, and in particular to a c-Met inhibitor and its medical use.

c-Met蛋白是由c-Met原癌基因密碼子的蛋白產物，是一個具有酪氨酸激酶活性的190Kd的跨膜異二聚體，同時也是肝細胞生長因子(Hepatocyte Growth Factor，HGF)受體。已被證實HGF/c-Met訊息途徑能顯示多種細胞反應，包括促有絲***、增殖、形態分化和促血管生成活動。抑制HGF/c-Met訊息途徑來治療癌症具有重大的潛力。The c-Met protein is a protein product of the c-Met protooncogene codon. It is a 190Kd transmembrane heterodimer with tyrosine kinase activity and is also a Hepatocyte Growth Factor (HGF) receptor. body. The HGF/c-Met signaling pathway has been shown to display a variety of cellular responses, including mitogenic, proliferative, morphological differentiation and pro-angiogenic activities. There is significant potential for inhibiting the HGF/c-Met signaling pathway to treat cancer.

本發明提供了一種結構式1的化合物：The present invention provides a compound of structural formula 1:

和/或其藥學上可接受的鹽，其中X是N；Y選自-O-、-S-或-N(R⁷ )-；R¹ 選自芳基和芳雜環基，芳基和芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基中的一個或多個基團所取代；或者X是N；Y不存在；以及R¹ 是稠合的雙環芳雜環基，稠合的雙環芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基中的一個或多個基團所取代；或者X是C(R⁶ )；Y是-O-、-S-或-N(R⁷ )-、或者不存在；R¹ 是芳雜環基，芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基中的一個或多個基團所取代；R² 和R³ 獨立地選自氫和烷基，或者R² 和R³ 及它們所連接的碳原子一起形成一個3至7元的環烷基或雜環烷基；R⁴ 選自烷基、環烷基、雜環、芳基和芳雜環基，任何一個烷基、環烷基、雜環、芳基和芳雜環基可以任選地被一個或多個基團取代，這些基團選自：短鏈烷烴，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以任選地被選自鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；環烷氧基，其可以任選地被選自鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；雜環烷氧基，其可以任選地被選自鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳雜環氧基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳雜環基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ ；R⁵ 選自氫、鹵素、CF₃ 、-CF₂ H、烷基、烯基和炔基；R⁶ 選自氫、-OH、-NH₂ 、-NHC(O)R¹¹ 、鹵素和烷基；R⁷ 選自氫和短鏈烷基；n各自獨立地是0、1或者2；R¹¹ 、R¹² 、R¹³ 和R¹⁴ 各自獨立地選自於氫、烷基、烯基、炔基、環烷基、芳基、芳雜環基和雜環，除氫外，每一個基團可任選地被選自鹵素、短鏈烷基、羥基和短鏈烷氧基中的一個或多個基團所取代；或者R¹³ 和R¹⁴ 及他們所連接的氮原子一起形成一個雜環，該雜環含有一個或多個包括-O-、-S-和-N(R¹⁵ )-在內的雜原子，同時雜環又可以任選地被選自鹵素、短鏈烷基、羥基和短鏈烷氧基中的一個或多個基團所取代；以及R¹⁵ 選自氫、短鏈烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-S(O)_n R¹² 和-S(O)_n NR¹³ R¹⁴ ；條件是：R¹ 不是取代的或非取代的苯基或4-吡啶基；當X是N；R² 是氫或甲基；R³ 和R⁵ 是氫；並且Y又不存在時；那麼R¹ 不是喹啉-6-基、7-氟喹啉-6-基、3-喹唑啉-6-基、2，3-二氫苯並呋喃-5-基或2，3-二氫苯並二氧六環-6-基；以及當X是N；R² 、R³ 和R⁵ 是氫；Y是-O-or-N(R⁷ )-；R¹ 是喹啉-6-基、7-氟喹啉-6-基、3-喹唑啉-6-基、2，3-二氫苯並呋喃-5-基或2，3-二氫苯並二氧六環-6-基時；R⁴ 是可以被隨機取代的芳雜環基。And/or a pharmaceutically acceptable salt thereof, wherein X is N; Y is selected from -O-, -S- or -N(R ⁷ )-; R ^{1 is} selected from aryl and aromatic heterocyclic groups, aryl and The aromatic heterocyclic group may be optionally a halogen, a -CF ₃ , a -CF ₂ H, a short-chain alkyl group, a hydroxy-substituted short-chain alkyl group, a short-chain alkoxy-substituted short-chain alkyl group, a cycloalkyl group, C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n Substituting one or more of R ¹² , —S(O) _n NR ¹³ R ¹⁴ , a heterocyclic ring, an aromatic heterocyclic group, an aryl group, an alkenyl group, an alkynyl group; or X is N; Y is absent; And R ¹ is a fused bicyclic aromatic heterocyclic group, and the fused bicyclic aromatic heterocyclic group may be optionally a halogen, a -CF ₃ , a -CF ₂ H, a short-chain alkyl group, a hydroxyl group-substituted short-chain alkyl group, Short-chain alkoxy-substituted short-chain alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C( O) NR ^{One or more of 13} R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, aromatic heterocyclic, aryl, alkenyl, alkynyl Substituted by a group; or X is C(R ⁶ ); Y is -O-, -S- or -N(R ⁷ )-, or absent; R ¹ is an aromatic heterocyclic group, and an aromatic heterocyclic group may be used. a short-chain alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a short-chain alkyl group, a hydroxyl group, a short-chain alkoxy group, a cycloalkyl group, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² ,- NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S( O) _n NR ¹³ R ¹⁴ , a heterocyclic ring, an aromatic heterocyclic group, an aryl group, an alkenyl group, an alkynyl group substituted by one or more groups; R ² and R ^{3 are} independently selected from hydrogen and an alkyl group, or R ² and R ³ together with the carbon atom to which they are attached form a 3 to 7 membered cycloalkyl or heterocycloalkyl group; R ^{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocyclic, aryl and heteroheterocyclic groups. Any one of an alkyl group, a cycloalkyl group, a heterocyclic ring, an aryl group and an aromatic heterocyclic group may be optionally one or more Groups, which are selected from the group: short chain alkanes, which may optionally be selected from hydroxy, short chain alkoxy, CN, ^{halo, -C (O) OR 11,} -C (O) NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , Substituting one or more groups of -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; a short-chain alkoxy group, which may be optionally selected from the group consisting of halogen, hydroxyl and Substituted by one or more groups of short-chain alkoxy groups; cycloalkoxy groups, which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and short-chain alkoxy; a cycloalkoxy group which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and short-chain alkoxy; heterocyclic ring, which may be optionally selected from short-chain alkyl groups, halogens Substituting one or more groups of a hydroxyl group and a short-chain alkoxy group; an aromatic heterocyclic oxy group, which may optionally be selected from one of a short-chain alkyl group, a halogen group, a hydroxyl group and a short-chain alkoxy group Or substituted with a plurality of groups; an aryl group, which may be optionally selected from the group consisting of short chain alkyl groups, halogens, hydroxyl groups Substituted by one or more groups in the short-chain alkoxy group; an aromatic heterocyclic group which may be optionally selected from one or more of a short-chain alkyl group, a halogen, a hydroxyl group and a short-chain alkoxy group Substituted; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ; -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ; -NR ¹³ C(O)OR ¹² ; -NR ¹³ C(O)NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ;-S( O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ ; R ^{5 is} selected from the group consisting of hydrogen, halogen, CF ₃ , -CF ₂ H, alkyl, alkenyl and alkynyl; R ^{6 is} selected from hydrogen, - OH, -NH ₂ , -NHC(O)R ¹¹ , halogen and alkyl; R ^{7 is} selected from hydrogen and short-chain alkyl; n is each independently 0, 1 or 2; R ¹¹ , R ¹² , R ¹³ and R ^{14 is} each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroheterocyclyl and heterocyclic, each of which may be optionally selected from halogen except for hydrogen. Substituting one or more groups of a short-chain alkyl group, a hydroxyl group, and a short-chain alkoxy group; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a heterocyclic ring containing one or more Including -O-, -S- -N (R ¹⁵⁾ - including the hetero atom, while the heterocycle in turn can optionally be substituted selected from halogen, short chain alkyl, hydroxy and short chain alkoxylated with one or more groups; and R ^{15 is} selected from the group consisting of hydrogen, short-chain alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -S(O) _n R ¹² and -S(O _n NR ¹³ R ¹⁴ ; with the proviso that R ¹ is not a substituted or unsubstituted phenyl or 4-pyridyl group; when X is N; R ² is hydrogen or methyl; R ³ and R ⁵ are hydrogen; When not present; then R ¹ is not quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodioxan-6-yl; and when X is N; R ² , R ³ and R ⁵ are hydrogen; Y is -O-or-N(R ⁷ )-; R ¹ Is quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzo When dioxane-6-yl; R ⁴ is an aromatic heterocyclic group which may be randomly substituted.

本發明還提供了一種組合物，包括該一種化合物和/或一種藥學上可接受的鹽，以及藥學上可接受的載體。The invention also provides a composition comprising the compound and/or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

本發明還提供了一種用於與受體接觸來抑制c-Met活性的藥物，包括有效量的該化合物和/或藥學上可接受的鹽。The invention also provides a medicament for contacting a receptor to inhibit c-Met activity, comprising an effective amount of the compound and/or a pharmaceutically acceptable salt.

本發明還提供了一種用於對抑制c-Met有效的治療癌症的藥物，包括有效量的該化合物和/或藥學上可接受的鹽。The invention also provides a medicament for the treatment of cancer effective for inhibiting c-Met, comprising an effective amount of the compound and/or a pharmaceutically acceptable salt.

本說明書所用的下列名詞、片語和符號，除非另有說明，一般按如下定義。下列說明縮寫和術語在整文中表示的意義：The following nouns, phrases and symbols used in the specification, unless otherwise indicated, are generally defined as follows. The following description of the meaning of abbreviations and terms in the text:

不在兩個字母和符號之間的短線“-”表示取代基連接的位點。例如，-CONH₂ 通過碳原子與別的基團相連。A short line "-" that is not between two letters and symbols indicates the site to which the substituent is attached. For example, -CONH ₂ is attached to another group through a carbon atom.

術語“烷基”指的是含有1至10個碳原子的直鏈或支鏈烷烴。例如，烷基包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基和叔丁基。“短鏈烷基”是指含有1至4個碳原子的直鏈或支鏈烷烴。The term "alkyl" refers to a straight or branched chain alkane containing from 1 to 10 carbon atoms. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. "Short chain alkyl" means a straight or branched chain alkane having from 1 to 4 carbon atoms.

術語“烷氧基”指的是通過一個氧原子連接的直鏈或支鏈烷烴基團，例如，甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、2-戊氧基、異戊氧基、新戊氧基、正己氧基、2-己氧基、3-己氧基、3-甲基戊氧以及類似的基團。烷氧基通常有通過氧橋鏈結的1至6個碳原子。“短鏈烷氧基”指的是直鏈或支鏈烷氧基，其中烷基部分包括1至4個碳原子。The term "alkoxy" refers to a straight or branched alkane group attached through an oxygen atom, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec. Butoxy, tert-butoxy, n-pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methyl Pentyloxy and similar groups. Alkoxy groups typically have from 1 to 6 carbon atoms bonded through an oxygen bridge. "Short chain alkoxy" refers to a straight or branched alkoxy group wherein the alkyl moiety includes from 1 to 4 carbon atoms.

術語“烯基”指的是含有一個或一個以上C=C雙鍵、碳原子數在2至10之間的直鏈或支鏈烷烴。例如，烯基包括但不限於乙烯基、2-丙烯基、2-丁烯基。The term "alkenyl" refers to a straight or branched chain alkane containing one or more C=C double bonds and having between 2 and 10 carbon atoms. For example, alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-butenyl.

術語“炔基”指的是含一個或一個以上C≡C三鍵、碳原子數在2至10之間的直鏈或支鏈烷烴。例如，炔基包括但不限於乙炔基、2-丙炔基、2-丁炔基。The term "alkynyl" refers to a straight or branched chain alkane having one or more C≡C triple bonds and having between 2 and 10 carbon atoms. For example, alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl.

術語“環烷基”指的是含有3至12碳原子的飽和或部分不飽和的環狀烷烴。例如，環烷基包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基和環辛基。環可以是飽和的，也可以含有一個或多個雙鍵(即部分不飽和)，但不是完全共軛的。The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkane containing from 3 to 12 carbon atoms. For example, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The ring may be saturated or may contain one or more double bonds (ie, partially unsaturated), but is not fully conjugated.

“芳基”包括：5至6元的碳芳香環，如，苯；雙環，其中至少有一個環是碳芳香環，如，萘、茚和1,2,3,4-四氫喹啉；以及三環，其中至少有一個環是碳芳香環，如，芴。"Aryl" includes: a 5 to 6 membered carbon aromatic ring, such as benzene; a bicyclic ring wherein at least one of the rings is a carbon aromatic ring such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; And a tricyclic ring in which at least one ring is a carbon aromatic ring, such as hydrazine.

例如，芳基包括含5至6元的碳芳香環並一個5至7元雜環，這個雜環包含一個或多個選自氮、氧和硫的雜原子，條件是連接點在碳芳香環上。通過取代的苯的衍生物且環上原子有自由價態的形成二價自由基，其命名為取代的亞苯基自由基。由命名以“基”結尾的單價多環烴自由基通過減少一個自由價態的氫原子衍生而來的二價自由基，其命名就是在相應的單價自由基的後面加上“亞基”，例如，有兩個連接點的萘基被稱為亞萘基。但是，芳基不包含、也不通過任何方式與下面分別定義的雜環芳基重疊。因此，在此定義，如果一個或多個碳芳香環與一個雜芳香環並環，由此產生的環系統是芳雜環基，而不是芳基。For example, an aryl group includes a 5- to 6-membered carbon aromatic ring and a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, provided that the point of attachment is in the carbon aromatic ring. on. A divalent radical is formed by a substituted benzene derivative and a free valence state of the atom on the ring, which is designated as a substituted phenylene radical. A divalent free radical derived from a monovalent polycyclic hydrocarbon radical named at the end of a "base" by reducing a free valence hydrogen atom, the name being the addition of a "subunit" after the corresponding monovalent radical, For example, a naphthyl group having two points of attachment is referred to as a naphthylene group. However, the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbon aromatic rings are ring bonded to a heteroaromatic ring, the resulting ring system is an aromatic heterocyclic group rather than an aryl group.

術語“鹵素”包括氟、氯、溴和碘。The term "halogen" includes fluoro, chloro, bromo and iodo.

術語“芳雜環基”指的是：5至8元的單環芳烴，含一個或多個選自N、O和S的雜原子，如1至4個雜原子，在一些實施例中，為1至3個雜原子，環上其他原子是碳原子；8至12元的雙環芳烴，含一個或多個選自N、O和S的雜原子，如1至4個雜原子，在一些實施例中，是1至3個雜原子，環上其他原子是碳原子；其中至少有一個環是芳香環；以及11至14元的三環芳烴，含一個或多個選自N、O和S的雜原子，如1至4個雜原子，在一些實施例中，是1至3個雜原子，環上其他原子是碳原子；其中至少有一個環是芳香環。The term "aromatic heterocyclic group" refers to a 5- to 8-membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as from 1 to 4 heteroatoms, in some embodiments, 1 to 3 heteroatoms, the other atoms on the ring are carbon atoms; 8 to 12 membered bicyclic aromatic hydrocarbons containing one or more heteroatoms selected from N, O and S, such as 1 to 4 heteroatoms, in some In the embodiment, it is 1 to 3 hetero atoms, the other atoms on the ring are carbon atoms; at least one of the rings is an aromatic ring; and the 11 to 14 membered tricyclic aromatic hydrocarbon contains one or more selected from N, O and The heteroatoms of S, such as from 1 to 4 heteroatoms, in some embodiments, are from 1 to 3 heteroatoms, the other atoms on the ring being carbon atoms; at least one of which is an aromatic ring.

例如，芳雜環基包括一個5至7元的雜芳香環並一個5至7元的環烷基。對於這樣的雙環並起來的雜芳環基，其中只有一個環含有一個或多個雜原子，鏈結位元點在雜芳香環上。For example, the aromatic heterocyclic group includes a 5- to 7-membered heteroaromatic ring and a 5- to 7-membered cycloalkyl group. For such a heterocyclic ring group in which the bicyclic rings are combined, only one of the rings contains one or more hetero atoms, and the chain sites are on the heteroaromatic ring.

當芳雜環基上的硫原子和氧原子總數超過1時，這些雜原子不會一一相鄰。在一些實施例中，硫原子和氧原子在芳雜環基中的總數不超過2。在一些實施例中，硫原子和氧原子在芳雜環基中的總數不超過1。When the total number of sulfur atoms and oxygen atoms on the aromatic heterocyclic group exceeds 1, these hetero atoms are not adjacent to each other. In some embodiments, the total number of sulfur and oxygen atoms in the aromatic heterocyclic group does not exceed two. In some embodiments, the total number of sulfur and oxygen atoms in the aromatic heterocyclic group does not exceed one.

芳雜環基的例子，包括但不限於，(連接點優先標記為1)，2-吡啶基、3-吡啶基、4-吡啶基、2,3-吡嗪基、3,4-吡嗪基、2,4-嘧啶基、3,5-嘧啶基、1-吡唑基、2,3-吡唑基、2,4-咪唑基、異惡唑基、惡唑基、噻唑、噻二唑、四唑基、噻吩基、苯並噻吩基、呋喃基、苯並呋喃基、苯並咪唑啉基、二氫吲哚基、噠嗪基、三氮唑基、喹啉基、吡唑基和5,6,7,8-四氫異喹啉基。Examples of the aromatic heterocyclic group include, but are not limited to, (the point of preference is 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazine , 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazole, thiadipine Azole, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indanyl, pyridazinyl, triazolyl, quinolyl, pyrazolyl And 5,6,7,8-tetrahydroisoquinolinyl.

由命名以“基”結尾的一價自由基通過減少一個自由價態的氫原子衍生而來的二價芳雜環基自由基，其命名是通過在相應的一價自由基名稱後面加上“亞基”。例如，吡啶基有兩個連接位點則稱為亞吡啶基。芳雜環不包括、也不與前面所述的芳基重疊。A divalent aromatic heterocyclic radical derived from a hydrogen atom whose name is terminated by a "base" by reducing a free valence hydrogen atom, which is named by adding "after the corresponding monovalent radical name" Subunit." For example, a pyridyl group having two attachment sites is referred to as a pyridylene group. The aromatic heterocycle does not include or overlap with the aryl groups previously described.

取代的芳雜環基也包括被一個或多個氧(-O-)取代芳雜環基，如N-氧吡啶基。Substituted aromatic heterocyclic groups also include substituted heterocyclic groups such as N-oxypyridyl groups by one or more oxygen (-O-) groups.

術語“雜環”指的是通常為3至7元的單環脂肪環，其包括至少2個碳原子和1至3個雜原子，雜原子獨立的選自氧、硫和氮，以及包括前面所述至少一個雜原子的組合。“雜環”也包括一個5至7元含一個或多個氮、氧或硫雜原子的雜環並一個5至6元的碳芳香環，條件是連接位點在雜環上。雜環可以是飽和的，也可以有一個或多個雙鍵(即部分不飽和)。雜環可能被氧代取代。與其他原子的鏈結位元點可以是碳原子或雜原子。The term "heterocycle" refers to a monocyclic aliphatic ring, typically 3 to 7 members, which comprises at least 2 carbon atoms and 1 to 3 heteroatoms, independently selected from the group consisting of oxygen, sulfur and nitrogen, and including the former a combination of the at least one hetero atom. "Heterocycle" also includes a 5 to 7 membered heterocyclic ring containing one or more nitrogen, oxygen or sulfur heteroatoms and a 5 to 6 membered carbon aromatic ring, provided that the attachment site is on the heterocyclic ring. The heterocycle can be saturated or it can have one or more double bonds (ie, partially unsaturated). The heterocyclic ring may be substituted by oxo. The link point with other atoms may be a carbon atom or a hetero atom.

相應的雜環包括，例如(連接位元點優先標記為1)、1-吡咯啉基、2-吡咯啉基、2,4-咪唑烷基、2,3-吡唑烷基、1-呱啶基、2-呱啶基、3-呱啶基、4-呱啶基和2,5-呱嗪基。嗎啉基也是這樣設計的，包括2-嗎啉基和3-嗎啉基(氧原子優先記為1)。取代的雜環也包括有一個或一個以上氧代基團的環，例如，N-氧呱啶基、N-氧嗎啉基、1-氧代-1-硫代嗎啉基和1，1-二氧代-1-硫代嗎啉基。Corresponding heterocycles include, for example, (linker position preferentially labeled 1), 1-pyrrolidino, 2-pyrroline, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1-oxime Pyridyl, 2-acridinyl, 3-acridinyl, 4-acridinyl and 2,5-pyridazinyl. The morpholinyl group is also designed in this way, including 2-morpholinyl and 3-morpholinyl (the oxygen atom is preferentially referred to as 1). Substituted heterocycles also include rings having one or more oxo groups, for example, N-oxaacridinyl, N-oxymorpholinyl, 1-oxo-1-thiomorpholinyl, and 1,1 - Dioxo-1-thiomorpholinyl.

所謂“任選(option)”、“任選的(optional)”或“任選地(optionally)”的意思是指後續描述的事件或情形可能會也可能不會發生，並且該描述包括事物或情形發生和不發生兩種情況。例如，“被任選取代的烷基”包括下文定義的“烷基”和“取代烷基”。關於任一基團包含一個或多個取代基，本領域一般技術人員均可理解，但不包括不切實際的高位阻、合成上不可行的和(或)內在不穩定的取代基。By "option," "optional," or "optionally", it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes things or There are two situations in which the situation occurs and does not occur. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined below. The inclusion of one or more substituents for any group will be understood by those of ordinary skill in the art, but does not include impractical high steric hindrance, synthetically unfeasible, and/or inherently labile substituents.

所用的術語“取代的”是指在特定的原子或基團中的一個或多個氫原子被從指定範圍選出的基團替換，前提是特定原子的價態正常。當取代基是氧代(例如：=O)即意味著指定原子上的兩個氫被取代了。只要組合能得到穩定的化合物或有用的合成中間體，取代基的組合和/或變化是允許的。穩定的化合物或穩定的結構意味著它穩定到能從反應混合物中分離出來，並至少在隨後的製劑過程中有實用價值。除特別說明，取代基被命名進母核結構。例如，簡單的說，當環烷基烷基是作為一個可能的取代基，母核上這個取代基的連接位點在烷基上。The term "substituted" as used herein means that one or more hydrogen atoms in a particular atom or group are replaced by a group selected from a specified range, provided that the valence of the particular atom is normal. When the substituent is oxo (for example: =O), it means that two hydrogens on the designated atom are replaced. Combinations and/or variations of substituents are permissible as long as the combination results in a stable compound or a useful synthetic intermediate. A stable compound or stable structure means that it is stable enough to be separated from the reaction mixture and at least useful in subsequent formulation processes. Unless otherwise stated, the substituents are named into the parent core structure. For example, to put it simply, when a cycloalkylalkyl group is used as a possible substituent, the attachment site for this substituent on the parent nucleus is on the alkyl group.

在一些實施例中，“被一個或多個基團取代”是指在特定的原子或基團中的兩個氫原子分別被指定範圍的基團中選出的相同或不同的基團替換。在一些實施例中，“被一個或多個基團取代”是指在特定的原子或基團中的三個氫原子分別被指定範圍的基團中選出的相同或不同的基團替換。在一些實施例中，“被一個或多個基團取代”是指在特定的原子或基團中的四個氫原子分別被指定範圍的基團中選出的相同或不同的基團替換。In some embodiments, "substituted with one or more groups" refers to the replacement of two hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups, respectively. In some embodiments, "substituted with one or more groups" refers to the replacement of three hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups, respectively. In some embodiments, "substituted with one or more groups" refers to the replacement of four hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups, respectively.

該化合物，包括但不限於，它們的光學異構體、外消旋體、及其他混合物。在這些情況下，單一對映體或非對映體，例如具有光學活性的結構，可通過不對稱合成或由外消旋混合物或非對映體混合物拆分得到。對於消旋混合物或非對映體混合物的拆分，可以用傳統的方法分離，例如使用拆分試劑結晶；也可以用層析法分離，例如對掌高效液相層析(HPLC)柱。另外，這類化合物包含Z-和E-型(或順-和反-式)的含C=C雙鍵化合物。本文所述化合物存在各種互變異構體，術語“化合物”包括該化合物的所有互變異構形式。這裏化合物也包括其不同的晶體形式，包含多晶和包合物。同樣，術語“鹽”也包括了該化合物的所有異構體、消旋體、其他混合物、Z-和E-型、互變異構體和晶體形式。Such compounds include, but are not limited to, their optical isomers, racemates, and other mixtures. In these cases, a single enantiomer or diastereomer, such as an optically active structure, can be obtained by asymmetric synthesis or by resolution of a racemic mixture or mixture of diastereomers. For the resolution of the racemic mixture or mixture of diastereomers, it can be isolated by conventional methods, for example, using a resolving agent; or it can be separated by chromatography, for example, a high performance liquid chromatography (HPLC) column. Additionally, such compounds contain Z- and E-type (or cis- and trans-) compounds containing C=C double bonds. The compounds described herein exist in various tautomers, and the term "compound" includes all tautomeric forms of the compound. The compounds herein also include their different crystalline forms, including polycrystals and clathrates. Likewise, the term "salt" also includes all isomers, racemates, other mixtures, Z- and E-forms, tautomers, and crystalline forms of the compound.

術語“藥學上可接受的鹽”包括但不限於與無機酸形成的鹽，如鹽酸鹽、磷酸鹽、二磷酸鹽、氫溴酸鹽、硫酸鹽、亞磺酸鹽、硝酸鹽、及其類似鹽；也包括與有機酸形成的鹽，如蘋果酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、琥珀酸鹽、檸檬酸鹽、醋酸鹽、乳酸鹽、磺酸鹽、對甲苯磺酸鹽、2-羥乙基磺酸鹽、苯甲酸鹽、水楊酸鹽、硬脂酸鹽和鏈烷酸鹽如醋酸鹽，HOOC-(CH₂ )_n -COOH其中n是0至4的鹽，及其類似鹽。類似地，藥學上可接受的陽離子包括但不限於鈉、鉀、鈣、鋁、鋰和銨。The term "pharmaceutically acceptable salts" includes, but is not limited to, salts formed with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and Similar salts; also include salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, sulfonate, p-toluene Sulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoate such as acetate, HOOC-(CH ₂ ) _n -COOH wherein n is 0 to 4 salts, and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

此外，如果該化合物是一種與酸形成的鹽，其游離鹼可以通過鹼化該鹽溶液獲得。相反地，如果化合物是游離鹼，則其鹽特別是藥學上可接受的鹽可以通過由鹼製酸的常規程序製得，即將游離鹼溶於合適的有機溶劑後用酸處理。本領域一般技術人員可識別各種可能用來製備無毒的藥學上可接受的鹽的合成方法。Further, if the compound is a salt formed with an acid, the free base thereof can be obtained by alkalizing the salt solution. Conversely, if the compound is the free base, the salt, especially the pharmaceutically acceptable salt, can be prepared by conventional procedures for the acid formation from the base, i.e., by dissolving the free base in a suitable organic solvent and then treating the acid. One of ordinary skill in the art can recognize a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable salts.

