HK40105408A - Tead inhibitors - Google Patents
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- HK40105408A HK40105408A HK62024093403.9A HK62024093403A HK40105408A HK 40105408 A HK40105408 A HK 40105408A HK 62024093403 A HK62024093403 A HK 62024093403A HK 40105408 A HK40105408 A HK 40105408A
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技术领域Technical Field
本发明涉及用于抑制转录增强子相关结构域(TEAD)的治疗活性化合物，以及含有这些化合物的药物组合物。所述化合物用于治疗与TEAD活性或TEAD表达增加相关的疾病或障碍，例如各种癌症和慢性疼痛。This invention relates to therapeutically active compounds for inhibiting transcription enhancer-associated domains (TEADs), and pharmaceutical compositions containing these compounds. The compounds are intended for treating diseases or disorders associated with increased TEAD activity or expression, such as various cancers and chronic pain.
背景技术Background Technology
TEA结构域转录因子(TEAD1-4)是DNA结合转录因子家族，其调节涉及细胞增殖、细胞命运、细胞分化、器官过度生长和器官再生的基因的表达。YAP和TAZ是TEAD转录共激活因子，它们可以在细胞质和细胞核之间穿梭。改变的肌动蛋白动力学和Hippo信号通路促进YAP和TAZ磷酸化、细胞质滞留和蛋白酶体降解，从而导致YAP和TAZ核水平和TEAD转录活性降低。TEA domain transcription factors (TEAD1-4) are a family of DNA-binding transcription factors whose regulation involves the expression of genes involved in cell proliferation, cell fate, cell differentiation, organ overgrowth, and organ regeneration. YAP and TAZ are TEAD transcriptional coactivators that can shuttle between the cytoplasm and the nucleus. Altered actin dynamics and the Hippo signaling pathway promote YAP and TAZ phosphorylation, cytoplasmic retention, and proteasome degradation, leading to decreased nuclear levels of YAP and TAZ and reduced TEAD transcriptional activity.
进化上保守的Hippo信号通路由大肿瘤抑制因子1/2(LATS1/2)、丝氨酸/苏氨酸激酶、不育20样激酶1/2(MST1/2)和衔接蛋白Salvador同源物1(SAV1)和MOB激酶激活因子1A/B(MOB1A/B)组成。肿瘤抑制神经纤维瘤蛋白2(NF2)(也称为Merlin)参与这些激酶的上游，通过促进通路的激活来抑制YAP和TAZ活性。Hippo通路与肿瘤发生的许多方面有关，包括细胞增殖、细胞分化、癌症转移和癌症治疗抗性。因此，Hippo通路信号传导的失调已显示驱动各种癌症类型的肿瘤发生。亦有报道指出，YAP和TAZ是慢性疼痛，例如慢性神经性疼痛和慢性肌肉骨骼痛的发病机理的核心机制。The evolutionarily conserved Hippo signaling pathway consists of large tumor suppressor 1/2 (LATS1/2), serine/threonine kinases, sterility 20-like kinase 1/2 (MST1/2), and adaptor proteins Salvador homolog 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B). The tumor suppressor neurofibromatosis protein 2 (NF2) (also known as Merlin) is involved upstream of these kinases, inhibiting YAP and TAZ activity by promoting pathway activation. The Hippo pathway is involved in many aspects of tumorigenesis, including cell proliferation, cell differentiation, cancer metastasis, and cancer treatment resistance. Therefore, dysregulation of Hippo pathway signaling has been shown to drive tumorigenesis in various cancer types. YAP and TAZ have also been reported as core mechanisms in the pathogenesis of chronic pain, such as chronic neuropathic pain and chronic musculoskeletal pain.
具有TEAD抑制活性的化合物已经公开在例如WO 2020/081572、WO 2020/070181和WO 2020051099中。TEAD抑制剂K-975在体内对恶性胸膜间皮瘤的抗肿瘤作用已在Am JCancer Res，2020；10(12)：4399-4415中报道。Compounds with TEAD inhibitory activity have been disclosed, for example, in WO 2020/081572, WO 2020/070181 and WO 2020051099. The in vivo antitumor activity of the TEAD inhibitor K-975 against malignant pleural mesothelioma has been reported in Am J Cancer Res, 2020; 10(12): 4399-4415.
需要靶向与Hippo通路组分失调相关的疾病的化合物，例如靶向YAP-TEAD相互作用的化合物。这些化合物可用于治疗需要抑制TEAD的疾病或病症，例如慢性疼痛(包括神经性疼痛)和各种癌症(包括对其它治疗如化学疗法、免疫疗法和靶向疗法有抗性的癌症)。There is a need for compounds that target diseases associated with dysregulation of Hippo pathway components, such as compounds that target the YAP-TEAD interaction. These compounds could be used to treat diseases or conditions that require inhibition of TEAD, such as chronic pain (including neuropathic pain) and various cancers (including cancers resistant to other treatments such as chemotherapy, immunotherapy, and targeted therapy).
发明概述Invention Overview
已经发现式(I)的化合物是YAP-TEAD相互作用的有效抑制剂。因此，所述化合物可用于治疗需要抑制TEAD的病症和疾病。这些病症和疾病包括但不限于慢性疼痛，特别是慢性神经性疼痛和慢性肌肉骨骼疼痛，以及癌症，特别是与Hippo通路组分包括YAP-TEAD的失调相关的癌症。具体的癌症包括但不限于间皮瘤、鳞状细胞癌、妇科癌症(gynaecologicalcancer)、膀胱癌、胃癌、肝癌、肺癌和结肠癌。Compounds of formula (I) have been found to be potent inhibitors of the YAP-TEAD interaction. Therefore, these compounds can be used to treat conditions and diseases requiring inhibition of TEAD. These conditions and diseases include, but are not limited to, chronic pain, particularly chronic neuropathic pain and chronic musculoskeletal pain, and cancers, particularly those associated with dysregulation of Hippo pathway components, including YAP-TEAD. Specific cancers include, but are not limited to, mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, gastric cancer, liver cancer, lung cancer, and colon cancer.
本发明涉及式(I)的化合物或其药学上可接受的盐，This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.
其中：in:
A是吡啶基、四氢吡喃基、4-10元碳环；A is pyridyl, tetrahydropyranyl, or a 4-10 membered carbon ring;
L是-O-、-S-、-NH-、-C1-7烷基-、-C2-7烯基-、-C1-7烷基-O-、-O-C1-7烷基-或-NH-C1-7烷基-；L is -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, -OC 1-7 alkyl-, or -NH-C 1-7 alkyl-;
R1为氢、C1-7烷基、C1-7烷氧基、卤素、羟基、氰基、-C(O)NR36R37或任选取代的5-6元杂环，所述杂环具有1-3个独立地选自O、S和N的作为环原子的杂原子； R1 is a 5-6 membered heterocycle consisting of hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or optionally substituted, wherein the heterocycle has 1-3 heteroatoms independently selected from O, S, and N as ring atoms;
R2为氢、C1-7烷基、C1-7烷氧基或卤素； R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen;
R3为氢、C1-7烷基、C1-7烷氧基、卤素、卤素C1-7烷基或氰基，或R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子； R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl or cyano, or R1 and R3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
R4为氢、C1-7烷基、C1-7烷氧基、卤素、卤素C1-7烷基、卤素C1-7烷氧基、氰基或C1-7烷基羰基； R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl.
R5为氢、C1-7烷基、C1-7烷氧基、卤素、硝基、氨基、羟基、卤素C1-7烷基、卤素C1-7烷氧基，或R4和R5与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有1-3个独立地选自O、S和N的作为环原子的杂原子； R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the carbon atom to which they are attached form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms;
Z是-CH(NHR25)-(CH2)2-COOH或下式基团Z is -CH(NHR 25 )-(CH 2 ) 2 -COOH or a group of the following formula.
其中B是以下基团中的任何一个：Where B is any of the following groups:
条件是：The conditions are:
当B是环(2)时，则L是-O-或-O-C1-7烷基-，和R1是C1-7烷氧基；When B is a ring (2), then L is -O- or -OC 1-7 alkyl-, and R 1 is C 1-7 alkoxy;
当B是环(3)时，则L是-O-；When B is a ring (3), then L is -O-;
当B是环(4)时，则L是-O-和R1是C1-7烷氧基；When B is a ring (4), then L is -O- and R1 is a C1-7 alkoxy group;
当B是环(20)、(21)、(23)、(25)或(26)时，则L是-O-和R1是C1-7烷氧基；When B is a ring (20), (21), (23), (25) or (26), then L is -O- and R1 is a C1-7 alkoxy group;
当L为-C1-7烷基-O-时，则R1为C1-7烷氧基或R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子；When L is -C 1-7 alkyl-O-, then R 1 is C 1-7 alkoxy or R 1 and R 3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
当A是4-、5-、7-、8-、9-或10-元碳环时，则R1是C1-7烷氧基；When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbon ring, then R1 is a C1-7 alkoxy group;
R6和R9独立地为氢、C1-7烷基、C3-7环烷基、C3-7环烷基C1-7烷基、-C(O)-RX、C1-7烷氧基C1-7烷基、C1-7烷氧基羰基C1-7烷基、-SO2C1-7烷基、-C1-7烷基-C(O)-NR23R24或任选取代的4-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子； R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl- C1-7 alkyl, -C(O) -RX , C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxy carbonyl- C1-7 alkyl, -SO2 -C1-7 alkyl , -C1-7 alkyl -C(O) -NR23R24 or optionally substituted 4-6 membered rings having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
RX为C1-7烷基、C3-7环烷基、C1-7烷氧基C1-7烷基、C1-7烷基-NR36R37或任选取代的4-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子；R X is a C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy- C1-7 alkyl, C1-7 alkyl-NR 36 R 37 or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
R7、R8、R10、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22和R26独立地为氢、C1-7烷基、C3-7环烷基、羟基、C1-7烷氧基或C1-7烷基羰基； R7 , R8 , R10 , R12, R13 , R14 , R15 , R16 , R17 , R18 , R19 , R20 , R21 , R22 and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl , hydroxyl, C1-7 alkoxy or C1-7 alkylcarbonyl;
R11为氢、C1-7烷基、卤素C1-7烷基或C1-7烷基羰基；R 11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl;
R23、R24、R27、R28、R29、R31、R32、R33、R34、R35、R36、R37、R40、R41、R42、R43、R44和R45独立地为氢或C1-7烷基； R23 , R24 , R27 , R28 , R29 , R31 , R32 , R33 , R34 , R35 , R36 , R37 , R40 , R41 , R42 , R43 , R44 and R45 are independently hydrogen or C1-7 alkyl;
R25为C1-7烷基；R 25 is a C1-7 alkyl group;
R30为C1-7烷基、C1-7烷基羰基或-SO2C1-7烷基；R 30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO2 C1-7 alkyl;
R38为氢、C1-7烷基、C1-7烷基羰基、C1-7烷氧基C1-7烷基羰基或-C1-7烷基-C(O)-NR23R24；R 38 is hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR 23 R 24 ;
R39为氢、C1-7烷基或羟基；R 39 is hydrogen, C1-7 alkyl or hydroxyl;
其中任选的取代基，在每次出现时，是1-2个独立地选自C1-7烷基、卤素、卤素C1-7烷基、C1-7烷氧基和氧代的取代基；The optional substituents, each time appearing, are 1-2 independent substituents selected from C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy and oxo substituents;
条件是，式(I)的化合物不是：The condition is that the compound of formula (I) is not:
N-[2-甲基-3-(苯氧基甲基)苯基]-5-氧代-2-吡咯烷甲酰胺；N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-2-pyrrolidinecarboxamide;
N-[5-[(3-氟苯氧基)甲基]-2-甲氧基苯基]-1-甲基-5-氧代-2-吡咯烷甲酰胺；N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide;
N-[3-[(4-氯苯基)甲基]苯基]-5-氧代-2-吡咯烷甲酰胺；N-[3-[(4-chlorophenyl)methyl]phenyl]-5-oxo-2-pyrrolidinecarboxamide;
N-[3-[(环己氧基)甲基]苯基]-1-甲基-5-氧代-2-吡咯烷甲酰胺；N-[3-[(cyclohexyloxy)methyl]phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide;
N-[4-甲基-3-[(4-甲基-2-吡啶基)氧基]苯基]-5-氧代-2-吡咯烷甲酰胺；N-[4-methyl-3-[(4-methyl-2-pyridyl)oxy]phenyl]-5-oxo-2-pyrrolidinecarboxamide;
N-[3-(环戊基氨基)苯基]-1-甲基-5-氧代-2-吡咯烷甲酰胺；N-[3-(cyclopentylamino)phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide;
N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-6-氧代-3-哌啶甲酰胺；N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-piperidinecarboxamide;
1-乙基-5-氧代-N-(3-苯氧基苯基)-3-吡咯烷甲酰胺；1-Ethyl-5-oxo-N-(3-phenoxyphenyl)-3-pyrrolidinecarboxamide;
N-[5-[(3-氟苯氧基)甲基]-2-甲氧基苯基]-2-吡咯烷甲酰胺；N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-2-pyrrolidinecarboxamide;
1-(1-乙基丙基)-N-[5-[(3-氟苯氧基)甲基]-2-甲氧基苯基]-5-氧代-3-吡咯烷甲酰胺；1-(1-Ethylpropyl)-N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-5-oxo-3-pyrrolidinecarboxamide;
N-[3-[(4-氯苯基)甲基]苯基]-1,6-二氢-6-氧代-3-吡啶甲酰胺；N-[3-[(4-chlorophenyl)methyl]phenyl]-1,6-dihydro-6-oxo-3-pyridinecarboxamide;
1,6-二氢-N-[4-甲氧基-3-(苯基甲基)苯基]-6-氧代-3-吡啶甲酰胺；1,6-Dihydro-N-[4-methoxy-3-(phenylmethyl)phenyl]-6-oxo-3-pyridinecarboxamide;
1,6-二氢-6-氧代-N-[3-[2-(2-吡啶基)乙烯基]苯基]-3-吡啶甲酰胺；1,6-Dihydro-6-oxo-N-[3-[2-(2-pyridyl)vinyl]phenyl]-3-pyridinecarboxamide;
N-[3-[(3-氟苯氧基)甲基]苯基]-2,3-二氢-2-氧代-1H-咪唑-4-甲酰胺；N-[3-[(3-fluorophenoxy)methyl]phenyl]-2,3-dihydro-2-oxo-1H-imidazol-4-carboxamide;
1-甲基-N-[2-甲基-3-(苯氧基甲基)苯基]-5-氧代-3-吡咯烷甲酰胺；1-Methyl-N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-3-pyrrolidinecarboxamide;
N-[3-[(1,3-苯并间二氧杂环戊烯-5-基氧基)甲基]苯基]-1-(2-甲基丙基)-5-氧代-3-吡咯烷甲酰胺；N-[3-[(1,3-benzodioxacyclopenten-5-yloxy)methyl]phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide;
1,6-二氢-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-6-氧代-3-吡啶甲酰胺；1,6-Dihydro-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-pyridinecarboxamide;
N-[3-[(环己氧基)甲基]苯基]-1-乙基-5-氧代-3-吡咯烷甲酰胺；N-[3-[(cyclohexyloxy)methyl]phenyl]-1-ethyl-5-oxo-3-pyrrolidinecarboxamide;
1-甲基-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-5-氧代-3-吡咯烷甲酰胺；1-Methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-5-oxo-3-pyrrolidinecarboxamide;
2,3-二氢-3-甲基-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-2-氧代-1H-咪唑-4-甲酰胺；2,3-Dihydro-3-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazol-4-carboxamide;
2,3-二氢-1,3-二甲基-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-2-氧代-1H-咪唑-4-甲酰胺；2,3-Dihydro-1,3-dimethyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazol-4-carboxamide;
1-乙基-N-[4-甲氧基-3-(4-吡啶基甲氧基)苯基]-5-氧代-3-吡咯烷甲酰胺；1-Ethyl-N-[4-methoxy-3-(4-pyridylmethoxy)phenyl]-5-oxo-3-pyrrolidinecarboxamide;
N-[4-甲氧基-3-(4-甲氧基苯氧基)苯基]-1-(2-甲基丙基)-5-氧代-3-吡咯烷甲酰胺或N-[4-methoxy-3-(4-methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide or
6-氧代-N-(3-苯氧基苯基)-2-哌嗪甲酰胺。6-Oxo-N-(3-phenoxyphenyl)-2-piperazine carboxamide.
根据一个实施方案，本发明提供了治疗其中需要抑制TEAD的疾病或病症的方法，该方法包括向有需要的个体施用治疗有效量的式(I)化合物或其药学上可接受的盐，According to one embodiment, the present invention provides a method for treating a disease or condition in which TEAD needs to be suppressed, the method comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
其中：in:
A是吡啶基、四氢吡喃基、4-10元碳环；A is pyridyl, tetrahydropyranyl, or a 4-10 membered carbon ring;
L是-O-、-S-、-NH-、-C1-7烷基-、-C2-7烯基-、-C1-7烷基-O-、-O-C1-7烷基-或-NH-C1-7烷基-；L is -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, -OC 1-7 alkyl-, or -NH-C 1-7 alkyl-;
R1为氢、C1-7烷基、C1-7烷氧基、卤素、羟基、氰基、-C(O)NR36R37或任选取代的5-6元杂环，所述杂环具有1-3个独立地选自O、S和N的作为环原子的杂原子； R1 is a 5-6 membered heterocycle consisting of hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or optionally substituted, wherein the heterocycle has 1-3 heteroatoms independently selected from O, S, and N as ring atoms;
R2为氢、C1-7烷基、C1-7烷氧基或卤素； R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen;
R3为氢、C1-7烷基、C1-7烷氧基、卤素、卤素C1-7烷基或氰基，或R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子； R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl or cyano, or R1 and R3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
R4为氢、C1-7烷基、C1-7烷氧基、卤素、卤素C1-7烷基、卤素C1-7烷氧基、氰基或C1-7烷基羰基； R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl.
R5为氢、C1-7烷基、C1-7烷氧基、卤素、硝基、氨基、羟基、卤素C1-7烷基、卤素C1-7烷氧基，或R4和R5与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有1-3个独立地选自O、S和N的作为环原子的杂原子； R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the carbon atom to which they are attached form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms;
Z是-CH(NHR25)-(CH2)2-COOH或下式基团Z is -CH(NHR 25 )-(CH 2 ) 2 -COOH or a group of the following formula.
其中B是以下基团中的任何一个：Where B is any of the following groups:
条件是：The conditions are:
当B是环(2)时，则L是-O-或-O-C1-7烷基-，和R1是C1-7烷氧基；When B is a ring (2), then L is -O- or -OC 1-7 alkyl-, and R 1 is C 1-7 alkoxy;
当B是环(3)时，则L是-O-；When B is a ring (3), then L is -O-;
当B是环(4)时，则L是-O-和R1是C1-7烷氧基；When B is a ring (4), then L is -O- and R1 is a C1-7 alkoxy group;
当B是环(20)、(21)、(23)、(25)或(26)时，则L是-O-和R1是C1-7烷氧基；When B is a ring (20), (21), (23), (25) or (26), then L is -O- and R1 is a C1-7 alkoxy group;
当L为-C1-7烷基-O-时，则R1为C1-7烷氧基或R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子；When L is -C 1-7 alkyl-O-, then R 1 is C 1-7 alkoxy or R 1 and R 3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
当A是4-、5-、7-、8-、9-或10-元碳环时，则R1是C1-7烷氧基；When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbon ring, then R1 is a C1-7 alkoxy group;
R6和R9独立地为氢、C1-7烷基、C3-7环烷基、C3-7环烷基C1-7烷基、-C(O)-RX、C1-7烷氧基C1-7烷基、C1-7烷氧基羰基C1-7烷基、-SO2C1-7烷基、-C1-7烷基-C(O)-NR23R24或任选取代的4-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子； R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl- C1-7 alkyl, -C(O) -RX , C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxy carbonyl- C1-7 alkyl, -SO2 -C1-7 alkyl , -C1-7 alkyl -C(O) -NR23R24 or optionally substituted 4-6 membered rings having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
RX为C1-7烷基、C3-7环烷基、C1-7烷氧基C1-7烷基、C1-7烷基-NR36R37或任选取代的4-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子；R X is a C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy- C1-7 alkyl, C1-7 alkyl-NR 36 R 37 or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
R7、R8、R10、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22和R26独立地为氢、C1-7烷基、C3-7环烷基、羟基、C1-7烷氧基或C1-7烷基羰基； R7 , R8 , R10 , R12, R13 , R14 , R15 , R16 , R17 , R18 , R19 , R20 , R21 , R22 and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl , hydroxyl, C1-7 alkoxy or C1-7 alkylcarbonyl;
R11为氢、C1-7烷基、卤素C1-7烷基或C1-7烷基羰基；R 11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl;
R23、R24、R27、R28、R29、R31、R32、R33、R34、R35、R36、R37、R40、R41、R42、R43、R44和R45独立地为氢或C1-7烷基； R23 , R24 , R27 , R28 , R29 , R31 , R32 , R33 , R34 , R35 , R36 , R37 , R40 , R41 , R42 , R43 , R44 and R45 are independently hydrogen or C1-7 alkyl;
R25为C1-7烷基；R 25 is a C1-7 alkyl group;
R30为C1-7烷基、C1-7烷基羰基或-SO2C1-7烷基；R 30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO2 C1-7 alkyl;
R38为氢、C1-7烷基、C1-7烷基羰基、C1-7烷氧基C1-7烷基羰基或-C1-7烷基-C(O)-NR23R24；R 38 is hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR 23 R 24 ;
R39为氢、C1-7烷基或羟基；R 39 is hydrogen, C1-7 alkyl, or hydroxyl;
其中任选的取代基，在每次出现时，是1-2个独立地选自C1-7烷基、卤素、卤素C1-7烷基、C1-7烷氧基和氧代的取代基。The optional substituents, each time appearing, are 1-2 independent substituents selected from C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and oxo.
根据一个实施方案，其中需要抑制TEAD的疾病或病症是癌症，例如间皮瘤、鳞状细胞癌、妇科癌症、膀胱癌、胃癌、肝癌、肺癌和结肠癌。According to one implementation plan, the disease or condition for which TEAD needs to be suppressed is cancer, such as mesothelioma, squamous cell carcinoma, gynecological cancer, bladder cancer, stomach cancer, liver cancer, lung cancer, and colon cancer.
根据一个实施方案，其中需要抑制TEAD的疾病或病症是慢性疼痛，例如慢性神经性疼痛和慢性肌肉骨骼疼痛。According to one implementation plan, the disease or condition for which TEAD needs to be suppressed is chronic pain, such as chronic neuropathic pain and chronic musculoskeletal pain.