“溶劑化物”如“水合物”，是由溶劑和化合物互相作用形成。術語“化合物”，應該包括了化合物的溶劑化物(包括化合物的水合物)。同樣，“鹽”也包括了鹽的溶劑化物(如鹽的水合物)。合適的溶劑化物是藥學上可接受的，例如水合物，它包括了單水合物和半水合物。"Solvate" such as "hydrate" is formed by the interaction of a solvent and a compound. The term "compound" shall include solvates of the compounds (including hydrates of the compounds). Similarly, "salts" also include solvates of salts (such as hydrates of salts). Suitable solvates are pharmaceutically acceptable, such as hydrates, which include monohydrates and hemihydrates.

“螯合物”，是由化合物與金屬離子在兩個(或更多的)點配位而成。術語“化合物”應該包括化合物的螯合物。同樣，“鹽”也包括鹽的螯合物。A "chelate" is a compound that is coordinated to a metal ion at two (or more) points. The term "compound" shall include a chelate of the compound. Similarly, "salts" also include salts of salts.

“非共價複合物”是由一個化合物和另一分子通過非共價鍵相互作用形成的。例如，複合物可以通過凡得瓦力、氫鍵和靜電相互作用(也稱為離子鍵)形成。這些非共價複合物也包含在術語“化合物”的概念中。A "non-covalent complex" is formed by the interaction of one compound and another molecule through a non-covalent bond. For example, the composite can be formed by van der Waals, hydrogen bonding, and electrostatic interactions (also known as ionic bonds). These non-covalent complexes are also included in the concept of the term "compound".

術語“氫鍵”是指電負性原子(也稱為氫鍵受體)和一個連接在另一相對電負性原子上的氫原子(也稱為氫鍵給體)作用的形式。合適的氫鍵給體和受體見於各種著名的藥物化學書籍(G. C. Pimentel和A. L. McClellan,The Hydrogen Bond,Freeman,San Francisco,1960;R. Taylor and O. Kennard,"Hydrogen Bond Geometry in Organic Crystals",Accounts of Chemical Research,17,pp. 320-326(1984))。The term "hydrogen bond" refers to a form in which an electronegative atom (also referred to as a hydrogen bond acceptor) and a hydrogen atom (also referred to as a hydrogen bond donor) attached to another relatively electronegative atom. Suitable hydrogen bond donors and acceptors are found in various well-known books on medicinal chemistry (GC Pimentel and AL McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals" , Accounts of Chemical Research, 17, pp. 320-326 (1984)).

本文使用的術語“基團”，“基”或“片段”為同義詞，用於代表功能基團或連接於某一根鍵的片段或其他分子片段。The term "group", "base" or "fragment" as used herein is synonymous and is used to refer to a functional group or a fragment or other molecular fragment attached to a certain bond.

術語“活性成分”表示一種具有生物活性的化學物質。在一些例中，“活性成分”是一種具有醫藥效用的化學物質。The term "active ingredient" means a biologically active chemical. In some instances, an "active ingredient" is a chemical that has a medicinal effect.

“處理”、“治療”或“減緩”指的是給予一患有癌症、具有癌症的症狀、或有易患癌症體質的個體該的化合物和/或藥學上可接受的鹽，用以治癒、治療、緩和、舒解、改變、醫治、改善、改良或是影響癌症、癌症的症狀、或易患癌症的體質。"Treatment," "treating," or "mitigating" refers to the administration of a compound and/or a pharmaceutically acceptable salt to a subject having cancer, symptoms of cancer, or susceptibility to cancer, for healing, Treat, alleviate, relieve, alter, heal, improve, improve, or affect cancer, cancer, or cancer.

術語”有效量”指的是，該化合物和/或藥學上可接受的鹽對於能有效“治療”個體的一種疾病或不適的用量。如果是癌症時，有效量可引起前面定義“處理”、“治療”和“減緩”中所述個體任何一種可見的或可檢測的變化。例如，有效量能減少癌症或腫瘤細胞的數目；縮小腫瘤的大小；抑制或阻止腫瘤細胞向周邊器官的侵入，例如，腫瘤蔓延入軟組織或骨骼中；抑制或阻止腫瘤的轉移；抑制或阻止腫瘤的生長；一定程度上減輕一種或多種與癌症相關的症狀；減少發病率和死亡率；提高生活品質；或者是上述效果的結合。有效量可以是通過抑制c-Met活性來減少疾病症狀的用量。對於癌症治療，體內實驗的效果可以通過評估如存活期、疾病進展時間(Time to Disease Progression，TTP)、反應率(Response Rates，RR)、持續反應期和/或生活品質來測量。專業人員已經意識到，有效量可以隨著給藥的途徑、賦形劑的劑量、以及與其他藥物的合用而變化。The term "effective amount" refers to an amount of the compound and/or pharmaceutically acceptable salt that is effective to "treat" a disease or condition in an individual. In the case of cancer, an effective amount can cause any one of the visible or detectable changes in the individual as defined in the "treatment", "treatment" and "mitigation" previously defined. For example, an effective amount can reduce the number of cancer or tumor cells; reduce the size of the tumor; inhibit or prevent the invasion of tumor cells into peripheral organs, for example, tumors spread into soft tissues or bones; inhibit or prevent tumor metastasis; inhibit or prevent tumors Growth; to some extent alleviate one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount that reduces the symptoms of the disease by inhibiting c-Met activity. For cancer treatment, the effects of in vivo experiments can be measured by assessing, for example, survival, Time to Disease Progression (TTP), Response Rates (RR), duration of response, and/or quality of life. The skilled person has recognized that an effective amount can vary with the route of administration, the dosage of the excipient, and the combination with other drugs.

術語“抑制”指的是一種生物活動或生物過程的基礎活性的降低。“抑制c-Met活性”指的是相對於在沒有該化合物和/或藥學上可接受的鹽時c-Met的活性，由該化合物和/或藥學上可接受的鹽直接或間接的作用導致c-Met的活性降低。活性的降低可以是該化合物和/或藥學上可接受的鹽與c-Met直接的相互作用引起的，或者是由於該化合物和/或藥學上可接受的鹽與其他一種或多種因數的相互作用進而最終影響了c-Met的活性引起的。例如，該化合物和/或藥學上可接受的鹽，可通過直接與c-Met結合而降低其活性，可通過直接或間接地影響其他因素來降低c-Met活性，或通過直接或間接得降低細胞或器官中c-Met的數量，來降低c-Met的活性。The term "inhibition" refers to a decrease in the basal activity of a biological activity or biological process. "Inhibiting c-Met activity" refers to the direct or indirect action of the compound and/or pharmaceutically acceptable salt relative to the activity of c-Met in the absence of the compound and/or pharmaceutically acceptable salt. The activity of c-Met is reduced. The decrease in activity may be due to the direct interaction of the compound and/or pharmaceutically acceptable salt with c-Met, or due to the interaction of the compound and/or pharmaceutically acceptable salt with one or more other factors. This in turn ultimately affects the activity of c-Met. For example, the compound and/or pharmaceutically acceptable salt can reduce its activity by directly binding to c-Met, can reduce c-Met activity by directly or indirectly affecting other factors, or can be reduced directly or indirectly. The amount of c-Met in cells or organs to reduce the activity of c-Met.

本發明的具體的一或多種較佳方式將在下面列出。Specific one or more preferred aspects of the invention are listed below.

本發明提供了結構式1的化合物：The present invention provides a compound of structural formula 1:

和/或其藥學上可接受的鹽，其中X是N；Y選自-O-、-S-或-N(R⁷ )-；R¹ 選自芳基和芳雜環基，芳基和芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基中的一個或多個基團所取代；或者X是N；Y不存在；以及R¹ 是稠合的雙環芳雜環基，稠合的雙環芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基中的一個或多個基團所取代；或者X是C(R⁶ )；Y是-O-、-S-或-N(R⁷ )-、或者不存在；R¹ 是芳雜環基，芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基中的一個或多個基團所取代；R² 和R³ 獨立地選自氫和烷基，或者R² 和R³ 及它們所連接的碳原子一起形成一個3至7元的環烷基或雜環烷基；R⁴ 選自烷基、環烷基、雜環、芳基和芳雜環基，任何一個烷基、環烷基、雜環、芳基和芳雜環基可以任選地被一個或多個基團取代，這些基團選自：短鏈烷烴，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以任選地被選自鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；環烷氧基，其可以任選地被選自鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；雜環烷氧基，其可以任選地被選自鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳雜環氧基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳雜環基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ ；R⁵ 選自氫、鹵素、CF₃ 、-CF₂ H、烷基、烯基和炔基；R⁶ 選自氫、-OH、-NH₂ 、-NHC(O)R¹¹ 、鹵素和烷基；R⁷ 選自氫和短鏈烷基；n各自獨立地是0、1或者2；R¹¹ 、R¹² 、R¹³ 和R¹⁴ 各自獨立地選自於氫、烷基、烯基、炔基、環烷基、芳基、芳雜環基和雜環，除氫外，每一個基團可任選地被選自鹵素、短鏈烷基、羥基和短鏈烷氧基中的一個或多個基團所取代；或者R¹³ 和R¹⁴ 及他們所連接的氮原子一起形成一個雜環，該雜環含有一個或多個包括-O-、-S-和-N(R¹⁵ )-在內的雜原子，同時雜環又可以任選地被選自鹵素、短鏈烷基、羥基和短鏈烷氧基中的一個或多個基團所取代；以及R¹⁵ 選自氫、短鏈烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-S(O)_n R¹² 和-S(O)_n NR¹³ R¹⁴ ；條件是：R¹ 不是經取代的或非經取代的苯基或4-吡啶基；當X是N；R² 是氫或甲基；R³ 和R⁵ 是氫；並且Y又不存在時；那麼R¹ 不是喹啉-6-基、7-氟喹啉-6-基、3-喹唑啉-6-基、2，3-二氫苯並呋喃-5-基或2，3-二氫苯並二氧六環-6-基；以及當X是N；R² 、R³ 和R⁵ 是氫；Y是-O-or-N(R⁷ )-；R¹ 是喹啉-6-基、7-氟喹啉-6-基、3-喹唑啉-6-基、2，3-二氫苯並呋喃-5-基或2，3-二氫苯並二氧六環-6-基時；R⁴ 是可以被隨機取代的芳雜環基在一些實施方案中，X是N；在一些實施方案中，X是C(R⁶ )；在一些實施方案中，R⁶ 選自氫、鹵素和短鏈烷基；在一些實施方案中，R⁶ 是氫。And/or a pharmaceutically acceptable salt thereof, wherein X is N; Y is selected from -O-, -S- or -N(R ⁷ )-; R ^{1 is} selected from aryl and aromatic heterocyclic groups, aryl and The aromatic heterocyclic group may be optionally a halogen, a -CF ₃ , a -CF ₂ H, a short-chain alkyl group, a hydroxy-substituted short-chain alkyl group, a short-chain alkoxy-substituted short-chain alkyl group, a cycloalkyl group, C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n Substituting one or more of R ¹² , —S(O) _n NR ¹³ R ¹⁴ , a heterocyclic ring, an aromatic heterocyclic group, an aryl group, an alkenyl group, an alkynyl group; or X is N; Y is absent; And R ¹ is a fused bicyclic aromatic heterocyclic group, and the fused bicyclic aromatic heterocyclic group may be optionally a halogen, a -CF ₃ , a -CF ₂ H, a short-chain alkyl group, a hydroxyl group-substituted short-chain alkyl group, Short-chain alkoxy-substituted short-chain alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C( O) NR ^{One or more of 13} R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, aromatic heterocyclic, aryl, alkenyl, alkynyl Substituted by a group; or X is C(R ⁶ ); Y is -O-, -S- or -N(R ⁷ )-, or absent; R ¹ is an aromatic heterocyclic group, and an aromatic heterocyclic group may be used. a short-chain alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a short-chain alkyl group, a hydroxyl group, a short-chain alkoxy group, a cycloalkyl group, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² ,- NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S( O) _n NR ¹³ R ¹⁴ , a heterocyclic ring, an aromatic heterocyclic group, an aryl group, an alkenyl group, an alkynyl group substituted by one or more groups; R ² and R ^{3 are} independently selected from hydrogen and an alkyl group, or R ² and R ³ together with the carbon atom to which they are attached form a 3 to 7 membered cycloalkyl or heterocycloalkyl group; R ^{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocyclic, aryl and heteroheterocyclic groups. Any one of an alkyl group, a cycloalkyl group, a heterocyclic ring, an aryl group and an aromatic heterocyclic group may be optionally one or more Groups, which are selected from the group: short chain alkanes, which may optionally be selected from hydroxy, short chain alkoxy, CN, ^{halo, -C (O) OR 11,} -C (O) NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , Substituting one or more groups of -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; a short-chain alkoxy group, which may be optionally selected from the group consisting of halogen, hydroxyl and Substituted by one or more groups of short-chain alkoxy groups; cycloalkoxy groups, which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and short-chain alkoxy; a cycloalkoxy group which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and short-chain alkoxy; heterocyclic ring, which may be optionally selected from short-chain alkyl groups, halogens Substituting one or more groups of a hydroxyl group and a short-chain alkoxy group; an aromatic heterocyclic oxy group, which may optionally be selected from one of a short-chain alkyl group, a halogen group, a hydroxyl group and a short-chain alkoxy group Or substituted with a plurality of groups; an aryl group, which may be optionally selected from the group consisting of short chain alkyl groups, halogens, hydroxyl groups Substituted by one or more groups in the short-chain alkoxy group; an aromatic heterocyclic group which may be optionally selected from one or more of a short-chain alkyl group, a halogen, a hydroxyl group and a short-chain alkoxy group Substituted; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ; -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ; -NR ¹³ C(O)OR ¹² ; -NR ¹³ C(O)NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ;-S( O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ ; R ^{5 is} selected from the group consisting of hydrogen, halogen, CF ₃ , -CF ₂ H, alkyl, alkenyl and alkynyl; R ^{6 is} selected from hydrogen, - OH, -NH ₂ , -NHC(O)R ¹¹ , halogen and alkyl; R ^{7 is} selected from hydrogen and short-chain alkyl; n is each independently 0, 1 or 2; R ¹¹ , R ¹² , R ¹³ and R ^{14 is} each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroheterocyclyl and heterocyclic, each of which may be optionally selected from halogen except for hydrogen. Substituting one or more groups of a short-chain alkyl group, a hydroxyl group, and a short-chain alkoxy group; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a heterocyclic ring containing one or more Including -O-, -S- -N (R ¹⁵⁾ - including the hetero atom, while the heterocycle in turn can optionally be substituted selected from halogen, short chain alkyl, hydroxy and short chain alkoxylated with one or more groups; and R ^{15 is} selected from the group consisting of hydrogen, short-chain alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -S(O) _n R ¹² and -S(O _n NR ¹³ R ¹⁴ ; with the proviso that R ¹ is not substituted or unsubstituted phenyl or 4-pyridyl; when X is N; R ² is hydrogen or methyl; R ³ and R ⁵ are hydrogen; And when Y is not present; then R ¹ is not quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5- Or 2,3-dihydrobenzodiox-6-yl; and when X is N; R ² , R ³ and R ⁵ are hydrogen; Y is -O-or-N(R ⁷ )-; R ¹ is quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydro Benzodioxet-6-yl; R ⁴ is an aromatic heterocyclic group which may be randomly substituted. In some embodiments, X is N; in some embodiments, X is C(R ⁶ ); embodiment, R ⁶ is selected from hydrogen, halogen, and short chain alkyl; in some embodiments, R ⁶ is hydrogen.

在一些實施方案中，Y是-O-；在一些實施方案中，Y是-S-；在一些實施方案中，Y是-N(R⁷ )-；在一些實施方案中，R⁷ 是氫或甲基；在一些實施方案中，R⁷ 是氫；在一些實施方案中，Y不存在。In some embodiments, Y is -O-; In some embodiments, Y is -S-; In some embodiments, Y is -N (R ⁷⁾ -; In some embodiments, R ⁷ is hydrogen or methyl; in some embodiments, R ⁷ is hydrogen; in some embodiments, Y is absent.

在一些實施方案中，R¹ 是8至10元芳雜環基，其中芳雜環基可以任選地被選自鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² ，-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基和炔基中的一個或者多個基團所取代。在一些實施方案中，R¹ 是8至10元芳雜環基，其中芳雜環基可以任選地被選自鹵素、短鏈烷基、羥基取代的短鏈烷基和短鏈烷氧基取代的短鏈烷基中的一個或者多個基團所取代。In some embodiments, R ¹ is an 8- to 10-membered aromatic heterocyclic group, wherein the aromatic heterocyclic group can be optionally shortly selected from the group consisting of halogen, —CF ₃ , —CF ₂ H, short-chain alkyl, and hydroxy. Alkenyl, short-chain alkoxy-substituted short-chain alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ ,- NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² ,- NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic ring, aromatic heterocyclic group, aryl group, alkenyl group and alkyne Substituted by one or more groups in the group. In some embodiments, R ¹ is an 8- to 10-membered aromatic heterocyclic group, wherein the aromatic heterocyclic group can be optionally selected from the group consisting of halogen, short-chain alkyl, hydroxy-substituted short-chain alkyl, and short-chain alkoxy Substituted by one or more of the substituted short chain alkyl groups.

在一些實施方案中，R¹ 選自喹啉-6-基、噻吩並[3,2-c]吡啶-2-基、苯並[d]噻唑-6-基和咪唑並[1,2-a]吡啶-6-基，它們可以任選地被選自鹵素、短鏈烷基、羥基取代的短鏈烷基和短鏈烷氧基取代的短鏈烷基中的一個或多個基團所取代。在一些實施方案中，R¹ 選自喹啉-6-基，其可以任選地被選自鹵素、短鏈烷基、羥基取代的短鏈烷基和短鏈烷氧基取代的短鏈烷基的一個或者多個基團所取代。In some embodiments, R ^{1 is} selected from the group consisting of quinoline-6-yl, thieno[3,2-c]pyridin-2-yl, benzo[d]thiazol-6-yl, and imidazo[1,2- a] pyridin-6-yl, which may optionally be one or more groups selected from the group consisting of halogen, short-chain alkyl, hydroxy-substituted short-chain alkyl and short-chain alkoxy-substituted short-chain alkyl Replaced. In some embodiments, R ^{1 is} selected from quinolin-6-yl, which may be optionally substituted with a short alkane selected from the group consisting of halogen, short chain alkyl, hydroxy substituted short chain alkyl, and short chain alkoxy Substituted by one or more groups of the group.

在一些實施方案中，R¹ 選自以下這些芳雜環基：In some embodiments, R ^{1 is} selected from the group consisting of:

其中任何一個環可以任選地被選自鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基和炔基中的一個或多個基團所取代。Any one of the rings may be optionally selected from the group consisting of halogen, -CF ₃ , -CF ₂ H, short-chain alkyl, hydroxy-substituted short-chain alkyl, short-chain alkoxy-substituted short-chain alkyl, cycloalkyl , -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S (O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O Substituting one or more of _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , a heterocyclic ring, an aromatic heterocyclic group, an aryl group, an alkenyl group and an alkynyl group.

在一些實施方案中，R¹ 選自下面這些芳雜環基：In some embodiments, R ^{1 is} selected from the group consisting of the following aromatic heterocyclic groups:

其中任何一個環可以任選地被一個或者多個基團取代，這些基團選自鹵素、-CF₃ 、-CF₂ H、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、環烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 、-NR¹³ C(O)NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 、雜環、芳雜環基、芳基、烯基、炔基。為了避免疑惑，上述的各個環在所示位置附著於支承R² 和R³ 的碳上。Any one of the rings may be optionally substituted by one or more groups selected from the group consisting of halogen, -CF ₃ , -CF ₂ H, short-chain alkyl, hydroxy-substituted short-chain alkyl, short-chain alkoxy Substituted short chain alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic ring, aromatic heterocyclic group, aryl group, alkenyl group, alkynyl group. For the avoidance of doubt, the various rings described above are attached to the carbon supporting R ² and R ³ at the locations shown.

在一些實施方案中，R² 和R³ 獨立地選自氫和C₁ 至C₆ 的烷基；或者R² 和R³ 及他們所連接的碳原子一起形成一個環丙基。在一些實施方案中，R² 是氫，並且R³ 選自氫和C₁ 至C₆ 的烷基。在一些實施方案中，R² 是氫並且R³ 選自氫和甲基。在一些實施方案中，R² 和R³ 都是氫。在一些實施方案中，R² 和R³ 及他們所連接的碳原子一起形成一個環丙基。In some embodiments, R ² and R ^{3 are} independently selected from hydrogen and C ₁ to C ₆ alkyl; or R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group. In some embodiments, R ² is hydrogen and R ^{3 is} selected from hydrogen and C ₁ to C ₆ alkyl. In some embodiments, R ² is hydrogen and R ^{3 is} selected from hydrogen and methyl. In some embodiments, both R ² and R ³ are hydrogen. In some embodiments, R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group.

在一些實施方案中，R⁴ 是芳基，該芳基可以任選地被一個或多個基團取代，這些基團選自：短鏈烷基，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以任選地被鹵素、羥基和短鏈烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳雜環氧基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；芳雜環基，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。In some embodiments, R ⁴ is aryl, which may be optionally substituted with one or more groups selected from the group consisting of short-chain alkyl groups, which may be optionally selected from hydroxyl groups, short Alkenyloxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , one of -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ or Substituted by a plurality of groups; a short-chain alkoxy group which may be optionally substituted by one or more of a halogen, a hydroxyl group and a short-chain alkoxy group; a heterocyclic ring which may optionally be selected from short Substituted by one or more of the alkyl, halo, hydroxy, and short-chain alkoxy groups; an aromatic heterocyclic oxy group, which may be optionally selected from the group consisting of short-chain alkyl groups, halogens, hydroxyl groups, and short-chain alkylneses Substituted by one or more groups in the oxy group; an aryl group, which may be optionally substituted with one or more groups selected from the group consisting of short-chain alkyl groups, halogens, hydroxyl groups, and short-chain alkoxy groups; a heterocyclic group, which may be optionally selected from the group consisting of short-chain alkyl groups, halogens, hydroxyl groups, and short-chain alkoxy groups; ^{Cyano; -C (O) R 11;} -C (O) OR 11; -NR 13 R 14; -NR 13 C (O) R 11; -NR 13 S (O) n R 12; -NR 13 S (O) _n NR ¹³ R ¹⁴ ; -NR ¹³ C(O)OR ¹² ; -NR ¹³ C(O)NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; And -S(O) _n NR ¹³ R ¹⁴ .

在一些實施方案中，R⁴ 是芳基，其可以任選地被選自鹵素、羥基、短鏈烷氧基、短鏈烷基、羥基取代的短鏈烷基、短鏈烷氧基取代的短鏈烷基、羥基取代的短鏈烷氧基、短鏈烷氧基取代的短鏈烷氧基和-NR¹³ S(O)_n R¹² 中的一個或多個基團所取代。In some embodiments, R ⁴ is aryl, which may be optionally substituted with a halogen, hydroxy, short chain alkoxy, short chain alkyl, hydroxy substituted short chain alkyl, short chain alkoxy The short-chain alkyl group, the hydroxy-substituted short-chain alkoxy group, the short-chain alkoxy-substituted short-chain alkoxy group, and one or more groups of -NR ¹³ S(O) _n R ¹² are substituted.

在一些實施方案中，R⁴ 是苯基，其可以任選地被選自短鏈烷氧基、羥基取代的短鏈烷氧基和短鏈烷氧基取代的短鏈烷氧基中的一個或多個基團所取代。In some embodiments, R ⁴ is phenyl, which may be optionally one of a short chain alkoxy group selected from a short chain alkoxy group, a hydroxy substituted short chain alkoxy group, and a short chain alkoxy group. Or substituted by multiple groups.

在一些實施方案中，R⁴ 是雜環，其任選地被一個或多個基團取代，這些基團選自：短鏈烷基，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以任選地被鹵素、羥基和短鏈烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。In some embodiments, R ⁴ is heterocyclyl, which is optionally substituted with one or more groups selected from these groups: short-chain alkyl group, which may optionally be selected from hydroxy, short chain alkoxy Base, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ one or more Substituted; a short-chain alkoxy group which may be optionally substituted by one or more of a halogen, a hydroxyl group and a short-chain alkoxy group; a heterocyclic ring which may be optionally selected from a short-chain alkyl group Substituted by one or more of halogen, hydroxy, and short-chain alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

在一些實施方案中，R⁴ 選自吡咯-1-基、呱啶-1-基、四氫-2H-吡喃-4-基、嗎啡啉-4-基和6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基，其中任何一個基團都可以任選地被一個或者多個基團取代，這些基團選自：短鏈烷基，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以任選地被鹵素、羥基和短鏈烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)nNR¹³ R¹⁴ 。In some embodiments, R ^{4 is} selected from pyrrol-1-yl, acridin-1-yl, tetrahydro-2H-pyran-4-yl, morphinolin-4-yl, and 6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-yl, wherein any one of the groups may be optionally substituted by one or more groups selected from the group consisting of short-chain alkyl groups, optionally The ground is selected from the group consisting of a hydroxyl group, a short chain alkoxy group, CN, a halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR Substituted by one or more groups of ¹³ R ¹⁴ ; a short-chain alkoxy group which may be optionally substituted by one or more of a halogen, a hydroxyl group and a short-chain alkoxy group; Optionally substituted with one or more groups selected from the group consisting of short-chain alkyl, halogen, hydroxy, and short-chain alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ; -NR ¹³ C(O)R ¹¹ ; -NR ¹³ S(O) _n R ¹² ; -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; and -S(O)nNR ¹³ R ¹⁴ .

在一些實施方案中，R⁴ 選自吡咯-1-基、呱啶-1-基、四氫呋喃-2氫-吡喃-4-基、嗎菲林-4-基和6，7-二氫噻吩並[3,2-c]吡啶-5(4氫)-基，其中任何一個都可以任選地被選自鹵素、CF₃ 、-CF₂ H、羥基、短鏈烷基、羥基取代的短鏈烷基和短鏈烷氧基取代的短鏈烷基中的一個或多個基團所取代。In some embodiments, R ⁴ is selected from pyrrol-1-yl, piperidine-1-yl, tetrahydrofuran hydrogen -2 - pyran-4-yl, morpholin-4-yl and 6,7-dihydro-film thieno [3,2-c]pyridine-5(4-hydro)-yl, any of which may optionally be short chain selected from the group consisting of halogen, CF ₃ , —CF ₂ H, hydroxyl, short-chain alkyl, hydroxy Substituted by one or more of the alkyl and short chain alkoxy substituted short chain alkyl groups.