根据一个实施方案，本发明提供了一种药物组合物，其包含式(I)的化合物和药学上可接受的载体。According to one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
发明详述Invention Details
本申请提供了新的式(I)的化合物或其药学上可接受的盐，其可用作TEAD抑制剂。This application provides a novel compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be used as a TEAD inhibitor.
本发明的实施方案之一提供了式(I)的化合物或其药学上可接受的盐，One embodiment of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
其中：in:
A是吡啶基、四氢吡喃基、4-10元碳环；A is pyridyl, tetrahydropyranyl, or a 4-10 membered carbon ring;
L是-O-、-S-、-NH-、-C1-7烷基-、-C2-7烯基-、-C1-7烷基-O-、-O-C1-7烷基-或-NH-C1-7烷基-；L is -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alkenyl-, -C 1-7 alkyl-O-, -OC 1-7 alkyl-, or -NH-C 1-7 alkyl-;
R1为氢、C1-7烷基、C1-7烷氧基、卤素、羟基、氰基、-C(O)NR36R37或任选取代的5-6元杂环，所述杂环具有1-3个独立地选自O、S和N的作为环原子的杂原子； R1 is a 5-6 membered heterocycle consisting of hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, hydroxyl, cyano, -C(O)NR 36 R 37 , or optionally substituted, wherein the heterocycle has 1-3 heteroatoms independently selected from O, S, and N as ring atoms;
R2为氢、C1-7烷基、C1-7烷氧基或卤素； R2 is hydrogen, C1-7 alkyl, C1-7 alkoxy, or halogen;
R3为氢、C1-7烷基、C1-7烷氧基、卤素、卤素C1-7烷基或氰基，或R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子； R3 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl or cyano, or R1 and R3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
R4为氢、C1-7烷基、C1-7烷氧基、卤素、卤素C1-7烷基、卤素C1-7烷氧基、氰基或C1-7烷基羰基； R4 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, cyano, or C1-7 alkyl carbonyl.
R5为氢、C1-7烷基、C1-7烷氧基、卤素、硝基、氨基、羟基、卤素C1-7烷基、卤素C1-7烷氧基，或R4和R5与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有1-3个独立地选自O、S和N的作为环原子的杂原子； R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, halogen, nitro, amino, hydroxyl, halogenated C1-7 alkyl, halogenated C1-7 alkoxy, or R4 and R5 together with the carbon atom to which they are attached form an optionally substituted 5-6 membered ring having 1-3 heteroatoms independently selected from O, S and N as ring atoms;
Z是-CH(NHR25)-(CH2)2-COOH或下式基团Z is -CH(NHR 25 )-(CH 2 ) 2 -COOH or a group of the following formula.
其中B是以下基团中的任何一个：Where B is any of the following groups:
条件是：The conditions are:
当B是环(2)时，则L是-O-或-O-C1-7烷基-，和R1是C1-7烷氧基；When B is a ring (2), then L is -O- or -OC 1-7 alkyl-, and R 1 is C 1-7 alkoxy;
当B是环(3)时，则L是-O-；When B is a ring (3), then L is -O-;
当B是环(4)时，则L是-O-和R1是C1-7烷氧基；When B is a ring (4), then L is -O- and R1 is a C1-7 alkoxy group;
当B是环(20)、(21)、(23)、(25)或(26)时，则L是-O-和R1是C1-7烷氧基；When B is a ring (20), (21), (23), (25) or (26), then L is -O- and R1 is a C1-7 alkoxy group;
当L为-C1-7烷基-O-时，则R1为C1-7烷氧基或R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子；When L is -C 1-7 alkyl-O-, then R 1 is C 1-7 alkoxy or R 1 and R 3 together with the carbon atoms to which they are attached form an optionally substituted 5-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
当A是4-、5-、7-、8-、9-或10-元碳环时，则R1是C1-7烷氧基；When A is a 4-, 5-, 7-, 8-, 9-, or 10-membered carbon ring, then R1 is a C1-7 alkoxy group;
R6和R9独立地为氢、C1-7烷基、C3-7环烷基、C3-7环烷基C1-7烷基、-C(O)-RX、C1-7烷氧基C1-7烷基、C1-7烷氧基羰基C1-7烷基、-SO2C1-7烷基、-C1-7烷基-C(O)-NR23R24或任选取代的4-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子； R6 and R9 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl- C1-7 alkyl, -C(O) -RX , C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxy carbonyl- C1-7 alkyl, -SO2 -C1-7 alkyl , -C1-7 alkyl -C(O) -NR23R24 or optionally substituted 4-6 membered rings having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
RX为C1-7烷基、C3-7环烷基、C1-7烷氧基C1-7烷基、C1-7烷基-NR36R37或任选取代的4-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子；R X is a C1-7 alkyl, C3-7 cycloalkyl, C1-7 alkoxy- C1-7 alkyl, C1-7 alkyl-NR 36 R 37 or an optionally substituted 4-6 membered ring having 0-3 heteroatoms independently selected from O, S and N as ring atoms;
R7、R8、R10、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22和R26独立地为氢、C1-7烷基、C3-7环烷基、羟基、C1-7烷氧基或C1-7烷基羰基； R7 , R8 , R10 , R12, R13 , R14 , R15 , R16 , R17 , R18 , R19 , R20 , R21 , R22 and R26 are independently hydrogen, C1-7 alkyl, C3-7 cycloalkyl , hydroxyl, C1-7 alkoxy or C1-7 alkylcarbonyl;
R11为氢、C1-7烷基、卤素C1-7烷基或C1-7烷基羰基；R 11 is hydrogen, C1-7 alkyl, halogenated C1-7 alkyl, or C1-7 alkyl carbonyl;
R23、R24、R27、R28、R29、R31、R32、R33、R34、R35、R36、R37、R40、R41、R42、R43、R44和R45独立地为氢或C1-7烷基； R23 , R24 , R27 , R28 , R29 , R31 , R32 , R33 , R34 , R35 , R36 , R37 , R40 , R41 , R42 , R43 , R44 and R45 are independently hydrogen or C1-7 alkyl;
R25为C1-7烷基；R 25 is a C1-7 alkyl group;
R30为C1-7烷基、C1-7烷基羰基或-SO2C1-7烷基；R 30 is a C1-7 alkyl, C1-7 alkyl carbonyl, or -SO2 C1-7 alkyl;
R38为氢、C1-7烷基、C1-7烷基羰基、C1-7烷氧基C1-7烷基羰基或-C1-7烷基-C(O)-NR23R24；R 38 is hydrogen, C1-7 alkyl, C1-7 alkyl carbonyl, C1-7 alkoxy C1-7 alkyl carbonyl, or -C1-7 alkyl-C(O)-NR 23 R 24 ;
R39为氢、C1-7烷基或羟基；R 39 is hydrogen, C1-7 alkyl, or hydroxyl;
其中任选的取代基，在每次出现时，是1-2个独立地选自C1-7烷基、卤素、卤素C1-7烷基、C1-7烷氧基和氧代的取代基；The optional substituents, each time appearing, are 1-2 independent substituents selected from C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy and oxo substituents;
条件是，式(I)的化合物不是：The condition is that the compound of formula (I) is not:
N-[2-甲基-3-(苯氧基甲基)苯基]-5-氧代-2-吡咯烷甲酰胺；N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-2-pyrrolidinecarboxamide;
N-[5-[(3-氟苯氧基)甲基]-2-甲氧基苯基]-1-甲基-5-氧代-2-吡咯烷甲酰胺；N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide;
N-[3-[(4-氯苯基)甲基]苯基]-5-氧代-2-吡咯烷甲酰胺；N-[3-[(4-chlorophenyl)methyl]phenyl]-5-oxo-2-pyrrolidinecarboxamide;
N-[3-[(环己氧基)甲基]苯基]-1-甲基-5-氧代-2-吡咯烷甲酰胺；N-[3-[(cyclohexyloxy)methyl]phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide;
N-[4-甲基-3-[(4-甲基-2-吡啶基)氧基]苯基]-5-氧代-2-吡咯烷甲酰胺；N-[4-methyl-3-[(4-methyl-2-pyridyl)oxy]phenyl]-5-oxo-2-pyrrolidinecarboxamide;
N-[3-(环戊基氨基)苯基]-1-甲基-5-氧代-2-吡咯烷甲酰胺；N-[3-(cyclopentylamino)phenyl]-1-methyl-5-oxo-2-pyrrolidinecarboxamide;
N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-6-氧代-3-哌啶甲酰胺；N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-piperidinecarboxamide;
1-乙基-5-氧代-N-(3-苯氧基苯基)-3-吡咯烷甲酰胺；1-Ethyl-5-oxo-N-(3-phenoxyphenyl)-3-pyrrolidinecarboxamide;
N-[5-[(3-氟苯氧基)甲基]-2-甲氧基苯基]-2-吡咯烷甲酰胺；N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-2-pyrrolidinecarboxamide;
1-(1-乙基丙基)-N-[5-[(3-氟苯氧基)甲基]-2-甲氧基苯基]-5-氧代-3-吡咯烷甲酰胺；1-(1-Ethylpropyl)-N-[5-[(3-fluorophenoxy)methyl]-2-methoxyphenyl]-5-oxo-3-pyrrolidinecarboxamide;
N-[3-[(4-氯苯基)甲基]苯基]-1,6-二氢-6-氧代-3-吡啶甲酰胺；N-[3-[(4-chlorophenyl)methyl]phenyl]-1,6-dihydro-6-oxo-3-pyridinecarboxamide;
1,6-二氢-N-[4-甲氧基-3-(苯基甲基)苯基]-6-氧代-3-吡啶甲酰胺；1,6-Dihydro-N-[4-methoxy-3-(phenylmethyl)phenyl]-6-oxo-3-pyridinecarboxamide;
1,6-二氢-6-氧代-N-[3-[2-(2-吡啶基)乙烯基]苯基]-3-吡啶甲酰胺；1,6-Dihydro-6-oxo-N-[3-[2-(2-pyridyl)vinyl]phenyl]-3-pyridinecarboxamide;
N-[3-[(3-氟苯氧基)甲基]苯基]-2,3-二氢-2-氧代-1H-咪唑-4-甲酰胺；N-[3-[(3-fluorophenoxy)methyl]phenyl]-2,3-dihydro-2-oxo-1H-imidazol-4-carboxamide;
1-甲基-N-[2-甲基-3-(苯氧基甲基)苯基]-5-氧代-3-吡咯烷甲酰胺；1-Methyl-N-[2-methyl-3-(phenoxymethyl)phenyl]-5-oxo-3-pyrrolidinecarboxamide;
N-[3-[(1,3-苯并间二氧杂环戊烯-5-基氧基)甲基]苯基]-1-(2-甲基丙基)-5-氧代-3-吡咯烷甲酰胺；N-[3-[(1,3-benzodioxacyclopenten-5-yloxy)methyl]phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide;
1,6-二氢-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-6-氧代-3-吡啶甲酰胺；1,6-Dihydro-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-6-oxo-3-pyridinecarboxamide;
N-[3-[(环己氧基)甲基]苯基]-1-乙基-5-氧代-3-吡咯烷甲酰胺；N-[3-[(cyclohexyloxy)methyl]phenyl]-1-ethyl-5-oxo-3-pyrrolidinecarboxamide;
1-甲基-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-5-氧代-3-吡咯烷甲酰胺；1-Methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-5-oxo-3-pyrrolidinecarboxamide;
2,3-二氢-3-甲基-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-2-氧代-1H-咪唑-4-甲酰胺；2,3-Dihydro-3-methyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazol-4-carboxamide;
2,3-二氢-1,3-二甲基-N-[3-[[(3-甲基环己基)氧基]甲基]苯基]-2-氧代-1H-咪唑-4-甲酰胺；2,3-Dihydro-1,3-dimethyl-N-[3-[[(3-methylcyclohexyl)oxy]methyl]phenyl]-2-oxo-1H-imidazol-4-carboxamide;
1-乙基-N-[4-甲氧基-3-(4-吡啶基甲氧基)苯基]-5-氧代-3-吡咯烷甲酰胺；1-Ethyl-N-[4-methoxy-3-(4-pyridylmethoxy)phenyl]-5-oxo-3-pyrrolidinecarboxamide;
N-[4-甲氧基-3-(4-甲氧基苯氧基)苯基]-1-(2-甲基丙基)-5-氧代-3-吡咯烷甲酰胺或N-[4-methoxy-3-(4-methoxyphenoxy)phenyl]-1-(2-methylpropyl)-5-oxo-3-pyrrolidinecarboxamide or
6-氧代-N-(3-苯氧基苯基)-2-哌嗪甲酰胺。6-Oxo-N-(3-phenoxyphenyl)-2-piperazine carboxamide.
应当理解，接头L的变体的左键与式(I)的环A连接，右键与苯基连接。基团B的变体中的波浪线表示与甲酰胺基团连接的位点。It should be understood that in variants of connector L, the left-hand bond is connected to ring A of formula (I), and the right-hand bond is connected to a phenyl group. The wavy lines in variants of group B indicate sites connected to formamide groups.
根据一个实施方案，具体提供根据式(I)的化合物，其中A是苯基、吡啶基或环己基。在上述实施方案的亚组中，A是苯基或环己基。在另一个亚组中，A是苯基或吡啶基。在另一个亚组中，A是苯基。在另一亚组，A是环己基。在另一个亚组中，A是吡啶基。According to one embodiment, a compound according to formula (I) is specifically provided, wherein A is phenyl, pyridyl, or cyclohexyl. In one subgroup of the above embodiments, A is phenyl or cyclohexyl. In another subgroup, A is phenyl or pyridyl. In yet another subgroup, A is phenyl. In yet another subgroup, A is cyclohexyl. In yet another subgroup, A is pyridyl.
根据又一个实施方案，具体提供根据上述任一实施方案的化合物，其中R42是氢。According to yet another implementation, a compound according to any of the above implementations is specifically provided, wherein R 42 is hydrogen.
根据一个实施方案，具体提供根据式(Ia)的化合物或其药学上可接受的盐，According to one embodiment, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is specifically provided.
其中A、L、B、R1、R2、R3、R4、R5、R33和R42如上所定义。A, L, B, R1 , R2 , R3 , R4 , R5 , R33 and R42 are defined as above.
根据又一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中B是环(1a)、(3)、(4)、(6)、(8)、(9)、(10)、(11)、(12)、(13)、(16)、(17)或(18)。在前述实施方案的亚组中，B是环(1a)、(4)、(10)、(11)、(12)、(13)、(16)或(17)。在另一个亚组中，B是环(1a)、(10)、(11)或(12)。在另一个亚组中，B是环(1a)或(12)。在另一个亚组中，B是环(1a)。在另一个亚组中，B是环(12)。According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein B is a ring (1a), (3), (4), (6), (8), (9), (10), (11), (12), (13), (16), (17), or (18). In a subgroup of the aforementioned embodiments, B is a ring (1a), (4), (10), (11), (12), (13), (16), or (17). In another subgroup, B is a ring (1a), (10), (11), or (12). In another subgroup, B is a ring (1a) or (12). In another subgroup, B is a ring (1a). In another subgroup, B is a ring (12).
在其中B是环(1a)的化合物的亚组中，所述化合物是其中R7和R8是氢的化合物。在前述实施方案的另一亚组中，所述化合物是其中R6是氢、C1-7烷基或C3-7环烷基的化合物。根据另一亚组，所述化合物是其中R6是-C(O)-RX的化合物，其中RX是C1-7烷基或任选取代的4-6元环，所述环具有1-3个独立地选自O、S和N的作为环原子的杂原子。这种环的具体实施例是吡咯烷和氮杂环丁烷环，其任选地被1-2个独立地选自C1-7烷基和氧代的取代基取代。In the subgroup of compounds in which B is a ring (1a), the compound is a compound in which R7 and R8 are hydrogen. In another subgroup of the foregoing embodiments, the compound is a compound in which R6 is hydrogen, a C1-7 alkyl, or a C3-7 cycloalkyl. According to another subgroup, the compound is a compound in which R6 is -C(O) -RX , wherein RX is a C1-7 alkyl or optionally substituted 4-6 membered ring having 1-3 heteroatoms independently selected from O, S, and N as ring atoms. Specific examples of such rings are pyrrolidine and azirrobutane rings, optionally substituted with 1-2 substituents independently selected from C1-7 alkyl and oxo groups.
在其中B是环(12)的化合物的亚组中，所述化合物是其中R20是氢和R18是C1-7烷基或C3-7环烷基的化合物。在上述实施方案的另一亚组中，所述化合物是其中R21是氢或C1-7烷基的化合物。In the subgroup of compounds in which B is a ring (12), the compound is a compound in which R 20 is hydrogen and R 18 is a C1-7 alkyl or C3-7 cycloalkyl. In another subgroup of the above embodiments, the compound is a compound in which R 21 is hydrogen or a C1-7 alkyl.
根据又一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中L是-O-、-S-、-NH-、-C1-7烷基-，-C2-7烯基-、-C1-7烷基-O-或-O-C1-7烷基-。在前述实施方案的一个亚组中，所述化合物是其中L是-O-、-C2-7烯基-、-C1-7烷基-O-或-O-C1-7烷基-。在前述实施方案的一个亚组中，所述化合物是其中L是-O-、-C2-7烯基-或-O-C1-7烷基-的化合物。在另一个亚组中，L是-O-或-C2-7烯基-。在另一个亚组中，L是-O-。L为C1-7烷基的具体实施例是L为-CH2-基团。L为-C2-7烯基-的具体实施例是L为-CH＝CH-基团。L为-C1-7烷基-O-的具体实施例是L为-CH2-O-基团。L为-O-C1-7烷基-的具体实施例是L为-O-CH2-基团。According to yet another embodiment, a compound according to any of the above embodiments is specifically provided, wherein L is -O-, -S-, -NH-, -C 1-7 alkyl-, -C 2-7 alken-, -C 1-7 alkyl-O-, or -OC 1-7 alkyl-. In one subgroup of the foregoing embodiments, the compound is one wherein L is -O-, -C 2-7 alken-, -C 1-7 alkyl-O-, or -OC 1-7 alkyl-. In one subgroup of the foregoing embodiments, the compound is one wherein L is -O-, -C 2-7 alken-, or -OC 1-7 alkyl-. In another subgroup, L is -O- or -C 2-7 alken-. In another subgroup, L is -O-. A specific example of L being C 1-7 alkyl is that L is a -CH 2- group. A specific example of L being -C 2-7 alken- is that L is a -CH=CH- group. A specific example of L being -C 1-7 alkyl-O- is L being a -CH 2 -O- group. A specific example of L being -OC 1-7 alkyl- is L being an -O-CH 2- group.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中R1是氢、C1-7烷氧基或卤素。在前述实施方案的一个亚组中，所述化合物是其中R1是C1-7烷氧基或卤素的化合物。在前述实施方案的一个亚组中，所述化合物是其中R1是C1-7烷氧基、特别是甲氧基的化合物。根据一个实施方案，R1是任选取代的5-6元杂环，所述环具有1-3个独立地选自O、S和N的作为环原子的杂原子。这种环的具体实施例包括噁二唑基和吡唑基环，其任选地被1-2个C1-7烷基或氧代取代基取代。According to one embodiment, a compound according to any of the above embodiments is provided, wherein R1 is hydrogen, a C1-7 alkoxy group, or a halogen. In a subgroup of the above embodiments, the compound is a compound wherein R1 is a C1-7 alkoxy group or a halogen. In a subgroup of the above embodiments, the compound is a compound wherein R1 is a C1-7 alkoxy group, particularly a methoxy group. According to one embodiment, R1 is an optionally substituted 5-6 membered heterocycle having 1-3 heteroatoms independently selected from O, S, and N as ring atoms. Specific examples of such rings include oxadiazolyl and pyrazolyl rings, optionally substituted with 1-2 C1-7 alkyl or oxo substituents.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中R2为氢、C1-7烷氧基或卤素。在前述实施方案的亚组中，所述化合物是其中R2为氢或卤素的化合物。在前述实施方案的亚组中，所述化合物是其中R2为氢的化合物。According to one embodiment, a compound according to any of the above embodiments is provided, wherein R2 is hydrogen, a C1-7 alkoxy group, or a halogen. In a subgroup of the foregoing embodiments, the compound is a compound wherein R2 is hydrogen or a halogen. In a subgroup of the foregoing embodiments, the compound is a compound wherein R2 is hydrogen.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中R3为氢、卤素或C1-7烷氧基。在一个亚组中，所述化合物是其中R3为氢或C1-7烷氧基的化合物。在一个亚组中，所述化合物是其中R3为氢的化合物。According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein R3 is hydrogen, halogen, or C1-7 alkoxy. In one subgroup, the compound is a compound wherein R3 is hydrogen or C1-7 alkoxy. In another subgroup, the compound is a compound wherein R3 is hydrogen.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中R1和R3与它们所连接的碳原子一起形成任选取代的5-6元环，所述环具有0-3个独立地选自O、S和N的作为环原子的杂原子。在一个亚组中，所述化合物是其中R1和R3与它们所连接的碳原子一起形成5-6元环的化合物，所述环具有1-2个独立地选自O和N的作为环原子的杂原子。在一个亚组中，所述化合物是其中R1和R3与它们所连接的碳原子一起形成具有1-2个杂原子的5-6元环的化合物，其中所述杂原子是O。这种环的具体实施例是呋喃基、二氢呋喃基、四氢呋喃基、二噁烷基、二氧戊环基、噁嗪基、吡啶基、2,3-二氢-1,4-二噁烯基、2,3-二氢-1,4-噁嗪基环，其任选地被1-2个独立地选自C1-7烷基或氧代的取代基取代。According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein R1 and R3, together with the carbon atoms to which they are attached, form an optionally substituted 5-6 membered ring, said ring having 0-3 heteroatoms independently selected from O, S, and N as ring atoms. In one subgroup, said compound is a compound in which R1 and R3, together with the carbon atoms to which they are attached, form a 5-6 membered ring, said ring having 1-2 heteroatoms independently selected from O and N as ring atoms. In another subgroup, said compound is a compound in which R1 and R3 , together with the carbon atoms to which they are attached, form a 5-6 membered ring having 1-2 heteroatoms, wherein said heteroatom is O. Specific examples of such a ring are furanyl, dihydrofuranyl, tetrahydrofuranyl, dioxalkyl, dioxopentyl, oxazinyl, pyridyl, 2,3-dihydro-1,4-dioxenyl, 2,3-dihydro-1,4-oxazinyl rings, which are optionally substituted by one or two independent substituents selected from C1-7 alkyl or oxazinyl groups.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中R1和R3与它们所连接的苯环一起形成任选取代的稠环，其由以下基团中的任一个表示：According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein R1 and R3 together with the benzene ring to which they are attached form an optionally substituted fused ring, which is represented by any of the following groups:
其中左波浪线表示与L基团连接的位点，右波浪线表示与甲酰胺基团连接的位点。任选的取代可以是1-2个独立地选自C1-7烷基、卤素、卤素C1-7烷基、C1-7烷氧基和氧代、特别是C1-7烷基或氧代的取代基。The left wavy line indicates the site connected to the L group, and the right wavy line indicates the site connected to the formamide group. Optional substitutions may be one or two substituents independently selected from C1-7 alkyl, halogen, halogenated C1-7 alkyl, C1-7 alkoxy, and oxo, especially C1-7 alkyl or oxo substituents.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中R4为氢、卤素、C1-7烷基、C1-7烷氧基、卤素C1-7烷基或卤素C1-7烷氧基，且R5为氢、C1-7烷基、C1-7烷氧基、氰基、氨基或卤素。在一个亚组中，所述化合物是其中R4为卤素、C1-7烷基、卤素C1-7烷基或卤素C1-7烷氧基和R5为氢、C1-7烷基、氰基或卤素的化合物。在一个亚组中，所述化合物是其中R4为卤素C1-7烷基或卤素C1-7烷氧基和R5为氢或卤素的化合物。在一个亚组中，所述化合物是其中R4为卤素C1-7烷基或卤素C1-7烷氧基和R5为氢的化合物。在另一个亚组中，所述化合物是其中R4和R5都为C1-7烷基，例如甲基的化合物。在另一个亚组中，所述化合物是其中R4和R5都为卤素，例如氟的化合物。R4为卤素C1-7烷基的具体实例是R4为-CF3和-CHF2基团。R4为卤素C1-7烷氧基的具体实例是R4为-OCF3基团。According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein R4 is hydrogen, halogen, C1-7 alkyl, C1-7 alkoxy, halogenated C1-7 alkyl, or halogenated C1-7 alkoxy, and R5 is hydrogen, C1-7 alkyl, C1-7 alkoxy, cyano, amino, or halogen. In one subgroup, the compound is a compound wherein R4 is halogen, C1-7 alkyl, halogenated C1-7 alkyl, or halogenated C1-7 alkoxy, and R5 is hydrogen, C1-7 alkyl, cyano, or halogen. In another subgroup, the compound is a compound wherein R4 is halogenated C1-7 alkyl or halogenated C1-7 alkoxy, and R5 is hydrogen or halogen. In yet another subgroup, the compound is a compound wherein R4 is halogenated C1-7 alkyl or halogenated C1-7 alkoxy, and R5 is hydrogen. In another subgroup, the compound is one in which both R4 and R5 are C1-7 alkyl groups, such as methyl. In another subgroup, the compound is one in which both R4 and R5 are halogens, such as fluorine. Specific examples of R4 being a halogenated C1-7 alkyl group are R4 being either -CF3 or -CHF2 groups. Specific examples of R4 being a halogenated C1-7 alkoxy group are R4 being -OCF3 groups.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中环A与R4和R5一起表示以下基团中的任一个：According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein ring A together with R4 and R5 represents any of the following groups:
其中X是卤素，并且波浪线表示与L基团连接的位点。Where X is a halogen, and the wavy line indicates the site where it is attached to the L group.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中A与R4和R5一起为基团(1’)、(2’)、(3’)、(4’)、(7’)、(8’)、(10’)、(11’)或(13’)。在一个亚组中，提供了根据上述实施方案中任一个的化合物，其中A与R4和R5一起为基团(1’)、(4’)、(7’)、(8’)、(10’)或(11’)。According to one embodiment, a compound according to any one of the above embodiments is specifically provided, wherein A together with R4 and R5 is a group (1'), (2'), (3'), (4'), (7'), (8'), (10'), (11'), or (13'). In a subgroup, a compound according to any one of the above embodiments is provided, wherein A together with R4 and R5 is a group (1'), (4'), (7'), (8'), (10'), or (11').
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中环A与R4和R5一起由以下基团表示：According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein ring A, together with R4 and R5, is represented by the following groups:
其中波浪线表示与L基团连接的位点。The wavy line indicates the site where the L group is attached.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中A与R4和R5一起为基团(1”)、(2”)、(3”)、(4”)、(7”)、(11”)、(12”)、(13”)、(15”)、(17”)、(19”)或(21”)。在一个亚组中，提供了根据上述实施方案中任一个的化合物，其中A与R4和R5一起为基团(1”)、(2”)、(4”)、(7”)、(11”)、(12”)、(15”)或(21”)。According to one embodiment, a compound according to any one of the above embodiments is specifically provided, wherein A, together with R4 and R5, is a group (1”), (2”), (3”), (4”), (7”), (11”), (12”), (13”), (15”), (17”), (19”), or (21”). In a subgroup, a compound according to any one of the above embodiments is provided, wherein A, together with R4 and R5, is a group (1”), (2”), (4”), (7”), (11”), (12”), (15”), or (21”).
根据一个实施方案，具体提供根据任何上述实施方案的化合物，其中A是苯基或吡啶基，L是-O-，R1是C1-7烷氧基，R2、R3、R5、R33和R42是氢，Z是环(1a)或(12)和R4是卤素C1-7烷基。According to one embodiment, a compound according to any of the above embodiments is specifically provided, wherein A is phenyl or pyridyl, L is -O-, R1 is C1-7 alkoxy, R2 , R3 , R5 , R33 and R42 are hydrogen, Z is cyclo(1a) or (12) and R4 is halogenated C1-7 alkyl.
根据一个实施方案，具体提供根据上述实施方案中任一个的化合物，其中Z还可以是-CH(NHR25)-(CH2)2-COOH。According to one embodiment, a compound according to any one of the above embodiments is specifically provided, wherein Z may also be -CH(NHR 25 )-(CH 2 ) 2 -COOH.
根据一个实施方案，具体提供式(Ib)的化合物或其药学上可接受的盐，According to one embodiment, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof is specifically provided.
其中：in:
D为CH或N；D is either CH or N;
R2为H或卤素； R2 is H or a halogen;
R4为H、卤素或氰基； R4 is H, halogen, or cyano;
R5为卤素或卤素C1-7烷基； R5 is a halogen or a halogenated C1-7 alkyl group;
B是环(1a)、(10)或(12)；B is a ring (1a), (10), or (12);
R1为-OCH3或卤素，或R1和R3与它们所连接的苯环一起形成由以下基团中的任一个表示的稠环： R1 is -OCH3 or a halogen, or R1 and R3 together with the benzene ring to which they are attached form a fused ring represented by any of the following groups:
根据一个实施方案，具体提供根据式(Ic)的化合物或其药学上可接受的盐，According to one embodiment, a compound of formula (Ic) or a pharmaceutically acceptable salt thereof is specifically provided.
其中：in:
L是-O-或-CH＝CH-；L is -O- or -CH=CH-;
R2为H或卤素； R2 is H or a halogen;
R4为H、C1-7烷基或卤素； R4 is H, C1-7 alkyl, or halogen;
R5为卤素、C1-7烷基或卤素C1-7烷基； R5 is a halogen, a C1-7 alkyl group, or a halogenated C1-7 alkyl group;
B是环(1a)、(10)或(12)；B is a ring (1a), (10), or (12);
R1为-OCH3或卤素，或R1和R3与它们所连接的苯环一起形成由以下基团中的任一个表示的稠环： R1 is -OCH3 or a halogen, or R1 and R3 together with the benzene ring to which they are attached form a fused ring represented by any of the following groups:
根据另一个实施方案，本发明提供了治疗其中需要抑制TEAD的疾病或病症如癌症和慢性疼痛的方法，该方法包括向有需要的个体施用治疗有效量的如上述实施方案的任一个所定义的式(I)的化合物。According to another embodiment, the present invention provides a method for treating diseases or conditions in which TEAD needs to be suppressed, such as cancer and chronic pain, the method comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) as defined in any of the above embodiments.
本发明的化合物可以使用合适的起始原料、通过与文献中已知的方法类似的多种合成途径制备。式(I)的化合物可以例如类似地或根据以下反应方案制备。包括在式(I)中的一些化合物可以通过转化根据以下方案获得的其它式(I)化合物的官能团、通过公知的反应步骤如氧化、还原、水解、酰化、烷基化、酰胺化、胺化、磺化等来获得。应当注意，在合成过程中可以以公知的方式使用任何合适的离去基团，例如N-保护基，如叔丁氧基羰基(t-BOC)或苯磺酰基，以提高反应步骤的选择性。The compounds of the present invention can be prepared using suitable starting materials via a variety of synthetic routes similar to those known in the literature. Compounds of formula (I) can be prepared, for example, similarly or according to the following reaction scheme. Some compounds included in formula (I) can be obtained by transforming the functional groups of other compounds of formula (I) obtained according to the following scheme, via known reaction steps such as oxidation, reduction, hydrolysis, acylation, alkylation, amidation, amination, sulfonation, etc. It should be noted that any suitable leaving group, such as an N-protecting group, such as tert-butoxycarbonyl (t-BOC) or benzenesulfonyl, can be used in a known manner during the synthesis to improve the selectivity of the reaction steps.
式(I)的化合物可以例如根据方案1制备，其中A、L、Z、R1、R2、R3、R4、R5、R33和R42如上所定义。在方案1的方法中，在合适的偶联剂如N,N,N',N'-四甲基氯甲脒(tetramethylchloroformamidinium)六氟磷酸盐和1-甲基-1H-咪唑的组合或氮杂苯并三唑四甲基脲鎓六氟磷酸盐(HATU)和N,N-二异丙基乙胺(DIPEA)的组合的存在下、在合适的溶剂如无水乙腈或DMF中，将式[1]的苯胺化合物与式[2]的羧酸衍生物偶联，生成式(I)的化合物。The compound of formula (I) can be prepared, for example, according to scheme 1, wherein A, L, Z, R1 , R2 , R3 , R4 , R5 , R33 and R42 are as defined above. In the method of scheme 1, the aniline compound of formula [1] is coupled with the carboxylic acid derivative of formula [2] in the presence of a suitable coupling agent such as a combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 1-methyl-1H-imidazolium or a combination of azirzotriazole tetramethylureonium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in a suitable solvent such as anhydrous acetonitrile or DMF to generate the compound of formula (I).
方案lOption 1
或者，其中R42为H的式(I)的化合物可根据方案2制备，其中A、L、Z、R1、R2、R3、R4、R5和R33如上所定义，并且X为卤素，例如溴。在方案2的方法中，在碱如碳酸铯和合适的催化剂体系如Pd2(dba)和4,5-双(二苯基膦基)-9,9-二甲基呫吨(XantPhos)的组合或碘化铜和N1,N2-二甲基环己烷-1,2-二胺的组合的存在下、在合适的溶剂如甲苯中，将式[3]的化合物与式[4]的甲酰胺化合物偶联，生成式(I)的化合物。Alternatively, the compound of formula (I), in which R 42 is H, can be prepared according to scheme 2, wherein A, L, Z, R 1 , R 2 , R 3 , R 4 , R 5 and R 33 are as defined above, and X is a halogen, such as bromine. In the method of scheme 2, the compound of formula [3] is coupled with the formamide compound of formula [4] in the presence of a base such as cesium carbonate and a suitable catalyst system such as a combination of Pd 2 (dba) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthos or a combination of copper iodide and N1,N2-dimethylcyclohexane-1,2-diamine, in a suitable solvent such as toluene, to generate the compound of formula (I).
方案2Option 2
其中L为-O-的式(I)化合物也可以例如根据方案3制备，其中A、Z、R1、R2、R3、R4和R5如上所定义。在方案3的方法中，在Mitsunobu试剂如三苯基膦(TPP)和偶氮二甲酸二乙酯(DEAD)的存在下、在合适的溶剂如四氢呋喃中，将式[3]的化合物与式[4]的化合物缩合，生成式(I)的化合物。Compounds of formula (I) where L is -O- can also be prepared, for example, according to scheme 3, where A, Z, R1 , R2 , R3 , R4 and R5 are as defined above. In the method of scheme 3, the compound of formula [3] is condensed with the compound of formula [4] in the presence of Mitsunobu reagents such as triphenylphosphine (TPP) and diethyl azodicarbonate (DEAD) in a suitable solvent such as tetrahydrofuran to generate the compound of formula (I).
方案3Option 3
中间体化合物可以根据文献中公开的方法或如本公开中公开的方法制备。The intermediate compound can be prepared according to the methods disclosed in the literature or as disclosed in this disclosure.
例如，其中L是-O-的式[1A]的中间体化合物可以根据方案4制备，其中A、R1、R2、R3、R4、R5和R33如上所定义。在方案4的方法中，在碱如吡啶和催化剂如二乙酰氧基铜的存在下、在合适的溶剂如二氯甲烷中，将式[7]的化合物与式[8]的化合物偶联，生成式[8]的化合物，随后可以将其还原，例如通过在合适的催化剂如钯碳存在下氢化，得到式[1a]的中间体。For example, the intermediate compound of formula [1A], where L is -O-, can be prepared according to scheme 4, wherein A, R1 , R2 , R3 , R4 , R5 , and R33 are as defined above. In the method of scheme 4, the compound of formula [7] is coupled with the compound of formula [8] in the presence of a base such as pyridine and a catalyst such as copper diacetoxy, in a suitable solvent such as dichloromethane to generate the compound of formula [8], which can then be reduced, for example by hydrogenation in the presence of a suitable catalyst such as palladium on carbon, to obtain the intermediate of formula [1a].
方案44Option 44
其中L为-O-的式[3A]的中间体化合物可以例如根据方案5制备，其中A、R1、R2、R3、R4、R5和R33如上所定义，并且X为卤素，例如溴。在方案5的方法中，在碱如吡啶和催化剂如二乙酰氧基铜的存在下、在合适的溶剂如二氯甲烷中，将式[9]的化合物与式[10]的化合物偶联，生成式[3a]的化合物。The intermediate compound of formula [3A], where L is -O-, can be prepared, for example, according to scheme 5, wherein A, R1 , R2 , R3 , R4 , R5 and R33 are as defined above, and X is a halogen, such as bromine. In the method of scheme 5, the compound of formula [9] is coupled with the compound of formula [10] in the presence of a base such as pyridine and a catalyst such as copper diacetoxy, in a suitable solvent such as dichloromethane, to generate the compound of formula [3a].
方案5Option 5
式[5]的中间体化合物可以例如根据方案6制备，其中Z、R1、R2和R3如上所定义。在方案6的方法中，在碱如N,N-二异丙基乙胺(DIPEA)和偶联剂如氮杂苯并三唑四甲基脲鎓六氟磷酸盐(HATU)的存在下、在合适的溶剂如DMF中，将式[11]的化合物与式[12]的化合物偶联，生成式[5]的中间体。The intermediate compound of formula [5] can be prepared, for example, according to scheme 6, wherein Z, R1 , R2 and R3 are as defined above. In the method of scheme 6, the compound of formula [11] is coupled with the compound of formula [12] in the presence of a base such as N,N-diisopropylethylamine (DIPEA) and a coupling agent such as azirbenzotriazole tetramethylurea hexafluorophosphate (HATU) in a suitable solvent such as DMF to generate the intermediate of formula [5].
方案(6Option (6)
或者，式(I)的化合物可以如本公开的具体实施例中公开的那样制备。Alternatively, the compound of formula (I) can be prepared as disclosed in the specific embodiments of this disclosure.
除非另有定义，本文所用的所有技术和科学术语具有与本文主题所属领域的技术人员通常理解的相同的含义。如本文所用，提供以下定义以便于理解本发明。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject pertains. As used herein, the following definitions are provided to facilitate understanding of the invention.
如本文所用，术语“个体(subject)”是指人和动物。As used in this article, the term "subject" refers to both humans and animals.
如本文所用，术语“卤代”或“卤素”本身或作为另一基团的一部分，是指氯、溴、氟或碘。优选的卤素是氯和氟。As used herein, the term "halogenated" or "halogen" itself, or as part of another group, refers to chlorine, bromine, fluorine, or iodine. Preferred halogens are chlorine and fluorine.
如本文所用，术语“C1-7烷基”本身或作为另一基团的一部分，是指具有1、2、3、4、5、6或7个碳原子的直链或支链饱和烃基。C1-7烷基的代表性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基和正己基。“C1-7烷基”的一个优选实施方案是C1-3烷基。术语“C1-3烷基”是指具有1、2或3个碳原子的“C1-7烷基”的一个实施方案。“C1-3烷基”的实施例包括但不限于甲基、乙基、正丙基和异丙基。一个优选的“C1-7烷基”是甲基。As used herein, the term " C1-7 alkyl" itself, or as part of another group, refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. Representative examples of C1-7 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl. A preferred embodiment of " C1-7 alkyl" is C1-3 alkyl. The term " C1-3 alkyl" refers to an embodiment of " C1-7 alkyl" having 1, 2, or 3 carbon atoms. Examples of " C1-3 alkyl" include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl. A preferred " C1-7 alkyl" is methyl.
如本文所用，术语“C2-7烯基”本身或作为另一基团的一部分，是指具有2、3、4、5、6或7个碳原子并含有一个或几个双键的脂肪烃基。代表性实施例包括但不限于乙烯基、丙烯基和己烯基。“C2-7烯基”的一个优选实施方案是C2-4烯基。术语“C2-4烯基”是指具有2、3或4个碳原子的“C2-7烯基”的一个实施方案。代表性实施例包括但不限于乙烯基、丙烯基和丁烯基。一种优选的“C2-7烯基”是-CH＝CH-基团。As used herein, the term "C 2-7 alkenyl" itself, or as part of another group, refers to an aliphatic hydrocarbon group having 2, 3, 4, 5, 6, or 7 carbon atoms and containing one or more double bonds. Representative embodiments include, but are not limited to, vinyl, propenyl, and hexenyl. A preferred embodiment of "C 2-7 alkenyl" is C 2-4 alkenyl. The term "C 2-4 alkenyl" refers to an embodiment of "C 2-7 alkenyl" having 2, 3, or 4 carbon atoms. Representative embodiments include, but are not limited to, vinyl, propenyl, and butenyl. A preferred "C 2-7 alkenyl" is a -CH=CH- group.
如本文所用，术语“C3-7环烷基”本身或作为另一基团的一部分，是指含有3、4、5、6或7个碳原子的饱和环烃基。环烷基的代表性实施例包括但不限于环丙基、环丁基、环戊基和环己基。一个优选的“C3-7环烷基”是环丙基。As used herein, the term "C 3-7 cycloalkyl" itself, or as part of another group, refers to a saturated cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A preferred "C 3-7 cycloalkyl" is cyclopropyl.
如本文所用，术语“羟基”本身或作为另一基团的一部分，是指-OH基团。As used herein, the term "hydroxyl group" itself, or as part of another group, refers to the -OH group.
如本文所用，术语“氰基”本身或作为另一基团的一部分，是指-CN基团。As used herein, the term "cyano" itself, or as part of another group, refers to the -CN group.
如本文所用，术语“羧基”本身或作为另一基团的一部分，是指-COOH基团。As used herein, the term "carboxyl group" itself, or as part of another group, refers to the -COOH group.
如本文所用，术语“羰基”本身或作为另一基团的一部分，是指碳原子双键连接氧原子(C＝O)。As used herein, the term "carbonyl" itself, or as part of another group, refers to a carbon atom double bonded to an oxygen atom (C=O).
如本文所用，术语“氧代基”本身或作为另一基团的一部分，是指氧原子通过双键连接另一原子(＝O)。As used herein, the term "oxo-group" itself, or as part of another group, refers to an oxygen atom bonded to another atom (=O) via a double bond.
如本文所用，术语“C1-7烷氧基”本身或作为另一基团的一部分，是指如本文所定义的C1-7烷基通过氧原子连接到母体分子部分。C1-7烷氧基的代表性实施例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。“C1-7烷氧基”的一个优选实施方案是C1-3烷氧基。术语“C1-3烷氧基”是指具有1、2或3个碳原子的“C1-7烷氧基”的一个实施方案。C1-3烷氧基的代表性实施例包括但不限于甲氧基、乙氧基、丙氧基。一个优选的“C1-7烷氧基”是甲氧基。As used herein, the term " C1-7 alkoxy" itself, or as part of another group, refers to a C1-7 alkyl group as defined herein, connected to a parent molecule portion via an oxygen atom. Representative embodiments of C1-7 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferred embodiment of " C1-7 alkoxy" is C1-3 alkoxy. The term " C1-3 alkoxy" refers to an embodiment of a " C1-7 alkoxy" having 1, 2, or 3 carbon atoms. Representative embodiments of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, and propoxy. A preferred " C1-7 alkoxy" is methoxy.
如本文所用，术语“羟基C1-7烷基”是指至少一个如本文所定义的羟基通过如本文所定义的C1-7烷基连接到母体分子部分。羟基C1-7烷基的代表性实施例包括但不限于羟甲基、2，2-二羟乙基、1-羟乙基、3-羟丙基、1-甲基-1-羟乙基和1-甲基-1-羟丙基。As used herein, the term "hydroxyl C1-7 alkyl" means at least one hydroxyl group as defined herein linked to a parent molecule moiety via a C1-7 alkyl group as defined herein. Representative examples of hydroxyl C1-7 alkyl groups include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, and 1-methyl-1-hydroxypropyl.
如本文所用，术语“卤素C1-7烷基”是指至少一个如本文所定义的卤素通过如本文所定义的C1-7烷基连接到母体分子部分。卤素C1-7烷基的代表性实施例包括但不限于氟甲基、二氟甲基、三氟甲基、2-氯乙基和3-溴丙基。优选的“卤素C1-7烷基”是三氟甲基和二氟甲基。As used herein, the term "halogenated C1-7 alkyl" means at least one halogen as defined herein linked to a parent molecule moiety via a C1-7 alkyl group as defined herein. Representative examples of halogenated C1-7 alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl. Preferred "halogenated C1-7 alkyl" groups are trifluoromethyl and difluoromethyl.
如本文所用，术语“卤素C1-7烷氧基”是指至少一个如本文所定义的卤素通过如本文所定义的C1-7烷氧基连接到母体分子部分。As used herein, the term "halogen C1-7 alkoxy" means at least one halogen as defined herein attached to a parent molecule moiety via a C1-7 alkoxy group as defined herein.
如本文所用，术语“C1-7烷氧基C1-7烷基”本身或作为另一基团的一部分，是指至少一个如本文所定义的C1-7烷氧基通过如本文所定义的C1-7烷基连接到母体分子部分。As used herein, the term “ C1-7 alkoxy- C1-7 alkyl”, either on its own or as part of another group, refers to at least one C1-7 alkoxy group as defined herein, which is attached to a parent molecule moiety by a C1-7 alkyl group as defined herein.