在一些實施方案中，R⁴ 是芳雜環基，其可以任選地被一個或多個基團取代，這些基團選自短鏈烷基，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以任選地被鹵素、羥基和短鏈烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。In some embodiments, R ⁴ is an aromatic heterocyclic group, which may be optionally substituted with one or more groups selected from short-chain alkyl groups, which may be optionally selected from the group consisting of hydroxyl groups, short chains Alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ one or more Substituted by a group; a short-chain alkoxy group which may be optionally substituted by one or more of a halogen, a hydroxyl group and a short-chain alkoxy group; a heterocyclic ring which may optionally be selected from a short chain Substituted by one or more of an alkyl group, a halogen, a hydroxyl group and a short chain alkoxy group; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ; -NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

在一些實施方案中，R⁴ 選自1H-吡唑-1-基、1H-吡唑-3-基、1H-吡唑-4-基、1H-咪唑-1-基、1H-咪唑-4-基、噁唑-2-基、噻唑-2-基、異噁唑-3-基、異噁唑-5-基、1H-吡咯-2-基、1H-吡咯-3-基、噻吩-2-基，噻吩-3-基、吡啶-2-基、吡啶-3-基和吡啶-4-基，上述的基團可以任選地被以下一個或者多個基團取代，這些基團選自短鏈烷基，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；短鏈烷氧基，其可以隨機的被鹵素、羥基和短鏈烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-NR¹³ S(O)_n NR¹³ R¹⁴ ；-NR¹³ C(O)OR¹² ；-NR¹³ C(O)NR¹³ R¹⁴ ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。In some embodiments, R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazole-4 -yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophene- 2-Based, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, the above groups may be optionally substituted by one or more of the following groups selected from these groups From a short-chain alkyl group, which may be optionally selected from the group consisting of a hydroxyl group, a short chain alkoxy group, CN, a halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR Substituted with one or more groups of ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; a short-chain alkoxy group which may be randomly one or more of a halogen, a hydroxyl group and a short-chain alkoxy group a group substituted; a heterocyclic ring, which may be optionally substituted with one or more groups selected from the group consisting of short-chain alkyl groups, halogens, hydroxyl groups, and short-chain alkoxy groups; halogen; cyano; -C(O) R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

在一些實施方案中，R⁴ 選自1H-吡唑-1-基、1H-吡唑-3-基、1H-吡唑-4-基、1H-咪唑-1-基、1H-咪唑-4-基、噁唑-2-基、噻唑-2-基、異噁唑-3-基、異噁唑-5-基、1H-吡咯-2-基、1H-吡咯-3-基、噻吩-2-基，噻吩-3-基、吡啶-2-基、吡啶-3-基和吡啶-4-基，上述的基團可以任選地被以下一個或者多個基團取代，這些基團選自短鏈烷基，其可以任選地被選自羥基、短鏈烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；雜環，其可以任選地被選自短鏈烷基、鹵素、羥基和短鏈烷氧基中的一個或多個基團所取代。In some embodiments, R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazole-4 -yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophene- 2-Based, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, the above groups may be optionally substituted by one or more of the following groups selected from these groups From a short-chain alkyl group, which may be optionally selected from the group consisting of a hydroxyl group, a short chain alkoxy group, CN, a halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR Substituted with one or more groups of ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; a heterocyclic ring which may be optionally selected from the group consisting of short-chain alkyl groups, halogens, hydroxyl groups and short-chain alkoxy groups Replaced by one or more groups.

在一些實施方案中，R⁴ 選自1H-吡唑-1-基、1H-吡唑-3-基、1H-吡唑-4-基、1H-咪唑-1-基、1H-咪唑-4-基、噁唑-2-基、噻唑-2-基、異噁唑-3-基、異噁唑-5-基、1H-吡咯-2-基、1H-吡咯-3-基、噻吩-2-基，噻吩-3-基、吡啶-2-基、吡啶-3-基和吡啶-4-基，其可以任選地被一個或者多個選自短鏈烷基的基團所取代，其中短鏈烷基可以任選地被一個或者多個選自羥基、短鏈烷氧基、氰基或鹵素的基團取代。In some embodiments, R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazole-4 -yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophene- 2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, which may be optionally substituted by one or more groups selected from short-chain alkyl groups, Wherein the short-chain alkyl group may be optionally substituted by one or more groups selected from a hydroxyl group, a short-chain alkoxy group, a cyano group or a halogen.

在一些實施方案中，R⁴ 是短鏈烷基。In some embodiments, R ⁴ is a short chain alkyl group.

在一些實施方案中，R⁵ 是氫。In some embodiments, R ⁵ is hydrogen.

在一些實施方案中，n是0。在一些實施方案中，n是1。在一些實施方案中，n是2。In some embodiments, n is zero. In some embodiments, n is one. In some embodiments, n is 2.

本發明還提供了一種選自該化合物1至264中的化合物和/或其藥學上可接受的鹽。The present invention also provides a compound selected from the compounds 1 to 264 and/or a pharmaceutically acceptable salt thereof.

本發明所述的化合物和/或其藥學可接受的鹽都可以用商業上可獲得的原料、通過已知的方法合成得到。下面的兩個路線中顯示了大部分化合物的合成方法。在每一個路線中，LG和LG’表示相同或者不同的離去基團。Y’是-NHR⁷ 、-OH、-SH、-B(OH)₂ 或B(OR’)₂ ，R¹ 、R² 、R³ 、R⁴ 、R⁵ 和Y已經在如前定義。The compound of the present invention and/or its pharmaceutically acceptable salt can be synthesized by a known method using a commercially available raw material. The synthesis of most of the compounds is shown in the following two routes. In each route, LG and LG' represent the same or different leaving groups. Y' is -NHR ⁷ , -OH, -SH, -B(OH) ₂ or B(OR') ₂ , and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y have been defined as before.

路線IRoute I

路線IIRoute II

所得的化合物可以進一步通過對外周位置進行修飾而獲得本發明的其他目標化合物。The obtained compound can be further modified by the peripheral position to obtain other target compounds of the present invention.

所述的合成化學改造是現有技術中公知的技術，如R. Larock,Comprehensive Organic Transformations ,VCH Publishers(1989)；T.W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis,3^rd Ed.,John Wiley and Sons(1999)；L. Fieser and M. Fieser,Fieser and Fieser’s Reagents for Organic Synthesis ,John Wiley and Sons(1994)；and L. Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis ,John Wiley and Sons(1995)及其後續的版本中都有公開。The synthetic chemical modifications described are well known in the art, such as R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley and Sons. (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) It is publicly available in subsequent versions.

在使用前，該化合物和/或藥物上可接受的鹽可以通過柱層析、高效液相層析、結晶或其他適當的條件進行純化。The compound and/or pharmaceutically acceptable salt can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable conditions prior to use.

本發明還提供了一種組合物，包括該化合物和/或藥學上可接受的鹽，以及藥學上可接受的載體。The invention also provides a composition comprising the compound and/or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

包括該化合物和/或藥學上可接受的鹽的組合物，可以口服、非腸道式、吸入劑噴霧、或是植入式貯器等方式給藥。這裏用到的術語“非腸道式”，指的是包括皮下、皮內、靜脈、肌肉、關節內、動脈內、滑膜內、胸骨內、脊椎內、患處內、以及顱內注射或輸注技術。Compositions comprising the compound and/or pharmaceutically acceptable salts can be administered orally, parenterally, by inhalation spray, or in an implantable reservoir. The term "parenteral" as used herein, refers to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional, and intracranial injection or infusion. technology.

口服用的組合物可以是任何一種可接受的口服劑型，包括但不限於：片劑、膠囊、乳劑、以及水相懸浮劑、分散劑以及溶液。常用的片劑載體包括乳糖和玉米澱粉。片劑中也常加入如硬脂酸鎂之類的潤滑劑。以膠囊形式口服時，有效的稀釋劑可包括乳糖以及乾燥的玉米澱粉。當口服水相懸浮液或乳劑提供口服時，可用乳化劑或懸浮劑使活性成分懸浮或溶解於一油相中。若有需要，還可添加一定的甜味、香料、或色素。The compositions for oral administration can be any of the acceptable oral dosage forms including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in a capsule form, effective diluents can include lactose as well as dried corn starch. When the oral aqueous suspension or emulsion is provided orally, the active ingredient may be suspended or dissolved in an oily phase using an emulsifying or suspending agent. Add some sweetness, flavor, or color if needed.

無菌可注射組合物(如水狀或油狀懸浮液)可按照任何一種已知技術，使用適合的分散劑或潤濕劑(如：Tween 80)以及懸浮劑來完成製備。無菌可注射組合物也可製備成無菌的可注射溶液或懸浮液，溶於一無毒性的可用於非腸道式的稀釋劑或溶劑中，例如，1,3-丁二醇溶液。在可接受的載體與溶劑中，可使用的是甘露糖醇、水、林格爾氏液、以及生理鹽水。此外，無菌的低沸點油，如合成的單-或雙-酸甘油酯，通常為溶劑或懸浮介質。脂肪酸，例如油酸以及其甘油脂衍生物，以及天然的藥學可接受的油脂，例如橄欖油或蓖麻油，尤其是聚乙氧基化的形態，常用於製備可注射溶液。這些油溶液或懸浮液亦可含有一長鏈的醇類稀釋劑、分散劑、或羧甲基纖維素、或其類似的分散劑。Sterile injectable compositions (e.g., aqueous or oily suspensions) can be prepared according to any of the known techniques using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions can also be prepared in a sterile injectable solution or dispersion in a non-toxic parenteral diluent or solvent, for example, a 1,3-butanediol solution. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and physiological saline. In addition, sterile low boiling oils, such as synthetic mono- or di-glycerides, are typically solvents or suspending media. Fatty acids, such as oleic acid and its glycerolipid derivatives, as well as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in the form of polyethoxylated, are commonly used in the preparation of injectable solutions. These oil solutions or suspensions may also contain a long chain alcohol diluent, dispersant, or carboxymethyl cellulose, or a similar dispersing agent.

一吸入劑組合物可依相關已知的藥物配方技術而製得，且可製備於生理鹽水中，再添加苯甲醇或其他合適的防腐劑、增加生物利用度之吸收促進劑、氟碳、以及/或本技術領域中其他已知之增溶劑或分散劑。An inhalant composition can be prepared according to known pharmaceutical formulation techniques and can be prepared in physiological saline with the addition of benzyl alcohol or other suitable preservatives, bioavailability absorption enhancers, fluorocarbons, and / or other solubilizers or dispersants known in the art.

用於皮膚的組合物可配方為油脂、霜劑、乳液、軟膏、以及類似的產品。用於組合物的合適載體可包括：植物或礦物油、白礦脂(一種白色軟石蠟)、支鏈脂肪或油脂、動物脂肪、以及高分子量的醇類(大於12個碳)。較佳的載體可以為活性成分能溶解於其中者。此外，在添加增加顏色或香味成分之外，亦可依需要加入乳化劑、增溶劑、稀釋劑、以及抗氧化劑。而外皮滲透促進劑也可添加於這些典型配方中。這類促進劑的例子可見於美國專利3,989,816和4,444,762。Compositions for the skin can be formulated as oils, creams, lotions, ointments, and the like. Suitable carriers for the compositions may include: vegetable or mineral oil, white petrolatum (a white soft paraffin), branched chain fats or fats, animal fats, and high molecular weight alcohols (greater than 12 carbons). Preferred carriers may be those in which the active ingredient is soluble. In addition, emulsifiers, solubilizers, diluents, and antioxidants may be added as needed in addition to adding color or aroma components. Skin penetration enhancers can also be added to these typical formulations. Examples of such accelerators can be found in U.S. Patents 3,989,816 and 4,444,762.

霜劑配方可將礦物油、自體乳化之蜂蠟、以及水混合後之混合物，其中混合之活性成分係溶解於一小量的油脂中，例如杏仁油，再摻雜於其中。此類乳液的一範例是包括約40重量份的水、約20重量份的蜂蠟、約40重量份的礦物油、以及約1重量份的杏仁油。軟膏可混合一活性成分溶於一植物油中(例如杏仁油)、以及溫的軟石蠟，並讓混合物冷卻而製備。這類軟膏的一範例，是包括約30%重量百分比的杏仁油和約70%重量百分比的白軟石蠟。The cream formulation may be a mixture of mineral oil, self-emulsified beeswax, and water, wherein the mixed active ingredients are dissolved in a small amount of oil, such as almond oil, and then doped therein. An example of such an emulsion is comprising about 40 parts by weight of water, about 20 parts by weight of beeswax, about 40 parts by weight of mineral oil, and about 1 part by weight of almond oil. The ointment can be prepared by mixing an active ingredient in a vegetable oil (for example, almond oil), and warm soft paraffin, and allowing the mixture to cool. An example of such an ointment is about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

“藥學上可接受的載體”，指的是能與組合物中的活性成分相容，甚至在一些較佳方式中能穩定活性成分，而且不能對於欲治療的個體有危害。例如，環糊精(能與該化合物和/或藥學上可接受的鹽形成特定的、溶解性更強的複合物)之類的增溶劑，可作為醫藥用的載體來傳送活性化合物。其他載體的例子包括膠態二氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉、以及色素如D&C黃色10號(D&C Yellow#10)。"Pharmaceutically acceptable carrier" means that it is compatible with the active ingredient in the composition, even in some preferred ways, to stabilize the active ingredient, and is not deleterious to the individual to be treated. For example, a cyclodextrin (a solubilizing agent capable of forming a specific, more soluble complex with the compound and/or a pharmaceutically acceptable salt) can be used as a pharmaceutical carrier to deliver the active compound. Examples of other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10.

合適的體外實驗可用於早期評價該化合物和/或藥學上可接受的鹽抑制c-Met活性的效果，其治療癌症的效果可進一步通過體內實驗檢驗。例如，該化合物和/或藥學上可接受的鹽可給予有癌症的動物(如小鼠模型)，然後檢測其治療效果。根據上述結果，還可以決定其對動物(如，人)適合的劑量和給藥方式。Suitable in vitro assays can be used to early evaluate the effect of the compound and/or pharmaceutically acceptable salt on inhibiting c-Met activity, and its effect in treating cancer can be further tested by in vivo experiments. For example, the compound and/or pharmaceutically acceptable salt can be administered to an animal having a cancer (e.g., a mouse model) and then tested for therapeutic effects. Based on the above results, it is also possible to determine the dosage and mode of administration appropriate for the animal (e.g., human).

本發明還提供了一種抑制c-Met活性的方法，該方法包括將能有效抑制c-Met活性的量的該化合物和/或藥學上可接受的鹽與該受體接觸。因此本發明還提供了一種用於與受體接觸來抑制c-Met活性的藥物，包括有效量的該化合物和/或其藥學上可接受的鹽。The invention also provides a method of inhibiting c-Met activity, the method comprising contacting the receptor with an amount of the compound and/or a pharmaceutically acceptable salt effective to inhibit c-Met activity. The invention therefore also provides a medicament for contacting a receptor for inhibiting c-Met activity, comprising an effective amount of the compound and/or a pharmaceutically acceptable salt thereof.

本發明還提供了一種用於治療對抑制c-Met有效的癌症的藥物，包括有效量的該化合物和/或藥學上可接受的鹽。The invention also provides a medicament for treating a cancer effective for inhibiting c-Met, comprising an effective amount of the compound and/or a pharmaceutically acceptable salt.

該化合物和/或藥學上可接受的鹽可用來達到一種有益的治療或預防效果，例如，在患有癌症的個體中。這裏所用的術語“癌症”指的是細胞紊亂，其特徵為不可控或不可調的細胞增殖、細胞分化的減少、不恰當的侵入周圍組織的能力、和/或在異常部位建立新的生長的能力。術語“癌症”，包括但不限於實體腫瘤和血液腫瘤。術語“癌症”包含皮膚、組織、器官、骨骼、軟骨、血液和血管的疾病。術語“癌症”進一步包含原發癌症和轉移性癌。The compound and/or pharmaceutically acceptable salt can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual having cancer. The term "cancer" as used herein, refers to a cellular disorder characterized by uncontrolled or non-adjustable cell proliferation, decreased cell differentiation, inappropriate invasion of surrounding tissues, and/or establishment of new growth at abnormal sites. ability. The term "cancer" includes, but is not limited to, solid tumors and hematological tumors. The term "cancer" encompasses diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term "cancer" further encompasses primary cancers and metastatic cancers.

實體腫瘤的非限定性例子包括胰腺癌、膀胱癌、結腸直腸癌、乳腺癌(包括轉移性乳腺癌)、***癌(包括雄激素依賴的和非雄激素依賴的***癌)、腎癌(包括轉移性的腎細胞癌)、肝細胞癌、肺癌(包括非小細胞肺癌(non-small cell lung cancer，NSCLC))、細支氣管肺泡癌(bronchioloalveolar carcinoma(BAC))和肺腺癌、卵巢癌(包括進展性表皮癌或進展性原發性腹膜癌)、宮頸癌、胃癌、食管癌、頭頸癌(包括頭頸部鱗狀細胞癌)、皮膚癌(包括惡性黑色素瘤)、神經內分泌系統癌症(包括轉移性神經內分泌瘤)、腦瘤(包括例如神經膠質瘤、間變性少突膠質細胞瘤、成人多形性膠質母細胞瘤)、骨癌、軟組織肉瘤、和甲狀腺癌。Non-limiting examples of solid tumors include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer (including metastatic breast cancer), prostate cancer (including androgen-dependent and non-androgen-dependent prostate cancer), and renal cancer (including Metastatic renal cell carcinoma), hepatocellular carcinoma, lung cancer (including non-small cell lung cancer (NSCLC)), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma, ovarian cancer ( Including progressive epidermal cancer or progressive primary peritoneal cancer), cervical cancer, gastric cancer, esophageal cancer, head and neck cancer (including head and neck squamous cell carcinoma), skin cancer (including malignant melanoma), neuroendocrine system cancer (including Metastatic neuroendocrine tumors, brain tumors (including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme), bone cancer, soft tissue sarcoma, and thyroid cancer.

血液腫瘤的非限定性例子包括急性髓細胞性白血病(acute myeloid leukemia(AML))、慢性髓細胞性白血病(chronic myelogenous leukemia(CML))(包括加速期的慢性髓細胞性白血病和急變期的慢性髓細胞性白血病(CML-BP))、急性淋巴細胞性白血病(acute lymphoblastic leukemia(ALL))、慢性淋巴細胞性白血病(chronic lymphocytic leukemia(CLL))、何傑金氏病(Hodgkin's disease(HD))、非何傑金氏淋巴瘤(non-Hodgkin's lymphoma(NHL))(包括濾泡性淋巴瘤和套細胞淋巴瘤)、B細胞淋巴瘤(B-cell lymphoma)、T細胞淋巴瘤(T-cell lymphoma)、多發性骨髓瘤(multiple myeloma(MM))、瓦爾登斯特倫氏巨球蛋白症(Waldenstrom's macroglobulinemia)、骨髓增生異常綜合症(myelodysplastic syndromes(MDS))(包括難治性貧血(refractory anemia(RA))、RAR型貧血(refractory anemia with ringed siderblasts(RARS))、過量芽細胞頑固性貧血(refractory anemia with excess blasts(RAEB))、和過量芽細胞頑固性貧血合併急性轉化(RAEB in transformation(RAEB-T))、以及骨髓增生綜合症。Non-limiting examples of hematological tumors include acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) (including chronic myeloid leukemia during accelerated phase and chronic blast crisis) Myeloid leukemia (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD) ), non-Hodgkin's lymphoma (NHL) (including follicular lymphoma and mantle cell lymphoma), B-cell lymphoma, T-cell lymphoma (T- Cell lymphoma), multiple myeloma (MM), Waldenstrom's macroglobulinemia, myelodysplastic syndromes (MDS) (including refractory) Anemia (RA)), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), and excessive bud cell stubbornness Anemia associated with acute transformation (RAEB in transformation (RAEB-T)), and myeloproliferative syndrome.

在一些實施方案中，能夠治療的癌症的例子，包括但不限於，肺癌、頭頸癌、結腸直腸癌、胰腺癌、結腸癌、乳腺癌、卵巢癌、***癌、胃癌、腎癌、肝癌、腦癌、骨癌和白血病。In some embodiments, examples of cancers that can be treated include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain Cancer, bone cancer and leukemia.

本發明還提供了一種用於治療對抑制c-Met有效的癌症的藥物組合，包括有效量的該化合物和/或其藥學上可接受的鹽；和一定量的不同於該化合物和/或其藥學上可接受的鹽的治療製劑(較佳為抗腫瘤製劑)。The present invention also provides a pharmaceutical combination for treating a cancer effective for inhibiting c-Met, comprising an effective amount of the compound and/or a pharmaceutically acceptable salt thereof; and an amount of the compound and/or A therapeutic preparation (preferably an anti-tumor preparation) of a pharmaceutically acceptable salt.

在一些實施方案中，該化合物和/或藥學上可接受的鹽，可與其他治療製劑聯合用藥。在一些實施方案中，其他的治療製劑是一種具有被治療的疾病或症狀的病人通常服用的製劑。該化合物和/或藥學上可接受的鹽，可與其他的治療製劑以單一劑量的形式服用，或以分開的劑量形式服用。當以分開的劑量形式服用時，其他的治療製劑可以在該化合物和/或藥學上可接受的鹽服用之前、同時或之後服用。In some embodiments, the compound and/or pharmaceutically acceptable salt can be administered in combination with other therapeutic agents. In some embodiments, the additional therapeutic agent is a formulation that is typically administered to a patient having the disease or condition being treated. The compound and/or pharmaceutically acceptable salt can be administered in a single dose with other therapeutic agents or in divided doses. When administered in separate dosage forms, other therapeutic formulations can be administered before, concurrently with, or after administration of the compound and/or pharmaceutically acceptable salt.

在一些實施方案中，該化合物和/或至少一種藥學上可接受的鹽，可與其他抗腫瘤製劑聯合用藥。這裏所用的術語“抗腫瘤製劑”指得是任何一種用於腫瘤患者治療腫瘤的製劑。抗腫瘤製劑的非限定性例子包括：放療製劑、免疫療法製劑、DNA損傷的化療製劑和干擾細胞複製的化療製劑。In some embodiments, the compound and/or at least one pharmaceutically acceptable salt can be administered in combination with other anti-tumor agents. The term "anti-tumor preparation" as used herein refers to any preparation for treating a tumor in a tumor patient. Non-limiting examples of anti-tumor agents include: radiotherapeutic formulations, immunotherapeutic formulations, chemotherapeutic agents for DNA damage, and chemotherapeutic agents that interfere with cell replication.

DNA損傷的化療製劑的非限定性例子包括，局部異構酶I的抑制劑(如，依立替康(irinotecan)、托泊替康(topotecan)和喜樹鹼(camptothecin)以及他們的類似物、代謝物，以及阿黴素(doxorubicin))；局部異構酶Ⅱ抑制劑(如，依託泊苷(etoposide)、替尼泊苷(teniposide)、和道諾黴素(daunorubicin))；烷化劑(如，左旋溶肉瘤素(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、三胺硫磷(thiotepa)、異環磷醯胺(ifosfamide)、亞硝基脲氮芥(carmustine)、環己亞硝脲(lomustine)、甲基環己亞硝脲(semustine)、鏈脲黴素(streptozocin)、氨烯咪胺(decarbazine)、甲氨蝶呤(methotrexate)、絲裂黴素C(mitomycin C)和環磷醯胺(cyclophosphamide))；DNA***劑(如，順鉑(cisplatin)、奧沙利鉑(oxaliplatin)和卡波鉑(carboplatin))；DNA***劑和自由基產生劑如博來黴素(bleomycin)；以及核苷模仿劑(如5-氟尿嘧啶(5-fluorouracil)、卡培他濱(capecitibine)、2,2-二氟去氧胞嘧啶核苷(gemcitabine)、氟達拉濱(fludarabine)、阿糖胞苷(cytarabine)、巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、噴司他丁(pentostatin)和羥基脲(hydroxyurea))。Non-limiting examples of chemotherapeutic agents for DNA damage include inhibitors of topical isomerase I (eg, irinotecan, topotecan, and camptothecin, and their analogs, Metabolites, and doxorubicin); topoisomerase II inhibitors (eg, etoposide, teniposide, and daunorubicin); alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard (carmustine), lomustine, semustine, streptozocin, decarbazine, methotrexate, mitosis Molecular C (mitomycin C) and cyclophosphamide; DNA inserts (eg, cisplatin, oxaliplatin, and carboplatin); DNA inserts and freedom a base generator such as bleomycin; and a nucleoside mimicking agent such as 5-fluorouracil or capecitibine 2,2-difluorodeoxycytidine (gemcitabine), fludarabine (fludarabine), cytarabine, mercaptopurine, thioguanine, pentastatin ( Pentostatin) and hydroxyurea).

干擾細胞複製的化療製劑包括：紫杉醇(paclitaxel)、紫杉萜(docetaxel)、及有關的類似物；長春新鹼(vincristine)、長春滅瘟鹼(vinblastin)，及有關的類似物；鎮靜劑(thalidomide)及有關的類似物(如：CC-5013和CC-4047)；蛋白酪氨酸激酶抑制劑(如，甲磺酸伊馬替尼(imatinib mesylate)和格非替尼(gefitinib))；蛋白酶體抑制劑(如，硼替佐米(bortezomib))；NF-κB抑制劑，包括lκB激酶抑制劑；與腫瘤中過度表達的蛋白結合，從而下調細胞複製的抗體，(如曲妥單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)和貝伐單抗(bevacizuma))；以及其他的蛋白或酶抑制劑，已知這些蛋白或酶在腫瘤中會被調高、過度表達或啟動，對這些蛋白或酶的抑制能夠抑制細胞複製。Chemotherapeutic agents that interfere with cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; sedatives (thalidomide) And related analogues (eg CC-5013 and CC-4047); protein tyrosine kinase inhibitors (eg imatinib mesylate and gefitinib); proteasome Inhibitors (eg, bortezomib); NF-κB inhibitors, including lκB kinase inhibitors; bind to overexpressed proteins in tumors, thereby downregulating antibodies to cell replication (eg trastuzumab) , rituximab, cetuximab and bevacizuma; and other protein or enzyme inhibitors, these proteins or enzymes are known to be elevated in tumors Overexpression or initiation, inhibition of these proteins or enzymes can inhibit cell replication.

下述實施例應確定為純粹地作為示例，而不應當是以任何方式對本發明的限制。用到的資料(如，量、溫度等)力爭保證其準確性，但是也會有一些實驗誤差和偏移。除非另外說明，份數是重量份數，溫度為攝氏溫度，壓力為或接近大氣壓。所有質譜資料均由安捷倫(Agilent)6120和1100測得。本發明所用的所有試劑(除了中間體)均為商業管道獲得。所有化合物的名字(除了試劑)由軟體Chemdraw 8.0產生。The following examples are to be considered in all respects as illustrative and not restrictive. The data used (eg, volume, temperature, etc.) strives to ensure its accuracy, but there are also some experimental errors and offsets. Unless otherwise stated, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. All mass spectral data were measured by Agilent 6120 and 1100. All reagents (except intermediates) used in the present invention are obtained commercially. The names of all compounds (except reagents) were generated by the software Chemdraw 8.0.

以下例子中使用到的縮寫列表：A list of abbreviations used in the following examples:

AIBN　偶氮二異丁腈AIBN azobisisobutyronitrile

BINAP　雙二苯基磷醯聯萘BINAP bis-diphenylphosphonium naphthalene

Boc　叔丁氧甲醯基Boc tert-butoxymethyl thiol

Boc2O　二碳酸二叔丁酯Boc2O di-tert-butyl dicarbonate

i-BuNO2　亞硝酸異丁酯i-BuNO2 isobutyl nitrite

DMF　N,N-二甲基甲醯胺DMF N,N-dimethylformamide

DMAP　4-二甲氨基吡啶DMAP 4-dimethylaminopyridine

DPPA　疊氮磷酸二苯酯DPPA diphenyl phosphate

DBU　1,8-二氮雜雙環[5.4.0]十一碳-7-烯DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

Et3N　三乙胺Et3N triethylamine

HATU　2-(7-偶氮苯並三氮唑)-四甲基脲六氟磷酸酯HATU 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate

HMTA　六甲基四胺HMTA hexamethyltetramine

NBS　N-溴代丁二醯亞胺NBS N-brominated diimide

Pd(dppf)Cl₂ 　[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex

Pd2(dba)3　三(二亞苄基丙酮)二鈀.Pd2(dba)3 tris(dibenzylideneacetone)dipalladium.