如本文所用，术语“4-10元碳环”是指具有4至10个仅由碳原子组成的环原子的饱和、部分饱和或芳香环。“4-10元碳环”的一个实施方案是“5-6元碳环”，其是指具有5至6个仅由碳原子组成的环原子的饱和、部分饱和或芳香环。4-10元碳环的代表性实施例包括但不限于苯基、环己基、环己烯基、环戊基、环戊烯基和环丁基环。As used herein, the term "4-10 membered carbon ring" refers to a saturated, partially saturated, or aromatic ring having 4 to 10 ring atoms consisting only of carbon atoms. One embodiment of "4-10 membered carbon ring" is a "5-6 membered carbon ring," which refers to a saturated, partially saturated, or aromatic ring having 5 to 6 ring atoms consisting only of carbon atoms. Representative examples of 4-10 membered carbon rings include, but are not limited to, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, and cyclobutyl rings.
如本文所用，如果没有另外定义，与各种残基有关的术语“取代的”是指卤素取代基，例如氟、氯、溴、碘或C1-7烷基、C3-7环烷基、羟基、氨基、硝基、氰基、巯基C1-7烷基、甲基磺酰基、C1-7烷氧基、卤代C1-7烷基、羟基C1-7烷基或氨基C1-7烷基取代基。优选卤素、C1-7烷基、羟基、氨基、卤代C1-7烷基、C1-7烷氧基和甲基磺酰基取代基。一组优选的取代基是1-2个选自C1-7烷基或卤素取代基，特别是C1-3烷基或卤素取代基，特别是甲基、乙基、氯、氟或溴取代基的取代基。As used herein, unless otherwise defined, the term "substituted" in relation to various residues refers to a halogen substituent, such as fluorine, chlorine, bromine, iodine, or C1-7 alkyl, C3-7 cycloalkyl, hydroxyl, amino, nitro, cyano, mercapto- C1-7 alkyl, methanesulfonyl, C1-7 alkoxy, halo- C1-7 alkyl, hydroxy -C1-7 alkyl, or amino- C1-7 alkyl substituents. Halogen, C1-7 alkyl, hydroxyl, amino, halo -C1-7 alkyl , C1-7 alkoxy, and methanesulfonyl substituents are preferred. A preferred set of substituents consists of one or two substituents selected from C1-7 alkyl or halogen substituents, particularly C1-3 alkyl or halogen substituents, especially methyl, ethyl, chlorine, fluorine, or bromine substituents.
如果没有另外定义，“取代的”基团可以含有1至3个，优选1或2个上述取代基。Unless otherwise defined, the "substituted" group may contain 1 to 3, preferably 1 or 2 of the above-mentioned substituents.
式(I)的化合物的光学活性对映异构体或非对映异构体可以例如通过用已知方法拆分外消旋终产物或通过使用合适的光学活性起始原料制备。类似地，式(I)的外消旋化合物可以通过使用外消旋起始原料制备。式(I)的外消旋化合物或其外消旋起始原料的拆分可以例如通过与光学活性酸反应将外消旋化合物转化为其非对映异构体盐混合物，随后通过结晶分离非对映异构体来进行。所述光学活性酸的代表性实施例包括但不限于D-酒石酸和二苯甲酰基-D-酒石酸。或者，制备手性色谱法可用于拆分外消旋混合物。Optically active enantiomers or diastereomers of compounds of formula (I) can be prepared, for example, by resolving racemic end products using known methods or by using suitable optically active starting materials. Similarly, racemic compounds of formula (I) can be prepared using racemic starting materials. The resolution of racemic compounds of formula (I) or their racemic starting materials can be carried out, for example, by reacting the racemic compound with an optically active acid to convert the racemic compound into a mixture of its diastereomer salts, followed by separation of the diastereomers by crystallization. Representative examples of such optically active acids include, but are not limited to, D-tartaric acid and dibenzoyl-D-tartaric acid. Alternatively, preparative chiral chromatography can be used to resolve racemic mixtures.
药学上可接受的盐在药物领域是公知的。合适的盐的非限制性实施例包括金属盐、铵盐、含有有机碱的盐、含有无机酸的盐、含有有机酸的盐和含有碱性或酸性氨基酸的盐。金属盐的非限制性实施例包括碱金属盐，例如钠盐和钾盐；碱土金属盐，例如钙盐、镁盐。含有无机或有机酸的盐的非限制性实施例包括氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲磺酸盐、甲酸盐、酒石酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐、乙酸盐、草酸盐、富马酸盐、半富马酸盐和琥珀酸盐。当可应用时，药学上可接受的酯可以通过已知的方法使用药学上可接受的酸来制备，所述酸在药物领域是常规的并且保留游离形式的药理学性质。这些酯的非限制性实施例包括脂肪族或芳香醇的酯，例如甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、仲丁酯、叔丁酯。磷酸酯和碳酸酯也在本发明的范围内。Pharmaceutically acceptable salts are well known in the pharmaceutical field. Non-limiting examples of suitable salts include metal salts, ammonium salts, salts containing organic bases, salts containing inorganic acids, salts containing organic acids, and salts containing basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts, such as sodium and potassium salts; and alkaline earth metal salts, such as calcium and magnesium salts. Non-limiting examples of salts containing inorganic or organic acids include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbic acid salts, acetates, oxalates, fumarates, hemifumarates, and succinates. When applicable, pharmaceutically acceptable esters can be prepared by known methods using pharmaceutically acceptable acids that are conventional in the pharmaceutical field and retain the pharmacological properties of their free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, sec-butyl ester, and tert-butyl ester. Phosphate esters and carbonates are also within the scope of this invention.
上述式(I)的定义包括化合物的所有可能的同位素和异构体，如立体异构体，包括几何异构体，例如Z和E异构体(顺式和反式异构体)，和光学异构体，例如非对映异构体和对映异构体，和前药酯，例如磷酸酯和碳酸酯。The definition of formula (I) above includes all possible isotopes and isomers of the compound, such as stereoisomers, including geometric isomers, such as Z and E isomers (cis and trans isomers), and optical isomers, such as diastereomers and enantiomers, and prodrug esters, such as phosphate esters and carbonates.
本领域技术人员将理解，本发明化合物可以含有至少一个手性中心。因此，化合物可以以光学活性或外消旋形式存在。应当理解，式(I)包括任何外消旋或光学活性形式或其混合物。在一个实施方案中，化合物是纯的(R)-异构体。在另一实施方案中，化合物是纯的(S)-异构体。在另一实施方案中，化合物是(R)和(S)异构体的混合物。在另一实施方案中，化合物是包含等量(R)和(S)异构体的外消旋混合物。所述化合物可以含有两个手性中心。在这种情况下，根据一个实施方案，化合物是非对映异构体的混合物。根据另一个实施方案，本发明的化合物是对映异构体的混合物。根据另一个实施方案，化合物是纯的对映异构体。单独的异构体可以使用起始原料的相应异构体形式获得，或者可以将它们在根据常规分离方法制备最终化合物之后分离。为了从其混合物中分离光学异构体，例如对映异构体或非对映异构体，可以使用常规的拆分方法，例如分步结晶。Those skilled in the art will understand that the compounds of the present invention may contain at least one chiral center. Therefore, the compounds may exist in optically active or racemic forms. It should be understood that formula (I) includes any racemic or optically active form or a mixture thereof. In one embodiment, the compound is a pure (R)-isomer. In another embodiment, the compound is a pure (S)-isomer. In another embodiment, the compound is a mixture of (R) and (S) isomers. In another embodiment, the compound is a racemic mixture containing equal amounts of (R) and (S) isomers. The compound may contain two chiral centers. In this case, according to one embodiment, the compound is a mixture of diastereomers. According to another embodiment, the compounds of the present invention are a mixture of enantiomers. According to another embodiment, the compound is a pure enantiomer. Individual isomers can be obtained using the corresponding isomer forms of the starting materials, or they can be separated after preparing the final compound according to conventional separation methods. To separate optical isomers, such as enantiomers or diastereomers, from their mixtures, conventional resolution methods, such as stepwise crystallization, can be used.
本发明的化合物还可以互变异构体或其平衡混合物的形式存在，其中化合物的质子从一个原子转移到另一个原子。互变异构的实施例包括但不限于酰氨基-亚氨基、酮-烯醇、苯酚-酮、肟-亚硝基、硝基-酸(aci)、亚胺-烯胺、杂环如吡唑环的环状互变异构等。互变异构形式旨在包括在式(I)的化合物中，尽管可能仅描述了一种互变异构形式。The compounds of the present invention may also exist as tautomers or equilibrium mixtures thereof, wherein a proton of the compound is transferred from one atom to another. Examples of tautomers include, but are not limited to, amide-imino, keto-enol, phenol-ketone, oxime-nitroso, nitro-acid (ACI), imine-enamine, and cyclic tautomers of heterocycles such as pyrazole rings. Tautomer forms are intended to be included in compounds of formula (I), although only one tautomer form may be described.
一组式(I)的优选的化合物的实施例包括：Examples of preferred compounds of formula (I) include:
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物1)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 1);
1-乙酰基-N-(5-(3-氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物2)；1-Acetyl-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (Compound 2);
1-乙酰基-N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物3)；1-Acetyl-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 3);
N-(5-((3-氟苯氧基)甲基)-2,4-二甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物4)；N-(5-((3-fluorophenoxy)methyl)-2,4-dimethoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 4);
1-(2-氟乙基)-N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)氮杂环丁烷-3-甲酰胺(化合物5)；1-(2-Fluoroethyl)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)azacyclobutane-3-carboxamide (compound 5);
外消旋-(反式)-N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-3-甲基-5-氧代吡咯烷-2-甲酰胺(化合物6)；Racemic-(trans)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-5-oxopyrrolidine-2-carboxamide (compound 6);
4-氧代-N-(3-(3-(三氟甲基)苯氧基)苯基)氮杂环丁烷-2-甲酰胺(化合物7)；4-O-N-(3-(3-(trifluoromethyl)phenoxy)phenyl)azacyclobutane-2-carboxamide (compound 7);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-4-氧代氮杂环丁烷-2-甲酰胺(化合物8)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-4-oxoazacyclobutane-2-carboxamide (compound 8);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-2-(5-氧代吡咯烷-2-基)乙酰胺(化合物9)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-(5-oxopyrrolidone-2-yl)acetamide (compound 9);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物10)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 10);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物11)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 11);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)四氢噻吩-3-甲酰胺1,1-二氧化物(化合物12)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)tetrahydrothiophene-3-carboxamide 1,1-dioxide (compound 12);
N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-2-甲基异噻唑啉烷-3-甲酰胺1,1-二氧化物(化合物13)；N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-2-methylisothiazolinone-3-carboxamide 1,1-dioxide (compound 13);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-2-甲基-5-氧代吡咯烷-2-甲酰胺(化合物14)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-methyl-5-oxopyrrolidine-2-carboxamide (compound 14);
N-(5-(3-氟苯氧基)-2-甲氧基苯基)-2-甲基-5-氧代吡咯烷-2-甲酰胺(化合物15)；N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-2-methyl-5-oxopyrrolidine-2-carboxamide (compound 15);
5-氧代-N-(3-(3-(三氟甲基)苯氧基)苯基)吡咯烷-2-甲酰胺(化合物16)；5-O-N-(3-(3-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 16);
N-(5-((3-氟苯氧基)甲基)苯并呋喃-7-基)-5-氧代吡咯烷-2-甲酰胺(化合物17)；N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 17);
N-(5-(3-氟苯氧基)-2-甲氧基苯基)-5-氧代四氢吡咯并[2,1-b]噻唑-7a(5H)-甲酰胺(化合物18)；N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formamide (compound 18);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代四氢吡咯并[2,1-b]噻唑-7a(5H)-甲酰胺(化合物19)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formamide (compound 19);
外消旋-(顺式)-N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-3-甲基-5-氧代吡咯烷-2-甲酰胺(化合物20)；Racemic-(cis)-N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-5-oxopyrrolidine-2-carboxamide (Compound 20);
(E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物21)；(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 21);
(E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物22)；(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 22);
(E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体1(化合物23)；(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 23);
(E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体1(化合物24)；(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 24);
(R)-N-(5-(3-氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物25)；(R)-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 25);
N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-3-甲基-2-氧代吡咯烷-3-甲酰胺(化合物26)；N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxopyrrolidine-3-carboxamide (compound 26);
N-(6-((3-氟苯氧基)甲基)苯并[d][1,3]间二氧杂环戊烯-4-基)-5-氧代吡咯烷-2-甲酰胺(化合物27)；N-(6-((3-fluorophenoxy)methyl)benzo[d][1,3]m-dioxacyclopenten-4-yl)-5-oxopyrrolidine-2-carboxamide (compound 27);
1-甲基-5-氧代-N-(5-(3-(三氟甲基)苯氧基)苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物28)；1-Methyl-5-oxo-N-(5-(3-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidine-2-carboxamide (compound 28);
1-乙酰基-N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物29)；1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 29);
1-乙酰基-N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体2(化合物30)；1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 30);
N-(5-((3-氟苯氧基)甲基)-2,3-二氢苯并呋喃-7-基)-5-氧代吡咯烷-2-甲酰胺(化合物31)；N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 31);
N-(5-((3-氟苯氧基)甲基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物32)；N-(5-((3-fluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 32);
5-氧代-N-(6-(3-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)吡咯烷-2-甲酰胺(化合物33)；5-Oxo-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidine-2-carboxamide (compound 33);
1-甲基-5-氧代-N-(6-(3-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)吡咯烷-2-甲酰胺(化合物34)；1-Methyl-5-oxo-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidine-2-carboxamide (compound 34);
N-(3-氟-5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物35)；N-(3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 35);
N-(3-氟-5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物36)；N-(3-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 36);
1-乙基-N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物37)；1-Ethyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 37);
1-(环丙烷羰基)-N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物38)；1-(cyclopropanecarbonyl)-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 38);
1-乙酰基-N-(4-氟-2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物39)；1-Acetyl-N-(4-fluoro-2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 39);
1-乙酰基-N-(2-氟-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物40)；1-Acetyl-N-(2-fluoro-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 40);
N-(2-氟-5-(3-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物41)；N-(2-fluoro-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 41);
N-(5-(2,4-二氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物42)；N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 42);
N-(5-(2,4-二氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物43)；N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 43);
1-乙酰基-N-(5-(2,4-二氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物44)；1-Acetyl-N-(5-(2,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (Compound 44);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物45)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 45);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物46)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 46);
1-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物47)；1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 47);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物48)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 48);
N-(2-甲氧基-5-((3-(三氟甲基)苯氧基)甲基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物49)；N-(2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 49);
1-乙酰基-N-(2-甲氧基-5-((3-(三氟甲基)苯氧基)甲基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物50)；1-Acetyl-N-(2-methoxy-5-((3-(trifluoromethyl)phenoxy)methyl)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 50);
1-乙酰基-N-(2-甲氧基-5-((3-(三氟甲基)苄基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物51)；1-Acetyl-N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 51);
N-(2-甲氧基-5-((3-(三氟甲基)苄基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物52)；N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 52);
N-(2-甲氧基-5-((3-(三氟甲基)苄基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物53)；N-(2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 53);
N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)异噻唑烷-3-甲酰胺1,1-二氧化物(化合物54)；N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)isothiazolidin-3-carboxamide 1,1-dioxide (compound 54);
5-氧代-N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物55)；5-Oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (compound 55);
1-乙酰基-5-氧代-N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物56)；1-Acetyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (compound 56);
N-(7-((3-氟苯氧基)甲基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-5-氧代吡咯烷-2-甲酰胺(化合物57)；N-(7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-5-oxopyrrolidine-2-carboxamide (compound 57);
N-(7-((3-氟苯氧基)甲基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物58)；N-(7-((3-fluorophenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 58);
N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物59)；N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 59);
N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物60)；N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 60);
N-(8-甲基-7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-5-氧代吡咯烷-2-甲酰胺(化合物61)；N-(8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-5-oxopyrrolidine-2-carboxamide (compound 61);
N-(2-甲氧基-5-((6-(三氟甲基)吡啶-3-基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物62)；N-(2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 62);
N-(2-甲氧基-5-((6-(三氟甲基)吡啶-3-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物63)；N-(2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 63);
(E)-N-(2-甲氧基-5-(2-(四氢-2H-吡喃-4-基)乙烯基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物64)；(E)-N-(2-methoxy-5-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 64);
(E)-N-(2-甲氧基-5-(2-(四氢-2H-吡喃-4-基)乙烯基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物65)；(E)-N-(2-methoxy-5-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 65);
5-氧代-N-(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物66)；5-Oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (compound 66);
1-甲基-5-氧代-N-(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物67)；1-Methyl-5-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (compound 67);
1-乙基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物68)；1-Ethyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 68);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物69)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 69);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物70)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 70);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-2-甲基-1,2-硫杂氮杂环丁烷-3-甲酰胺1,1-二氧化物(化合物71)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-methyl-1,2-thiazazacyclobutane-3-carboxamide 1,1-dioxide (compound 71);
N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-2-甲基-1,2-硫杂氮杂环丁烷-3-甲酰胺1,1-二氧化物(化合物72)；N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-2-methyl-1,2-thiazazacyclobutane-3-carboxamide 1,1-dioxide (compound 72);
N-(4-氟-5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物73)；N-(4-fluoro-5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 73);
N-(2-甲氧基-5-((4-(三氟甲基)苯基)氨基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物74)；N-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 74);
N-(2-氟-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物75)；N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 75);
N-(2-氟-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物76)；N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 76);
1-乙酰基-N-(5-(3,5-二氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物77)；1-Acetyl-N-(5-(3,5-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (Compound 77);
N-(5-(3,5-二氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物78)；N-(5-(3,5-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 78);
N-(5-(2,5-二氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物79)；N-(5-(2,5-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 79);
3-氧代-N-(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)四氢-1H-吡咯里嗪(pyrrolizine)-7a(5H)-甲酰胺(化合物80)；3-Oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)tetrahydro-1H-pyrrolizine-7a(5H)-formamide (compound 80);
1-异丙基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物81)；1-Isopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 81);
N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-1-异丙基-5-氧代吡咯烷-2-甲酰胺(化合物82)；N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-isopropyl-5-oxopyrrolidine-2-carboxamide (compound 82);
N-(2-(1,3,4-噁二唑-2-基)-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物83)；N-(2-(1,3,4-oxadiazol-2-yl)-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 83);
N-(2-(1,3,4-噁二唑-2-基)-5-(3-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物84)；N-(2-(1,3,4-oxadiazol-2-yl)-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 84);
N-(5-(3,4-二氟苯氧基)-2-(1-甲基-1H-吡唑-3-基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物85)；N-(5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazol-3-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 85);
N-(5-(3,4-二氟苯氧基)-2-(1-甲基-1H-吡唑-5-基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物86)；N-(5-(3,4-difluorophenoxy)-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 86);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物87)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 87);
N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物88)；N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 88);
N-(5-((3,4-二氟苯氧基)甲基)-2-甲氧基苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物89)；N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 89);
N-(5-((3-氟苯氧基)甲基)-2-甲氧基苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物90)；N-(5-((3-fluorophenoxy)methyl)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 90);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-硫代吡咯烷-2-甲酰胺(化合物91)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-thiopyrrolidine-2-carboxamide (compound 91);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-硫代吡咯烷-2-甲酰胺(化合物92)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-thiopyrrolidine-2-carboxamide (compound 92);
(R)-N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物93)；(R)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 93);
(S)-N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物94)；(S)-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 94);
N-(5-((3,4-二氟苯氧基)甲基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物95)；N-(5-((3,4-difluorophenoxy)methyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 95);
N-(5-(双环[2.2.1]庚-2-基氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物96)；N-(5-(bicyclo[2.2.1]hept-2-yloxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 96);
(R)-N-(7-(3,4-二氟苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物97)；(R)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 97);
(S)-N-(7-(3,4-二氟苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物98)；(S)-N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 98);
(R)-1-甲基-5-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物99)；(R)-1-methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 99);
(S)-N-(5-(3,4-二氟苯氧基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物100)；(S)-N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 100);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物101)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 101);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物102)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 102);
(R)-N-(2-甲氧基-5-(((反式)-4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物103)；(R)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 103);
N-(5-((4,4-二氟环己基)氧基)-2-甲氧基苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物104)；N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 104);
(S)-N-(2-甲氧基-5-(((反式)-4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物105)；(S)-N-(2-methoxy-5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 105);
1-甲基-5-氧代-N-(3-氧代-7-(3-(三氟甲基)苯氧基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-5-基)吡咯烷-2-甲酰胺(化合物106)；1-Methyl-5-oxo-N-(3-oxo-7-(3-(trifluoromethyl)phenoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)pyrrolidine-2-carboxamide (compound 106);
(S)-1-甲基-5-氧代-N-(5-(((顺式)-4-(三氟甲基)环己基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物107)；(S)-1-methyl-5-oxo-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 107);
(R)-1-甲基-5-氧代-N-(5-(((顺式)-4-(三氟甲基)环己基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物108)；(R)-1-methyl-5-oxo-N-(5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 108);
1-环丙基-5-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物109)；1-Cyclopropyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 109);
1-环丙基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物110)；1-Cyclopropyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 110);
1-环丙基-N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物111)；1-Cyclopropyl-N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (Compound 111);
N-(2-甲氧基-5-((5-(三氟甲氧基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物112)；N-(2-methoxy-5-((5-(trifluoromethoxy)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 112);
N-(7-(((4,4-二氟环己基)氧基)甲基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物113)；N-(7-(((4,4-difluorocyclohexyl)oxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 113);
1-环丙基-5-氧代-N-(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物114)；1-Cyclopropyl-5-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (compound 114);
N-(2-甲氧基-5-((5-(三氟甲氧基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物115)；N-(2-methoxy-5-((5-(trifluoromethoxy)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 115);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)四氢噻吩-3-甲酰胺1,1-二氧化物(化合物116)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)tetrahydrothiophene-3-carboxamide 1,1-dioxide (compound 116);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物117)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 117);
N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物118)；N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 118);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-6-氧代哌啶-3-甲酰胺(化合物119)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxopiperidin-3-carboxamide (compound 119);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-6-氧代哌啶-3-甲酰胺(化合物120)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxopiperidin-3-carboxamide (compound 120);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-6-氧代哌啶-3-甲酰胺(化合物121)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-6-oxopiperidin-3-carboxamide (compound 121);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-6-氧代-1,6-二氢吡啶-3-甲酰胺(化合物122)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 122);
N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3,4-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物123)；N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3,4-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 123);
(R)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物124)；(R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 124);
(S)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物125)；(S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 125);
(R)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物126)；(R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 126);
3-乙基-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-2-氧代咪唑烷-4-甲酰胺(化合物127)；3-Ethyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 127);
(R)-1-环丙基-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物128)；(R)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 128);
(S)-1-环丙基-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物129)；(S)-1-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 129);
(S)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物130)；(S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 130);
3-环丙基-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-2-氧代咪唑烷-4-甲酰胺(化合物131)；3-Cyclopropyl-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 131);