Pd(PPh3)4　四三苯基膦鈀Pd(PPh3)4 tetrakistriphenylphosphine palladium

PPh3　三苯基膦PPh3 triphenylphosphine

Ti(i-OPr)4　四異丙氧基鈦Ti(i-OPr)4 tetraisopropoxy titanium

Xantphos　4,5-雙二苯基膦-9,9-二甲基氧雜蒽Xantphos 4,5-bis-diphenylphosphino-9,9-dimethyloxaxan

胺的合成(路線I和路線II中的NH₂ CR¹ R² R³ )：Synthesis of amines (NH ₂ CR ¹ R ² R ³ in Route I and Route II):

中間體A:Intermediate A:

化合物A-2Compound A-2

將原料A-1(7.23克，61.2毫莫耳)溶解在醋酸(20毫升)和水(40毫升)的混合溶劑中，向其中加入HMTA(9.42克，67.3毫莫耳)，然後在120℃攪拌反應6小時。反應結束後，冰浴冷卻，有沉澱析出，過濾、乾燥，得白色固體產物，7.90克。收率：88%。MS(m/z)：147(M+1)⁺ 。The starting material A-1 (7.23 g, 61.2 mmol) was dissolved in a mixed solvent of acetic acid (20 ml) and water (40 ml), and HMTA (9.42 g, 67.3 mmol) was added thereto at 120 ° C The reaction was stirred for 6 hours. After completion of the reaction, the mixture was cooled in an ice-bath, and precipitated, which was filtered and dried to give white crystals, 7. Yield: 88%. MS (m/z): 147 (M + 1) ⁺ .

化合物A-3Compound A-3

將原料A-2(5.0克，34.21毫莫耳)溶解在乙醇(150毫升)溶液中，向其中分批加入硼氫化鈉(1.30克，34.21毫莫耳)。反應混合物於室溫攪拌0.5小時，濃縮後，經柱層析(二氯甲烷/甲醇=25：1至10：1)純化得到白色固體產物5.0克。收率：87%。MS(m/z)：149(M+1)⁺ 。Starting material A-2 (5.0 g, 34.21 mmol) was dissolved in ethanol (150 ml), and sodium borohydride (1.30 g, 34.21 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 0.5 hr. Yield: 87%. MS (m/z): 149 (M + 1) ⁺ .

化合物A-4Compound A-4

將原料A-3(1.0克，6.75毫莫耳)溶解在無水四氫呋喃(50毫升)中，依次向其中加入DPPA(3.71克，13.5毫莫耳)和DBU(0.821克，5.4毫莫耳)，混合物在氮氣保護下回流6小時。反應結束後，濃縮，將殘留物溶於乙酸乙酯中，用飽和食鹽水洗滌，經無水硫酸鈉乾燥，濃縮，柱層析純化(乙酸乙酯/石油醚=5：1)得到白色固體產物0.587克。收率：50%。MS(m/z)：174(M+1)⁺ 。The material A-3 (1.0 g, 6.75 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml), and then, DPPA (3.71 g, 13.5 mmol) and DBU (0.821 g, 5.4 m. The mixture was refluxed for 6 hours under a nitrogen atmosphere. After completion of the reaction, the residue was evaporated. EtOAcjjjjjjjjjjjj 0.587 grams. Yield: 50%. MS (m/z): 174 (M + 1) ⁺ .

化合物ACompound A

將原料A-4(1.50克，8.63毫莫耳)溶解在乙酸乙酯(150毫升)中，然後加入10%Pd/C(1.10克)，反應混合物在氫氣條件下室溫攪拌3小時。反應結束後，過濾，濾液濃縮得到白色固體產物(1.15克)。產率：91%。MS(m/z)：148(M+1)⁺ 。Starting material A-4 (1.50 g, 8.63 mmol) was dissolved in ethyl acetate (150 ml), then 10% Pd/C (1.10 g) was added and the mixture was stirred at room temperature under hydrogen for 3 hours. After completion of the reaction, the mixture was filtered. Yield: 91%. MS (m/z): 148 (M + 1) ⁺ .

中間體B：Intermediate B:

化合物B-2Compound B-2

在0℃條件下，將甲基溴化鎂(42毫升，3M)逐步滴加到B-1(7.88克，50.0毫莫耳)的無水四氫呋喃溶液(100毫升)中，加畢後，先在0℃條件下攪拌0.5小時，然後室溫反應過夜。反應結束後，倒入冰水中(150毫升)，用乙酸乙酯萃取(200毫升×2)，合併有機相，用無水硫酸鈉乾燥，濃縮，得到黃色油狀物7.5克。收率：90.63%。MS(m/z)：156(M+1)⁺ 。Methylmagnesium bromide (42 ml, 3 M) was gradually added dropwise to a solution of B-1 (7.88 g, 50.0 mmol) in anhydrous tetrahydrofuran (100 ml) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hour and then allowed to react at room temperature overnight. After the reaction was completed, EtOAc EtOAc m. Yield: 90.63%. MS (m/z): 156 (M + 1) ⁺ .

化合物B-3Compound B-3

將原料B-2(6克，38.6毫莫耳)溶解於吡啶(80毫升)中，向其中加入85%水合肼(9.1克，154.4毫莫耳)，反應液回流過夜。冷卻後，濃縮，加入水(80毫升)，用乙酸乙酯萃取(100毫升×3)，合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，得到的黃色固體，直接用於下一步反應。MS(m/z)：134(M+1)⁺ 。Starting material B-2 (6 g, 38.6 mmol) was dissolved in pyridine (80 ml), and 85% hydrazine hydrate (9.1 g, 154.4 mmol) was added thereto, and the reaction mixture was refluxed overnight. After chilling, EtOAc (3 mL, dry. One step reaction. MS (m/z): 134 (M + 1) ⁺ .

化合物B-4Compound B-4

將原料B-3溶於乙酸乙酯(300毫升)中，依次向其中加入(Boc)₂ O(16.4克，75毫莫耳)，DMAP(610毫克，5毫莫耳)和Et₃ N(10克，100毫莫耳)，室溫攪拌過夜。反應結束後，濃縮，殘餘物經柱層析分離((石油醚/乙酸乙酯=5/1至1/1))得黃色固體，5.3克。MS(m/z)：134。Starting material B-3 was dissolved in ethyl acetate (300 ml), and (Boc) ₂ O (16.4 g, 75 mmol), DMAP (610 mg, 5 mmol) and Et ₃ N ( 10 g, 100 mmol), stirred at room temperature overnight. After completion of the reaction, the mixture was evaporated. MS (m/z): 134.

化合物B-5Compound B-5

將原料B-4(699毫克，3毫莫耳)溶於四氯化碳(15毫升)，向其中加入NBS(641毫克，3.6毫莫耳)和AIBN(70毫克，0.3毫莫耳)，反應回流過夜。反應結束後，濾去固體，反應液用飽和碳酸鈉溶液洗滌，無水硫酸鈉乾燥，濃縮，殘餘物直接用於下一步反應。MS(m/z)：212(M+1)⁺ 。Starting material B-4 (699 mg, 3 mmol) was dissolved in carbon tetrachloride (15 mL), and NBS (641 mg, 3.6 mmol) and AIBN (70 mg, 0.3 mmol) were added. The reaction was refluxed overnight. After completion of the reaction, the solid was filtered off, the mixture was washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate and evaporated. MS (m/z): 212 (M + 1) ⁺ .

化合物B-6Compound B-6

將上一步粗產物B-5溶於DMF(6毫升)，向其中加入疊氮化鈉(390毫克，6毫莫耳)，於80℃反應1.5小時。冷卻後，加入水(25毫升)，用乙酸乙酯萃取(40毫升×3)，合併有機相，經飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，柱層析分離(石油醚/乙酸乙酯=5/1至2/1)，得黃色固體，152毫克。兩步收率：29.1%。MS(m/z)：175(M+1)⁺ 。The crude product B-5 from the previous step was dissolved in DMF (6 ml), sodium azide (390 mg, 6 mmol) was added thereto, and the mixture was reacted at 80 ° C for 1.5 hours. After cooling, water (25 ml), EtOAc (EtOAc (EtOAc) = 5/1 to 2/1) gave a yellow solid, 152 mg. Two-step yield: 29.1%. MS (m/z): 175 (M + 1) ⁺ .

化合物BCompound B

將原料B-6(152毫克，0.87毫莫耳)，PPh₃ (465毫克，1.74毫莫耳)和1毫升氨水加入到20毫升四氫呋喃中，室溫攪拌過夜。反應結束後，濃縮，殘餘物溶於5毫升乙酸乙酯，加入1M氯化氫/乙酸乙酯溶液，攪拌片刻，有固體析出，過濾，得黃色固體121毫克。收率：74.7%。MS(m/z)：149(M+1)⁺ 。The starting material B-6 (152 mg, 0.87 mmol), PPh ₃ (465 mg, 1.74 mmol) and 1 ml of aqueous ammonia was added to 20 ml of tetrahydrofuran, stirred overnight at room temperature. After completion of the reaction, the mixture was evaporated. Yield: 74.7%. MS (m/z): 149 (M + 1) ⁺ .

中間體C：Intermediate C:

化合物C-2Compound C-2

將原料C-1(1.01克，7.29毫莫耳)和碳酸鉀(1.10克，7.96毫莫耳)溶解在DMF(10毫升)和水(1毫升)的混合溶劑中，往該溶液中滴入巰基乙酸甲酯(0.709毫升，7.93毫莫耳)，反應液在40℃下攪拌3小時。反應結束後，倒入冰水(70毫升)中，過濾析出的固體，然後，將該固體溶解在氯仿中，經無水硫酸鈉乾燥，濃縮，得到化合物。收率：73%。MS(m/z)：209(M+1)⁺ 。The raw material C-1 (1.01 g, 7.29 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were dissolved in a mixed solvent of DMF (10 ml) and water (1 ml), and the solution was added dropwise. Methyl thioglycolate (0.709 ml, 7.93 mmol) was stirred at 40 ° C for 3 hours. After completion of the reaction, it was poured into ice water (70 ml), and the precipitated solid was filtered, and the solid was dissolved in chloroform, dried over anhydrous sodium sulfate and concentrated to give compound. Yield: 73%. MS (m/z): 209 (M + 1) ⁺ .

化合物C-3Compound C-3

將化合物C-2(930毫克，4.47毫莫耳)溶解在50%次亞磷酸(35毫升)中，在冰浴條件下將亞硝酸鈉(620毫克，8.98毫莫耳)水(少量)溶液滴加入該溶液中，反應液在冰浴條件下繼續攪拌3小時。反應結束後，將反應液的pH值調至7.0左右，用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後，濃縮，得到紅色固體產物。收率：11.6%。MS(m/z)：194(M+1)⁺ 。Compound C-2 (930 mg, 4.47 mmol) was dissolved in 50% hypophosphite (35 mL) and a solution of sodium nitrite (620 mg, 8.98 mmol) in water (small amount) under ice bath The solution was added dropwise to the solution, and the reaction solution was further stirred under ice bath for 3 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to about 7.0, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated. Yield: 11.6%. MS (m/z): 194 (M + 1) ⁺ .

化合物C-4Compound C-4

將原料C-3(600毫克，3.1毫莫耳)溶解在無水四氫呋喃(30毫升)中，在冰浴冷卻下，向其中緩慢滴入氫化鋁鋰(472毫克，12.4毫莫耳)的四氫呋喃溶液，然後在0℃下繼續攪拌反應20分鐘。反應結束後，加入飽和氯化銨水溶液，過濾，濾液濃縮，所得殘餘物經層析分離得到白色固體產物。收率：97.5%。MS(m/z)：166(M+1)⁺ 。The material C-3 (600 mg, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml), and a solution of lithium aluminum hydride (472 mg, 12.4 mmol) in tetrahydrofuran was slowly added dropwise thereto under ice cooling. Then, the reaction was further stirred at 0 ° C for 20 minutes. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, filtered, and the filtrate was concentrated. Yield: 97.5%. MS (m/z): 166 (M + 1) ⁺ .

化合物C-5Compound C-5

將原料C-4(17毫克，0.1毫莫耳)溶解在乾燥的二氯甲烷(20毫升)中，往該溶液中加入氯化亞碸(120毫克)，室溫反應2小時後，濃縮，即得產物。MS(m/z)：184(M+1)⁺ 。The material C-4 (17 mg, 0.1 mmol) was dissolved in dry methylene chloride (20 mL). Toluene (120 mg) was added to the solution. That is the product. MS (m/z): 184 (M + 1) ⁺ .

化合物CCompound C

將原料C-5(183毫克，1毫莫耳)溶解在氨氣的甲醇溶液(7M，10毫升)中，然後在密閉體系中於50℃下反應16小時，冷卻後，濃縮，所得殘餘物經柱層析分離得產物。收率：61%。MS(m/z)：165(M+1)⁺ 。The starting material C-5 (183 mg, 1 mmol) was dissolved in a methanol solution of ammonia (7M, 10 ml), then reacted in a closed system at 50 ° C for 16 hours, cooled and concentrated to give a residue. The product was isolated by column chromatography. Yield: 61%. MS (m/z): 165 (M + 1) ⁺ .

中間體D和D’：Intermediates D and D':

化合物D-2Compound D-2

將原料D-1(1.4克，10毫莫耳)溶解在10毫升DMF和1毫升水的混合溶劑中，在冰浴冷卻下，向其中緩慢加入碳酸鉀(1.66克，12毫莫耳)和α-巰基乙酸甲酯(1.07毫升，12毫莫耳)，然後在45℃下反應過夜。反應結束後，加入冰水，有固體析出，過濾並乾燥，得到白色固體產物，(1.23克，63.7%)。MS(m/z)：194(M+1)⁺ 。The raw material D-1 (1.4 g, 10 mmol) was dissolved in a mixed solvent of 10 ml of DMF and 1 ml of water, and potassium carbonate (1.66 g, 12 mmol) was slowly added thereto under cooling in an ice bath. Methyl α-mercaptoacetate (1.07 mL, 12 mmol) was then reacted at 45 ° C overnight. After the reaction was completed, ice water was added, and a solid was precipitated, which was filtered and dried to give a white solid product (1.23 g, 63.7%). MS (m/z): 194 (M + 1) ⁺ .

化合物D-3Compound D-3

在0℃條件下，將原料D-2(15克，77.6毫莫耳)溶解於250毫升乾燥四氫呋喃中，向其中分批緩慢加入氫鋁化鋰(4.42克，116.4毫莫耳)，然後攪拌反應1小時。反應結束後，用飽和氯化銨水溶液淬滅，過濾，濾液用飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，所得產物直接用於下一步。(10.3克，80.5%)。The raw material D-2 (15 g, 77.6 mmol) was dissolved in 250 ml of dry tetrahydrofuran at 0 ° C, and lithium aluminum hydride (4.42 g, 116.4 mmol) was slowly added thereto in portions, followed by stirring. Reaction for 1 hour. After completion of the reaction, the mixture was washed with EtOAc EtOAc. (10.3 g, 80.5%).

化合物D-4Compound D-4

將原料D-3(3.2克，19.4毫莫耳)溶解在乾燥的四氫呋喃中，向其中加入DPPA(8克，6.26毫升，29.1毫莫耳)，攪拌5分鐘，然後在0℃下加入DBU(4.43克，4毫升，29.1毫莫耳)，反應液回流過夜。冷卻後，加入水，用***萃取三次，有機相用硫酸鈉乾燥，濃縮，所得殘餘物經柱層析分離得到無色油狀產物。(3.27克，88.6%)。The material D-3 (3.2 g, 19.4 mmol) was dissolved in dry tetrahydrofuran, DPPA (8 g, 6.26 ml, 29.1 mmol) was added thereto, stirred for 5 minutes, and then DBU was added at 0 ° C ( 4.43 g, 4 ml, 29.1 mmol, and the reaction was refluxed overnight. After cooling, water was added, and the mixture was evaporated. (3.27 g, 88.6%).

化合物DCompound D

將原料D-4(3克，15.8毫莫耳)溶解在乾燥的四氫呋喃(50毫升)中，向其中分別加入Ph₃ P(8.27克，31.5毫莫耳)和氨水(2毫升)，室溫攪拌過夜。反應結束後，濃縮，所得殘餘物經柱層析分離得到產物。(2.5克，96.5%)。The material D-4 (3 g, 15.8 mmol) was dissolved in dry tetrahydrofuran (50 ml), and then Ph ₃ P (8.27 g, 31.5 mmol) and aqueous ammonia (2 ml) were added thereto at room temperature. Stir overnight. After completion of the reaction, it was concentrated, and the obtained residue was purified by column chromatography. (2.5 g, 96.5%).

化合物D’-1Compound D'-1

將原料D-2(12克，62.1毫莫耳)溶解在甲醇(50毫升)和水(15毫升)的混合溶劑中，向其中加入LiOH.H₂ O(5.2克，124.2毫莫耳)，攪拌過夜。反應結束後，用1N的鹽酸溶液調pH值至3左右，過濾並乾燥，得固體到產物。收率：90.1%。MS(m/z)：179(M)⁺ 。The raw material D-2 (12 g, 62.1 mmol) was dissolved in a mixed solvent of methanol (50 ml) and water (15 ml), and LiOH.H ₂ O (5.2 g, 124.2 mmol) was added thereto. Stir overnight. After completion of the reaction, the pH was adjusted to about 3 with a 1N hydrochloric acid solution, filtered and dried to give a solid to product. Yield: 90.1%. MS (m/z): 179 (M) ⁺ .

化合物D’-2Compound D'-2

將原料D’-1(11.5克，64.2毫莫耳)溶解在200毫升二氯甲烷和20毫升DMF的混合溶劑中，分別向其中加入Et₃ N(19.5克，26.6毫升，192.6毫莫耳)和HATU(36.6克，96.3毫莫耳)，室溫下攪拌20分鐘，然後加入N,O -二甲基羥胺鹽酸鹽(6.9克，70.6毫莫耳)，繼續攪拌過夜。原料消耗完後，減壓蒸除二氯甲烷，所得殘餘物用乙酸乙酯溶解，並用水和飽和食鹽水洗滌，有機相乾燥後濃縮，經矽膠柱分離得到產物。(收率：81.1%)。MS(m/z)：223(M+1)⁺ 。The raw material D'-1 (11.5 g, 64.2 mmol) was dissolved in a mixed solvent of 200 ml of dichloromethane and 20 ml of DMF, and Et ₃ N (19.5 g, 26.6 ml, 192.6 mmol) was added thereto. And HATU (36.6 g, 96.3 mmol), stirred at room temperature for 20 min then added N,O -dimethylhydroxylamine hydrochloride (6.9 g, 70.6 mmol) and stirring was continued overnight. After the consumption of the starting material, the methylene chloride was evaporated under reduced pressure, and the obtained residue was crystallised eluted with ethyl acetate, washed with water and brine, and then evaporated. (Yield: 81.1%). MS (m/z): 223 (M + 1) ⁺ .

化合物D’-3Compound D'-3

在0℃冰浴及氮氣保護條件下，將原料D’-2(11.1克，50毫莫耳)溶解在乾燥的THF(150毫升)溶液中，向其中加入MeMgBr的***溶液(3M***溶液，25毫升，75毫莫耳)，升至室溫，並攪拌過夜。反應結束後，加入飽和NH₄ Cl溶液萃滅反應，用乙酸乙酯萃取，有機相經乾燥、濃縮，得產物。(收率：85.8%)。MS(m/z)：178(M+1)⁺ 。The material D'-2 (11.1 g, 50 mmol) was dissolved in a dry THF (150 ml) solution, and a solution of MeMgBr in diethyl ether (3M diethyl ether) was added to the mixture. 25 ml, 75 mmol, warmed to room temperature and stirred overnight. After completion of the reaction, saturated NH ₄ Cl solution was quenched reaction was extracted with ethyl acetate, the organic phase was dried and concentrated to give the product. (Yield: 85.8%). MS (m/z): 178 (M + 1) ⁺ .

化合物D’-4Compound D'-4

在0℃條件下，將原料D’-3(3.5克，1毫莫耳)溶解在四氫呋喃溶液(50毫升)中，向其中分批加入氫鋁化鋰(1.13克，1.5毫莫耳)，在該溫度下攪拌反應1小時，然後加入飽和氯化銨溶液萃滅反應，過濾，並用適量四氫呋喃洗滌濾餅，濾液用飽和食鹽水洗滌，濃縮，直接用於下一步。(收率：57.1%)。The material D'-3 (3.5 g, 1 mmol) was dissolved in tetrahydrofuran solution (50 ml) at 0 ° C, and lithium aluminum hydride (1.13 g, 1.5 mmol) was added portionwise. The reaction was stirred at the same temperature for 1 hour, then the mixture was evaporated, and then filtered, and then filtered and washed with brine, (Yield: 57.1%).

化合物D’Compound D’

該化合物是以D’-4為原料，按照從中間體A-3到A的合成方法製備。This compound was prepared by the synthesis of Intermediate A-3 to A using D'-4 as a starting material.

中間體E：Intermediate E:

化合物E-2Compound E-2

該化合物是以E-1為原料，按照從中間體A-2到A-3的合成方法製備。MS(m/z)：166(M+1)⁺ 。This compound was prepared by the synthesis of Intermediate A-2 to A-3 using E-1 as a starting material. MS (m/z): 166 (M + 1) ⁺ .

化合物ECompound E

該化合物是以E-2為原料，按照從中間體C-4到C的合成方法製備。MS(m/z)：165(M+1)⁺ 。This compound was prepared by the synthesis of Intermediate C-4 to C using E-2 as a starting material. MS (m/z): 165 (M + 1) ⁺ .

中間體F：Intermediate F:

化合物F-2Compound F-2

將F-1(14.0克，0.1莫耳)溶於甲醇(250毫升)，向其中加入濃硫酸(2.0毫升)，回流反應48小時。冷卻後，濃縮，加入乙酸乙酯稀釋，用碳酸鈉溶液洗滌，無水硫酸鈉乾燥，濃縮，得到無色液體13.4克。收率：86%。F-1 (14.0 g, 0.1 mol) was dissolved in methanol (250 ml), and concentrated sulfuric acid (2.0 ml) was added thereto, and the reaction was refluxed for 48 hours. After cooling, it was concentrated, diluted with ethyl~~~~~~~~~~~~~~~~~~~~~~~~~~ Yield: 86%.

化合物F-3Compound F-3

將原料F-2(13.4克，86.0毫莫耳)溶於濃硫酸(30毫升)中，冰水浴冷卻下，向其中逐滴加入發煙硝酸(7.2毫升，111.5毫莫耳)和濃硫酸(20毫升)的混合溶液，反應液在0℃中攪拌10分鐘，然後倒入冰水中，有固體析出，過濾，固體用水洗滌3次，得白色固體14.8克。收率：86%。MS(m/z)：202(M+1)⁺ 。The raw material F-2 (13.4 g, 86.0 mmol) was dissolved in concentrated sulfuric acid (30 ml), and the mixture was cooled with ice-water bath, and fuming nitric acid (7.2 ml, 111.5 mmol) and concentrated sulfuric acid were added dropwise thereto. A mixed solution of 20 ml), the reaction solution was stirred at 0 ° C for 10 minutes, then poured into ice water, a solid precipitated, filtered, and the solid was washed three times with water to give a white solid (14.8 g). Yield: 86%. MS (m/z): 202 (M + 1) ⁺ .

化合物F-4Compound F-4

將原料F-3(14.8克，73.6毫莫耳)溶於甲醇和四氫呋喃的混合溶劑(1：1，300毫升)中，向其中加入Raney鎳，氫氣置換3次後，反應液在氫氣氛圍中攪拌過夜。反應結束後，過濾，濾液濃縮，所得殘餘物中加入1N的鹽酸溶液(150毫升)，濾去固體，濾液用1N的氫氧化鈉溶液調至pH值8至9，然後用乙酸乙酯萃取(60毫升×3)，合併有機相，用無水硫酸鈉乾燥，濃縮，得到棕色固體8.1克。收率：64%。MS(m/z)：172(M+1)⁺ 。The starting material F-3 (14.8 g, 73.6 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (1:1, 300 ml), Raney nickel was added thereto, and after replacing the hydrogen three times, the reaction liquid was under a hydrogen atmosphere. Stir overnight. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic phase was combined, dried over anhydrous sodium sulfate and evaporated. Yield: 64%. MS (m/z): 172 (M + 1) ⁺ .

化合物F-5Compound F-5

將原料F-4(5.1克，30毫莫耳)溶於甲苯(120毫升)，向其中加入醋酸酐(16.0克，0.12莫耳)和醋酸鉀(1.5克，15.1毫莫耳)，在100℃下攪拌3小時，然後冷卻至室溫，加入亞硝酸異丁酯(10.5克，90.0毫莫耳)，繼續在100℃下反應過夜。反應結束後，加入水(80毫升)，用乙酸乙酯萃取(100毫升×3)，合併有機相，飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，經柱層析分離(石油醚/乙酸乙酯=10/1)，得到黃色固體5.3克。收率：79%。MS(m/z)：225(M+1)⁺ 。Starting material F-4 (5.1 g, 30 mmol) was dissolved in toluene (120 mL), and acetic anhydride (16.0 g, 0.12 mol) and potassium acetate (1.5 g, 15.1 mmol) were added thereto at 100 After stirring at ° C for 3 hours, then cooling to room temperature, isobutyl nitrite (10.5 g, 90.0 mmol) was added and the reaction was continued at 100 ° C overnight. After completion of the reaction, water (80 ml) was added, and ethyl acetate (100 ml × 3) was evaporated. Ester = 10/1) gave 5.3 g of a yellow solid. Yield: 79%. MS (m/z): 225 (M + 1) ⁺ .

化合物F-6Compound F-6

將原料F-5(4.5克，20.0毫莫耳)溶於甲醇(30毫升)中，向其中緩慢加入硼氫化鈉(836毫克，22.0毫莫耳)，反應液在室溫下攪拌30分鐘。反應結束後，濃縮，得到一個白色固體。將此白色固體溶於乾燥的四氫呋喃(80毫升)中，0℃下緩慢加入氫化鋁鋰(1.5克，40.0毫莫耳)。反應在0℃條件下攪拌1小時後，滴加氯化銨飽和溶液淬滅反應，濾去固體，濾液用乙酸乙酯萃取(60毫升×3)，合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，得到白色固體2.9克。收率：94%。MS(m/z):155(M+1)⁺ 。Starting material F-5 (4.5 g, 20.0 mmol) was dissolved in methanol (30 ml), sodium borohydride (836 mg, 22.0 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, it was concentrated to give a white solid. This white solid was dissolved in dry tetrahydrofuran (80 mL) and lithium aluminum hydride (1.5 g, 40.0 mmol) was slowly added at 0 °C. After the reaction was stirred at 0 ° C for 1 hour, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Dry over sodium sulfate and concentrate to give 2.9 g. Yield: 94%. MS (m/z): 155 (M + 1) ⁺ .

化合物FCompound F

該化合物是以F-6為原料，按照從中間體D-3到D的合成方法製備。MS(m/z):154(M+1)⁺ 。This compound was prepared by the synthesis of Intermediate D-3 to D using F-6 as a starting material. MS (m/z): 154 (M + 1) ⁺ .