1-(环丙基甲基)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体1(化合物132)；1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 132);
1-(环丙基甲基)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体2(化合物133)；1-(cyclopropylmethyl)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 133);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1,2-二甲基-5-氧代吡咯烷-2-甲酰胺(化合物134)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-oxopyrrolidine-2-carboxamide (compound 134);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1,2-二甲基-5-氧代吡咯烷-2-甲酰胺(化合物135)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,2-dimethyl-5-oxopyrrolidine-2-carboxamide (compound 135);
1-(2-氨基-2-氧代乙基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物136)；1-(2-amino-2-oxoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 136);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(1-甲基-1H-吡唑-4-基)-5-氧代吡咯烷-2-甲酰胺(化合物137)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-1H-pyrazol-4-yl)-5-oxopyrrolidine-2-carboxamide (compound 137);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(四氢呋喃-3-基)吡咯烷-2-甲酰胺(化合物138)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide (compound 138);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物139)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 139);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物140)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 140);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物141)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 141);
3-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-2-氧代咪唑烷-4-甲酰胺(化合物142)；3-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 142);
(2S)-4-甲氧基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物143)；(2S)-4-methoxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 143);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-2-氧代咪唑烷-4-甲酰胺(化合物144)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxoimidazolidine-4-carboxamide (compound 144);
N-(2-甲氧基-4-(4-(三氟甲基)苯氧基)苯基)-1-(2-(甲基氨基)-2-氧代乙基)-5-氧代吡咯烷-2-甲酰胺(化合物145)；N-(2-methoxy-4-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-(methylamino)-2-oxoethyl)-5-oxopyrrolidine-2-carboxamide (compound 145);
1-(2-(二甲基氨基)-2-氧代乙基)-N-(2-甲氧基-4-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物146)；1-(2-(dimethylamino)-2-oxoethyl)-N-(2-methoxy-4-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 146);
1-(环丙基甲基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体1(化合物147)；1-(cyclopropylmethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 147);
1-(环丙基甲基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，对映异构体2(化合物148)；1-(cyclopropylmethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 148);
N-(5-(4-(二氟甲基)苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物149)；N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 149);
(S)-1-甲基-5-氧代-N-(5-(((反式)-4-(三氟甲基)环己基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物150)；(S)-1-methyl-5-oxo-N-(5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 150);
(R)-1-甲基-5-氧代-N-(5-(((反式)-4-(三氟甲基)环己基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物151)；(R)-1-methyl-5-oxo-N-(5-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 151);
N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物152)；N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 152);
N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物153)；N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 153);
(R)-N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)-氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物154)；(R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)-oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 154);
(R)-N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物155)；(R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 155);
(S)-N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物156)；(S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 156);
(S)-N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物157)；(S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 157);
N-(5-(2-氯-4-(三氟甲基)苯氧基)-4-氟-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物158)；N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 158);
3-甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物159)；3-Methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 159);
2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)哌啶-4-甲酰胺(化合物160)；2-Oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidin-4-carboxamide (compound 160);
6-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)哌啶-3-甲酰胺(化合物161)；6-Oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)piperidin-3-carboxamide (compound 161);
(R)-1-甲基-5-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物162)；(R)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 162);
(S)-1-甲基-5-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物163)；(S)-1-methyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 163);
3-环丙基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物164)；3-Cyclopropyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (Compound 164);
(S)-1-环丙基-5-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物165)；(S)-1-Cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (Compound 165);
(R)-1-环丙基-5-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物166)；(R)-1-Cyclopropyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (Compound 166);
3-乙基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物167)；3-Ethyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (Compound 167);
(S)-3-甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物168)；(S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 168);
(R)-3-甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物169)；(R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 169);
(R)-1-乙基-5-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物170)；(R)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 170);
(S)-1-乙基-5-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物171)；(S)-1-ethyl-5-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 171);
(2R)-1-甲基-N-(2-甲基-5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)-5-氧代吡咯烷-2-甲酰胺，对映异构体1(化合物172)；(2R)-1-methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 172);
(2R)-1-甲基-N-(2-甲基-5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)-5-氧代吡咯烷-2-甲酰胺，对映异构体2(化合物173)；(2R)-1-methyl-N-(2-methyl-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 173);
(S)-1-甲基-5-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并二氢吡喃-8-基)吡咯烷-2-甲酰胺(化合物174)；(S)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzodihydropyran-8-yl)pyrrolidine-2-carboxamide (compound 174);
(R)-1-甲基-5-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并二氢吡喃-8-基)吡咯烷-2-甲酰胺(化合物175)；(R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzodihydropyran-8-yl)pyrrolidine-2-carboxamide (compound 175);
3-甲基-2-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并二氢吡喃-8-基)咪唑烷-4-甲酰胺(化合物176)；3-Methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzodihydropyran-8-yl)imidazolidine-4-carboxamide (compound 176);
1-甲基-5-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并二氢吡喃-8-基)吡咯烷-2-甲酰胺(化合物177)；1-Methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzodihydropyran-8-yl)pyrrolidine-2-carboxamide (compound 177);
3-甲基-2-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)咪唑烷-4-甲酰胺(化合物178)；3-Methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-carboxamide (compound 178);
1-环丙基-5-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)吡咯烷-2-甲酰胺(化合物179)；1-Cyclopropyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)pyrrolidine-2-carboxamide (compound 179);
(S)-3-甲基-2-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)咪唑烷-4-甲酰胺(化合物180)；(S)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-carboxamide (compound 180);
(R)-3-甲基-2-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)咪唑烷-4-甲酰胺(化合物181)；(R)-3-methyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-carboxamide (compound 181);
3-甲基-2-氧代-N-(7-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)咪唑烷-4-甲酰胺(化合物182)；3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)imidazolidine-4-carboxamide (compound 182);
3-甲基-2-氧代-N-(7-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)咪唑烷-4-甲酰胺，对映异构体1(化合物183)；3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)imidazolidine-4-carboxamide, enantiomer 1 (compound 183);
3-甲基-2-氧代-N-(7-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)咪唑烷-4-甲酰胺，对映异构体2(化合物184)；3-Methyl-2-oxo-N-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)imidazolidine-4-carboxamide, enantiomer 2 (compound 184);
1-甲基-5-氧代-N-(5-(4-(三氟甲基)苯氧基)苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物185)；1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)benzofuran-7-yl)pyrrolidine-2-carboxamide (compound 185);
3-甲基-2-氧代-N-(6-(4-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)咪唑烷-4-甲酰胺(化合物186)；3-Methyl-2-oxo-N-(6-(4-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-carboxamide (compound 186);
2-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)哌啶-4-甲酰胺(化合物187)；2-Oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperidine-4-carboxamide (compound 187);
1-(2-(甲基氨基)-2-氧代乙基)-5-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物188)；1-(2-(methylamino)-2-oxoethyl)-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 188);
1-(2-氨基-2-氧代乙基)-5-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物189)；1-(2-amino-2-oxoethyl)-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 189);
N-(5-((4,4-二氟环己基)氧基)-2,3-二氢苯并呋喃-7-基)-6-氧代哌啶-3-甲酰胺(化合物190)；N-(5-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzofuran-7-yl)-6-oxopiperidin-3-carboxamide (compound 190);
N-(7-((4,4-二氟环己基)氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-6-氧代哌啶-3-甲酰胺(化合物191)；N-(7-((4,4-difluorocyclohexyl)oxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-6-oxopiperidin-3-carboxamide (compound 191);
3-甲基-2-氧代-N-(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)咪唑烷-4-甲酰胺(化合物192)；3-Methyl-2-oxo-N-(7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)imidazolidine-4-carboxamide (compound 192);
3-甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-1H-吲唑-7-基)咪唑烷-4-甲酰胺(化合物193)；3-Methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazol-7-yl)imidazolidine-4-carboxamide (compound 193);
1-甲基-N-(1-甲基-5-((5-(三氟甲基)吡啶-4-基)氧基)-1H-吲唑-7-基)-5-氧代吡咯烷-2-甲酰胺(化合物194)；1-Methyl-N-(1-methyl-5-((5-(trifluoromethyl)pyridin-4-yl)oxy)-1H-indazol-7-yl)-5-oxopyrrolidine-2-carboxamide (compound 194);
(S)-N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物195)；(S)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 195);
(R)-N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物196)；(R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 196);
N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物197)；N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 197);
(R)-N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物198)；(R)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 198);
(S)-N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物199)；(S)-N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 199);
N-(2-甲氧基-5-((4-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物200)；N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 200);
N-(2-甲氧基-5-((4-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物201)；N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 201);
N-(5-((5-氟吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物202)；N-(5-((5-fluoropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 202);
N-(5-((5-氯吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物203)；N-(5-((5-chloropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 203);
N-(5-(2-氟-4-硝基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物204)；N-(5-(2-fluoro-4-nitrophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 204);
N-(5-(((4,4-二氟环己基)氧基)甲基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物205)；N-(5-(((4,4-difluorocyclohexyl)oxy)methyl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 205);
N-(5-((4,4-二氟环己基)甲氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物206)；N-(5-((4,4-difluorocyclohexyl)methoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 206);
(2S)-N-(5-((4,4-二氟环庚基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物207)；(2S)-N-(5-((4,4-difluorocycloheptyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 207);
(R)-N-(2-甲氧基-5-((4-(三氟甲基)环己基)氧基)苯基)-3-甲基-2-氧代噁唑烷-4-甲酰胺(化合物208)；(R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-3-methyl-2-oxooxazolidine-4-carboxamide (compound 208);
(R)-N-(2-甲氧基-5-(((顺式)-4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物209)；(R)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 209);
(S)-N-(2-甲氧基-5-(((顺式)-4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物210)；(S)-N-(2-methoxy-5-(((cis)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 210);
N-(5-((5-(二氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物211)；N-(5-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 211);
N-(5-((5-(二氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物212)；N-(5-((5-(difluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 212);
N-(5-(4-(二氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物213)；N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 213);
(S)-N-(5-(4-(二氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物214)；(S)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 214);
(R)-N-(5-(4-(二氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物215)；(R)-N-(5-(4-(difluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 215);
(S)-3-甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物216)；(S)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazolidine-4-carboxamide (compound 216);
(R)-3-甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)苯并呋喃-7-基)咪唑-4-甲酰胺(化合物217)；(R)-3-methyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzofuran-7-yl)imidazol-4-carboxamide (compound 217);
(S)-3-甲基-N-(1-甲基-6-((5-(三氟甲基)吡啶-2-基)氧基)-1H-苯并[d]咪唑-4-基)-2-氧代咪唑烷-4-甲酰胺(化合物218)；(S)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-oxoimidazolidine-4-carboxamide (compound 218);
(R)-3-甲基-N-(1-甲基-6-((5-(三氟甲基)吡啶-2-基)氧基)-1H-苯并[d]咪唑-4-基)-2-氧代咪唑烷-4-甲酰胺(化合物219)；(R)-3-methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-2-oxoimidazolidine-4-carboxamide (compound 219);
(S)-N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物220)；(S)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 220);
(R)-N-(4-氟-2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物221)；(R)-N-(4-fluoro-2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 221);
N-(5-(3,4-二氯苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物222)；N-(5-(3,4-dichlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 222);
N-(5-(3-氯-4-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物223)；N-(5-(3-chloro-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 223);
N-(5-(3,4-二氟苯氧基)-2-(1,3,4-噁二唑-2-基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物224)；N-(5-(3,4-difluorophenoxy)-2-(1,3,4-oxadiazol-2-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 224);
1-甲基-5-氧代-N-(5-(4-(三氟甲基)苯氧基)-1H-吲唑-7-基)吡咯烷-2-甲酰胺(化合物225)；1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-1H-indazol-7-yl)pyrrolidine-2-carboxamide (compound 225);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物226)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 226);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物227)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 227);
4-羟基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-3-甲酰胺(化合物228)；4-Hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (compound 228);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(5-氧代吡咯烷-2-羰基)吡咯烷-2-甲酰胺(化合物229)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (compound 229);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(1-甲基-5-氧代吡咯烷-2-羰基)-5-氧代吡咯烷-2-甲酰胺(化合物230)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-methyl-5-oxopyrrolidine-2-carbonyl)-5-oxopyrrolidine-2-carboxamide (compound 230);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(4-氧代氮杂环丁烷-2-羰基)吡咯烷-2-甲酰胺(化合物231)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(4-oxoazacyclobutane-2-carbonyl)pyrrolidine-2-carboxamide (compound 231);
N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-5-氧代-1-(4-氧代氮杂环丁烷-2-羰基)吡咯烷-2-甲酰胺(化合物232)；N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-5-oxo-1-(4-oxoazacyclobutane-2-carbonyl)pyrrolidine-2-carboxamide (compound 232);
1-甲基-5-氧代-N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物233)；1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (compound 233);
1-甲基-5-氧代-N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺，对映异构体1(化合物234)；1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide, enantiomer 1 (compound 234);
1-甲基-5-氧代-N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺，对映异构体2(化合物235)；1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide, enantiomer 2 (compound 235);
1-甲基-N-(8-甲基-7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-5-氧代吡咯烷-2-甲酰胺(化合物236)；1-Methyl-N-(8-methyl-7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-5-oxopyrrolidine-2-carboxamide (compound 236);
1-甲基-5-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物237)；1-Methyl-5-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 237);
1-甲基-5-氧代-N-(5-((3-(三氟甲基)苄基)氧基)-2,3-二氢苯并呋喃-7-基)吡咯烷-2-甲酰胺(化合物238)；1-Methyl-5-oxo-N-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydrobenzofuran-7-yl)pyrrolidine-2-carboxamide (compound 238);
N-(5-(3,4-二氟苯氧基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物239)；N-(5-(3,4-difluorophenoxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 239);
N-(7-(3,4-二氟苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物240)；N-(7-(3,4-difluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 240);
N-(7-(4-氟苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物241)；N-(7-(4-fluorophenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 241);
N-(5-((3,4-二氟苯氧基)甲基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物242)；N-(5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 242);
N-(6-((3,4-二氟苯氧基)甲基)-2,3-二氢苯并呋喃-4-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物243)；N-(6-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 243);
1-甲基-N-(1-甲基-6-((5-(三氟甲基)吡啶-2-基)氧基)-1H-苯并[d]咪唑-4-基)-5-氧代吡咯烷-2-甲酰胺，对映异构体1(化合物244)；1-Methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 1 (compound 244);
1-甲基-N-(1-甲基-6-((5-(三氟甲基)吡啶-2-基)氧基)-1H-苯并[d]咪唑-4-基)-5-氧代吡咯烷-2-甲酰胺，对映异构体2(化合物245)；1-Methyl-N-(1-methyl-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-benzo[d]imidazol-4-yl)-5-oxopyrrolidine-2-carboxamide, enantiomer 2 (compound 245);
N-(5-(((3-氟苯基)氨基)甲基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物246)；N-(5-(((3-fluorophenyl)amino)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 246);
N-(5-((4,4-二氟环己基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物247)；N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 247);
N-(5-((3,4-二氟苄基)氧基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物248)；N-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 248);
N-(5-((3-氟苯氧基)甲基)苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物249)；N-(5-((3-fluorophenoxy)methyl)benzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 249);
N-(2-氟-3-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物250)；N-(2-fluoro-3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 250);
N-(5-(3,4-二氟苯氧基)-2-氟-3-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物251)；N-(5-(3,4-difluorophenoxy)-2-fluoro-3-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 251);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代四氢吡咯并[2,1-b]噻唑-7a(5H)-甲酰胺1,1-二氧化物(化合物252)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formamide 1,1-dioxide (compound 252);
N-(3-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物253)；N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 253);
(E)-N-(5-(3-氟苯乙烯基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物254)；(E)-N-(5-(3-fluorostyryl)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 254);
N-(2-甲氧基-5-((4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物255)；N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 255);
N-(2-甲氧基-5-(3-(三氟甲基)苄基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物256)；N-(2-methoxy-5-(3-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 256);
N-(2-甲氧基-5-(4-(三氟甲基)苄基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物257)；N-(2-methoxy-5-(4-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 257);
N-(2-氯-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物258)；N-(2-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 258);
N-(4-甲氧基-3-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物259)；N-(4-methoxy-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 259);
N-(5-(4-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物260)；N-(5-(4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 260);
N-(3-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物261)；N-(3-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 261);
N-(5-((6-氟-5-甲基吡啶-3-基)氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物262)；N-(5-((6-fluoro-5-methylpyridin-3-yl)oxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 262);
(R)-N-(5-((6-氟-5-甲基吡啶-3-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物263)；(R)-N-(5-((6-fluoro-5-methylpyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 263);
N-(2-甲氧基-5-((4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物264)；N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 264);
(R)-N-(2-甲氧基-5-((4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物265)；(R)-N-(2-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 265);
N-(2-甲氧基-5-(((1R,3S)-3-(三氟甲基)环己基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物266)；N-(2-methoxy-5-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 266);
N-(2-甲氧基-5-(((1S,3S)-3-(三氟甲基)环己基)氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物267)；N-(2-methoxy-5-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 267);
(R)-N-(2-甲氧基-5-(((1R，3S)-3-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物268)；(R)-N-(2-methoxy-5-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 268);
(R)-N-(2-甲氧基-5-(((1S，3S)-3-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物269)；(R)-N-(2-methoxy-5-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 269);
N-(2-氟-5-((4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物270)；N-(2-fluoro-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 270);
(R)-N-(4-甲氧基-3-(((1r，4R)-4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物271)；(R)-N-(4-methoxy-3-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 271);
(R)-N-(4-甲氧基-3-(((1s，4S)-4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物272)；(R)-N-(4-methoxy-3-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 272);
N-(3-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物273)；N-(3-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 273);
N-(3-(4-氯-3-(三氟甲基)苯氧基)-5-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物274)；N-(3-(4-chloro-3-(trifluoromethyl)phenoxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 274);
(R)-N-(3-((4,4-二氟环己基)氧基)-5-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物275)；(R)-N-(3-((4,4-difluorocyclohexyl)oxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 275);
N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物276)；N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 276);
N-(3-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物277)；N-(3-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 277);
(R)-N-(3-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物278)；(R)-N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 278);
N-(3-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物279)；N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 279);
1-甲基-5-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)喹啉-8-基)吡咯烷-2-甲酰胺(化合物280)；1-Methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline-8-yl)pyrrolidine-2-carboxamide (compound 280);
(R)-1-甲基-5-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)喹啉-8-基)吡咯烷-2-甲酰胺(化合物281)；(R)-1-methyl-5-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline-8-yl)pyrrolidine-2-carboxamide (compound 281);
(R)-N-(3-甲氧基-5-((4-(三氟甲基)环己基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物282)；(R)-N-(3-methoxy-5-((4-(trifluoromethyl)cyclohexyl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 282);
(R)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物283)；(R)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 283);
N-(3-(3,4-二氟苯氧基)-5-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物284)；N-(3-(3,4-difluorophenoxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 284);
(R)-N-(3-(3,4-二氟苯氧基)-5-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物285)；(R)-N-(3-(3,4-difluorophenoxy)-5-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 285);
N-(5-(环己基氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物286)；N-(5-(cyclohexyloxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 286);
N-(5-(环己-2-烯-1-基氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物287)；N-(5-(cyclohex-2-en-1-yloxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 287);
(S)-N-(5-((5-氯吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物288)；(S)-N-(5-((5-chloropyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 288);
1-乙酰基-N-(2-甲氧基-5-(3-(三氟甲基)苯氧基)苯基)氮杂环丁烷-3-甲酰胺(化合物289)；1-Acetyl-N-(2-methoxy-5-(3-(trifluoromethyl)phenoxy)phenyl)azacyclobutane-3-carboxamide (compound 289);
(R)-N-(2-甲氧基-5-(4-(三氟甲氧基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物290)；(R)-N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 290);
N-(2-甲氧基-5-(3-(三氟甲氧基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物291)；N-(2-methoxy-5-(3-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 291);
N-(5-(4-(二氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物292)；N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 292);
(R)-N-(5-(4-氟-3-甲氧基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物293)；(R)-N-(5-(4-fluoro-3-methoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 293);
N-(5-(环己基甲氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物294)；N-(5-(cyclohexylmethoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 294);
N-(5-(3-氟-4-甲氧基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物295)；N-(5-(3-fluoro-4-methoxyphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 295);
N-(5-((4,4-二甲基环己基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物296)；N-(5-((4,4-dimethylcyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 296);
N-(5-((3,4-二氟苯基)硫基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物297)；N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 297);
N-(5-((3,4-二氟苯基)硫基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物298)；N-(5-((3,4-difluorophenyl)thio)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 298);
N-(5-(3-溴苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物299)；N-(5-(3-bromophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 299);
N-(2-甲氧基-5-(4-(三氟甲氧基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物300)；N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 300);
N-(5-(4-异丙氧基苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物301)；N-(5-(4-isopropoxyphenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 301);
N-(5-((3，3-二氟环丁基)甲氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物302)；N-(5-((3,3-difluorocyclobutyl)methoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 302);
N-(3-(4-氟苯氧基)-5-(三氟甲基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物303)；N-(3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 303);
N-(5-(4-氯苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物304)；N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 304);
N-(5-(4-氯-3-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物305)；N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 305);
N-(3-氰基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物306)；N-(3-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 306);
(S)-N-(5-(4-氯苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物307)；(S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 307);
(R)-N-(5-(4-氯苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物308)；(R)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 308);
N-(5-(3-氯-4-氰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物309)；N-(5-(3-chloro-4-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 309);
(S)-N-(5-(3-氯-4-氰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物310)；(S)-N-(5-(3-chloro-4-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 310);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(甲基磺酰基)吡咯烷-2-甲酰胺(化合物311)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxamide (compound 311);
(S)-N-(5-(4-氯-3-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物312)；(S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 312);
(S)-N-(5-(4-(二氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物313)；(S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 313);
N-(2-甲氧基-5-((1-甲基-1H-吲哚-5-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物314)；N-(2-methoxy-5-((1-methyl-1H-indol-5-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 314);
N-(5-((2,3-二氢苯并呋喃-5-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物315)；N-(5-((2,3-dihydrobenzofuran-5-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 315);
N-(5-(3-氯苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物316)；N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 316);
N-(5-(4-氰基-3-甲基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物317)；N-(5-(4-cyano-3-methylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 317);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(2-甲氧基乙基)-5-氧代吡咯烷-2-甲酰胺(化合物318)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyethyl)-5-oxopyrrolidine-2-carboxamide (compound 318);
(R)-N-(5-(4-(二氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物319)；(R)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 319);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-6-氧代哌啶-2-甲酰胺(化合物320)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperidin-2-carboxamide (compound 320);
N-(5-(3,4-二氟苯氧基)-2-甲氧基苯基)-1-甲基-6-氧代哌啶-2-甲酰胺(化合物321)；N-(5-(3,4-difluorophenoxy)-2-methoxyphenyl)-1-methyl-6-oxopiperidin-2-carboxamide (compound 321);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-2-氧代哌啶-4-甲酰胺(化合物322)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopiperidine-4-carboxamide (compound 322);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-2-氧代哌啶-4-甲酰胺(化合物323)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxopiperidin-4-carboxamide (compound 323);
N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-2-氧代哌啶-4-甲酰胺，对映异构体1(化合物324)；N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxopiperidin-4-carboxamide, enantiomer 1 (compound 324);
N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-2-氧代哌啶-4-甲酰胺，对映异构体2(化合物325)；N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxopiperidine-4-carboxamide, enantiomer 2 (compound 325);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(甲基磺酰基)吡咯烷-3-甲酰胺(化合物326)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-3-carboxamide (compound 326);
N-(2-甲氧基-5-((4-(三氟甲基)吡啶-2-基)氧基)苯基)-2-氧代哌啶-4-甲酰胺，对映异构体1(化合物327)；N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2-oxopiperidin-4-carboxamide, enantiomer 1 (compound 327);
N-(2-氟-5-(4-(三氟甲氧基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物328)；N-(2-fluoro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 328);
N-(2-氯-5-(4-(三氟甲氧基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物329)；N-(2-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 329);
N-(2-氨基甲酰基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物330)；N-(2-carbamoyl-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 330);
N-(2-甲氧基-5-((4-(三氟甲基)-吡啶-2-基)氧基)苯基)-1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酰胺(化合物331)；N-(2-methoxy-5-((4-(trifluoromethyl)-pyridin-2-yl)oxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (compound 331);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-2-氧代咪唑烷-4-甲酰胺(化合物332)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 332);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酰胺(化合物333)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (compound 333);
N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酰胺(化合物334)；N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (compound 334);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-3-甲酰胺(化合物335)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 335);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(2-甲氧基乙酰基)吡咯烷-2-甲酰胺(化合物336)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide (compound 336);
(S)-1-(2-氨基-2-氧代乙基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-2-甲酰胺(化合物337)；(S)-1-(2-amino-2-oxoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 337);
(S)-N-(5-(4-氯-3-氟苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物338)；(S)-N-(5-(4-chloro-3-fluorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 338);
(S)-N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物339)；(S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 339);
(S)-N-(5-(4-(二氟甲基)苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物340)；(S)-N-(5-(4-(difluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 340);
2-(1,3-二甲基-2，5-二氧代咪唑烷-4-基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)乙酰胺(化合物341)；2-(1,3-Dimethyl-2,5-dioxoimidazolidine-4-yl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)acetamide (compound 341);
(S)-3-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-2-氧代咪唑烷-4-甲酰胺(化合物342)；(S)-3-acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 342);
(S)-3-乙酰基-N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-2-氧代咪唑烷-4-甲酰胺(化合物343)；(S)-3-acetyl-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide (compound 343);
N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-5-氧代吡咯烷-3-甲酰胺(化合物344)；N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 344);
(S)-N-(5-((3-氯-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物345)；(S)-N-(5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 345);
(S)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物346)；(S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 346);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(2-甲氧基乙酰基)吡咯烷-2-甲酰胺(化合物347)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(2-methoxyacetyl)pyrrolidine-2-carboxamide (compound 347);
(S)-N-(5-(3-氯苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物348)；(S)-N-(5-(3-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 348);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-3-甲酰胺(化合物349)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (compound 349);
N-(5-(2-氯-4-(三氟甲基)苯氧基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物350)；N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (compound 350);
(S)-N-(3-氯-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物351)；(S)-N-(3-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 351);
N-(3-氯-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物352)；N-(3-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 352);
(S)-N-(5-(4-(氟甲基)苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物353)；(S)-N-(5-(4-(fluoromethyl)phenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 353);
2-(2-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基甲酰基)-5-氧代吡咯烷-1-基)乙酸甲酯(化合物354)；2-(2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidone-1-yl)methyl acetate (compound 354);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-3-甲酰胺(化合物355)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 355);
(S)-N-(5-(4-氯苯氧基)-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物356)；(S)-N-(5-(4-chlorophenoxy)-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 356);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-3-甲酰胺(化合物357)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-3-carboxamide (compound 357);
(S)-1-乙酰基-N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)吡咯烷-2-甲酰胺(化合物358)；(S)-1-acetyl-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (compound 358);
(S)-N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物359)；(S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 359);
(S)-1,3-二甲基-2-氧代-N-(6-((5-(三氟甲基)吡啶-2-基)氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)咪唑烷-4-甲酰胺(化合物360)；(S)-1,3-dimethyl-2-oxo-N-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)imidazolidine-4-carboxamide (compound 360);
(S)-N-(2,4-二氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物361)；(S)-N-(2,4-difluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 361);
(S)-N-(3-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物362)；(S)-N-(3-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 362);
(S)-N-(2-氟-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物363)；(S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 363);
(S)-1,3-二甲基-2-氧代-N-(5-((5-(三氟甲基)吡啶-2-基)氧基)-2,3-二氢苯并呋喃-7-基)咪唑烷-4-甲酰胺(化合物364)；(S)-1,3-dimethyl-2-oxo-N-(5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-dihydrobenzofuran-7-yl)imidazolidine-4-carboxamide (compound 364);
(S)-N-(2-氟-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物365)；(S)-N-(2-fluoro-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 365);
N-(2-溴-5-(3-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物366)；N-(2-bromo-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 366);
N-(2-氰基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物367)；N-(2-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 367);
N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物368)；N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 368);
N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物369)；N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 369);
(2S，4R)-4-羟基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-2-甲酰胺(化合物370)；(2S,4R)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 370);
(S)-1-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物371)；(S)-1-acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 371);
N-(2-羟基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物372)；N-(2-hydroxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 372);
(S)-N-(2-羟基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物373)；(S)-N-(2-hydroxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 373);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-6-氧代哌嗪-2-甲酰胺(化合物374)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperazine-2-carboxamide (compound 374);
4-氨基-5-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基)-5-氧代戊酸(化合物375)；4-Amino-5-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)amino)-5-oxovaleric acid (compound 375);
1-甲基-6-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)哌嗪-2-甲酰胺(化合物376)；1-Methyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazin-2-carboxamide (compound 376);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(1H-吡唑-4-基)吡咯烷-2-甲酰胺(化合物377)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazol-4-yl)pyrrolidine-2-carboxamide (compound 377);
(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(1H-吡唑-4-基)吡咯烷-2-甲酰胺(化合物378)；(R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazol-4-yl)pyrrolidine-2-carboxamide (compound 378);
1-(3-氨基-3-氧代丙基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物379)；1-(3-amino-3-oxopropyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (compound 379);
(2S,4S)-4-羟基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物380)；(2S,4S)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 380);
1-亚胺基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)六氢-1λ6-噻喃-4-甲酰胺1-氧化物(化合物381)；1-Imine-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)hexahydro- 1λ6 -thiaran-4-carboxamide 1-oxide (compound 381);
N-(4-氟-2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物382)；N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 382);
1,4-二甲基-6-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)哌嗪-2-甲酰胺(化合物383)；1,4-Dimethyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazin-2-carboxamide (compound 383);
N-(5-(4-氨基-2-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物384)；N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 384);
N-(5-(4-氯-2-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物385)；N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 385);
N-(5-(3-乙酰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物386)；N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 386);
N-(5-(3-乙酰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物387)；N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 387);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-2-氧代-2,3-二氢噁唑-4-甲酰胺(化合物388)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxo-2,3-dihydrooxazol-4-carboxamide (compound 388);
N-(3-(3,4-二氟苯氧基)-6-甲氧基-2-甲基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物389)；N-(3-(3,4-difluorophenoxy)-6-methoxy-2-methylphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 389);
N-(5-(3-氰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物390)；N-(5-(3-cyanophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 390);
N-(2-甲氧基-5-(3-甲氧基-4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物391)；N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 391);
N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1H-四唑-5-甲酰胺(化合物392)；N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1H-tetrazole-5-carboxamide (compound 392);
(R)-N-(2-甲氧基-5-((4-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物393)；(R)-N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 393);
(S)-N-(2-甲氧基-5-((4-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物394)；(S)-N-(2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 394);
N-(2-甲氧基-5-(3-甲氧基-4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物395)；N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 395);
N-(5-(4-氰基-3-(三氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物396)；N-(5-(4-cyano-3-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 396);
N-(5-(3-氰基-4-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物397)；N-(5-(3-cyano-4-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 397);
(S)-N-(5-(2-氟-4-(三氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物398)；(S)-N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 398);
(N-(5-((5-氟-6-(三氟甲基)吡啶-3-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物399)；(N-(5-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 399);
N-(5-((6-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物400)；N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 400);
(S)-N-(5-((6-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物401)；(S)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 401);
(R)-N-(5-((6-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物402)；(R)-N-(5-((6-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 402);
(S)-N-(2-甲氧基-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物403)；(S)-N-(2-methoxy-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 403);
(E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2-甲氧基苯基)-2-氧代咪唑烷-4-甲酰胺(化合物404)；(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-2-oxoimidazolidine-4-carboxamide (compound 404);
(R,E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物405)；(R,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 405);
(S,E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物406)；(S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 406);
(S,E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2,3-二氢苯并呋喃-7-基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物407)；(S,E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 407);
(E)-N-(5-(2-(4,4-二氟环己基)乙烯基)-2-甲氧基苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物408)；(E)-N-(5-(2-(4,4-difluorocyclohexyl)vinyl)-2-methoxyphenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (compound 408);
((S,E)-N-(6-(2-(4,4-二氟环己基)乙烯基)苯并[d][1,3]间二氧杂环戊烯-4-基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物409)；((S,E)-N-(6-(2-(4,4-difluorocyclohexyl)vinyl)benzo[d][1,3]m-dioxacyclopenten-4-yl)-3-methyl-2-oxoimidazolidine-4-carboxamide (compound 409);
N-(2-羟基-5-(3-甲氧基-4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物410)；N-(2-hydroxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 410);
N-(5-(2-羟基-4-(三氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物411)；N-(5-(2-hydroxy-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 411);
1-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-3-甲酰胺(化合物412)；1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-3-carboxamide (compound 412);
1-乙酰基-N-(5-(3-氟苯氧基)-2-甲氧基苯基)吡咯烷-3-甲酰胺(化合物413)；1-Acetyl-N-(5-(3-fluorophenoxy)-2-methoxyphenyl)pyrrolidine-3-carboxamide (compound 413);
1-甘氨酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，HCl(化合物414)；1-Glycyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, HCl (compound 414);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-2-甲酰胺(化合物415)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (compound 415);
(S)-N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)吡咯烷-2-甲酰胺(化合物416)；(S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (compound 416);
(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-N,1-二甲基-5-氧代吡咯烷-2-甲酰胺(化合物417)；(S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-N,1-dimethyl-5-oxopyrrolidine-2-carboxamide (compound 417);
和其互变异构体和药学上可接受的盐。And its tautomers and pharmaceutically acceptable salts.
本发明的化合物可以以治疗有效量向患者施用，所述治疗有效量的范围通常为约0.5至约2000mg，更典型地为约1至约500mg，例如约2至约100mg，每天取决于年龄、性别、体重、人种、患者的状况、待治疗的状况、施用途径和所用的活性成分。本发明的化合物可以使用本领域已知的原理配制成剂型。化合物可以以片剂、颗粒剂、胶囊剂、栓剂、乳剂、混悬剂或溶液剂的形式本身或与合适的药物赋形剂组合给予患者。为组合物选择合适的成分是本领域普通技术人员的常规操作。也可使用合适的载体、溶剂、凝胶形成成分、分散体形成成分、抗氧化剂、着色剂、甜味剂、润湿化合物和该技术领域中通常使用的其它成分。含有活性化合物的组合物可以经肠或肠胃外给药，优选口服途径。组合物中活性化合物的含量为总组合物重量的约0.5至100％，通常约0.5至约20％。The compounds of the present invention can be administered to patients in therapeutically effective amounts, typically ranging from about 0.5 to about 2000 mg, more typically from about 1 to about 500 mg, for example from about 2 to about 100 mg daily, depending on age, sex, weight, race, patient condition, treatment status, route of administration, and active ingredient used. The compounds of the present invention can be formulated into dosage forms using principles known in the art. The compounds can be administered to patients alone or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions, or solutions. Selecting suitable ingredients for the composition is a routine practice for those skilled in the art. Suitable carriers, solvents, gel-forming components, dispersion-forming components, antioxidants, colorants, sweeteners, wetting compounds, and other ingredients commonly used in this art can also be used. Compositions containing the active compound can be administered enterally or parenterally, preferably orally. The content of the active compound in the composition is about 0.5% to 100% of the total composition weight, typically about 0.5% to about 20%.
本发明的化合物可以作为唯一的活性成分给予个体，或者与一种或多种其它活性成分组合给予个体，用于治疗特定疾病。The compounds of the present invention can be administered to an individual as the sole active ingredient, or in combination with one or more other active ingredients, for the treatment of a specific disease.
在治疗需要抑制TEAD的疾病和病症如各种癌症或慢性疼痛中，治疗剂和/或其它治疗(例如放射治疗)的组合通常是有利的。待施用的第二(或第三)药剂可以具有与主要治疗剂相同或不同的作用机制。In the treatment of diseases and conditions requiring suppression of TEADs, such as various cancers or chronic pain, a combination of the therapeutic agent and/or other treatments (e.g., radiation therapy) is often advantageous. The second (or third) agent to be administered may have the same or different mechanisms of action as the primary therapeutic agent.
因此，本发明的化合物可以与用于治疗癌症的其它抗癌治疗组合施用。例如，本发明的化合物可以与说明书一起包装，所述说明书是化合物将与其它抗癌剂和治疗癌症的治疗方法组合使用的说明书。类似地，本发明的化合物可以与用于治疗慢性疼痛的其它疼痛缓解剂联合施用。例如，本发明的化合物可以与说明书一起包装，所述说明书是该化合物与其它抗癌剂和治疗癌症的治疗剂，或与其它疼痛缓解剂和治疗慢性疼痛的治疗剂组合使用的说明书。本发明还包括本发明的化合物和一种或多种试剂盒形式的附加剂的组合，例如，其中它们被包装在一起或放置在单独的包装中作为试剂盒一起出售，或其中它们被包装以配制在一起。Therefore, the compounds of the present invention can be administered in combination with other anticancer therapies for treating cancer. For example, the compounds of the present invention can be packaged with an instruction manual that specifies the use of the compound in combination with other anticancer agents and treatments for cancer. Similarly, the compounds of the present invention can be administered in combination with other pain relievers for treating chronic pain. For example, the compounds of the present invention can be packaged with an instruction manual that specifies the use of the compound in combination with other anticancer agents and treatments for cancer, or with other pain relievers and treatments for chronic pain. The present invention also includes combinations of the compounds of the present invention and one or more adjuvants in the form of kits, for example, wherein they are packaged together or placed in separate packages and sold as kits, or wherein they are packaged for formulation.
根据本发明的一个实施方案，治疗有效量的式(I)的化合物或其药学上可接受的盐与一种或多种抗癌剂或疼痛缓解剂共同施用。According to one embodiment of the invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is co-administered with one or more anticancer agents or pain relievers.
除了式(I)的化合物或其药学上可接受的盐之外，可以施用的任选的其它抗癌剂包括但不限于，In addition to compounds of formula (I) or their pharmaceutically acceptable salts, other optional anticancer agents that may be administered include, but are not limited to,
-化疗剂(例如多西他赛和紫杉醇)，- Chemotherapy agents (such as docetaxel and paclitaxel),
-酪氨酸激酶抑制剂，包括EGFR抑制剂(例如吉非替尼和奥希替尼)、VEGFR抑制剂(例如贝伐单抗)和FGFR抑制剂(例如厄达替尼)；- Tyrosine kinase inhibitors, including EGFR inhibitors (such as gefitinib and osimertinib), VEGFR inhibitors (such as bevacizumab), and FGFR inhibitors (such as erdatinib);
-免疫检查点抑制剂(例如纳武单抗和帕博利珠单抗)，- Immune checkpoint inhibitors (such as nivolumab and pembrolizumab),
-表观遗传调节剂(例如BET抑制剂和HDAC抑制剂)，- Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors),
-mTOR抑制剂(例如依维莫司)；-mTOR inhibitors (e.g., everolimus);
-AKT抑制剂(例如AZ5363)；-AKT inhibitors (e.g., AZ5363);
-放射性药物(例如α-放射素)；- Radiopharmaceuticals (e.g., alpha-radioactive substances);
-GnRH/LHRH类似物(例如亮丙瑞林)；-GnRH/LHRH analogues (e.g., leuprolide);
-PI3K抑制剂(例如艾代拉里斯(idelalisib))；和-PI3K inhibitors (such as idelalisib); and
-CDK4/6抑制剂(例如瑞波西利(ribocyclib))-CDK4/6 inhibitors (e.g., ribocyclib)
-类固醇生成抑制剂(例如CYP17A1抑制剂，如乙酸阿比特龙酯和seviteronel)；和- Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and seviteronel); and
-非甾体雄激素受体拮抗剂(例如恩杂鲁胺、阿帕鲁胺和达洛鲁胺)。- Nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and daloulamide).
根据另一个实施方案，本发明提供了一种药物组合，其包含式(I)的化合物或其药学上可接受的盐和至少一种选自下列的另外的活性成分，According to another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active ingredient selected from the following:
-化疗剂(例如多西他赛和紫杉醇)，- Chemotherapy agents (such as docetaxel and paclitaxel),
-酪氨酸激酶抑制剂，包括EGFR抑制剂(例如吉非替尼和奥希替尼)、VEGFR抑制剂(例如贝伐单抗)和FGFR抑制剂(例如厄达替尼)；- Tyrosine kinase inhibitors, including EGFR inhibitors (such as gefitinib and osimertinib), VEGFR inhibitors (such as bevacizumab), and FGFR inhibitors (such as erdatinib);
-免疫检查点抑制剂(例如纳武单抗和帕博利珠单抗)，- Immune checkpoint inhibitors (such as nivolumab and pembrolizumab),
-表观遗传调节剂(例如BET抑制剂和HDAC抑制剂)，- Epigenetic regulators (e.g., BET inhibitors and HDAC inhibitors),
-mTOR抑制剂(例如依维莫司)；-mTOR inhibitors (e.g., everolimus);
-AKT抑制剂(例如AZ5363)；-AKT inhibitors (e.g., AZ5363);
-放射性药物(例如α-放射素)；- Radiopharmaceuticals (e.g., alpha-radioactive substances);
-GnRH/LHRH类似物(例如亮丙瑞林)；-GnRH/LHRH analogues (e.g., leuprolide);
-PI3K抑制剂(例如艾代拉里斯)；和-PI3K inhibitors (such as ederaris); and
-CDK4/6抑制剂(例如瑞波西利)-CDK4/6 inhibitors (e.g., ripociclib)
-类固醇生成抑制剂(例如CYP17A1抑制剂，如乙酸阿比特龙酯和seviteronel)；和- Steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate and seviteronel); and
-非甾体雄激素受体拮抗剂(例如恩杂鲁胺、阿帕鲁胺和达洛鲁胺)，- Nonsteroidal androgen receptor antagonists (such as enzalutamide, apalutamide, and dalolutamide),
用于同时、分开或顺序施用。Used for simultaneous, separate, or sequential application.
当与本发明化合物组合使用时，上述其它治疗剂可以例如以Physicians'DeskReference(PDR)中所示的量或如本领域普通技术人员以其它方式确定的量使用。When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used, for example, in the amounts shown in the Physicians' Desk Reference (PDR) or in amounts otherwise determined by those skilled in the art.
本发明的化合物可以使用合适的起始原料通过与文献中已知的方法类似的多种合成途径制备。通过以下实验和实施例将更详细地阐释本发明。所述实验和实施例仅用于说明目的，而不限制权利要求书中定义的本发明的范围。The compounds of this invention can be prepared using suitable starting materials via a variety of synthetic routes similar to those known in the literature. The invention will be illustrated in more detail by the following experiments and examples. These experiments and examples are for illustrative purposes only and do not limit the scope of the invention as defined in the claims.
实施例：Example:
使用的纯化方法：Purification method used:
A)反相HPLC(水/乙腈，2-8min 0-65％，30mL/min，柱：SunFire 100*19mm)。A) Reversed-phase HPLC (water/acetonitrile, 2-8 min 0-65%, 30 mL/min, column: SunFire 100*19 mm).
B)反相HPLC(水/甲醇，2-8min 0-65％，30mL/min，柱：SunFire 100*19mm)。B) Reversed-phase HPLC (water/methanol, 2-8 min 0-65%, 30 mL/min, column: SunFire 100*19 mm).
C)反相HPLC(水/乙腈/甲酸，2-10min 0-40％，30mL/min，柱：SunFire100*19mm)。C) Reversed-phase HPLC (water/acetonitrile/formic acid, 2-10 min 0-40%, 30 mL/min, column: SunFire 100*19 mm).
D)反相HPLC(水/乙腈/氨，2-8min 0-65％，30mL/min，柱：SunFire100*19mm)。D) Reversed-phase HPLC (water/acetonitrile/ammonia, 2-8 min 0-65%, 30 mL/min, column: SunFire 100*19 mm).
E)反相HPLC(水/甲醇/氨，2-10min，40-50％，30mL/min，柱：SunFire100*19mm)。E) Reversed-phase HPLC (water/methanol/ammonia, 2-10 min, 40-50%, 30 mL/min, column: SunFire 100*19 mm).
F)反相HPLC(水/乙腈/三氟乙酸，2-10min 0-50％，30mL/min，柱：SunFire100*19mm)。F) Reversed-phase HPLC (water/acetonitrile/trifluoroacetic acid, 2-10 min 0-50%, 30 mL/min, column: SunFire 100*19 mm).
G)反相HPLC(水/甲醇/三氟乙酸，2-10min 10-50％，30mL/min，柱：SunFire100*19mm)。G) Reversed-phase HPLC (water/methanol/trifluoroacetic acid, 2-10 min 10-50%, 30 mL/min, column: SunFire 100*19 mm).
H)制备手性HPLC(甲醇/异丙醇，50-50，12mL/min，柱：Chiralpak AD-H(250*20mm)。H) Preparation of chiral HPLC (methanol/isopropanol, 50-50, 12 mL/min, column: Chiralpak AD-H (250*20 mm).
I)制备手性HPLC(甲醇/IPA/己烷，25-25-50，0.6mL/min，柱：Chiralpak IC(250*4.6mm)。I) Preparation of chiral HPLC (methanol/IPA/hexane, 25-25-50, 0.6 mL/min, column: Chiralpak IC (250*4.6 mm).
J)制备手性HPLC(甲醇/CO2，50-50，2mL/min，柱：Chiralpak AD-H(250*4.6mm)。J) Preparation of chiral HPLC (methanol/CO2, 50-50, 2 mL/min, column: Chiralpak AD-H (250*4.6 mm).