中間體G和G’：Intermediates G and G':

化合物G-1Compound G-1

將原料F-5(4.9克,21.8毫莫耳)溶於甲醇(15毫升)，向其中加入氫氧化鉀溶液(6N,10毫升)，在室溫下攪拌3小時。反應結束後，加入6N的鹽酸溶液調pH至5至6，有白色固體析出，過濾，得到產物3.0克。收率：82%。MS(m/z)：169(M+1)⁺ 。Starting material F-5 (4.9 g, 21.8 mmol) was dissolved in methanol (15 ml), and potassium hydroxide solution (6 N, 10 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a 6 N hydrochloric acid solution was added to adjust the pH to 5 to 6, and a white solid was precipitated and filtered to give a product of 3.0 g. Yield: 82%. MS (m/z): 169 (M + 1) ⁺ .

化合物G-2Compound G-2

將原料G-1(3.0克，17.9毫莫耳)溶於甲醇(50毫升)，向其中加入濃硫酸(0.3毫升)，回流2天。冷卻後，減壓蒸除溶劑，加入乙酸乙酯稀釋，並用飽和碳酸氫鈉溶液洗滌，無水硫酸鈉乾燥，濃縮，得到白色固體2.4克。收率：73.7%。(m/z)：183(M+1)⁺ 。Starting material G-1 (3.0 g, 17.9 mmol) was dissolved in methanol (50 ml), and concentrated sulfuric acid (0.3 ml) was added thereto and refluxed for 2 days. After cooling, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated Yield: 73.7%. (m/z): 183 (M+1) ⁺ .

化合物G-3和G’-3Compound G-3 and G'-3

將原料G-2(760毫克，4.2毫莫耳)溶於DMF(4毫升)，向其中加入溴乙烷(915毫克，8.3毫莫耳)和K₂ CO₃ (1.7克，12.6毫莫耳)，110℃下反應3小時。冷卻至室溫後，加入水，用乙酸乙酯萃取(30毫升×3)，合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，柱層析分離得到兩個黃色固體。The feed G-2 (760 mg, 4.2 mmol) was dissolved in DMF (4 ml), and thereto was added ethyl bromide (915 mg, 8.3 mmol) and K ₂ CO ₃ (1.7 g, 12.6 mmol ), reacted at 110 ° C for 3 hours. After cooling to room temperature, water was added, and the mixture was evaporated.

(G-3)351毫克，收率：40%。MS(m/z)：211(M+1)⁺ 。(G-3) 351 mg, yield: 40%. MS (m/z): 211 (M + 1) ⁺ .

(G’-3)272毫克，收率：31%。MS(m/z)：211(M+1)⁺ 。(G'-3) 272 mg, yield: 31%. MS (m/z): 211 (M + 1) ⁺ .

化合物GCompound G

該化合物是以G-3為原料，按照從中間體D-2到D的合成方法製備。MS(m/z)：182(M+1)⁺ 。This compound was prepared from G-3 as a starting material according to the synthesis from Intermediate D-2 to D. MS (m/z): 182 (M + 1) ⁺ .

化合物G’Compound G'

該化合物是以G’-3為原料，按照從中間體D-2到D的合成方法製備。MS(m/z)：182(M+1)⁺ 。This compound was prepared by the synthesis of intermediate D-2 to D using G'-3 as a starting material. MS (m/z): 182 (M + 1) ⁺ .

中間體H和H’：Intermediates H and H':

化合物H-2Compound H-2

將原料H-1(880毫克，5.0毫莫耳)溶解在2毫升甲醇中，向其中加入6毫升氨水，80℃加熱過夜。反應結束後，冷卻到室溫，蒸除溶劑，得到黃色固體產物(805毫克)，未進一步純化，直接用於下一步反應。MS(m/z)：162(M+1)⁺ 。Raw material H-1 (880 mg, 5.0 mmol) was dissolved in 2 ml of methanol, 6 ml of aqueous ammonia was added thereto, and heated at 80 ° C overnight. After completion of the reaction, the mixture was cooled to EtOAc. MS (m/z): 162 (M + 1) ⁺ .

化合物HCompound H

將原料H-2(805毫克，5.0毫莫耳)溶解在乾燥的10毫升四氫呋喃中，冰浴冷卻下，向其中緩慢加入LiAlH₄ (570毫克，15毫莫耳)，加完後，攪拌0.5小時，緩慢升溫80℃回流過夜。反應結束後，冷卻到室溫，加入飽和NH₄ Cl溶液，過濾，濾液用矽膠柱層析(二氯甲烷/甲醇=10：1)純化得到黃色固體720毫克，收率為99.0%。MS(m/z)：148(M+1)⁺ 。The raw material H-2 (805 mg, 5.0 mmol) was dissolved in dry 10 ml of tetrahydrofuran, and the mixture was cooled in an ice bath, and LiAlH ₄ (570 mg, 15 mmol) was slowly added thereto, and after the addition, the mixture was stirred. After an hour, slowly heat up at 80 ° C and reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, a saturated aqueous solution of NH ₄ Cl was added and filtered, and the filtrate was purified by silica gel column chromatography (dichloromethane/methanol = 10:1) to yield y. MS (m/z): 148 (M + 1) ⁺ .

化合物H’-1Compound H'-1

將原料H-1(528毫克，3.0毫莫耳)溶解在無水四氫呋喃中，冷卻到0℃，向其中緩慢加入氫化鈉(240毫克，6毫莫耳)，在氮氣保護下攪拌半小時，然後滴加2-(三甲矽烷基)乙氧甲基氯(526毫克，3.0毫莫耳)，室溫反應2小時。反應結束後，加入水，用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，濃縮，得黃色固體750毫克，收率為81.7%，直接用於下步反應。MS(m/z)：307(M+1)⁺ 。The starting material H-1 (528 mg, 3.0 mmol) was dissolved in anhydrous tetrahydrofuran, cooled to 0 ° C, sodium hydride (240 mg, 6 mM) was slowly added thereto, and stirred under nitrogen for half an hour, then 2-(Trimethyldecyl)ethoxymethyl chloride (526 mg, 3.0 mmol) was added dropwise and allowed to react at room temperature for 2 hours. After the reaction was completed, water was added, and ethyl acetate was evaporated. MS (m/z): 307 (M + 1) ⁺ .

化合物H’Compound H’

該化合物是以H’-1為原料，按照從中間體D-2到D的合成方法製備。MS(m/z)：278(M+1)⁺ 。This compound was prepared by the synthesis of intermediate D-2 to D using H'-1 as a starting material. MS (m/z): 278 (M + 1) ⁺ .

中間體I：Intermediate I:

該化合物是以I-1為原料，按照中間體H的合成方法製備。MS(m/z)：148(M+1)⁺ 。This compound was prepared by the synthesis method of Intermediate H using I-1 as a raw material. MS (m/z): 148 (M + 1) ⁺ .

中間體J：Intermediate J:

化合物J-2Compound J-2

將原料J-1(13克，0.1莫耳)溶解在195毫升濃鹽酸中，在0⁰ C下，往該溶液中分批加入25克錫粒。當大部分錫粒溶解後，加入70毫升乙醇和無水氯化鋅(6克)，反應液升溫至85℃，然後加入丙二醛二乙縮醛(17.2克，0.078莫耳)的乙醇(30毫升)溶液，85℃下反應1小時。反應結束後，倒入冰中，用氨水調至鹼性，水溶液用二氯甲烷萃取，有機相濃縮後所得粗產物，通過柱層析分離得到黃色油狀物。收率：40%。MS(m/z)：135(M)⁺ 。Raw material J-1 (13 g, 0.1 mol) was dissolved in 195 ml of concentrated hydrochloric acid, and 25 g of tin particles were added portionwise to the solution at 0 ⁰ C. After most of the tin particles were dissolved, 70 ml of ethanol and anhydrous zinc chloride (6 g) were added, and the reaction liquid was heated to 85 ° C, and then malondialdehyde diethyl acetal (17.2 g, 0.078 mol) of ethanol was added (30 ML) solution, reacted at 85 ° C for 1 hour. After the reaction was completed, it was poured into ice, and the mixture was made to basic with aqueous ammonia, and the aqueous solution was extracted with dichloromethane. Yield: 40%. MS (m/z): 135 (M) ⁺ .

化合物J-3Compound J-3

將原料J-2(1.35克，10毫莫耳)，磷酸氫二鉀(940毫克，5.4毫莫耳)，碳酸氫鈉(840毫克，10毫莫耳)，無水硫酸鎂(2.0克，16.7毫莫耳)懸浮在氯仿(40毫升)中，回流16小時，然後往該溶液中滴入液溴(2.08克，13毫莫耳)，然後回流反應24小時。冷卻後，過濾，濾渣用二氯甲烷洗滌數次，濾液濃縮所得粗產物經柱層析分離得產物。收率：37.4%。MS(m/z)：214(M+1)⁺ 。Starting material J-2 (1.35 g, 10 mmol), dipotassium hydrogen phosphate (940 mg, 5.4 mmol), sodium bicarbonate (840 mg, 10 mmol), anhydrous magnesium sulfate (2.0 g, 16.7) The mixture was suspended in chloroform (40 ml), refluxed for 16 hours, and then liquid bromine (2.08 g, 13 mmol) was added dropwise to the solution, followed by refluxing for 24 hours. After cooling, it was filtered, and the residue was washed several times with dichloromethane, and the filtrate was concentrated to give the product. Yield: 37.4%. MS (m/z): 214 (M + 1) ⁺ .

化合物J-4Compound J-4

將原料J-3(107毫克，0.5毫莫耳)和氰化亞銅(60毫克，0.67毫莫耳)溶解在4毫升無水DMF中，往該溶液中加入Pd(PPh₃ )₄ (57毫克，0.05毫莫耳)，氮氣置換數次，於120℃下反應5小時。冷卻後，濃縮反應液，殘餘物經柱層析分離得白色固體產物。收率：62.5%。MS(m/z)：161(M+1)⁺ 。The raw material J-3 (107 mg, 0.5 mmol) and cuprous cyanide (60 mg, 0.67 mmol) were dissolved in 4 ml of anhydrous DMF, and Pd(PPh ₃ ) ₄ (57 mg) was added to the solution. , 0.05 mmol; nitrogen was replaced several times and reacted at 120 ° C for 5 hours. After cooling, the reaction mixture was concentrated. Yield: 62.5%. MS (m/z): 161 (M + 1) ⁺ .

化合物JCompound J

將原料J-4(320毫克，2毫莫耳)溶解在25毫升氨的乙醇溶液中，往該溶液中加入Ranye/Ni(約300毫克)，反應液用氫氣置換後，室溫反應2小時。過濾，所得濾液濃縮得無色油狀物，未進一步純化，直接用於下一步反應。收率：60%。MS(m/z)：165(M+1)⁺ 。Raw material J-4 (320 mg, 2 mmol) was dissolved in 25 ml of ammonia in ethanol, and Ranye/Ni (about 300 mg) was added to the solution. The reaction solution was replaced with hydrogen and reacted at room temperature for 2 hours. . Filtration and concentration of the filtrate were obtained as a colourless oil. Yield: 60%. MS (m/z): 165 (M + 1) ⁺ .

中間體K：Intermediate K:

化合物K-2Compound K-2

將原料K-1(4.0克，33.6毫莫耳)溶解在乙醇(160毫升)中，向其中加入乙醛水溶液(40%，27.5毫升，168毫莫耳)，反應液回流4小時。冷卻後，減壓蒸除溶劑，將所得殘留物溶解在水中，用飽和碳酸氫鈉水溶液調節PH>7，有大量沉澱析出，過濾，乾燥後得到淺黃色固體產物4.80克。產率：98%。MS(m/z)：144(M+1)⁺ 。Raw material K-1 (4.0 g, 33.6 mmol) was dissolved in ethanol (160 ml), and aqueous acetaldehyde (40%, 27.5 ml, 168 mM) was added thereto, and the mixture was refluxed for 4 hr. After cooling, the solvent was evaporated under reduced pressure, and the residue was evaporated, evaporated, evaporated, evaporated Yield: 98%. MS (m/z): 144 (M + 1) ⁺ .

化合物KCompound K

該化合物是以K-2為原料，按照從中間體J-4到J的合成方法製備。This compound was prepared from K-2 as a starting material according to the synthesis from Intermediate J-4 to J.

中間體L：Intermediate L:

化合物L-2Compound L-2

將原料L-1(8.7克，73毫莫耳)溶解於DMF(30毫升)中，向其中加入N ,N -二甲基甲醯胺二甲基縮醛(35毫升，294毫莫耳)，然後在130℃反應過夜。反應液冷卻至室溫，減壓蒸除溶劑得中間體，棕色油狀物。將該中間體溶於甲醇(100毫升)中，加入吡啶(11.5毫升，143毫莫耳)，冰浴冷卻下，緩慢分批加入羥胺-O-磺酸(11.3克，100毫莫耳)，然後室溫反應過夜。反應結束後，濃縮，加入碳酸氫鈉水溶液和乙酸乙酯，分層，有機相依次用水、飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，濃縮，柱層析分離(石油醚/乙酸乙酯=90/10)，得淡黃色固體產物，5.5克，收率：53%。MS(m/z)：145(M+1)⁺ 。The material L-1 (8.7 g, 73 mmol) was dissolved in DMF (30 mL), and N , N -dimethylformamide dimethyl acetal (35 ml, 294 mM) was added thereto. Then, it was reacted at 130 ° C overnight. The reaction solution was cooled to room temperature, and the solvent was evaporated evaporated evaporated. The intermediate was dissolved in MeOH (100 mL). pyridine (11.5 mL, 143 m.m.). It was then reacted at room temperature overnight. After completion of the reaction, the mixture was concentrated. EtOAc EtOAc m. 90/10) gave pale yellow solid product, 5.5 g, yield: 53%. MS (m/z): 145 (M + 1) ⁺ .

化合物LCompound L

該化合物是以L-2為原料，按照從中間體J-4到J的合成方法製備。This compound was prepared by the synthesis method from Intermediate J-4 to J using L-2 as a raw material.

中間體M：Intermediate M:

該化合物是以M-1為原料，按照從中間體J-4到J的合成方法製備。MS(m/z)：149(M+1)⁺ 。This compound was prepared by the synthesis of Intermediate J-4 to J using M-1 as a starting material. MS (m/z): 149 (M + 1) ⁺ .

中間體N：Intermediate N:

該化合物是以6-喹啉甲酸為原料，按照文獻US2007 /0265272 中所述方法製備。This compound was prepared from 6-quinolinecarboxylic acid as described in the document US 2007 / 0265272 .

中間體O：Intermediate O:

化合物O-2Compound O-2

將原料O-1(2.0克，11.5毫莫耳)溶於二氯甲烷(250毫升)中，加入3滴DMF，冷卻至0℃，緩慢滴加草醯氯(7.3克，57.5毫莫耳)，加畢，低於5℃反應1小時。反應結束後，濃縮，得白色固體產物，2.2克。The starting material O-1 (2.0 g, 11.5 mmol) was dissolved in dichloromethane (250 ml), 3 drops of DMF were added, cooled to 0 ° C, and chloroform (7.3 g, 57.5 mmol) was slowly added dropwise. After the addition, the reaction was carried out at less than 5 ° C for 1 hour. After completion of the reaction, it was concentrated to give a white solid.

化合物O-3Compound O-3

將原料O-2(2.2克，11.5毫莫耳)溶於四氫呋喃(100毫升)中，向其中加入氨水(5毫升)，加畢，室溫反應1小時。反應結束後，濃縮，所得固體用水洗滌，乾燥，得淡黃色固體產物，1.5克。收率：76%。MS(m/z)：173(M+1)⁺ 。Starting material O-2 (2.2 g, 11.5 mmol) was dissolved in tetrahydrofuran (100 ml), and aqueous ammonia (5 ml) was added thereto, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the mixture was evaporated. Yield: 76%. MS (m/z): 173 (M + 1) ⁺ .

化合物O-4Compound O-4

將原料O-3(1.2克，7.2毫莫耳)溶於二氯甲烷(50毫升)中，加入三乙胺(2.2克，21.8毫莫耳)，冷卻至0℃，緩慢將三氟乙酸酐(1.9克，8.9毫莫耳)滴加到反應液中，加畢後，在0℃反應10分鐘，然後加水淬滅，用二氯甲烷萃取，有機層用無水硫酸鈉乾燥，過濾，濃縮，得白色固體產物，1.0克。收率：93%。MS(m/z)：154(M)⁺ 。The starting material O-3 (1.2 g, 7.2 mmol) was dissolved in dichloromethane (50 mL), triethylamine (2.2 g, 21.8 mmol) was added and cooled to 0 ° C, slowly trifluoroacetic anhydride (1.9 g, 8.9 mmol) was added dropwise to the reaction mixture. After the addition, the mixture was stirred at 0 ° C for 10 min, then quenched with EtOAc. The product was obtained as a white solid, 1.0 g. Yield: 93%. MS (m/z): 154 (M) ⁺ .

化合物OCompound O

將原料O-4(540毫克，3.5毫莫耳)加入到***(15毫升)中，再加入Ti(Oi-Pr)₄ (3.9毫莫耳，1.16毫升)，溶液冷卻至-70℃，然後向其中緩慢滴加乙基溴化鎂(7.7毫莫耳，3M，***溶液)，加畢，攪拌10分鐘後，自然升溫至室溫，繼續反應1.5小時，然後加入BF₃ .OEt₂ (7毫莫耳，0.88毫升)，攪拌1小時。反應結束後，依次加入1N鹽酸(11毫升)，***(40毫升)和氫氧化鈉水溶液(10%，30毫升)，分層，水層用***再萃取一次，合併有機層，無水硫酸鈉乾燥，過濾，濃縮，得粗產物，直接用於下一步反應。MS(m/z)：185(M+1)⁺ 。Starting material O-4 (540 mg, 3.5 mmol) was added to diethyl ether (15 mL), then Ti(Oi-Pr) ₄ (3.9 mM, 1.16 mL) was added and the solution was cooled to -70 ° C then Ethyl magnesium bromide (7.7 mmol, 3 M, diethyl ether solution) was slowly added dropwise thereto, and the mixture was stirred for 10 minutes, then naturally warmed to room temperature, and the reaction was continued for 1.5 hours, then BF ₃ .OEt ₂ (7) was added. Millions, 0.88 ml), stirred for 1 hour. After the reaction, 1N hydrochloric acid (11 ml), diethyl ether (40 ml), and aq. Filtration and concentration gave the crude product which was used directly in the next step. MS (m/z): 185 (M + 1) ⁺ .

中間體P：Intermediate P:

化合物P-2Compound P-2

將原料P-1(5.7克，30毫莫耳)、甘油(11.04克，120毫莫耳)、七水硫酸亞鐵(1.92克，6.9毫莫耳)和硝基苯(2.22克，18毫莫耳)混合，在室溫下攪拌10分鐘，然後向其中緩慢加入濃硫酸(9.8克，9.9毫莫耳)，反應液加熱回流10小時。反應結束後，冷卻到室溫，倒入冰水中，用濃氨水調pH至8，二氯甲烷萃取，合併有機相，乾燥，濃縮，殘餘物經矽膠柱層析(石油醚/乙酸乙酯=15/1)純化得到黃色固體6.78克，收率為99%。MS(m/z)：226(M+1)⁺ 。Raw material P-1 (5.7 g, 30 mmol), glycerin (11.04 g, 120 mmol), ferrous sulfate heptahydrate (1.92 g, 6.9 mmol) and nitrobenzene (2.22 g, 18 m) The mixture was stirred at room temperature for 10 minutes, and then concentrated sulfuric acid (9.8 g, 9.9 mmol) was slowly added thereto, and the reaction mixture was heated to reflux for 10 hours. After the reaction was completed, it was cooled to room temperature, poured into ice water, adjusted to pH 8 with concentrated aqueous ammonia, extracted with dichloromethane, combined organics, dried, concentrated, and the residue was purified by gel column chromatography ( petroleum ether / ethyl acetate = 15/1) Purification gave 6.78 g of a yellow solid, yield 99%. MS (m/z): 226 (M + 1) ⁺ .

化合物PCompound P

該化合物是以P-2為原料，按照從中間體J-3到J的合成方法製備。MS(m/z)：177(M+1)⁺ 。This compound was prepared by a synthesis method from Intermediate J-3 to J using P-2 as a raw material. MS (m/z): 177 (M + 1) ⁺ .

中間體Q：Intermediate Q:

化合物Q-2Compound Q-2

在5℃下，依次將硫氰酸鉀(93克，961毫莫耳)、原料Q-1(15克，117毫莫耳)加入到醋酸(125毫升)中，然後在冰鹽浴冷卻下，向其中緩慢滴加10毫升液溴和30毫升醋酸的混合溶液，滴加時保持體系低於5℃。加畢，於0℃反應2小時，然後升至室溫，反應過夜。反應結束後，加入60毫升水，加熱至90℃，攪拌片刻，趁熱過濾，所得濾餅溶於60毫升醋酸中，升溫至85℃，攪拌片刻，趁熱過濾。合併濾液，冷卻至室溫，用飽和氨水調PH=6，有大量固體析出，過濾，烘乾，得淡黃色固體產物，19克。收率：88%。MS(m/z)：186(M+1)⁺ 。Potassium thiocyanate (93 g, 961 mmol), starting material Q-1 (15 g, 117 mmol) were added to acetic acid (125 ml) at 5 ° C, then cooled in an ice salt bath. A mixed solution of 10 ml of liquid bromine and 30 ml of acetic acid was slowly added dropwise thereto, and the system was kept below 5 ° C when added dropwise. After the addition, the reaction was carried out at 0 ° C for 2 hours, then raised to room temperature and allowed to react overnight. After completion of the reaction, 60 ml of water was added, and the mixture was heated to 90 ° C, stirred for a while, and filtered while hot. The obtained cake was dissolved in 60 ml of acetic acid, and the mixture was warmed to 85 ° C, stirred for a while, and filtered while hot. The combined filtrates were cooled to room temperature and then taken to aq. Yield: 88%. MS (m/z): 186 (M + 1) ⁺ .

化合物Q-3Compound Q-3

將原料Q-2(19克，103毫莫耳)加入到20%的氫氧化鈉水溶液(150毫升)中，再加入2克亞硫酸鈉，回流反應過夜。冷卻至室溫後，用甲酸調至PH=7左右，大量固體析出，過濾，得金黃色固體產物，16.4克。收率：99%。MS(m/z)：161(M+1)⁺ 。Starting material Q-2 (19 g, 103 mmol) was added to a 20% aqueous sodium hydroxide solution (150 ml), and then 2 g of sodium sulfite was added and refluxed overnight. After cooling to room temperature, it was adjusted to pH = about 7 with formic acid, and a large amount of solid was precipitated and filtered to give a product as a yellow solid, 16.4 g. Yield: 99%. MS (m/z): 161 (M + 1) ⁺ .

化合物Q-4Compound Q-4

將原料Q-3(16.4克，103毫莫耳)加入到甲酸(80毫升)中，升溫至110℃，反應2小時。反應液冷卻至室溫後，用氨水調至PH=7，大量固體析出，過濾，得白色固體產物，14.5克。收率：83%。MS(m/z)：171(M+1)⁺ 。Starting material Q-3 (16.4 g, 103 mmol) was added to formic acid (80 ml), and the mixture was warmed to 110 ° C and reacted for 2 hours. After the reaction mixture was cooled to room temperature, it was adjusted to pH = 7 with aqueous ammonia, and a solid solid was precipitated and filtered to give white solid product, 14.5 g. Yield: 83%. MS (m/z): 171 (M + 1) ⁺ .

化合物Q-5Compound Q-5

將原料Q-4(460毫克，2.7毫莫耳)、氰化鋅(316毫克，2.7毫莫耳)、Pd₂ (dba)₃ (123毫克，0.13毫莫耳)、DPPF(150毫克，0.27毫莫耳)分別加入到裝有5毫升DMF(含水1%)的封管中，氮氣置換，密封，升溫至120℃，反應16小時。冷卻後，濃縮，殘餘物經柱層析(石油醚/乙酸乙酯=9/1)分離得黃色固體產物，151毫克。收率：34%。MS(m/z)：162.6(M+1)⁺ 。Starting material Q-4 (460 mg, 2.7 mmol), zinc cyanide (316 mg, 2.7 mmol), Pd ₂ (dba) ₃ (123 mg, 0.13 mmol), DPPF (150 mg, 0.27) Milligrams were separately added to a sealed tube containing 5 ml of DMF (1% aqueous), replaced with nitrogen, sealed, and warmed to 120 ° C for 16 hours. After cooling, the residue was crystalljjjjjjjjjj Yield: 34%. MS (m/z): 162.6 (M + 1) ⁺ .

化合物QCompound Q

該化合物是以Q-5為原料，按照從中間體J-4到J的合成方法製備。MS(m/z)：166(M+1)⁺ 。This compound was prepared by the synthesis of Intermediates J-4 to J using Q-5 as a starting material. MS (m/z): 166 (M + 1) ⁺ .

中間體R：Intermediate R:

化合物R-2Compound R-2

在0℃條件下，將6.5毫升三乙胺(46.7毫莫耳)加入到R-1(5克，38.9毫莫耳)的100毫升四氫呋喃溶液中，然後緩慢加入草醯氯單乙酯(5.84克，4.78毫升，42.8毫莫耳)的5毫升四氫呋喃溶液，室溫下攪拌1小時。反應結束後，減壓蒸除溶劑，所得油狀物用乙酸乙酯溶解，並用碳酸氫鈉溶液洗滌。乾燥有機相並濃縮得到褐色油狀物，直接用於下一步。MS(m/z)：229(M+1)⁺ 。6.5 ml of triethylamine (46.7 mmol) was added to a solution of R-1 (5 g, 38.9 mmol) in 100 ml of tetrahydrofuran at 0 ° C, then slowly added chlorohydrazine monoethyl ester (5.84) A solution of gram, 4.78 ml, 42.8 mmoles in 5 mL of THF was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure. The organic phase was dried and concentrated to give abr. MS (m/z): 229 (M + 1) ⁺ .

化合物R-3Compound R-3

在原料R-2(8克，35毫莫耳)的甲苯溶液(100毫升)中加入Lawesson's試劑(8.5克，21毫莫耳)，反應回流2小時。冷卻後，濃縮，所得殘餘物經柱層析純化得到產物。收率：55%。MS(m/z)：209(M+1)⁺ 。Lawesson's reagent (8.5 g, 21 mmol) was added to a solution of the starting material R-2 (8 g, 35 mmol) in toluene (100 mL). After cooling, it was concentrated and the residue obtained was purified by column chromatography. Yield: 55%. MS (m/z): 209 (M + 1) ⁺ .

化合物R-4Compound R-4

在0℃條件下，將NaBH₄ (0.9克，24毫莫耳)緩慢加入到R-3(5克，24毫莫耳)的乙醇溶液(100毫升)中，室溫下攪拌1小時，濃縮後，所得殘餘物用乙酸乙酯溶解，並用水洗滌，乾燥，濃縮，經柱層析純化得到產物。收率：60%。MS(m/z)：167(M+1)⁺ 。NaBH ₄ (0.9 g, 24 mmol) was slowly added to a solution of R-3 (5 g, 24 mmol) in ethanol (100 ml) at 0 ° C, stirring at room temperature for 1 hour, concentrated After that, the obtained residue was dissolved with ethyl acetate and washed with water. Yield: 60%. MS (m/z): 167 (M + 1) ⁺ .

化合物RCompound R

該化合物是以R-4為原料，按照從中間體A-3到A的合成方法製備。MS(m/z)：165(M)⁺ 。This compound was prepared by the synthesis of Intermediate A-3 to A using R-4 as a starting material. MS (m/z): 165 (M) ⁺ .

中間體S：Intermediate S:

化合物S-2Compound S-2

把原料S-1(12.8克，100毫莫耳)溶解在50毫升的二氯甲烷中，加入3毫升的Et₃ N，然後緩慢滴加8毫升乙醯氯，室溫攪拌過夜。反應結束後，加入碳酸氫鈉水溶液，用二氯甲烷萃取，有機相經無水硫酸鈉乾燥，濃縮得到白色固體17.1克，收率為100%。MS(m/z)：171.6(M+1)⁺ 。The starting material S-1 (12.8 g, 100 mmol) was dissolved in 50 ml of dichloromethane, 3 ml of Et ₃ N was added, and then 8 ml of acetonitrile was slowly added dropwise, and stirred at room temperature overnight. After completion of the reaction, an aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with methylene chloride. MS (m/z): 171.6 (M + 1) ⁺ .

化合物S-3Compound S-3

該化合物是以S-2為原料，按照從中間體R-2到R-3的合成方法製備。MS(m/z)：151.6(M+1)⁺ 。This compound is prepared by synthesizing the intermediate R-2 to R-3 using S-2 as a raw material. MS (m/z): 151.6 (M + 1) ⁺ .

化合物S-4Compound S-4

該化合物是以S-3為原料，按照從中間體B-4到B-5的合成方法製備。MS(m/z)：231(M+3)⁺ 。This compound was prepared by the synthesis of Intermediate B-4 to B-5 using S-3 as a starting material. MS (m/z): 231 (M+3) ⁺ .

化合物SCompound S

該化合物是以S-4為原料，按照從中間體C-5到C的合成方法製備。MS(m/z)：166(M+1)⁺ 。This compound was prepared by the synthesis of Intermediate C-5 to C using S-4 as a starting material. MS (m/z): 166 (M + 1) ⁺ .

中間體T和T’：Intermediates T and T':

化合物T-2Compound T-2

該化合物是以T-1為原料，按照從中間體F-1到F-2的合成方法製備。MS(m/z)：194(M+1)⁺ 。This compound was prepared by the method of synthesizing from the intermediates F-1 to F-2 using T-1 as a raw material. MS (m/z): 194 (M + 1) ⁺ .

化合物TCompound T

該化合物是以T-2為原料，按照從中間體D-2到D的合成方法製備。MS(m/z)：165(M+1)⁺ 。This compound was prepared from T-2 as a starting material according to the synthesis from Intermediate D-2 to D. MS (m/z): 165 (M + 1) ⁺ .

化合物T’Compound T’

該化合物是以T-1為原料，按照從中間體D’-1到D’-5和D-4到D的合成方法製備。MS(m/z)：179(M+1)⁺ 。This compound was prepared by the synthesis of intermediates D'-1 to D'-5 and D-4 to D using T-1 as a starting material. MS (m/z): 179 (M + 1) ⁺ .

中間體硼酸和硼酸酯的製備：Preparation of intermediate boronic acid and boric acid esters:

中間體U：Intermediate U:

化合物U-2Compound U-2

將原料U-1(1.02克，10毫莫耳)和Et₃ N(1毫升)溶解在20毫升二氯甲烷中，緩慢滴加2毫升甲磺醯氯，室溫攪拌1小時。反應結束後，倒入水中，用二氯甲烷萃取，有機相用無水硫酸鈉乾燥，濃縮，得產物1.8克。The feedstock U-1 (1.02 g, 10 mmol) and Et ₃ N (1 ml) was dissolved in 20 ml of methylene chloride, was slowly added dropwise 2 ml methanesulfonamide acyl chloride, stirred at room temperature for 1 hour. After completion of the reaction, the mixture was poured into water and extracted with dichloromethane.

化合物U-3Compound U-3

將原料U-2(1.8克，10毫莫耳)、4-溴-吡唑(1.46克，10毫莫耳)和碳酸鉀(1.4克，10毫莫耳)溶解在10毫升DMF中，在80℃下攪拌過夜。反應結束後，減壓蒸除溶劑，剩餘物用柱層析純化(甲醇/水=0至100%)得到白色固體861毫克，收率為37.3%。MS(m/z)：231(M+1)⁺ 。The starting material U-2 (1.8 g, 10 mmol), 4-bromo-pyrazole (1.46 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) were dissolved in 10 mL of DMF. Stir at 80 ° C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified (jjjjjjjj MS (m/z): 231 (M + 1) ⁺ .

化合物UCompound U

將原料U-3(1.03克，4.47毫莫耳)、聯硼酸頻那醇酯(861毫克，3.73毫莫耳)和醋酸鉀(12.43克，12.68毫莫耳)溶解在5毫升DMSO中，然後加入Pd(dppf)Cl₂ (172毫克，0.21毫莫耳)，氮氣保護下，在80℃攪拌過夜。反應結束後，倒入水中，用乙酸乙酯萃取，有機相經柱層析(甲醇：水=0至100%)純化得產物(170毫克，收率為16.4%)。MS(m/z)：279(M+1)⁺ 。Raw material U-3 (1.03 g, 4.47 mmol), pinacol borate (861 mg, 3.73 mmol) and potassium acetate (12.43 g, 12.68 mmol) were dissolved in 5 ml of DMSO, then Pd(dppf)Cl ₂ (172 mg, 0.21 mmol) was added and stirred at 80 ° C overnight under nitrogen. After completion of the reaction, it was poured into water, extracted with ethyl acetate, and the organic phase was purified by column chromatography (methanol: water = 0 to 100%) (170 mg, yield: 16.4%). MS (m/z): 279 (M + 1) ⁺ .

中間體V：Intermediate V:

將原料V-1(3克，15毫莫耳)溶於DMF(6毫升)，向其中加入溴乙烷(3.24克，30毫莫耳)和碳酸鉀(4.26克，30毫莫耳)，60℃反應過夜。反應結束後，加入乙酸乙酯，依次用水，飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，濃縮，得黃色油狀物產物，3.4克。收率：100%。MS(m/z)：223(M+1)⁺ 。Starting material V-1 (3 g, 15 mmol) was dissolved in DMF (6 mL), and ethyl bromide (3.24 g, 30 mmol) and potassium carbonate (4.26 g, 30 m. The reaction was carried out at 60 ° C overnight. After the reaction was completed, ethyl acetate was evaporated. Yield: 100%. MS (m/z): 223 (M + 1) ⁺ .

中間體W：Intermediate W:

化合物W-1Compound W-1

該化合物是以2-氯環戊酮為原料，按照中間體V的合成方法製備。MS(m/z)：277(M+1)⁺ 。This compound was prepared by the synthesis method of the intermediate V using 2-chlorocyclopentanone as a raw material. MS (m/z): 277 (M + 1) ⁺ .

化合物WCompound W

將原料W-1(550毫克，2毫莫耳)溶解在5毫升甲醇中，向其中緩慢加入硼氫化鈉(150毫克，4毫莫耳)，室溫攪拌1小時，反應結束後，加入1毫升水萃滅，濃縮，殘餘物用乙酸乙酯溶解，水洗，有機相用矽膠層析純化(二氯甲烷/甲醇=20/1)得到黃色液體(200毫克，收率為35.9%)。MS(m/z)：279(M+1)⁺ 。The raw material W-1 (550 mg, 2 mmol) was dissolved in 5 ml of methanol, sodium borohydride (150 mg, 4 mmol) was slowly added thereto, and stirred at room temperature for 1 hour. The mixture was concentrated with EtOAc (EtOAc)EtOAc. MS (m/z): 279 (M + 1) ⁺ .

中間體X：Intermediate X:

該化合物以4-溴吡唑為原料，按照文獻US2007/0265272 中所述方法製備。This compound was prepared from 4-bromopyrazole according to the method described in the document US 2007/0265272 .

其他吡唑類硼酸或硼酸酯按照中間體U到X的合成方法製備。Other pyrazole boronic acids or boronic esters are prepared according to the synthesis of intermediates U to X.

中間體Y：Intermediate Y:

中間體Y-2Intermediate Y-2

將N-羥基鄰苯二甲醯亞胺(20.0克，0.12莫耳)溶於丙酮(400毫升)，加入三乙胺(14.9克，0.15莫耳)，攪拌約10分鐘，然後再加入1-溴-2,4-二硝基苯Y-1(30.2克，0.12莫耳)。室溫攪拌2小時後，將反應液倒入冰水中，有黃色固體析出，濾出固體，並用少量冰甲醇洗滌3次，乾燥得黃色固體38.1克，收率：92%。N-hydroxyphthalimin (20.0 g, 0.12 mol) was dissolved in acetone (400 ml), triethylamine (14.9 g, 0.15 mol) was added, stirred for about 10 minutes, then 1 - Bromo-2,4-dinitrobenzene Y-1 (30.2 g, 0.12 mol). After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and then a white solid was evaporated, and the solid was filtered, and washed three times with a small amount of ice methanol to give a yellow solid (38.1 g, yield: 92%).

中間體Y-3Intermediate Y-3

將原料Y-2(20.0克，60.7毫莫耳)溶於二氯甲烷(400毫升)，0℃下加入水合肼的甲醇溶液(10毫升，85%的水合肼溶於60毫升甲醇)，然後在該溫度下攪拌6小時，隨後加入1N鹽酸溶液(400毫升)，抽濾除去固體，並用乙腈洗滌三次，濾液分出有機相，水相用二氯甲烷萃取，合併有機相，用無水硫酸鈉乾燥，濃縮，得棕色固體7.9克。收率：65%。MS(m/z)：183(M-16)^- 。The raw material Y-2 (20.0 g, 60.7 mmol) was dissolved in dichloromethane (400 ml), and a solution of hydrazine hydrate in methanol (10 ml, 85% hydrazine hydrate dissolved in 60 ml of methanol) was added at 0 ° C, then After stirring at this temperature for 6 hours, a 1N aqueous solution of hydrochloric acid (400 ml) was added, and the solid was removed by suction, and washed three times with acetonitrile, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. Dry and concentrate to give a brown solid 7.9 g. Yield: 65%. MS (m/z): 183 (M-16) ^- .

中間體Y-4Intermediate Y-4

將4-羥甲基吡啶(21.8克，0.20莫耳)溶於二氯甲烷(200毫升)，0℃下加入三乙胺(30.0克，0.30莫耳)和叔丁基二甲基氯矽烷(45.0克，0.30莫耳)。反應液在室溫下攪拌4小時，加入水淬滅，然後用二氯甲烷萃取，合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，柱層析分離(乙酸乙酯：石油醚=1：5)，得到中間體4-((叔丁基二甲基氯矽氧)甲基)吡啶無色液體32.1克。收率：96%。4-Hydroxymethylpyridine (21.8 g, 0.20 mol) was dissolved in dichloromethane (200 mL) and triethylamine (30.0 g, 0.30 mol) and tert-butyldimethylchloromethane ( 45.0 grams, 0.30 moles). The reaction mixture was stirred at room temperature for 4 hrs, EtOAc (EtOAc)EtOAc. =1: 5), 32.1 g of the intermediate 4-((tert-butyldimethylammonium oxy)methyl)pyridine as a colorless liquid was obtained. Yield: 96%.

取該中間體(8.7克，39.7毫莫耳)溶於乙腈(27毫升)，加入原料Y-3(7.9克，39.7毫莫耳)，反應在40℃下攪拌24小時。反應結束後，濃縮得到褐色油狀物17.1克，收率：98%。MS(m/z)：239(M-183)⁺ 。This intermediate (8.7 g, 39.7 mmol) was dissolved in acetonitrile (27 mL). EtOAc (EtOAc) After completion of the reaction, the mixture was concentrated to give 17.1 g of brown oil. MS (m/z): 239 (M-183) ⁺ .

中間體Y-5Intermediate Y-5

將原料Y-4(13.4克，31.6毫莫耳)溶於DMF(60毫升)，加入丙炔酸甲酯(2.7克，31.6毫莫耳)和碳酸鉀(6.5克，47.4毫莫耳)，反應液在室溫下攪拌24小時。反應結束後，加入水，反應液用乙酸乙酯萃取，合併有機相，用水、飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，柱層析分離(乙酸乙酯：石油醚=1：10)，得黃色油狀物2.9克。收率：29%。MS(m/Z)：321(M+1)⁺ 。Starting material Y-4 (13.4 g, 31.6 mmol) was dissolved in DMF (60 mL) and methyl propiolate (2.7 g, 31.6 mmol) and potassium carbonate (6.5 g, 47.4 mmol). The reaction solution was stirred at room temperature for 24 hours. After the completion of the reaction, water was added, and the mixture was combined with EtOAc. EtOAc. A yellow oil of 2.9 g was obtained. Yield: 29%. MS (m/Z): 321 (M + 1) ⁺ .

中間體Y-6Intermediate Y-6

將原料Y-5(2.9克，9.1毫莫耳)溶於乾燥的四氫呋喃(20毫升)，加入四丁基氟化銨(3.5克，13.7毫莫耳)，反應液在室溫下攪拌10分鐘後，加入乙酸乙酯稀釋，然後用飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，得到棕色固體1.9克，未經純化直接進行下一步反應。Starting material Y-5 (2.9 g, 9.1 mmol) was dissolved in dry tetrahydrofuran (20 mL), tetrabutylammonium fluoride (3.5 g, 13.7 mmol) was added and the mixture was stirred at room temperature for 10 min. After that, it was diluted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate

中間體Y-7Intermediate Y-7

將原料Y-6(1.9克，9.1毫莫耳)溶於40%的硫酸，反應液在80℃下攪拌24小時。反應冷卻後，加入3N NaOH溶液，把pH值調至7至8，用乙酸乙酯萃取，合併有機相，飽和食鹽水洗滌，無水硫酸鈉乾燥，濃縮，柱層析分離(乙酸乙酯：石油醚=1：1)，得黃色油狀物1.1克。收率：81%(兩步收率)。MS(m/z)：149(M+1)⁺ 。Raw material Y-6 (1.9 g, 9.1 mmol) was dissolved in 40% sulfuric acid, and the reaction solution was stirred at 80 ° C for 24 hours. After the reaction was cooled, 3N NaOH solution was added, the pH was adjusted to 7 to 8 and extracted with ethyl acetate. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate Ether = 1:1) gave 1.1 g of a yellow oil. Yield: 81% (two-step yield). MS (m/z): 149 (M + 1) ⁺ .

中間體YIntermediate Y

該化合物是以Y-7為原料，按照從中間體D-3到D的合成方法製備。MS(m/z)：148(M+1)⁺ 。This compound was prepared from Y-7 as a starting material according to the synthesis from Intermediate D-3 to D. MS (m/z): 148 (M + 1) ⁺ .

中間體Z：Intermediate Z:

中間體Z-2Intermediate Z-2

將原料Z-1(9.0克，59.21毫莫耳)溶解在無水乙醇(160毫升)中，向其中加入40%的氯乙醛水溶液(48.6毫升，296毫莫耳)，混合物加熱回流4小時。反應結束後，濃縮，殘餘物溶解在水裏，用碳酸氫鈉溶液調至鹼性，然後用乙酸乙酯萃取，有機相合併後用無水硫酸鈉乾燥，濃縮，並經柱層析分離得白色固體產物(乙酸乙酯/石油醚=3：1)，收率：63%。MS(m/Z)：177(M+1)⁺ 。Starting material Z-1 (9.0 g, 59.21 mmol) was dissolved in anhydrous ethanol (160 ml), and 40% aqueous chloroacetaldehyde (48.6 ml, 296 mmol) was added thereto, and the mixture was heated under reflux for 4 hours. After the reaction, the mixture was concentrated, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, Solid product (ethyl acetate / petroleum ether = 3:1), yield: 63%. MS (m/Z): 177 (M + 1) ⁺ .

中間體Z-3Intermediate Z-3

將原料Z-2(5.0克，28.4毫莫耳)和N-甲基-N-甲氧基胺(5.54克，56.8毫莫耳)混合在無水四氫呋喃(50毫升)中，在N₂ 保護下，於-20℃下，在30分鐘內向其中加入異丙基氯化鎂(56.8毫升，113.6毫莫耳)，然後在該溫度下，繼續攪拌反應30分鐘。反應結束後，加入20%氯化銨溶液，用乙酸乙酯萃取，合併有機相，用無水硫酸鈉乾燥，濃縮，經柱層析分離得油狀產物(乙酸乙酯/石油醚=1：1(3.0克)收率：52%。MS(m/z)：206(M+1)⁺ 。The starting material Z-2 (5.0 g, 28.4 mmol) (56.8 mmol 5.54 g mole) in dry tetrahydrofuran (50 ml), and the N- methyl -N- methoxy-N ₂ mixed protected amine Isopropylmagnesium chloride (56.8 ml, 113.6 mmol) was added thereto at -20 ° C over 30 minutes, and then the reaction was further stirred at this temperature for 30 minutes. After the reaction was completed, a 20% ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. EtOAc was evaporated. (3.0 g) yield: 52% .MS (m / z ): 206 (m + 1) +.

中間體ZIntermediate Z

該化合物是以Z-3為原料，按照從中間體D’-2到D’的合成方法製備。This compound was prepared from Z-3 as a starting material in the same manner as the synthesis from the intermediate D'-2 to D'.

實施例1Example 1

化合物1-aCompound 1-a

將2-氨基-3，5-二溴吡嗪(758毫克，3.0毫莫耳)、中間體A(442毫克，3.0毫莫耳)、乙基異丙基胺(1160毫克，9.0毫莫耳)分別加入到乙醇(70毫升)中，密封後，於150℃下反應過夜。冷卻後，濃縮，殘餘物經柱層析(甲醇/水=30%至100%)分離得產物，70毫克，收率：8%。MS(m/z)：319(M+1)⁺ 。2-Amino-3,5-dibromopyrazine (758 mg, 3.0 mmol), Intermediate A (442 mg, 3.0 mmol), ethyl isopropylamine (1160 mg, 9.0 mmol) They were separately added to ethanol (70 ml), sealed, and reacted at 150 ° C overnight. After cooling, it was concentrated, and the residue was purified by column chromatography (methanol / water = 30% to 100%). MS (m/z): 319 (M + 1) ⁺ .

化合物1-bCompound 1-b

將原料1-a(70毫克，0.22毫莫耳)加入到醋酸和水的混合溶劑(3毫升/3毫升)中，再加入NaNO₂ (30毫克，0.44毫莫耳)的0.5毫升水溶液，在冰浴下攪拌反應1小時，然後分別加入H₂ SO₄ (49%，0.1毫升)和第二批NaNO₂ (15毫克，0.22毫莫耳)的0.2毫升水溶液，升至室溫，攪拌反應過夜。反應結束後，用2N的氫氧化鈉溶液調至PH>8，用乙酸乙酯萃取，合併有機相，經無水硫酸鈉乾燥，濃縮，得產物30毫克，收率：41%。MS(m/z)：330(M+1)⁺ 。The starting material 1-a (70 mg, 0.22 mmol) was added to a mixed solvent of acetic acid and water (3 ml / 3 ml), and then a solution of NaNO ₂ (30 mg, 0.44 m. The reaction was stirred for 1 hour under ice-cooling, and then H ₂ SO ₄ (49%, 0.1 mL) and a second portion of NaNO ₂ (15 mg, 0.22 m. . After completion of the reaction, the mixture was adjusted to a pH of <RTI ID=0.0>> MS (m/z): 330 (M + 1) ⁺ .

化合物1Compound 1

將原料1-b(46毫克，0.14毫莫耳)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1氫-吡唑(77毫克，0.35毫莫耳)、PdCl₂ (dppf)(12毫克，0.014毫莫耳)和碳酸銫(137毫克，0.42毫莫耳)分別加入到二氧六環和水的混合溶液中(10：1，8毫升)，密封，在80℃下攪拌過夜。冷卻後，濃縮，殘餘物經柱層析純化的淺黃色固體，18毫克，收率：38%。MS(m/z)：332(M+H)⁺ Starting material 1-b (46 mg, 0.14 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Base)-1 hydrogen-pyrazole (77 mg, 0.35 mmol), PdCl ₂ (dppf) (12 mg, 0.014 mmol) and cesium carbonate (137 mg, 0.42 mmol) were added to the dioxane A mixture of rings and water (10:1, 8 mL) was sealed and stirred at 80 ° C overnight. After cooling, the residue was purified mjjjjjjjjj MS (m/z): 332 (M+H) ⁺

實施例2至59和265至272Examples 2 to 59 and 265 to 272

以下化合物按照實施例1的合成方法製備。在合適的條件下，採用相應的中間體、硼酸或硼酸酯。The following compounds were prepared in accordance with the synthetic procedure of Example 1. The appropriate intermediate, boric acid or borate is employed under suitable conditions.

¹² 光學純異構體採用對掌HPLC分離得到。柱子：dicel IA coloumn 2.0*25公分；溶劑：乙醇：D二乙胺=100：0.1；流速：5毫升/分鐘；紫外吸收：254奈米)。 ^{The 12} optically pure isomers were separated by HPLC on the palm. Column: dicel IA coloumn 2.0*25 cm; solvent: ethanol: D diethylamine = 100: 0.1; flow rate: 5 ml/min; UV absorption: 254 nm).

¹³ 化合物272是按照下面的路線從化合物33製備而來。 ¹³ Compound 272 was prepared from Compound 33 according to the following scheme.

將化合物33(66毫克，0.2毫莫耳)溶於醋酸(0.1毫升)中，加入醋酸鈉(60毫克，0.73毫莫耳)和濃度37%的甲醛水溶液(0.2毫升，2.8毫莫耳)，在100℃反應過夜。反應結束後，加入水，用飽和碳酸鈉調成鹼性，過濾，濾餅用柱層析分離得黃色固體產物，30毫克。收率：42%。Compound 33 (66 mg, 0.2 mmol) was dissolved in acetic acid (0.1 mL) and sodium acetate (60 mg, 0.73 m.m.) The reaction was carried out at 100 ° C overnight. After completion of the reaction, water was added, and the mixture was made basic with saturated sodium carbonate. Yield: 42%.

實施例60：Example 60:

化合物60-aCompound 60-a

將原料3-硝基-2,6-二氯吡啶(106毫克，0.55毫莫耳)溶解在異丙醇(3毫升)中，向其中依次加入Na₂ CO₃ (116毫克，1.1毫莫耳)和中間體R(100毫克，0.61毫莫耳)，室溫反應過夜。反應結束後，減壓蒸除溶劑，殘餘物用乙酸乙酯溶解，經水洗、乾燥，濃縮後經柱層析分離得產物，收率：67.8%。MS(m/z)：322(M)⁺ 。The starting material, 3-nitro-2,6-dichloropyridine (106 mg, 0.55 mmol) was dissolved in isopropyl alcohol (3 mL), and Na ₂ CO ₃ (116 mg, 1.1 m. And intermediate R (100 mg, 0.61 mmol), and allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was evaporated, evaporated, evaporated, MS (m/z): 322 (M) ⁺ .

化合物60-bCompound 60-b

將原料60-a(100毫克，0.31毫莫耳)溶解在甲醇(2毫升)和四氫呋喃(10毫升)的混合溶劑中，加入10%Pd/C(20毫克)，氫氣保護下，反應1小時，過濾，濾液濃縮後經柱層析分離得產物，收率：94.4%。MS(m/z)：292(M+1)⁺ 。The raw material 60-a (100 mg, 0.31 mmol) was dissolved in a mixed solvent of methanol (2 ml) and tetrahydrofuran (10 ml), and 10% Pd/C (20 mg) was added under a hydrogen atmosphere for 1 hour. After filtration, the filtrate was concentrated and the product was isolated by column chromatography, yield: 94.4%. MS (m/z): 292 (M + 1) ⁺ .

化合物60-cCompound 60-c

在0℃，將原料60-b(90毫克，0.31毫莫耳)溶解在醋酸(1毫升)和水(1毫升)的混合溶劑中，然後緩慢加入0.5毫升的亞硝酸鈉(42.5毫克，0.62毫莫耳)溶液，加畢，在該溫度下，繼續攪拌1小時。反應結束後，用30%的氫氧化鈉溶液調至pH9，有固體析出，過濾，乾燥得產物，收率：74.6%。MS(m/z)：303(M+1)⁺ 。The material 60-b (90 mg, 0.31 mmol) was dissolved in a mixed solvent of acetic acid (1 ml) and water (1 ml) at 0 ° C, then slowly added 0.5 ml of sodium nitrite (42.5 mg, 0.62) The solution was added, and after this temperature was added, stirring was continued for 1 hour. After the reaction, adjust to pH with 30% sodium hydroxide solution 9, a solid precipitated, filtered, dried to give the product, yield: 74.6%. MS (m/z): 303 (M + 1) ⁺ .

化合物60-dCompound 60-d

將原料60-c(64毫克，0.21毫莫耳)和中間體X(75毫克，0.23毫莫耳)加入到二氧六環(1.5毫升)和水(0.15毫升)的混合溶劑中，在氮氣保護下，向其中加入Pd(dppf)Cl₂ (32.7毫克，0.04毫莫耳)和碳酸銫(98毫克，0.3毫莫耳)，於120℃下反應攪拌過夜。冷卻後，減壓蒸除溶劑，殘餘物經柱層析分離得產物，收率：51.5%。MS(m/z)：463(M+1)⁺ 。Starting material 60-c (64 mg, 0.21 mmol) and intermediate X (75 mg, 0.23 mmol) were added to a mixed solvent of dioxane (1.5 ml) and water (0.15 ml). Under protection, Pd(dppf)Cl ₂ (32.7 mg, 0.04 mmol) and cesium carbonate (98 mg, 0.3 mmol) were added thereto, and the mixture was stirred at 120 ° C overnight. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography. MS (m/z): 463 (M + 1) ⁺ .

化合物60Compound 60

將原料60-d(20毫克，0.04毫莫耳)溶解在鹽酸/甲醇(2毫升)中，室溫下攪拌反應1小時，然後濃縮，殘餘物經柱層析分離得黃色固體的產物，收率：66.7%。MS(m/z)：379(M+1)⁺ 。The raw material 60-d (20 mg, 0.04 mmol) was dissolved in hydrochloric acid / methanol (2 ml), and the reaction was stirred for 1 hour at room temperature, then concentrated, and the residue was purified by column chromatography Rate: 66.7%. MS (m/z): 379 (M + 1) ⁺ .

實施例61至151Examples 61 to 151

以下化合物按照實施例60的合成方法製備。在合適的條件下，採用相應的中間體、硼酸或硼酸酯。The following compound was prepared according to the synthetic method of Example 60. The appropriate intermediate, boric acid or borate is employed under suitable conditions.

¹ 　光學純異構體採用對掌HPLC分離得到。分離條件：Gilson 215 prep. System;；柱子：Dicel IA 2.0*25公分；溶劑：甲基叔丁基醚：甲醇：甲酸=95：5：0.1；流速：20毫升/分鐘；紫外吸收：254奈米)。 ¹ Optically pure isomers were separated by HPLC on palm. Separation conditions: Gilson 215 prep. System;; Column: Dicel IA 2.0*25 cm; Solvent: methyl tert-butyl ether: methanol: formic acid = 95:5: 0.1; flow rate: 20 ml/min; UV absorption: 254 Nai Meter).

² 　中間體94-a是採用相應的中間體和硼酸(酯)，按照實施例60所描述的方法，並在該領域學者可理解的適當條件下製備。化合物94是按照下面的路線從中間體94-1製備而來。 ² Intermediate 94-a was prepared according to the method described in Example 60 using the corresponding intermediate and boronic acid, and under suitable conditions as understood by the skilled in the art. Compound 94 was prepared from Intermediate 94-1 according to the following route.