中间体1.5-溴-2-氟-4-甲氧基苯基甲酸酯Intermediate 1,5-bromo-2-fluoro-4-methoxyphenyl carbamate
在4℃下，向5-溴-2-氟-4-甲氧基苯甲醛(1.000g，1当量，4.291mmol)在CHCl3(20mL)中的溶液中加入3-氯过氧苯甲酸(1.851g，2.5当量，10.73mmol)，随后搅拌30min。将混合物用水(50mL)稀释，并将所得混合物用乙酸乙酯(3×10mL)萃取。合并有机层，用饱和的NaHCO3溶液(2×10mL)和盐水(10mL)洗涤，经硫酸钠干燥，过滤并浓缩，得到标题化合物。1H NMR(400MHz,DMSO-d6)δ:8.57(s,1H),7.69(dd,1H),7.29(dd,1H),3.86(d,3H)。At 4 °C, 3-chloroperoxybenzoic acid (1.851 g, 2.5 equivalents, 10.73 mmol) was added to a solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (1.000 g, 1 equivalent, 4.291 mmol) in CHCl3 (20 mL), followed by stirring for 30 min. The mixture was diluted with water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated NaHCO3 solution (2 × 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ: 8.57 (s, 1H), 7.69 (dd, 1H), 7.29 (dd, 1H), 3.86 (d, 3H).
根据中间体1所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。The following intermediates are prepared from the starting materials shown in the table according to the method described in intermediate 1. No data is displayed if there is no information in the LCMS/GCMS data.
中间体5.5-溴-2-氟-4-甲氧基苯酚Intermediate 5,5-bromo-2-fluoro-4-methoxyphenol
将氢氧化钠(1.606g，2.5当量，40.15mmol)加入到5-溴-2-氟-4-甲氧基苯基甲酸酯(4.0g，1当量，16.06mmol)在甲醇(100mL)中的溶液中。将混合物在25℃下搅拌12h。然后将混合物浓缩，用50mL水稀释，酸化至pH1，并用乙酸乙酯(3×30)萃取。合并的有机相经Na2SO4干燥并浓缩。粗产物通过柱色谱法使用己烷-MTBE和氯仿-乙腈体系纯化两次，得到标题化合物(1.4g，6.0mmol，37％，95％纯度)。1H NMR(500MHz,DMSO-d6)δ:9.66(s,1H),7.12(d,1H),7.04(d,1H),3.73(s,3H)。Sodium hydroxide (1.606 g, 2.5 equivalents, 40.15 mmol) was added to a solution of 5-bromo-2-fluoro-4-methoxyphenylcarbamate (4.0 g, 1 equivalent, 16.06 mmol) in methanol (100 mL). The mixture was stirred at 25 °C for 12 h. The mixture was then concentrated, diluted with 50 mL of water, acidified to pH 1, and extracted with ethyl acetate (3 × 30). The combined organic phases were dried over Na₂SO₄ and concentrated. The crude product was purified twice by column chromatography using a hexane-MTBE and chloroform-acetonitrile system to give the title compound (1.4 g, 6.0 mmol, 37%, 95% purity). ¹H NMR (500 MHz, DMSO-d₆) δ: 9.66 (s, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 3.73 (s, 3H).
根据中间体4所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。The following intermediates are prepared from the starting materials shown in the table according to the method described in intermediate 4. No data is displayed if there is no information in the LCMS/GCMS data.
中间体9.5-甲氧基-7-硝基苯并呋喃Intermediate 9,5-methoxy-7-nitrobenzofuran
将5-甲氧基-7-硝基苯并呋喃-2-甲酸(1g，1当量，4.22mmol)和铜(201mg，0.75当量，3.16mmol)在喹啉(20mL)中回流30min。冷却至RT后，过滤混合物，并将滤液倒入2N盐酸中，并过滤。将所得沉淀物用乙腈浓缩三次，得到标题化合物(710mg，3.5mmol)。1H NMR(500MHz,DMSO-d6)δ:8.20(s,1H),7.66(d,1H),7.10(s,1H),3.86(s,3H)。5-Methoxy-7-nitrobenzofuran-2-carboxylic acid (1 g, 1 equivalent, 4.22 mmol) and copper (201 mg, 0.75 equivalent, 3.16 mmol) were refluxed in quinoline (20 mL) for 30 min. After cooling to RT, the mixture was filtered, and the filtrate was poured into 2N hydrochloric acid and filtered again. The resulting precipitate was concentrated three times with acetonitrile to give the title compound (710 mg, 3.5 mmol). ¹H NMR (500 MHz, DMSO-d6) δ: 8.20 (s, 1H), 7.66 (d, 1H), 7.10 (s, 1H), 3.86 (s, 3H).
中间体10a.3-(4-甲氧基-2-硝基苯基)-1-甲基-1H-吡唑Intermediate 10a.3-(4-methoxy-2-nitrophenyl)-1-methyl-1H-pyrazole
在氩气气氛下，将1-溴-4-甲氧基-2-硝基苯(0.272g，1.17mmol)、1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(244mg，1.17mmol)和磷酸钾(746mg，3.52mmol)混合在二噁烷(4mL)和水(0.4mL)中，并将混合物加热至100℃。然后加入二(1-金刚烷基)-正丁基膦(21.0mg，0.05当量，58.6μmol)和(2'-氨基-[1,1'-联苯]-2-基)-((甲基磺酰基)氧基)钯(21.7mg，0.05当量，58.6μmol)，并将混合物在100℃下搅拌14h。冷却至RT后，将混合物在真空中浓缩。将残余物溶于乙酸乙酯(5mL)中，用盐水(2×5mL)洗涤，经硫酸钠干燥，过滤并在真空中浓缩，得到粗标题化合物(0.2g，0.73mmol)，其不经进一步纯化即可用于下一步。LCMS:m/z 234.2[M+H]+。Under an argon atmosphere, 1-bromo-4-methoxy-2-nitrobenzene (0.272 g, 1.17 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrazole (244 mg, 1.17 mmol), and potassium phosphate (746 mg, 3.52 mmol) were mixed in dioxane (4 mL) and water (0.4 mL), and the mixture was heated to 100 °C. Then, di(1-adamantyl)-n-butylphosphine (21.0 mg, 0.05 equivalent, 58.6 μmol) and (2'-amino-[1,1'-biphenyl]-2-yl)-((methanesulfonyl)oxy)palladium (21.7 mg, 0.05 equivalent, 58.6 μmol) were added, and the mixture was stirred at 100 °C for 14 h. After cooling to RT, the mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (5 mL), washed with brine (2 × 5 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the crude title compound (0.2 g, 0.73 mmol), which could be used in the next step without further purification. LCMS: m/z 234.2 [M+H] + .
中间体10b.4-(1-甲基-1H-吡唑-3-基)-3-硝基苯酚Intermediate 10b., 4-(1-methyl-1H-pyrazol-3-yl)-3-nitrophenol
将3-(4-甲氧基-2-硝基苯基)-1-甲基-1H-吡唑(1.2g，1当量，5.145mmol)与吡啶HCl(2.973g，5当量，25.73mmol)混合，随后在200℃下搅拌30h。冷却至RT后，将反应物料倒入水(10mL)中，并用乙酸乙酯(3×20mL)萃取。将合并的有机相经硫酸钠干燥，过滤并浓缩，得到标题化合物(0.90g，3.7mmol)。1H NMR(400MHz,DMSO-d6)δ:10.42(s,1H),7.70(d,1H),7.54(d,1H),7.10(d,1H),7.05(dd,1H),6.33(d,1H),3.81(s,3H)。3-(4-methoxy-2-nitrophenyl)-1-methyl-1H-pyrazole (1.2 g, 1 equivalent, 5.145 mmol) was mixed with pyridine HCl (2.973 g, 5 equivalent, 25.73 mmol) and stirred at 200 °C for 30 h. After cooling to RT, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give the title compound (0.90 g, 3.7 mmol). ¹H NMR (400 MHz, DMSO- d⁶ ) δ: 10.42 (s, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 7.05 (dd, 1H), 6.33 (d, 1H), 3.81 (s, 3H).
根据中间体10b所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 10b, the following intermediates are prepared from the starting materials shown in the table.
中间体12a.(4-氟-3-甲氧基苯氧基)三异丙基硅烷Intermediate 12a. (4-fluoro-3-methoxyphenoxy)triisopropylsilane
在RT下，向搅拌的4-氟-3-甲氧基苯酚(6g，1当量，42.21mmol)和咪唑(5.748g，2当量，84.43mmol)在DCM(60mL)中的溶液中加入氯三异丙基硅烷(8.546g，9.487mL，1.05当量，44.33mmol)。将混合物搅拌16h，然后倒入饱和NH4Cl水溶液(40mL)中，随后用DCM(3×50mL)萃取。合并的萃取液用盐水(30mL)洗涤，经Na2SO4干燥，并在真空中浓缩，得到标题化合物(10.00g，30mmol)。1H NMR(400MHz,氯仿-d)δ:6.87(dd,1H),6.48(dd,1H),6.34(dt,1H),3.82(s,3H),1.23(dh,3H),1.08(d,21H)。Under RT, chlorotriisopropylsilane (8.546 g, 9.487 mL, 1.05 equivalent, 44.33 mmol) was added to a stirred solution of 4-fluoro-3-methoxyphenol (6 g, 1 equivalent, 42.21 mmol) and imidazole (5.748 g, 2 equivalent, 84.43 mmol) in DCM (60 mL). The mixture was stirred for 16 h, then poured into a saturated aqueous solution of NH₄Cl (40 mL), followed by extraction with DCM (3 × 50 mL). The combined extracts were washed with brine ( 30 mL), dried over Na₂SO₄ , and concentrated under vacuum to give the title compound (10.00 g, 30 mmol). 1H NMR (400MHz, chloroform-d) δ: 6.87 (dd, 1H), 6.48 (dd, 1H), 6.34 (dt, 1H), 3.82 (s, 3H), 1.23 (dh, 3H), 1.08 (d, 21H).
中间体12b.(4-氟-3-碘-5-甲氧基苯氧基)三异丙基硅烷Intermediate 12b. (4-Fluoro-3-iodo-5-methoxyphenoxy)triisopropylsilane
在氩气气氛下，将(4-氟-3-甲氧基苯氧基)三异丙基硅烷(6.544g，1当量，21.93mmol)和2-甲基丙烷-2-醇钾(2.706g，1.1当量，24.12mmol)在THF(60mL)中混合，并冷却至-78℃，在-78℃下逐滴加入丁基锂(1.545g，9.647mL，2.5摩尔，1.1当量，24.12mmol)。然后在相同温度下搅拌混合物1h。在-78℃下逐滴加入碘(6.678g，1.2当量，26.31mmol)在THF(20mL)中的溶液。在RT下搅拌过夜后，将混合物冷却至-20℃，并逐滴加入氯化铵水溶液(20mL)。然后将溶液加热至RT。加入EtOAc(70mL)，并将有机层用盐水(2×30mL)洗涤，经硫酸钠干燥，过滤并浓缩。将残余物通过快速柱色谱法(己烷/MTBE)纯化，得到标题化合物(2.0g，3.3mmol)。GCMS:m/z 424[M]+。Under an argon atmosphere, (4-fluoro-3-methoxyphenoxy)triisopropylsilane (6.544 g, 1 equivalent, 21.93 mmol) and potassium 2-methylpropane-2-ol (2.706 g, 1.1 equivalent, 24.12 mmol) were mixed in THF (60 mL) and cooled to -78 °C. Butyllithium (1.545 g, 9.647 mL, 2.5 mol, 1.1 equivalent, 24.12 mmol) was added dropwise at -78 °C. The mixture was then stirred at the same temperature for 1 h. A solution of iodine (6.678 g, 1.2 equivalent, 26.31 mmol) in THF (20 mL) was added dropwise at -78 °C. After stirring overnight at RT, the mixture was cooled to -20 °C, and an aqueous solution of ammonium chloride (20 mL) was added dropwise. The solution was then heated to RT. Add EtOAc (70 mL), wash the organic layer with brine (2 × 30 mL), dry over sodium sulfate, filter, and concentrate. Purify the residue by rapid column chromatography (hexane/MTBE) to give the title compound (2.0 g, 3.3 mmol). GCMS: m/z 424 [M] + .
中间体12c.4-氟-3-碘-5-甲氧基苯酚Intermediate 12c,4-fluoro-3-iodo-5-methoxyphenol
将(4-氟-3-碘-5-甲氧基苯氧基)三异丙基硅烷(2.3g，1当量，5.420mmol)溶于THF(10mL)中，并逐滴加入氟化四丁基铵(3.543g，13.55mL，1摩尔，2.5当量，13.55mmol)。将混合物在RT下搅拌16h，然后在真空中浓缩。将残余物溶于EtOAc(20mL)中，用水(2×5mL)洗涤，在硫酸钠下干燥并在真空中浓缩。将获得的残余物通过快速色谱法(己烷/MTBE)纯化，得到标题化合物(0.575g，1.9mmol)。1H NMR(400MHz,氯仿-d)δ:6.72(t,1H),6.45(dd,1H),4.86(s,1H),3.82(s,3H)。中间体13.1-甲氧基-2-硝基-4-(4-(三氟甲基)苯氧基)苯(4-Fluoro-3-iodo-5-methoxyphenoxy)triisopropylsilane (2.3 g, 1 equivalent, 5.420 mmol) was dissolved in THF (10 mL), and tetrabutylammonium fluoride (3.543 g, 13.55 mL, 1 mol, 2.5 equivalent, 13.55 mmol) was added dropwise. The mixture was stirred at RT for 16 h and then concentrated under vacuum. The residue was dissolved in EtOAc (20 mL), washed with water (2 × 5 mL), dried over sodium sulfate, and concentrated under vacuum. The obtained residue was purified by rapid chromatography (hexane/MTBE) to give the title compound (0.575 g, 1.9 mmol). ¹H NMR (400 MHz, chloroform-d) δ: 6.72 (t, 1H), 6.45 (dd, 1H), 4.86 (s, 1H), 3.82 (s, 3H). Intermediate 13,1-methoxy-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene
将4-甲氧基-3-硝基苯酚(1g，1当量，6mmol)、(4-(三氟甲基)苯基)硼酸(2g，2当量，0.01mol)、吡啶(0.9g，1mL，2当量，0.01mol)、二乙酰氧基铜(1g，1.05当量，6mmol)和粉状分子筛(1g)悬浮于二氯甲烷(10mL)中。将空气通过所得溶液鼓泡30min，并将混合物在RT下搅拌过夜。过滤混合物。将滤液用水洗涤(2×30mL)，经硫酸钠干燥，过滤并在减压下除去溶剂。将残余物通过方法A纯化，得到标题化合物。LCMS:m/z 314.0[M+H]+。4-Methoxy-3-nitrophenol (1 g, 1 equivalent, 6 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2 g, 2 equivalent, 0.01 mol), pyridine (0.9 g, 1 mL, 2 equivalent, 0.01 mol), copper diacetoxy (1 g, 1.05 equivalent, 6 mmol), and powdered molecular sieve (1 g) were suspended in dichloromethane (10 mL). Air was bubbled through the resulting solution for 30 min, and the mixture was stirred overnight at RT. The mixture was filtered. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by method A to give the title compound. LCMS: m/z 314.0 [M+H] + .
根据中间体13所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。According to the method described for intermediate 13, the following intermediates are prepared from the starting materials shown in the table. No data is displayed if there is no information in the LCMS/GCMS data.
中间体48.2-氟-1-碘-3-甲氧基-5-(4-(三氟甲基)苯氧基)苯Intermediate 48,2-fluoro-1-iodo-3-methoxy-5-(4-(trifluoromethyl)phenoxy)benzene
在氩气气氛下，将1-氟-2-甲氧基-4-(4-(三氟甲基)苯氧基)苯(4.000g，1当量，13.97mmol)和2-甲基丙烷-2-醇钾(1.725g，1.1当量，15.37mmol)混合在THF(60mL)中，并冷却至-78℃。在-78℃下逐滴加入丁基锂(984.7mg，6.149mL，2.5摩尔，1.1当量，15.37mmol)，并在相同温度下搅拌混合物2h。在-78℃下，逐滴加入碘(4.256g，1.2当量，16.77mmol)在THF(20mL)中的溶液。在RT下搅拌过夜后，将混合物冷却至-20℃，并逐滴加入氯化铵水溶液(10mL)。然后将溶液加热至RT。加入EtOAc(100mL)，并将有机层用盐水(2×25mL)洗涤，经硫酸钠干燥，过滤并浓缩。将残余物通过快速色谱法(己烷/MTBE)纯化，得到标题化合物(0.900g，2.0mmol，14％，90％纯度)。Under an argon atmosphere, 1-fluoro-2-methoxy-4-(4-(trifluoromethyl)phenoxy)benzene (4.000 g, 1 equivalent, 13.97 mmol) and potassium 2-methylpropane-2-ol (1.725 g, 1.1 equivalent, 15.37 mmol) were mixed in THF (60 mL) and cooled to -78 °C. Butyllithium (984.7 mg, 6.149 mL, 2.5 mol, 1.1 equivalent, 15.37 mmol) was added dropwise at -78 °C, and the mixture was stirred at the same temperature for 2 h. Iodine (4.256 g, 1.2 equivalent, 16.77 mmol) in THF (20 mL) was added dropwise at -78 °C. After stirring overnight at RT, the mixture was cooled to -20 °C, and an aqueous solution of ammonium chloride (10 mL) was added dropwise. The solution was then heated to RT. Add EtOAc (100 mL), wash the organic layer with brine (2 × 25 mL), dry over sodium sulfate, filter, and concentrate. Purify the residue by rapid chromatography (hexane/MTBE) to give the title compound (0.900 g, 2.0 mmol, 14%, 90% purity).
中间体49.6-羟基-8-硝基苯并二氢吡喃-4-酮Intermediate 49,6-hydroxy-8-nitrobenzodihydropyran-4-one
将6-溴-8-硝基苯并二氢吡喃-4-酮(2.00g，1当量，7.35mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧杂环戊硼烷)(2.24g，1.2当量，8.82mmol)和乙酸钾(2.16g，3当量，22.1mmol)混合在1,4-二噁烷(20mL)中。在25℃下将氩气鼓泡到溶液中1h以除去任何过量的氧气。在氩气气氛下，将PdCl2(dppf)CH2Cl2(180mg，0.03当量，221μmol)加入到混合物中。将混合物加热至80℃并搅拌3h，直至反应完全。将混合物冷却至25℃然后过滤。用二噁烷(15mL)洗涤沉淀物。将过滤的溶液合并，浓缩，然后转移至反应器。加入过氧化氢(4.29g，4.29mL，35w-％，6当量，44.1mmol)，并将混合物加热至50℃并搅拌40min，直至反应完全。向混合物中加入水(10mL)，并用DCM(2×50mL)萃取混合物。收集有机相，用15％盐水(2×15mL)洗涤，并用15％Na2CO3(2×25mL)萃取。收集水相，用3M HCl将pH值调节至4-5。然后用乙酸乙酯(2×50mL)萃取水相。收集有机相，经Na2SO4干燥，并在减压下浓缩，得到标题化合物(810mg，3.6mmol)。LCMS:m/z 208.0[M+H]+。6-Bromo-8-nitrobenzodihydropyran-4-one (2.00 g, 1 equivalent, 7.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (2.24 g, 1.2 equivalent, 8.82 mmol), and potassium acetate (2.16 g, 3 equivalent, 22.1 mmol) were mixed in 1,4-dioxane (20 mL). Argon was bubbled into the solution at 25 °C for 1 h to remove any excess oxygen. PdCl₂ (dppf) CH₂Cl₂ (180 mg , 0.03 equivalent, 221 μmol) was added to the mixture under an argon atmosphere. The mixture was heated to 80 °C and stirred for 3 h until the reaction was complete. The mixture was cooled to 25 °C and then filtered. The precipitate was washed with dioxane (15 mL). The filtered solutions were combined, concentrated, and then transferred to a reactor. Hydrogen peroxide (4.29 g, 4.29 mL, 35 w-%, 6 equivalents, 44.1 mmol) was added, and the mixture was heated to 50 °C and stirred for 40 min until the reaction was complete. Water (10 mL) was added to the mixture, and the mixture was extracted with DCM (2 × 50 mL). The organic phase was collected, washed with 15% brine (2 × 15 mL ), and extracted with 15% Na₂CO₃ (2 × 25 mL). The aqueous phase was collected, and the pH was adjusted to 4–5 with 3 M HCl. The aqueous phase was then extracted with ethyl acetate (2 × 50 mL). The organic phase was collected, dried over Na₂SO₄ , and concentrated under reduced pressure to give the title compound (810 mg, 3.6 mmol). LCMS: m/z 208.0 [M+H] ⁺ .
根据中间体49所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 49, the following intermediates are prepared from the starting materials shown in the table.
中间体51.(7-硝基苯并[d][1,3]间二氧杂环戊烯-5-基)甲醇Intermediate 51. (7-Nitrobenzo[d][1,3]m-dioxacyclopenten-5-yl)methanol
将7-硝基苯并[d][1,3]间二氧杂环戊烯-5-甲醛(1000mg，1当量，5.125mmol)溶于无水甲醇(40mL)中。将混合物冷却至0℃，在10min内分批加入硼氢化钠(232.6mg，1.2当量，6.150mmol)。将混合物在RT下搅拌18h，然后在减压下浓缩。将所得残余物用饱和氯化铵溶液(30mL)处理，用乙酸乙酯(3×20mL)萃取，用无水硫酸钠干燥，并在减压下浓缩，得到标题化合物(0.693g，3.29mmol，64.1％，93.46％纯度)。1H NMR(500MHz,DMSO-d6)δ:7.50(s,1H),7.21(s,1H),6.28(s,2H),5.41(s,1H),4.45(s,2H)。7-Nitrobenzo[d][1,3]m-dioxacyclopentene-5-carboxaldehyde (1000 mg, 1 equivalent, 5.125 mmol) was dissolved in anhydrous methanol (40 mL). The mixture was cooled to 0 °C, and sodium borohydride (232.6 mg, 1.2 equivalent, 6.150 mmol) was added in portions over 10 min. The mixture was stirred at RT for 18 h, and then concentrated under reduced pressure. The resulting residue was treated with a saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.693 g, 3.29 mmol, 64.1%, 93.46% purity). 1 H NMR (500MHz, DMSO-d6) δ: 7.50 (s, 1H), 7.21 (s, 1H), 6.28 (s, 2H), 5.41 (s, 1H), 4.45 (s, 2H).
根据中间体51所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。According to the method described in intermediate 51, the following intermediates are prepared from the starting materials shown in the table. No data is displayed if there is no information in the LCMS/GCMS data.