將中間體94-a(30毫克，0.06毫莫耳)溶於三氟醋酸(2毫升)和二氯甲烷(2毫升)的混合溶劑，然後攪拌過夜。反應結束後，濃縮，殘餘物溶解在碳酸氫鈉的水溶液中，用乙酸乙酯萃取，有機相濃縮後，經柱層析分離得產物。Intermediate 94-a (30 mg, 0.06 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2 ml) and dichloromethane (2 ml) and then stirred overnight. After completion of the reaction, the mixture was concentrated. The residue was crystalljjjjjjjjj

³ 　化合物98以化合物61為原料按照下面的路線製備： ³ Compound 98 was prepared from compound 61 using the following route:

將化合物61溶於二氯甲烷(5毫升)中，向其中加入三乙胺(56微克)和乙醯氯(36微克)，反應液室溫攪拌3小時。反應結束後，加水，用二氯甲烷萃取，有機相合併後乾燥、濃縮，殘餘物經層析分離得產物。Compound 61 was dissolved in dichloromethane (5 ml), triethylamine (56 μg) and ethyl acetate (36 μg) were added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added, and the mixture was extracted with dichloromethane. The organic phase was combined, dried and concentrated.

⁴ 　化合物101是以化合物94為原料，按照以下描述製備： ⁴ Compound 101 was prepared from compound 94 as follows:

將化合物94(18毫克，0.044毫莫耳)溶於二氯甲烷(2毫升)中，在0℃下，依次加入三乙胺(12.2微升，0.088毫莫耳1)和碘甲烷(2.4微升，0.048毫莫耳)，緩慢升至室溫，繼續攪拌1小時。反應結束後，加入飽和碳酸氫鈉溶液，分層，水相用乙酸乙酯萃取，合併有機相，乾燥、濃縮，並經柱層析分離得產物。Compound 94 (18 mg, 0.044 mmol) was dissolved in dichloromethane (2 mL) and then triethylamine (12.2 liters, 0.088 mM 1) and io L, 0.048 mmol, slowly rise to room temperature and continue to stir for 1 hour. After completion of the reaction, a saturated sodium hydrogencarbonate solution was added, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, dried, concentrated, and purified by column chromatography.

⁵ 　化合物104是按照從中間體W-1到W的方法製備。中間體104-a是按照化合物60所描述的方法製備。 ⁵ Compound 104 was prepared according to the method from Intermediate W-1 to W. Intermediate 104-a was prepared as described for compound 60.

⁶ 　化合物105是以104-a為原料，按照以下路線製備： ⁶ Compound 105 was prepared from 104-a as follows:

中間體104-a(37毫克，0.1毫莫耳)的二甲胺/甲醇(5毫升)溶液室溫下攪拌1小時，然後向其中加入氰基硼氫化納(12毫克)，反應液繼續攪拌16小時。反應結束後，濃縮，加入飽和碳酸氫鈉溶液和二氯甲烷，分離，有機相濃縮後經層析分離得產物，8毫克，收率為20%。Intermediate 104-a (37 mg, 0.1 mmol) in dimethylamine/methanol (5 ml) was stirred at room temperature for 1 hour, then sodium cyanoborohydride (12 mg) was added and the mixture was stirred. 16 hours. After completion of the reaction, the mixture was concentrated, dried aqueous sodium hydrogen sulfate and methylene chloride, and the organic phase was concentrated and then purified by chromatography.

⁷ 　化合物108是按照以下路線，在實施例60所描述的合適條件下製備而來。中間體108-a是按照從中間體U-3到U方法製備。 ⁷ Compound 108 was prepared according to the following scheme under the appropriate conditions as described in Example 60. Intermediate 108-a was prepared according to the procedure from Intermediate U-3 to U.

⁸ 　化合物116是按照化合物94的方法製備 ⁸ compound 116 is prepared according to the method of compound 94

⁹ 　化合物138的製備過程中使用(t-Bu)₃ HBF₄ /Pd2(dba)3作為催化劑 ⁹ the preparation of compound 138 using _{(t-Bu) 3 HBF 4} / Pd2 (dba) 3 as a catalyst

¹⁰ 　化合物148是按照以下路線，在實施例60所描述的適當條件下製備而來。化合物149的製備方法同化合物148。 ¹⁰ Compound 148 was prepared according to the following scheme under the appropriate conditions as described in Example 60. Compound 149 was prepared in the same manner as Compound 148.

實施例152：Example 152:

化合物152Compound 152

將原料152-a(68毫克，0.2毫莫耳)(按實施例1步驟從6-氨甲基喹啉製備)和3-氨基-1-甲基吡唑(20毫克，0.22毫莫耳))溶於1，4-二氧六環(5毫升)中，加入碳酸銫(72毫克，0.22毫莫耳)和水(0.5毫升)，氮氣置換三次後，加入Pd₂ (dba)₃ (0.02毫莫耳，18毫克)和xantphos(0.04毫莫耳，23毫克)，然後氮氣保護下於80℃下攪拌過夜。冷卻後，蒸除溶劑，殘餘物經柱層析分離得到白色固體10毫克。收率：13%。MS(m/z)：358(M+1)⁺ 。Starting material 152-a (68 mg, 0.2 mmol) (prepared from 6-aminomethylquinoline as in Example 1) and 3-amino-1-methylpyrazole (20 mg, 0.22 mmol) Dissolved in 1,4-dioxane (5 ml), adding cesium carbonate (72 mg, 0.22 mmol) and water (0.5 ml), after replacing three times with nitrogen, adding Pd ₂ (dba) ₃ (0.02 Millol, 18 mg) and xantphos (0.04 mmol, 23 mg) were then stirred at 80 ° C overnight under nitrogen. After cooling, the solvent was evaporated. Yield: 13%. MS (m/z): 358 (M + 1) ⁺ .

實施例153至240Examples 153 to 240

以下化合物按照實施例152的合成方法製備。在合適的條件下，採用相應的中間體和胺。The following compound was prepared according to the synthetic procedure of Example 152. The appropriate intermediates and amines are employed under suitable conditions.

¹¹ 　化合物154是按照以下路線，在實施例152所描述的合適條件製備而來。中間體154-a是在合適條件下按照實施例244所描述的方法製備。化合物177和239的製備方法同化合物154。 ¹¹ Compound 154 was prepared according to the following scheme, under the appropriate conditions described in Example 152. Intermediate 154-a was prepared according to the procedure described in Example 244 under suitable conditions. Compounds 177 and 239 were prepared in the same manner as compound 154.

實施例244Example 244

將中間體244-a(60毫克，0.2毫莫耳)(按實施例60製備)，碳酸銫(195毫克，0.6毫莫耳)和4,5,6,7-四氫噻吩[3,2-c]吡啶鹽酸鹽(52毫克，0.3毫莫耳的DMF(1.5毫升)溶液在120℃下攪拌過夜，反應結束後，濃縮，殘餘物經層析分離得產物，收率：24%。MS(m/z)：399(M+1)⁺ 。Intermediate 244-a (60 mg, 0.2 mmol) (prepared as in Example 60), cesium carbonate (195 mg, 0.6 mmol) and 4,5,6,7-tetrahydrothiophene [3,2 -c] A solution of the pyridine hydrochloride (52 mg, 0.3 mmol) in DMF (1.5 mL). MS (m/z): 399 (M + 1) ⁺ .

實施例245至260Examples 245 to 260

以下化合物按照實施例244的合成方法製備。在合適的條件下，採用相應的中間體、胺、硫醇/酚或醇。The following compound was prepared according to the synthetic procedure of Example 244. The appropriate intermediate, amine, thiol/phenol or alcohol is employed under suitable conditions.

實施例261Example 261

化合物261-aCompound 261-a

將2,6-二氯-4-氨基吡啶(3.0克，18毫莫耳)緩慢加入到20毫升濃硫酸中，冷卻到零度，向其中滴加2.6毫升發煙硝酸，升溫到室溫，攪拌反應1小時，然後倒入冰中，析出固體，過濾，乾燥，得3.7克產物，直接用於下步反應。2,6-Dichloro-4-aminopyridine (3.0 g, 18 mmol) was slowly added to 20 ml of concentrated sulfuric acid, cooled to zero, and 2.6 ml of fuming nitric acid was added dropwise thereto, and the mixture was warmed to room temperature and stirred. The reaction was carried out for 1 hour, then poured into ice, and the solid was precipitated, filtered, and dried to give 3.7 g of product which was directly used for the next step.

化合物261-bCompound 261-b

將261-a(3.7克，18毫莫耳)加入到5毫升濃硫酸中，加熱反應半小時，冷卻到室溫後，倒入冰水中，用濃氨水調至pH~7，在-10℃下靜置過夜，過濾，乾燥，得產物，2.5克，收率：66.7%。MS(m/z)：208(M+1)⁺ 。Add 261-a (3.7 g, 18 mmol) to 5 ml of concentrated sulfuric acid, heat the reaction for half an hour, cool to room temperature, pour into ice water, and adjust to pH~7 with concentrated ammonia water at -10 °C. The mixture was allowed to stand overnight, filtered and dried to give a product, 2.5 g, yield: 66.7%. MS (m/z): 208 (M + 1) ⁺ .

化合物261-cCompound 261-c

將261-b(208毫克，1毫莫耳)溶解在2毫升醋酐中，回流過夜。反應結束後，冷卻到室溫，加碳酸鈉溶液調節pH=8，用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，濃縮，產物，240毫克，收率：96%。MS(m/z)：251(M+1)。261-b (208 mg, 1 mmol) was dissolved in 2 mL of acetic anhydride and refluxed overnight. After completion of the reaction, the mixture was cooled to room temperature, and then a sodium carbonate aqueous solution was adjusted to pH=8, and ethyl acetate was evaporated. The organic phase was dried over anhydrous sodium sulfate and evaporated. MS (m/z): 251 (M + 1).

化合物261-dCompound 261-d

將261-c(240毫克，0.96毫莫耳)和6-氨甲基喹啉(150毫克，0.96毫莫耳)溶解在乙腈(10毫升)中，加入0.5毫升三乙胺，在80℃反應1小時。反應結束後，冷卻到室溫，經矽膠柱層析(二氯甲烷/甲醇=50/1)純化得到黃色固體，220毫克，收率：62%。MS(m/z)：372(M+1)⁺ 。261-c (240 mg, 0.96 mmol) and 6-aminomethylquinoline (150 mg, 0.96 mmol) were dissolved in acetonitrile (10 mL), and 0.5 mL of triethylamine was added and reacted at 80 ° C 1 hour. After completion of the reaction, it was cooled to room temperature and purified by silica gel chromatography (dichloromethane/methanol=50/1) to afford a white solid (yield: 62%). MS (m/z): 372 (M + 1) ⁺ .

化合物261-eCompound 261-e

將261-d(220毫克，0.593毫莫耳)溶解在10毫升甲醇中，氮氣置換，加入催化量10% Pd/C，在1大氣壓的氫氣下，室溫攪拌1小時，反應結束後，濾除Pd/C，濾液濃縮得產物，直接用於下一步反應。MS(m/z)：342(M+1)⁺ 。261-d (220 mg, 0.593 mmol) was dissolved in 10 ml of methanol, replaced with nitrogen, and a catalytic amount of 10% Pd/C was added. The mixture was stirred at room temperature for 1 hour under 1 atmosphere of hydrogen. After the reaction was completed, the mixture was filtered. In addition to Pd/C, the filtrate was concentrated to give the product which was used directly in the next step. MS (m/z): 342 (M + 1) ⁺ .

化合物261-fCompound 261-f

將上一步的產物261-e溶解在2毫升的醋酸和2毫升水的混合溶劑中，冷卻到0℃，滴加溶解在0.3毫升的亞硝酸鈉(180毫克，2.6毫莫耳)水溶液，0℃下反應1小時。反應結束後，用30%氫氧化鈉調至pH=8，過濾，得產物，直接用於下步反應。MS(m/z)：353(M+1)⁺ 。The product 261-e of the previous step was dissolved in a mixed solvent of 2 ml of acetic acid and 2 ml of water, cooled to 0 ° C, and added dropwise to 0.3 ml of an aqueous solution of sodium nitrite (180 mg, 2.6 mmol), 0 The reaction was carried out at ° C for 1 hour. After completion of the reaction, the mixture was adjusted to pH = 8 with 30% sodium hydroxide and filtered to give a product which was used directly for the next step. MS (m/z): 353 (M + 1) ⁺ .

化合物261Compound 261

將261-f(80毫克，0.227毫莫耳)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1氫-吡唑(50毫克，0.24毫莫耳)和碳酸鈉(48毫克，0.25毫莫耳)溶解在10毫升的二氧六環和1毫升水的混合溶劑中，氮氣置換後，加入Pd(dppf)Cl₂ (20毫克，0.02毫莫耳)，反應液在氮氣保護下，於100℃攪拌過夜。反應結束後，冷卻到室溫，用柱層析(水：甲醇=100：0到0：100)純化得到黃色產物，7毫克，收率為7.3%。MS：399.9(M+1)⁺ 。261-f (80 mg, 0.227 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1 hydrogen-pyrazole (50 mg, 0.24 mmol) and sodium carbonate (48 mg, 0.25 mmol) dissolved in 10 ml of a mixed solvent of dioxane and 1 ml of water, after nitrogen replacement, Pd(dppf)Cl ₂ (20 mg, 0.02 mmol) was added, and the reaction mixture was stirred at 100 ° C overnight under nitrogen. After completion of the reaction, it was cooled to room temperature and purified by column chromatography (water:methanol=100:0 to 0:100) to yield a yellow product (yield 7.3%). MS: 399.9 (M + 1) ⁺ .

實施例262Example 262

化合物262-aCompound 262-a

將2,6-二氯-3-硝基-4-氨基吡啶(624毫克，3毫莫耳)和喹啉6-甲氨(316毫克，2毫莫耳)溶解在10毫升乙腈中，向其加入1毫升三乙胺，80℃條件下攪拌1小時。反應結束後，冷卻到室溫，濃縮，用層析矽膠(二氯甲烷/甲醇=50/1)分離得黃色固體產物，658毫克，收率：99%。MS(m/z)：330(M+1)⁺ 。2,6-Dichloro-3-nitro-4-aminopyridine (624 mg, 3 mmol) and quinoline 6-methylamine (316 mg, 2 mmol) were dissolved in 10 ml of acetonitrile. It was added with 1 ml of triethylamine and stirred at 80 ° C for 1 hour. After completion of the reaction, it was cooled to room temperature, concentrated, and then purified, mjjjjjjj MS (m/z): 330 (M + 1) ⁺ .

化合物262-bCompound 262-b

將262-a(658毫克，2毫莫耳)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1氫-吡唑(500毫克，2.4毫莫耳)和碳酸鈉(424毫克，4毫莫耳)在20毫升的二氧六環和2毫升水中混合，氮氣置換後加入Pd(dppf)Cl₂ (163毫克，0.2毫莫耳)，氮氣置換三次，氮氣保護下，於100℃攪拌過夜。反應結束後，冷卻到室溫，用柱層析(水/甲醇=100：0到0：100)純化得到黃色固體，300毫克，40%。MS(m/z)：376(M+1)⁺ 。262-a (658 mg, 2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1 hydrogen-pyrazole (500 mg, 2.4 mmol) and sodium carbonate (424 mg, 4 mmol) in 20 ml of dioxane and 2 ml of water, after nitrogen replacement, add Pd (dppf) Cl ₂ (163 mg, 0.2 mmol) was replaced with nitrogen three times and stirred at 100 ° C overnight. After completion of the reaction, it was cooled to room temperature and purified by column chromatography (water/methanol=100:0 to 0:100) to yield a yellow solid, 300 mg, 40%. MS (m/z): 376 (M + 1) ⁺ .

化合物262-cCompound 262-c

冰浴條件下，將262-b(260毫克，0.69毫莫耳)加入到HBF₄ (5毫升)中，然後向其滴加0.5毫升的亞硝酸鈉(96毫克，1.4毫莫耳)水溶液，0℃攪拌過夜。反應結束後，加入飽和碳酸氫鈉水溶液調到pH=8，有固體析出，過濾，所得到黃色固體經柱層析(水/甲醇=100：0到0：100)純化得產物200毫克，收率：77%。MS(m/z)：377(M+1)⁺ 。262-b (260 mg, 0.69 mmol) was added to HBF ₄ (5 ml) under ice-cooling, and then 0.5 ml of aqueous sodium nitrite (96 mg, 1.4 mmol) was added dropwise. Stir at 0 ° C overnight. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to adjust to pH=8, and a solid was precipitated and filtered, and the obtained yellow solid was purified by column chromatography (water/methanol=100:0 to 0:100) to obtain 200 mg of product. Rate: 77%. MS (m/z): 377 (M + 1) ⁺ .

化合物262-dCompound 262-d

將262-c(200毫克，0.53毫莫耳)溶解在10毫升的甲醇中，加入10%Pd/C(20毫克，0.1當量)，氫氣環境下，室溫攪拌1小時。反應結束後，過濾除去Pd/C，濾液濃縮得產物，170毫克，收率：92.3%，直接用於下步反應。MS(m/z)：347(M+1)⁺ 。262-c (200 mg, 0.53 mmol) was dissolved in 10 ml of methanol, and 10% Pd/C (20 mg, 0.1 eq.) was added, and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. After completion of the reaction, Pd/C was removed by filtration, and the filtrate was concentrated to give a product (yield: 92.3%). MS (m/z): 347 (M + 1) ⁺ .

化合物262Compound 262

將262-d(170毫克，0.49毫莫耳)溶解在3毫升醋酸和3毫升水中，0℃條件下滴加0.3毫升的亞硝酸鈉(69毫克，10毫莫耳)水溶液(0.3毫升)，然後於0℃攪拌1小時。反應結束後，用30%氫氧化鈉水溶液調pH到8，析出的黃色固體，過濾，濾餅經柱層析純化得到產物120毫克，收率：33.6%。MS(m/z)：358(M+1)⁺ 。262-d (170 mg, 0.49 mmol) was dissolved in 3 ml of acetic acid and 3 ml of water, and 0.3 ml of an aqueous solution of sodium nitrite (69 mg, 10 mmol) (0.3 ml) was added dropwise at 0 °C. It was then stirred at 0 ° C for 1 hour. After the completion of the reaction, the pH was adjusted to 8 with a 30% aqueous sodium hydroxide solution, and a white solid which precipitated was filtered, and the filter cake was purified by column chromatography to give the product 120 mg, yield: 33.6%. MS (m/z): 358 (M + 1) ⁺ .

實施例263Example 263

將化合物262(120毫克，0.336毫莫耳)溶解在三氯氧磷中，於1100℃攪拌1小時。反應結束後，用NaHCO₃ 溶液到將pH調節到8，用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，濃縮，經柱層析純化得到產物，25毫克，收率：19.9%。MS：376(M+1)⁺ 。Compound 262 (120 mg, 0.336 mmol) was dissolved in phosphorus oxychloride and stirred at 1100 ° C for 1 hour. After completion of the reaction, the pH was adjusted to 8 with NaHCO ₃ solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the product, 25 mg, yield: 19.9%. MS: 376 (M+1) ⁺ .

實施例264Example 264

化合物264-aCompound 264-a

將2,6-二氯-3-硝基-4-氨基吡啶(832毫克，4毫莫耳)溶解在10毫升的二氯甲烷中，加入DMAP(48毫克，0.4毫莫耳)，接著加入(Boc)₂ O(1.0克，4.6毫莫耳)，然後室溫下攪拌2小時。反應結束後，濃縮，殘餘物用層析矽膠柱(石油醚/乙酸乙酯=50/1)純化得到固體產物1.20克，收率為97.4%。2,6-Dichloro-3-nitro-4-aminopyridine (832 mg, 4 mmol) was dissolved in 10 mL of dichloromethane, DMAP (48 mg, 0.4 mmol) was added and then added (Boc) ₂ O (1.0 g, 4.6 mmol), then stirred at room temperature for 2 hours. After completion of the reaction, the mixture was evaporated. mjjjjjjj

化合物264-bCompound 264-b

在264-a(1.2克，3.9莫耳)和6-氨甲基喹啉(616毫克，3.9毫莫耳)的乙腈(15毫升)溶液中，加入1毫升三乙胺，80℃攪拌1小時。反應結束後，冷卻到室溫，用矽膠層析柱(二氯甲烷/甲醇=50/1)純化得到黃色固體1.6克，收率為95.6%。MS(m/z)：430(M+1)⁺ 。In a solution of 264-a (1.2 g, 3.9 mol) and 6-aminomethylquinoline (616 mg, 3.9 mmol) in acetonitrile (15 ml), 1 ml of triethylamine was added and stirred at 80 ° C for 1 hour. . After completion of the reaction, it was cooled to room temperature and purified by a silica gel chromatography column (dichloromethane/methanol = 50/1) to yield 1.6 g of a yellow solid. MS (m/z): 430 (M + 1) ⁺ .

化合物264-cCompound 264-c

將264-b(860毫克，2毫莫耳)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1氫-吡唑(416毫克，2毫莫耳)和碳酸鈉(424毫克，4毫莫耳)混合在20毫升的二氧六環和2毫升水中，氮氣置換後，向其加入Pd(dppf)Cl₂ (163毫克，0.2毫莫耳)，然後在氮氣保護下於100℃攪拌過夜。反應結束後，冷卻至室溫，濃縮，殘餘物用柱層析純化得到產物950毫克，收率為100%。MS(m/z)：476(M+1)⁺ 。264-b (860 mg, 2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1 Hydrogen-pyrazole (416 mg, 2 mmol) and sodium carbonate (424 mg, 4 mmol) were mixed in 20 ml of dioxane and 2 ml of water. After nitrogen replacement, Pd was added thereto. (dppf) Cl ₂ (163 mg, 0.2 mmol), then stirred at 100 ° C overnight under nitrogen. After completion of the reaction, it was cooled to room temperature, concentrated, and the residue was purified by column chromatography. MS (m/z): 476 (M + 1) ⁺ .

化合物264-dCompound 264-d

將264-c(950毫克，2毫莫耳)溶解在10毫升的甲醇中，加入10%Pd/C(95毫克，0.1當量)，在氫氣下，室溫攪拌1小時。反應結束後，過濾除去Pd/C，濾液濃縮，得到產物，直接用於下步反應。MS(m/z)：446(M+1)⁺ 。264-c (950 mg, 2 mmol) was dissolved in 10 mL of methanol, and 10% Pd/C (95 mg, 0.1 eq.) was added. After completion of the reaction, Pd/C was removed by filtration, and the filtrate was concentrated to give a product which was directly used for the next step. MS (m/z): 446 (M + 1) ⁺ .

化合物264Compound 264

將264-d(890毫克，2毫莫耳)加入到醋酸(95毫升)和水(5毫升)的混合溶液中，冷卻到0℃，向其滴加溶解在0.5毫升水中的亞硝酸鈉(300毫克，4毫莫耳)，0℃下攪拌1小時。反應結束後，用30%氫氧化鈉調pH=8，過濾得到黃色固體，抽乾，濾餅溶解在三氟醋酸(3毫升)中，再室溫攪拌1小時，然後加碳酸鈉水溶液調到pH=7，濃縮後用柱層析純化得到產物190毫克，收率為26.7%。MS：357(M+1)⁺ 。264-d (890 mg, 2 mmol) was added to a mixed solution of acetic acid (95 ml) and water (5 ml), cooled to 0 ° C, and sodium nitrite dissolved in 0.5 ml of water was added dropwise thereto ( 300 mg, 4 mmol, and stirred at 0 ° C for 1 hour. After the reaction was completed, the pH was adjusted to pH=8 with 30% sodium hydroxide, and filtered to give a yellow solid, which was dried, and the filtered cake was dissolved in trifluoroacetic acid (3 ml), and then stirred at room temperature for 1 hour, then adjusted with sodium carbonate aqueous solution After pH=7, it was concentrated and purified by column chromatography to yield 190 mg of product. MS: 357 (M + 1) ⁺ .

實施例265至272分別見前面的化合物265至272。Examples 265 to 272 are respectively seen in the foregoing compounds 265 to 272.

實施例273用Tanscreener FP方法測定c-met抑制劑對酶活的抑制作用Example 273 Determination of inhibition of enzyme activity by c-met inhibitors by the Tanscreener FP method

試劑與材料Reagents and materials

Transcreenen^TM KINASE Assy kit: Bellbrook Labs.，3003-10K；重組人c-Met激酶：Invitrogen，PV3143；Poly E4Y(酶促反應底物肽)：Sigma,P0275；5毫克/毫升，溶於MilliQ水；酶促反應緩衝液：67mM HEPES、0.013% Triton X-100、27mM MgCl₂ 、0.67mM MnCl₂ 、1.25mM DTT、PH 7.4；10mM ATP：Invitrogene，PV3227；500mM EDTA：Invitrogene，15575-038；Greiner 96孔黑板：Greiner，675076；Transcreenen ^TM KINASE Assy kit: Bellbrook Labs., 3003-10K; recombinant human c-Met kinase: Invitrogen, PV3143; Poly E4Y (enzymatic reaction substrate peptide): Sigma, P0275; 5 mg/ml, dissolved in MilliQ water; Enzymatic reaction buffer: 67 mM HEPES, 0.013% Triton X-100, 27 mM MgCl ₂ , 0.67 mM MnCl ₂ , 1.25 mM DTT, pH 7.4; 10 mM ATP: Invitrogene, PV3227; 500 mM EDTA: Invitrogene, 15575-038; Greiner 96 Hole Blackboard: Greiner, 675076;

配製反應液Preparation of reaction solution

化合物稀釋：將待測化合物3倍梯度稀釋到含有20% DMSO的去離子水中；配製酶/底物緩衝液：將重組人c-Met激酶和反應底物Poly E4Y一起稀釋在酶促反應緩衝液中。其終濃度分別為：c-Met(0.5微克/毫升)、Poly E4Y(62.5微克/毫升)。在使用前將酶/底物緩衝液置於冰面上預冷；配製ATP稀釋液：將10mM的ATP溶液稀釋於酶促反應緩衝液中，其終濃度為：25μM；配製ADP稀釋液：將500μM的ADP溶液稀釋於酶促反應緩衝液中，其終濃度為：25μM；按下表配製標準曲線溶液：Compound dilution: 3-fold gradient dilution of test compound into deionized water containing 20% DMSO; preparation of enzyme/substrate buffer: dilution of recombinant human c-Met kinase and reaction substrate Poly E4Y in enzymatic reaction buffer in. The final concentrations were: c-Met (0.5 μg/ml) and Poly E4Y (62.5 μg/ml). Pre-cool the enzyme/substrate buffer on ice before use; prepare ATP dilution: dilute 10 mM ATP solution in enzymatic reaction buffer to a final concentration of 25 μM; prepare ADP dilution: The 500 μM ADP solution was diluted in the enzymatic reaction buffer to a final concentration of 25 μM; the standard curve solution was prepared as follows:

酶促反應Enzymatic reaction

在96孔黑板相應的孔中分別加入5μL稀釋好的待測化合物或對照溶液(其中陽性對照孔加入5μL 20%DMSO；陰性對照孔加入5μL 500mM EDTA)；在各孔中加入10μL酶/底物緩衝液；在各孔中加入10μL ATP稀釋液以啟動酶促反應，暫態振盪反應板；在標準曲線所在孔中依次加入5μL 20%DMSO，10μL酶促反應緩衝液和10μL ATP標準曲線溶液；28℃下反應45分鐘，期間輕微搖動反應板。Add 5 μL of the diluted test compound or control solution to the corresponding wells of the 96-well blackboard (in which 5 μL of 20% DMSO was added to the positive control wells; 5 μL of 500 mM EDTA was added to the negative control wells); 10 μL of enzyme/substrate was added to each well. Buffer; 10 μL of ATP dilution was added to each well to initiate the enzymatic reaction, and the reaction plate was transiently shaken; 5 μL of 20% DMSO, 10 μL of enzymatic reaction buffer and 10 μL of ATP standard curve solution were sequentially added to the wells of the standard curve; The reaction was carried out at 28 ° C for 45 minutes while the reaction plate was shaken slightly.

中止酶反應並檢測ADPStop the enzyme reaction and detect ADP

配製ADP檢測液：將ADP Alexa633 tracer(1：100)，ADP抗體(1：158)，和中止及檢測緩衝液(1：10)按比例稀釋於去離子水中；配製含遊離Tracer的對照溶液：將ADP Alexa633 tracer(1：100)，和中止及檢測緩衝液(1：10)按比例稀釋於去離子水中；配製不含Tracer的對照溶液：將中止及檢測緩衝液(1：10)按比例稀釋於去離子水中；在28℃下反應1小時，期間輕微搖動反應板；在TECAN F500上檢測各孔的偏振螢光值。激發光：610奈米，散發光：670奈米。Prepare the ADP test solution: Dilute ADP Alexa633 tracer (1:100), ADP antibody (1:158), and stop and assay buffer (1:10) in deionized water; prepare a control solution containing free Tracer: Dilute ADP Alexa633 tracer (1:100), and stop and assay buffer (1:10) in deionized water; prepare a control solution without Tracer: proportional to stop and assay buffer (1:10) Dilute in deionized water; react at 28 ° C for 1 hour with gentle shaking of the reaction plate; detect the polarization fluorescence value of each well on TECAN F500. Excitation light: 610 nm, scattered light: 670 nm.

資料分析date analyzing

其中：among them:

藥物孔的ADP濃度是指含有待測藥物的孔的ADP濃度。The ADP concentration of the drug well refers to the ADP concentration of the well containing the drug to be tested.

陽性對照孔的ADP濃度是指含有20% DMSO的孔的ADP濃度。The ADP concentration of the positive control well refers to the ADP concentration of the well containing 20% DMSO.

ADP濃度是根據標準曲線得出的ADP濃度與毫偏值(mP)間的轉換公式將每孔的毫偏值換算為ADP濃度。而毫偏值的確定是根據每孔讀出的偏振光值按照試劑盒說明書提供的公式換算而得出，具體的計算公式可參看BellBrook Lab.的網站(www.bellbrooklabs.com)。The ADP concentration is a conversion formula between the ADP concentration and the milli-bias (mP) obtained from the standard curve, and the milli-bias value per well is converted into the ADP concentration. The determination of the partial bias value is based on the polarization value read out per well according to the formula provided in the kit manual. The specific calculation formula can be found on the website of BellBrook Lab. (www.bellbrooklabs.com).

應用XL-Fit 2.0軟體計算IC50值。IC50 values were calculated using XL-Fit 2.0 software.

實驗結果：大部分(約85%)化合物的IC50值(包括估計的和測量的)在0.001至1 μM之間，其他的大於1μM。Experimental results: Most (about 85%) of the compounds have IC50 values (both estimated and measured) between 0.001 and 1 μM, others greater than 1 μM.

Claims (35)

一種結構式1的化合物： 或其藥學上可接受的鹽，其中X是N；Y選自-O-、-S-或-N(R⁷ )-；R¹ 選自芳基和芳雜環基，芳基和芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、C_1-4 烷基、羥基取代的C_1-4 烷基、C_1-4 烷氧基取代的C_1-4 烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、及-S(O)_n NR¹³ R¹⁴ 中的一個或多個基團所取代；或者X是N；Y不存在；以及R¹ 是稠合的雙環芳雜環基，稠合的雙環芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、C_1-4 烷基、羥基取代的C_1-4 烷基、C_1-4 烷氧基取代的C_1-4 烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、及-S(O)_n NR¹³ R¹⁴ 中的一個或多個基團所取代；或者X是C(R⁶ )；Y是-O-、-S-或-N(R⁷ )-、或者不存在；R¹ 是芳雜環基，芳雜環基可以任選地被鹵素、-CF₃ 、-CF₂ H、C_1-4 烷基、羥基取代的C_1-4 烷基、C_1-4 烷氧基取代的C_1-4 烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-NR¹³ R¹⁴ 、-NO₂ 、 -S(O)_n R¹² 、及-S(O)_n NR¹³ R¹⁴ 中的一個或多個基團所取代；R² 和R³ 獨立地選自氫和C_1-10 烷基，或者R² 和R³ 及它們所連接的碳原子一起形成一個3至7元的環烷基或雜環烷基；R⁴ 選自C_1-10 烷基、C_3-12 環烷基、雜環、芳基和芳雜環基，任何一個C_1-10 烷基、C_3-12 環烷基、雜環、芳基和芳雜環基可以任選地被一個或多個基團取代，這些基團選自：C_1-4 烷烴，其可以任選地被選自羥基、C_1-4 烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 、-NR¹³ S(O)_n R¹² 、-NR¹³ S(O)_n NR¹³ R¹⁴ 、-NR¹³ C(O)OR¹² 和-NR¹³ C(O)NR¹³ R¹⁴ 中的一個或多個基團所取代；C_1-4 烷氧基，其可以任選地被選自鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；環烷氧基，其可以任選地被選自鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；雜環烷氧基，其可以任選地被選自鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；雜環，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；芳雜環氧基，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；芳基，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代； 芳雜環基，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ ；R⁵ 選自氫、鹵素、CF₃ 、-CF₂ H和C_1-10 烷基；R⁶ 選自氫、-OH、-NH₂ 、-NHC(O)R¹¹ 、鹵素和C_1-10 烷基；R⁷ 選自氫和C_1-4 烷基；n各自獨立地是0、1或者2；R¹¹ 、R¹² 、R¹³ 和R¹⁴ 各自獨立地選自於氫、C_1-10 烷基、C_3-12 環烷基、芳基、芳雜環基和雜環，除氫外，每一個基團可任選地被選自鹵素、C_1-4 烷基、羥基和C_1-4 烷氧基中的一個或多個基團所取代；或者R¹³ 和R¹⁴ 及他們所連接的氮原子一起形成一個雜環，該雜環含有一個或多個包括-O-、-S-和-N(R¹⁵ )-在內的雜原子，同時雜環又可以任選地被選自鹵素、C_1-4 烷基、羥基和C_1-4 烷氧基中的一個或多個基團所取代；以及R¹⁵ 選自氫和C_1-4 烷基；條件是：R¹ 不是經取代或非經取代苯基或4-吡啶基；當X是N；R² 是氫或甲基；R³ 和R⁵ 是氫；並且Y不存在時；那麼R¹ 不是喹啉-6-基、7-氟喹啉-6-基、3-喹唑啉-6-基、2，3-二氫苯並呋喃-5-基或2，3-二氫苯並二氧六環-6-基；以及 當X是N；R² 、R³ 和R⁵ 是氫；Y是-O-或-N(R⁷ )-；R¹ 是喹啉-6-基、7-氟喹啉-6-基、3-喹唑啉-6-基、2，3-二氫苯並呋喃-5-基或2，3-二氫苯並二氧六環-6-基時；R⁴ 是可以被任選取代的芳雜環基。A compound of formula 1: Or a pharmaceutically acceptable salt thereof, wherein X is N; Y is selected from -O-, -S- or -N(R ⁷ )-; R ^{1 is} selected from aryl and aromatic heterocyclic groups, aryl and aromatic cycloalkyl groups may be optionally substituted with _{halogen, -CF 3, -CF 2 H,} C 1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _1-4 alkoxy substituted C _1-4 alkyl , -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , and -S(O) _n NR ¹³ R ¹⁴ Substituting one or more of the groups; or X is N; Y is absent; and R ¹ is a fused bicyclic aromatic heterocyclic group, and the fused bicyclic aromatic heterocyclic group may be optionally halogen, -CF ₃ , -CF ₂ H, C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, C _1-4 alkoxy substituted C _1-4 alkyl, -C(O)R ¹¹ , -C Substituting one or more groups of (O)OR ¹¹ , -CN, -NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , and -S(O) _n NR ¹³ R ¹⁴ ; Or X is C(R ⁶ ); Y is -O-, -S- or -N(R ⁷ )-, or is absent; R ¹ is an aromatic heterocyclic group, and the aromatic heterocyclic group may be optionally halogen, -CF ₃ , -CF ₂ H, C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl, C _1-4 alkoxy-substituted C _1-4 alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -C Substituting one or more groups of N, -NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , and -S(O) _n NR ¹³ R ¹⁴ ; R ² and R ³ independently Selected from hydrogen and C _1-10 alkyl, or R ² and R ³ together with the carbon atom to which they are attached form a 3 to 7 membered cycloalkyl or heterocycloalkyl group; R ^{4 is} selected from C _1-10 alkane a C _3-12 cycloalkyl group, a heterocyclic ring, an aryl group and an aromatic heterocyclic group, any one of a C _1-10 alkyl group, a C _3-12 cycloalkyl group, a heterocyclic ring, an aryl group and an aromatic heterocyclic group Optionally substituted with one or more groups selected from: C _1-4 alkanes, which may optionally be selected from the group consisting of hydroxyl, C _1-4 alkoxy, CN, halogen, -C(O) OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR Substituting one or more groups of ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; C _1-4 alkoxy , which may be optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy and C _1-4 alkoxy; cycloalkoxy, which may be optionally selected from the group consisting of halogen, hydroxy and C _{1 -4} alkoxy groups with one or more substituted; heterocycloalkyl Group, which may optionally be substituted selected from halogen, hydroxyl and C _1-4 alkoxy groups with one or more groups; heterocyclic ring which may optionally be selected from C _1-4 alkyl, Substituted by one or more of a halogen, a hydroxyl group and a C _1-4 alkoxy group; an aromatic heterocyclic oxy group which may be optionally selected from C _1-4 alkyl, halogen, hydroxy and C _1- Substituted by one or more of the ₄ alkoxy groups; an aryl group, which may optionally be selected from one or more selected from the group consisting of C _1-4 alkyl, halogen, hydroxy, and C _1-4 alkoxy Substituted by a group; an aromatic heterocyclic group which may be optionally substituted by one or more groups selected from the group consisting of C _1-4 alkyl, halogen, hydroxy and C _1-4 alkoxy; halogen; ;;C(O)R ¹¹ ;-C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-C(O) NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ ; R ^{5 is} selected from the group consisting of hydrogen, halogen, CF ₃ , -CF ₂ H and C _1-10 alkyl; ^{6 is} selected from the group consisting of hydrogen, -OH, -NH ₂ , -NHC(O)R ¹¹ , halogen and C _1-10 alkyl; R ^{7 is} selected from hydrogen and C _1-4 alkyl; n is independently 0, 1 Or 2; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently selected From hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, aryl, heteroheterocyclyl and heterocyclic, each group may be optionally selected from halogen, C _1- except for hydrogen. ₄ alkyl, hydroxy and C _1-4 alkoxy groups with one or more substituted; together form a heterocyclic ring or R ¹³ and R ¹⁴ and the nitrogen atom to which they are attached, the heterocyclic ring containing one or more a hetero atom including -O-, -S-, and -N(R ¹⁵ )-, wherein the heterocyclic ring may be optionally selected from the group consisting of halogen, C _1-4 alkyl, hydroxy, and C _1-4 alkane. Substituting one or more groups in the oxy group; and R ^{15 is} selected from hydrogen and C _1-4 alkyl; provided that R ¹ is not substituted or unsubstituted phenyl or 4-pyridyl; when X is N; R ² is hydrogen or methyl; R ³ and R ⁵ are hydrogen; and when Y is absent; then R ¹ is not quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quinazoline -6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodiox-6-yl; and when X is N; R ² , R ³ and R ⁵ Is hydrogen; Y is -O- or -N(R ⁷ )-; R ¹ is quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quinazolin-6-yl, 2,3 -dihydrobenzofuran-5-yl or 2,3-dihydrobenzodioxan-6-yl R ⁴ is an aromatic heterocyclic group which may be optionally substituted. 如請求項1所述的化合物或其藥學上可接受的鹽，其中X為N。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N. 如請求項1所述的化合物或其藥學上可接受的鹽，其中X為C(R⁶ )。The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C(R ⁶ ). 如請求項3所述的化合物或其藥學上可接受的鹽，其中R⁶ 選自氫和C_1-4 烷基。The compound of claim 3, wherein R ^{6 is} selected from the group consisting of hydrogen and C _1-4 alkyl, or a pharmaceutically acceptable salt thereof. 如請求項4所述的化合物或其藥學上可接受的鹽，其中R⁶ 為氫。The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中Y為-O-。 The compound of any one of claims 1 to 5, wherein Y is -O-, or a pharmaceutically acceptable salt thereof. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中Y為-S-。 The compound of any one of claims 1 to 5, wherein Y is -S-, or a pharmaceutically acceptable salt thereof. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中Y為-N(R⁷ )-。The compound of any one of claims 1 to 5, wherein Y is -N(R ⁷ )-, or a pharmaceutically acceptable salt thereof. 如請求項8所述的化合物或其藥學上可接受的鹽，其中R⁷ 為氫或甲基。The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen or methyl. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中Y不存在。 The compound of any one of claims 1 to 5, wherein Y is absent, or a pharmaceutically acceptable salt thereof. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中R¹ 是8至10元芳雜環基，芳雜環基可以任選地被選自鹵素、-CF₃ 、-CF₂ H、C_1-4 烷基、羥基取代的 C_1-4 烷基、C_1-4 烷氧基取代的C_1-4 烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 和-S(O)_n NR¹³ R¹⁴ 中的一個或者多個基團所取代。The compound of any one of claims 1 to 5, wherein R ¹ is an 8- to 10-membered aromatic heterocyclic group, and the aryl-heterocyclic group may be optionally selected from the group consisting of halogen, CF ₃ , -CF ₂ H, C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl, C _1-4 alkoxy-substituted C _1-4 alkyl, -C(O)R ¹¹ ,- One or more groups of C(O)OR ¹¹ , -CN, -NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² and -S(O) _n NR ¹³ R ¹⁴ are substituted. 如請求項11所述的化合物或其藥學上可接受的鹽，其中R¹ 選自以下的芳雜環基： 其中任何一個芳雜環可以任選地被選自鹵素、-CF₃ 、-CF₂ H、C_1-4 烷基、羥基取代的C_1-4 烷基、C_1-4 烷氧基取 代的C_1-4 烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 和-S(O)_n NR¹³ R¹⁴ 中的一個或者多個基團所取代。The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of the following aromatic heterocyclic groups: Any one of the aromatic heterocyclic rings may be optionally substituted by a halogen, -CF ₃ , -CF ₂ H, a C _1-4 alkyl group, a hydroxy-substituted C _1-4 alkyl group, a C _1-4 alkoxy group. C _1-4 alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² and -S(O) Substituting one or more groups of _n NR ¹³ R ¹⁴ . 如請求項12所述的化合物或其藥學上可接受的鹽，其中R¹ 為選自以下的環系統： 其中各環系統可以任選地被鹵素、-CF₃ 、-CF₂ H、C_1-4 烷基、羥基取代的C_1-4 烷基、C_1- 4烷氧基取代的C_1-4 烷基、-C(O)R¹¹ 、-C(O)OR¹¹ 、-CN、-NR¹³ R¹⁴ 、-NO₂ 、-S(O)_n R¹² 、-S(O)_n NR¹³ R¹⁴ 中的一個或多個基團所取代。The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a ring system selected from the group consisting of: Wherein each ring system may be optionally substituted with _{halogen, -CF 3, -CF 2 H,} C 1-4 alkyl, hydroxy substituted C _1-4 alkyl, substituted C _1- 4 alkoxy C _1-4 Alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R One or more of the groups of ¹⁴ are substituted. 如請求項12所述的化合物或其藥學上可接受的鹽，其中R¹ 選自以下的芳雜環： The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of the following aromatic heterocycles: 如請求項14所述的化合物或其藥學上可接受的鹽，其中R¹ 為選自以下環系統 The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of the following ring systems 如請求項15所述的化合物或其藥學上可接受的鹽，其中R¹ 為 The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R ¹ is 如請求項15所述的化合物或其藥學上可接受的鹽，其中R¹ 為 The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R ¹ is 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中R² 和R³ 獨立地選自氫和C₁ -C₆ 的烷基；或者R² 和R³ 及他們所連接的碳原子一起形成一個環丙基。The compound of any one of claims 1 to 5, wherein R ² and R ^{3 are} independently selected from hydrogen and C ₁ -C ₆ alkyl; or R ² and R ³ , or a pharmaceutically acceptable salt thereof Together with the carbon atoms to which they are attached, they form a cyclopropyl group. 如請求項18所述的化合物或其藥學上可接受的鹽，其中R² 為氫且R³ 選自氫或甲基。The compound of claim 18 or a pharmaceutically acceptable salt thereof request entries, wherein R ² is hydrogen and R ³ is selected from hydrogen or methyl. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中R⁵ 為氫。The compound of any one of claims 1 to 5, wherein R ⁵ is hydrogen, or a pharmaceutically acceptable salt thereof. 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中R⁴ 是芳基，所述的芳基可以任選地被一個或多個基團取代，這些基團選自：C_1-4 烷基，其可以任選地被選自羥基、C_1-4 烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 和-NR¹³ S(O)_n R¹² 中的一個或多個基團所取代；C_1-4 烷氧基，其可以任選地被鹵素、羥基和C_1-4 烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自C_1-4 烷基、鹵素、羥基 和C_1-4 烷氧基中的一個或多個基團所取代；芳雜環氧基，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；芳基，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；芳雜環基，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。The compound of any one of claims 1 to 5, wherein R ⁴ is an aryl group, and the aryl group may be optionally substituted by one or more groups, such a group, or a pharmaceutically acceptable salt thereof The group is selected from: C _1-4 alkyl, which may be optionally selected from the group consisting of hydroxyl, C _1-4 alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ and -NR ¹³ S(O) _n R ¹² ; C _1-4 An alkoxy group which may be optionally substituted by one or more of a halogen, a hydroxyl group and a C _1-4 alkoxy group; a heterocyclic ring which may optionally be selected from a C _1-4 alkyl group, a halogen Substituted by one or more of the hydroxy group and the C _1-4 alkoxy group; an aromatic heterocyclic oxy group which may be optionally selected from the group consisting of C _1-4 alkyl, halogen, hydroxy and C _1-4 Substituted by one or more groups in the alkoxy group; an aryl group, which may optionally be selected from one or more of the group consisting of C _1-4 alkyl, halogen, hydroxy, and C _1-4 alkoxy radical substituted; aromatic heterocyclic group which may optionally be selected from C _1-4 alkyl, halo, hydroxy and C _1-4 alkoxy one or more groups Generation; halogen; ^{cyano; -C (O) R 11;} -C (O) OR 11; -NR 13 R 14; -NR 13 C (O) R 11; -NR 13 S (O) n R 12; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ . 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中R⁴ 是雜環，其任選地被一個或多個基團取代，這些基團選自：C_1-4 烷基，其可以任選地被選自羥基、C_1-4 烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 和-NR¹³ S(O)_n R¹² 中的一個或多個基團所取代；C_1-4 烷氧基，其可以隨機的被鹵素、羥基和C_1-4 烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。The compound of any one of claims 1 to 5, wherein R ⁴ is a heterocyclic ring, which is optionally substituted by one or more groups selected from the group consisting of: C, or a pharmaceutically acceptable salt thereof. _{a 1-4} alkyl group which may be optionally selected from the group consisting of hydroxyl, C _1-4 alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ^{14, -OC (O) R 11} , -NR 13 C (O) R 11 and -NR ¹³ S (O) _n R ¹² in one or more substituted groups; C _1-4 alkoxy which It may be randomly substituted with one or more of a halogen, a hydroxyl group and a C _1-4 alkoxy group; a heterocyclic ring, which may be optionally selected from a C _1-4 alkyl group, a halogen, a hydroxyl group, and a C _1- a ₄ alkoxy substituted with one or more groups; halo; ^{cyano; -C (O) R 11;} -C (O) oR 11; -NR 13 R 14; -NR 13 C (O) R ¹¹ ; -NR ¹³ S(O) _n R ¹² ; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ . 如請求項5所述的化合物或其藥學上可接受的鹽，其中R⁴ 選自吡咯-1-基、哌啶-1-基、四氫-2H-吡喃-4-基、嗎啡啉-4-基和6，7-二氫噻吩並[3,2-c]吡啶-5(4H)-基，其中任何一個基團都可以任選地被一個或者多個基團取代，這些基團選自：C_1-4 烷基，其可以任選地被選自羥基、C_1-4 烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 和-NR¹³ S(O)_n R¹² 中的一個或多個基團所取代；C_1-4 烷氧基，其可以隨機的被鹵素、羥基和C_1-4 烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)nNR¹³ R¹⁴ 。The compound of claim 5, wherein R ^{4 is} selected from pyrrol-1-yl, piperidin-1-yl, tetrahydro-2H-pyran-4-yl, morpholine, or a pharmaceutically acceptable salt thereof 4-yl and 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl, any of which may be optionally substituted by one or more groups, these groups Selected from: C _1-4 alkyl, which may be optionally selected from the group consisting of hydroxyl, C _1-4 alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , Substituting one or more groups of -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ and -NR ¹³ S(O) _n R ¹² ; C _1-4 alkane An oxy group which may be randomly substituted with one or more of a halogen, a hydroxy group and a C _1-4 alkoxy group; a heterocyclic ring which may be optionally selected from a C _1-4 alkyl group, a halogen group, a hydroxyl group And one or more groups in the C _1-4 alkoxy group; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;-NR ¹³ C (O) R ¹¹ ; -NR ¹³ S(O) _n R ¹² ;; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O)nNR ¹³ R ¹⁴ . 如請求項1至5中任一項所述的化合物或其藥學上可接受的鹽，其中R⁴ 是芳雜環基，其可以任選地被一個或多個基團取代，這些基團選自C_1-4 烷基，其可以任選地被選自羥基、C_1-4 烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 和-NR¹³ S(O)_n R¹² 中的一個或多個基團所取代；C_1-4 烷氧基，其可以隨機的被鹵素、羥基和C_1-4 烷氧 基中的一個或多個基團取代；雜環，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。The compound of any one of claims 1 to 5, wherein R ⁴ is an aromatic heterocyclic group, which may be optionally substituted by one or more groups, which are selected from the group, or a pharmaceutically acceptable salt thereof. From C _1-4 alkyl, which may be optionally selected from the group consisting of hydroxy, C _1-4 alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR Substituting one or more groups of ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ and -NR ¹³ S(O) _n R ¹² ; C _1-4 alkoxy , which may be randomly substituted with one or more of a halogen, a hydroxyl group and a C _1-4 alkoxy group; a heterocyclic ring, which may optionally be selected from a C _1-4 alkyl group, a halogen, a hydroxyl group, and a C Substituted by one or more groups in the _1-4 alkoxy group; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;-NR ¹³ C(O R ¹¹ ; -NR ¹³ S(O) _n R ¹² ; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ . 如請求項24所述的化合物或其藥學上可接受的鹽，其中R⁴ 選自1H-吡唑-1-基、1H-吡唑-3-基、1H-吡唑-4-基、1H-咪唑-1-基、1H-咪唑-4-基、噁唑-2-基、噻唑-2-基、異噁唑-3-基、異噁唑-5-基、1H-吡咯-2-基、1H-吡咯-3-基、噻吩-2-基，噻吩-3-基、吡啶-2-基、吡啶-3-基和吡啶-4-基，上述的基團可以任選地被以下一個或者多個基團取代，這些基團選自C_1-4 烷基，其可以任選地被選自羥基、C_1-4 烷氧基、CN、鹵素、-C(O)OR¹¹ 、-C(O)NR¹³ R¹⁴ 、-NR¹³ R¹⁴ 、-OC(O)R¹¹ 、-NR¹³ C(O)R¹¹ 和-NR¹³ S(O)_n R¹² 中的一個或多個基團所取代；C_1-4 烷氧基，其可以隨機的被鹵素、羥基和C_1-4 烷氧基中的一個或多個基團取代；雜環，其可以任選地被選自C_1-4 烷基、鹵素、羥基和C_1-4 烷氧基中的一個或多個基團所取代；鹵素；氰基；-C(O)R¹¹ ；-C(O)OR¹¹ ；-NR¹³ R¹⁴ ；-NR¹³ C(O)R¹¹ ；-NR¹³ S(O)_n R¹² ；-C(O)NR¹³ R¹⁴ ；-S(O)_n R¹² ；和-S(O)_n NR¹³ R¹⁴ 。The compound of claim 24, wherein R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H, or a pharmaceutically acceptable salt thereof -Imidazol-1-yl, 1H-imidazol-4-yl, oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrole-2- a group, 1H-pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, the above groups may optionally be Substituted by one or more groups selected from C _1-4 alkyl groups, which may be optionally selected from the group consisting of hydroxyl, C _1-4 alkoxy, CN, halogen, -C(O)OR ¹¹ , One or more of -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ and -NR ¹³ S(O) _n R ¹² Substituted by a group; C _1-4 alkoxy, which may be randomly substituted with one or more of a halogen, a hydroxy group and a C _1-4 alkoxy group; a heterocyclic ring, which may be optionally selected from Substituted by one or more of C _1-4 alkyl, halogen, hydroxy and C _1-4 alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; ^{-NR 13 R 14; -NR 13 C} (O) R 11; -NR 13 S (O) n R 12; -C (O) NR 13 R 14 -S (O) _n R ^12; and ^{_{-S (O) n NR 13 R}} 14. 如請求項25所述的化合物或其藥學上可接受的鹽，其中R⁴ 為1H-吡唑-4-基，其可以任選地被C_1-4 烷基取代。The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is 1H-pyrazol-4-yl, which may be optionally substituted by C _1-4 alkyl. 如請求項1所述的化合物或其藥學上可接受的鹽，其係 The compound of claim 1, or a pharmaceutically acceptable salt thereof, 如請求項1所述的化合物或其藥學上可接受的鹽，其係 The compound of claim 1, or a pharmaceutically acceptable salt thereof, 如請求項1所述的化合物或其藥學上可接受的鹽，其係選自下列結構式的化合物或其藥學上可接受的鹽： The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds of the formula: or a pharmaceutically acceptable salt thereof: 一種含有一或多種如請求項1至29中任一項所述的化合物或其藥學上可接受的鹽的組合物。 A composition comprising one or more compounds according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof. 一種如請求項1至29中任一項所述的化合物或其藥學上可接受的鹽之用途，係用於製備治療癌症的藥物。 The use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer. 如請求項31所述的用途，其中該癌症係選自肺癌、胃癌、結腸直腸癌、頭頸癌、肝癌、乳癌、腎癌及卵巢癌。 The use according to claim 31, wherein the cancer is selected from the group consisting of lung cancer, gastric cancer, colorectal cancer, head and neck cancer, liver cancer, breast cancer, kidney cancer, and ovarian cancer. 如請求項31所述的用途，其中該藥物係與另一抗腫瘤製劑併用。 The use of claim 31, wherein the drug is used in combination with another anti-tumor agent. 如請求項33所述的用途，其中該抗腫瘤製劑係紫杉萜(Docetaxel)。 The use of claim 33, wherein the anti-tumor preparation is Docetaxel. 如請求項33所述的用途，其中該抗腫瘤製劑係格非替尼(Gefitinib)。 The use of claim 33, wherein the anti-tumor preparation is Gefitinib.