中间体56.1-(氯甲基)-2,4-二甲氧基-5-硝基苯Intermediate 56.1-(chloromethyl)-2,4-dimethoxy-5-nitrobenzene
将2,4-二甲氧基-1-硝基苯(1g，1当量，5mmol)、甲醛(0.3g，2当量，0.01mol，水溶液40％)和氯化锌(II)(0.07g，0.1当量，0.5mmol)溶于盐酸(10mL)水溶液(37％)中，随后在100℃下搅拌12h。冷却至RT后，将反应混合物用二氯甲烷(2×50mL)萃取，合并有机层，用水(2×100mL)洗涤，经硫酸钠干燥，过滤并在真空中浓缩，得到粗标题化合物(312mg，1.46mmol，30％，100％纯度)，将其用方法A纯化。1H NMR(400MHz,DMSO-d6)δ:7.97(s,1H),6.81(d,1H),4.43(d,2H),4.01(d,1H),3.96(dd,6H)。2,4-Dimethoxy-1-nitrobenzene (1 g, 1 equivalent, 5 mmol), formaldehyde (0.3 g, 2 equivalents, 0.01 mol, 40% aqueous solution), and zinc(II) chloride (0.07 g, 0.1 equivalents, 0.5 mmol) were dissolved in 10 mL of hydrochloric acid (37%), and then stirred at 100 °C for 12 h. After cooling to RT, the reaction mixture was extracted with dichloromethane (2 × 50 mL), the organic layers were combined, washed with water (2 × 100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the crude title compound (312 mg, 1.46 mmol, 30%, 100% purity), which was purified by method A. 1 H NMR (400MHz, DMSO-d 6 ) δ: 7.97 (s, 1H), 6.81 (d, 1H), 4.43 (d, 2H), 4.01 (d, 1H), 3.96 (dd, 6H).
根据中间体56所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 56, the following intermediates are prepared from the starting materials shown in the table.
中间体58.5-(氯甲基)-1-氟-2-甲氧基-3-硝基苯Intermediate 58,5-(chloromethyl)-1-fluoro-2-methoxy-3-nitrobenzene
将(3-氟-4-甲氧基-5-硝基苯基)甲醇(610mg，1当量，3.03mmol)溶于DCM(7mL)中并加入DMF(2.22mg，2.35μL，0.01当量，30.3μmol)。将所得溶液冷却至0℃，并在相同温度下逐滴加入亚硫酰氯(722mg，443μL，2当量，6.07mmol)至该混合物中，并将该溶液在0℃下搅拌10min，随后加热至RT并在该温度下搅拌过夜。然后将溶液倒入10％碳酸氢钠水溶液(10mL)中并搅拌10min。然后用DCM(10mL)萃取水层。将合并的有机层经硫酸钠干燥，过滤，并将溶剂在真空下蒸发，得到标题化合物(602mg，2.4mmol，80％，88％纯度)，其在不进一步纯化的情况下用于下一步。LCMS:m/z 219.8[M+H]+。(3-Fluoro-4-methoxy-5-nitrophenyl)methanol (610 mg, 1 equivalent, 3.03 mmol) was dissolved in DCM (7 mL) and DMF (2.22 mg, 2.35 μL, 0.01 equivalent, 30.3 μmol) was added. The resulting solution was cooled to 0 °C, and thionyl chloride (722 mg, 443 μL, 2 equivalent, 6.07 mmol) was added dropwise to the mixture at the same temperature. The solution was stirred at 0 °C for 10 min, then heated to RT and stirred overnight at that temperature. The solution was then poured into a 10% sodium bicarbonate aqueous solution (10 mL) and stirred for 10 min. The aqueous layer was then extracted with DCM (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated under vacuum to give the title compound (602 mg, 2.4 mmol, 80%, 88% purity), which was used in the next step without further purification. LCMS:m/z 219.8[M+H] + .
根据中间体58所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。The following intermediates are prepared from the starting materials shown in the table according to the method described in intermediate 58. No data is displayed if there is no information in the LCMS/GCMS data.
中间体62.(3-氟苯基)(4-甲氧基-3-硝基苄基)氨基甲酸叔丁酯Intermediate 62. (3-Fluorophenyl)(4-Methoxy-3-nitrobenzyl)tert-butyl carbamate
在0℃下，向(3-氟苯基)氨基甲酸叔丁酯(1.048g，1当量，4.960mmol)的DMF(20mL)溶液中加入氢化钠(238.1mg，60％，1.2当量，5.952mmol)，并将该混合物在RT下搅拌30min。一次性加入4-(氯甲基)-1-甲氧基-2-硝基苯(1.000g，1当量，4.960mmol)，并将混合物在RT搅拌18h。过滤所得混合物，并将滤液用水(50mL)和乙酸乙酯(50mL)稀释。分离各层，将有机相用盐水(4×30mL)洗涤，经硫酸钠干燥，过滤，并将溶剂在减压下除去，得到标题化合物，其不经进一步纯化即可用于下一步。Sodium hydride (238.1 mg, 60%, 1.2 equivalent, 5.952 mmol) was added to a DMF (20 mL) solution of tert-butyl (3-fluorophenyl)carbamate (1.048 g, 1 equivalent, 4.960 mmol) at 0 °C, and the mixture was stirred at RT for 30 min. 4-(chloromethyl)-1-methoxy-2-nitrobenzene (1.000 g, 1 equivalent, 4.960 mmol) was added in a single batch, and the mixture was stirred at RT for 18 h. The resulting mixture was filtered, and the filtrate was diluted with water (50 mL) and ethyl acetate (50 mL). The layers were separated, the organic phase was washed with brine (4 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound, which could be used in the next step without further purification.
根据中间体62所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 62, the following intermediates are prepared from the starting materials shown in the table.
中间体69.4-((3,4-二氟苯氧基)甲基)-1-甲氧基-2-硝基苯Intermediate 69.4-((3,4-difluorophenoxy)methyl)-1-methoxy-2-nitrobenzene
将3,4-二氟苯酚(2.00g，1当量，15.4mmol)溶于DMF(20mL)中，在RT下加入氢化钠(676mg，60％，1.1当量，16.9mmol)，并将该混合物在该温度下搅拌30min。加入4-(氯甲基)-1-甲氧基-2-硝基苯(3.41g，1.1当量，16.9mmol)，并将混合物在100℃下加热16h。将溶液冷却至RT并浓缩。将残余物溶于乙酸乙酯(60mL)中。将所得溶液用盐水(3×50mL)洗涤，经硫酸钠干燥，过滤并蒸发，得到标题化合物(4.5g，14mmol，94％，95％纯度)。粗产物不经进一步纯化即可用于下一步。3,4-Difluorophenol (2.00 g, 1 equivalent, 15.4 mmol) was dissolved in DMF (20 mL), and sodium hydride (676 mg, 60%, 1.1 equivalent, 16.9 mmol) was added at RT. The mixture was stirred at this temperature for 30 min. 4-(chloromethyl)-1-methoxy-2-nitrobenzene (3.41 g, 1.1 equivalent, 16.9 mmol) was added, and the mixture was heated at 100 °C for 16 h. The solution was cooled to RT and concentrated. The residue was dissolved in ethyl acetate (60 mL). The resulting solution was washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (4.5 g, 14 mmol, 94%, 95% purity). The crude product was used in the next step without further purification.
根据中间体69所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。According to the method described in intermediate 69, the following intermediates are prepared from the starting materials shown in the table. No data is displayed if there is no information in the LCMS/GCMS data.
中间体75.4-(2,5-二氟苯氧基)-1-甲氧基-2-硝基苯Intermediate 75.4-(2,5-difluorophenoxy)-1-methoxy-2-nitrobenzene
将1,2,4-三氟苯(2.4g，1当量，18mmol)、4-甲氧基-3-硝基苯酚(3.1g，1当量，18mmol)和2-甲基丙烷-2-醇钾(2.2g，1.1当量，20mmol)溶于DMF(50mL)中，将所得混合物在80℃下搅拌10h。然后加入EtOAc(50mL)，将有机层用盐水洗涤(5×30mL)，干燥并在减压下蒸发，得到标题化合物，其不经进一步纯化即可用于下一步。GCMS:m/z 281[M]+。1,2,4-Trifluorobenzene (2.4 g, 1 equivalent, 18 mmol), 4-methoxy-3-nitrophenol (3.1 g, 1 equivalent, 18 mmol), and potassium 2-methylpropane-2-ol (2.2 g, 1.1 equivalent, 20 mmol) were dissolved in DMF (50 mL), and the resulting mixture was stirred at 80 °C for 10 h. Then, EtOAc (50 mL) was added, and the organic layer was washed with brine (5 × 30 mL), dried, and evaporated under reduced pressure to give the title compound, which could be used in the next step without further purification. GCMS: m/z 281 [M] + .
中间体76.(E)-2-甲氧基-5-(2-(四氢-2H-吡喃-4-基)乙烯基)苯胺Intermediate 76.(E)-2-methoxy-5-(2-(tetrahydro-2H-pyran-4-yl)vinyl)aniline
将5-溴-2-甲氧基苯胺(730mg，1当量，3.61mmol)，(E)-4,4,5,5-四甲基-2-(2-(四氢-2H-吡喃-4-基)乙烯基)-1,3,2-二氧杂环戊硼烷(1.29g，1.5当量，5.42mmol)、碳酸钠(383mg，1当量，3.61mmol)和PdCl2(dppf)-CH2Cl2加合物(295mg，0.1当量，361μmol)悬浮于脱气的1,4-二噁烷(12mL)和水(2.4mL)中。将混合物在氩气下于90℃加热过夜。冷却至RT后，将溶剂在真空中蒸发，将残余物溶于乙酸乙酯(30mL)中，用盐水(20mL)洗涤，经硫酸钠干燥，过滤，在真空中浓缩，并将残余物通过方法A纯化，得到标题化合物(205mg，839μmol，23.2％，95.5％纯度)。LCMS:m/z 234.2[M+H]+。5-Bromo-2-methoxyaniline (730 mg, 1 equivalent, 3.61 mmol), (E)-4,4,5,5-tetramethyl-2-(2-(tetrahydro-2H-pyran-4-yl)vinyl)-1,3,2-dioxane (1.29 g, 1.5 equivalent, 5.42 mmol), sodium carbonate (383 mg, 1 equivalent, 3.61 mmol), and PdCl₂ (dppf) -CH₂Cl₂ adduct (295 mg, 0.1 equivalent, 361 μmol) were suspended in degassed 1,4-dioxane (12 mL) and water (2.4 mL). The mixture was heated overnight at 90 °C under argon atmosphere. After cooling to RT, the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (30 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated under vacuum, and purified by method A to give the title compound (205 mg, 839 μmol, 23.2%, 95.5% purity). LCMS: m/z 234.2 [M+H] + .
根据中间体76所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 76, the following intermediates are prepared from the starting materials shown in the table.
中间体78.7-溴-5-((3,4-二氟苄基)氧基)-2,3-二氢苯并呋喃Intermediate 78,7-bromo-5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran
将7-溴-2,3-二氢苯并呋喃-5-醇(0.500g，1当量，2.33mmol)溶于N,N-二甲基甲酰胺(5mL)中，并加入碳酸铯(1.52g，2当量，4.65mmol)。将混合物在RT下搅拌10min，并加入4-(氯甲基)-1,2-二氟苯(378mg，1当量，2.33mmol)。将混合物在RT下搅拌12h。将所得溶液在减压下浓缩。将残余物溶于乙酸乙酯(20mL)中。将所得溶液用盐水(20mL)、水(20mL)洗涤，经硫酸钠干燥，过滤并蒸发，得到标题化合物。粗产物不经进一步纯化即可用于下一步。1HNMR(400MHz,CDCl3)δ:7.22–7.02(m,3H),6.85(s,1H),6.75(s,1H),4.90(s,2H),4.61(t,2H),3.26(t,2H)。7-Bromo-2,3-dihydrobenzofuran-5-ol (0.500 g, 1 equivalent, 2.33 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (1.52 g, 2 equivalent, 4.65 mmol) was added. The mixture was stirred at RT for 10 min, and 4-(chloromethyl)-1,2-difluorobenzene (378 mg, 1 equivalent, 2.33 mmol) was added. The mixture was stirred at RT for 12 h. The resulting solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL). The resulting solution was washed with brine (20 mL) and water (20 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound. The crude product was used in the next step without further purification. 1 HNMR(400MHz, CDCl 3 )δ:7.22–7.02(m,3H),6.85(s,1H),6.75(s,1H),4.90(s,2H),4.61(t,2H),3.26(t,2H).
根据中间体78所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。The following intermediates are prepared from the starting materials shown in the table according to the method described in intermediate 78. No data is displayed if there is no information in the LCMS/GCMS data.
中间体84.1-氟-2-((3-氟苯氧基)甲基)-5-甲氧基-4-硝基苯Intermediate 84.1-Fluoro-2-((3-fluorophenoxy)methyl)-5-methoxy-4-nitrobenzene
将1-(氯甲基)-2-氟-4-甲氧基-5-硝基苯(0.306g，1当量，1.39mmol)溶于乙腈(3mL)中，加入碳酸铯(908mg，2当量，2.79mmol)和碘化钠(209mg，1当量，1.39mmol)。将混合物搅拌10min，并加入3-氟苯酚(141mg，114μL，0.9当量，1.25mmol)。将混合物在RT下搅拌10h，过滤所得溶液并浓缩，得到标题化合物(0.362g，0.61mmol，44％，50％纯度)，其不经进一步纯化即可用于下一步。LCMS:m/z 297.2[M+H]+。1-(chloromethyl)-2-fluoro-4-methoxy-5-nitrobenzene (0.306 g, 1 equivalent, 1.39 mmol) was dissolved in acetonitrile (3 mL), and cesium carbonate (908 mg, 2 equivalent, 2.79 mmol) and sodium iodide (209 mg, 1 equivalent, 1.39 mmol) were added. The mixture was stirred for 10 min, and 3-fluorophenol (141 mg, 114 μL, 0.9 equivalent, 1.25 mmol) was added. The mixture was stirred at RT for 10 h, the resulting solution was filtered and concentrated to give the title compound (0.362 g, 0.61 mmol, 44%, 50% purity), which could be used for the next step without further purification. LCMS: m/z 297.2 [M+H] + .
中间体85.1-氟-5-甲氧基-4-硝基-2-(3-(三氟甲基)苯氧基)苯Intermediate 85.1-Fluoro-5-methoxy-4-nitro-2-(3-(trifluoromethyl)phenoxy)benzene
将1,5-二氟-2-硝基-4-(3-(三氟甲基)苯氧基)苯(150mg，1当量，470μmol)溶于甲苯(2mL)中。将溶液冷却至0℃，然后在0℃下加入甲醇(15.1mg，19.0μL，1当量，470μmol)。在0℃下向所得溶液中加入叔丁醇钾(52.7mg，1当量，470μmol)。将混合物在0℃下搅拌10min，然后将温度升至RT，随后搅拌12h。将反应混合物用水(15mL)淬灭，随后搅拌15min。向混合物中加入甲苯(10mL)。分离各层，并将水层用甲苯(2×10mL)萃取。合并的有机层用水(20mL)、盐水(20mL)洗涤，并经硫酸钠干燥。在减压下蒸发溶剂，得到标题化合物，其不经进一步纯化即可用于下一步。GCMS:m/z 331.0[M]+。1,5-Difluoro-2-nitro-4-(3-(trifluoromethyl)phenoxy)benzene (150 mg, 1 equivalent, 470 μmol) was dissolved in toluene (2 mL). The solution was cooled to 0 °C, and then methanol (15.1 mg, 19.0 μL, 1 equivalent, 470 μmol) was added at 0 °C. Potassium tert-butoxide (52.7 mg, 1 equivalent, 470 μmol) was added to the resulting solution at 0 °C. The mixture was stirred at 0 °C for 10 min, and then the temperature was raised to RT, followed by stirring for 12 h. The reaction mixture was quenched with water (15 mL), followed by stirring for 15 min. Toluene (10 mL) was added to the mixture. The layers were separated, and the aqueous layer was extracted with toluene (2 × 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound, which could be used in the next step without further purification. GCMS:m/z 331.0[M] + .
中间体86.7-溴-5-((3-氟苯氧基)甲基)苯并呋喃Intermediate 86,7-bromo-5-((3-fluorophenoxy)methyl)benzofuran
在惰性气氛下，将(7-溴苯并呋喃-5-基)甲醇(3.110g，1当量，13.70mmol)和三苯基膦(4.311g，1.2当量，16.44mmol)在THF(100mL)中的溶液冷却至0℃。缓慢加入(E)-二氮烯(diazene)-1,2-二甲酸二乙酯(2.863g，2.58mL，1.2当量，16.44mmol)，并将混合物搅拌30min，随后加入3-氟苯酚(1.612g，1.302mL，1.05当量，14.38mmol)。除去冰浴，并将混合物在RT下搅拌17h。蒸发THF，并将混合物溶于MTBE(10mL)中，用NaOH(3mL，10％)和水(3mL)洗涤，经Na2SO4干燥，并在真空中浓缩。将残余物通过快速色谱法(MTBE/己烷，流速30mL/min)纯化，得到标题化合物(1.42g，4.2mmol，31％，95％纯度)。1H NMR(400MHz,DMSO-d6)δ:8.03(s,1H),7.72(s,1H),7.59(s,1H),7.33–7.23(m,1H),7.03(d,1H),6.83(d,2H),6.75–6.65(m,1H),5.17(s,2H)。A solution of (7-bromobenzofuran-5-yl)methanol (3.110 g, 1 equivalent, 13.70 mmol) and triphenylphosphine (4.311 g, 1.2 equivalent, 16.44 mmol) in THF (100 mL) was cooled to 0 °C under an inert atmosphere. Diethyl (E)-diazene-1,2-dicarboxylate (2.863 g, 2.58 mL, 1.2 equivalent, 16.44 mmol) was slowly added, and the mixture was stirred for 30 min, followed by the addition of 3-fluorophenol (1.612 g, 1.302 mL, 1.05 equivalent, 14.38 mmol). The ice bath was removed, and the mixture was stirred at RT for 17 h. The THF was evaporated, and the mixture was dissolved in MTBE (10 mL), washed with NaOH (3 mL, 10%) and water (3 mL ), dried over Na₂SO₄ , and concentrated under vacuum. The residue was purified by rapid chromatography (MTBE/hexane, flow rate 30 mL/min) to give the title compound (1.42 g, 4.2 mmol, 31%, 95% purity). ¹H NMR (400 MHz, DMSO- d₆ ) δ: 8.03 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.33–7.23 (m, 1H), 7.03 (d, 1H), 6.83 (d, 2H), 6.75–6.65 (m, 1H), 5.17 (s, 2H).
根据中间体86所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。According to the method described for intermediate 86, the following intermediates are prepared from the starting materials shown in the table. No data is displayed if there is no information in the LCMS/GCMS data.
中间体97.2-(4-甲氧基-3-硝基苯氧基)双环[2.2.1]庚烷Intermediate 97.2-(4-methoxy-3-nitrophenoxy)bicyclo[2.2.1]heptane
将4-甲氧基-3-硝基苯酚(5.00g，1当量，29.6mmol)、三苯基膦(15.5g，2当量，59.1mmol)和双环[2.2.1]庚-2-醇(3.32g，1当量，29.6mmol)溶于THF(50mL)中。将混合物冷却至4℃，并加入二氮烯-1,2-二甲酸二异丙酯(12.0g，11.5mL，2当量，59.1mmol)。将混合物在RT下搅拌16h，然后浓缩并通过快速色谱法(MTBE/己烷，流速30mL/min)纯化，得到标题化合物。4-Methoxy-3-nitrophenol (5.00 g, 1 equivalent, 29.6 mmol), triphenylphosphine (15.5 g, 2 equivalent, 59.1 mmol), and bicyclo[2.2.1]hepta-2-ol (3.32 g, 1 equivalent, 29.6 mmol) were dissolved in THF (50 mL). The mixture was cooled to 4 °C, and diisopropyl diazepine-1,2-dicarboxylate (12.0 g, 11.5 mL, 2 equivalent, 59.1 mmol) was added. The mixture was stirred at RT for 16 h, then concentrated and purified by rapid chromatography (MTBE/hexane, flow rate 30 mL/min) to give the title compound.
根据中间体97所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。The following intermediates are prepared from the starting materials shown in the table according to the method described in intermediate 97. No data is displayed if there is no information in the LCMS/GCMS data.
中间体99.4-(2,4-二氟苯氧基)-1-甲氧基-2-硝基苯Intermediate 99.4-(2,4-difluorophenoxy)-1-methoxy-2-nitrobenzene
将2,4-二氟-1-(4-甲氧基苯氧基)苯(0.180g，1当量，762μmol)溶于乙酸(1mL)中，并将该溶液冷却到0℃。然后向该混合物中逐滴加入硝酸(144mg，102μL，3当量，2.29mmol)，并将所得溶液在RT下搅拌10h。然后将该混合物倒入冰冷的饱和碳酸钠溶液(5mL)中，并加入EtOAc(5mL)。分离有机层，经硫酸钠干燥并在真空中浓缩，得到标题化合物，其不经进一步纯化即可用于下一步。GCMS:m/z 281[M]+。2,4-Difluoro-1-(4-methoxyphenoxy)benzene (0.180 g, 1 equivalent, 762 μmol) was dissolved in acetic acid (1 mL), and the solution was cooled to 0 °C. Nitric acid (144 mg, 102 μL, 3 equivalent, 2.29 mmol) was then added dropwise to the mixture, and the resulting solution was stirred at RT for 10 h. The mixture was then poured into an ice-cold saturated sodium carbonate solution (5 mL), and EtOAc (5 mL) was added. The organic layer was separated, dried over sodium sulfate, and concentrated under vacuum to give the title compound, which was ready for use in the next step without further purification. GCMS: m/z 281 [M] + .
中间体100.8-硝基苯并二氢吡喃-6-醇Intermediate 100,8-nitrobenzyl dihydropyran-6-ol
将8-硝基苯并二氢吡喃-4,6-二醇(135mg，1当量，639μmol)溶于TFA(2mL)中，加入三乙基硅烷(372mg，0.511mL，5.00当量，3.20mmol)。将混合物在23℃下搅拌16h，然后浓缩，与己烷(10mL)混合并过滤。将所得沉淀物在减压下干燥，得到标题化合物(100mg，0.49mmol)。粗产物不经进一步纯化即可用于下一步。LCMS:m/z 196.0[M+H]+。8-Nitrobenzodihydropyran-4,6-diol (135 mg, 1 equivalent, 639 μmol) was dissolved in TFA (2 mL), and triethylsilane (372 mg, 0.511 mL, 5.00 equivalent, 3.20 mmol) was added. The mixture was stirred at 23 °C for 16 h, then concentrated, mixed with hexane (10 mL), and filtered. The resulting precipitate was dried under reduced pressure to give the title compound (100 mg, 0.49 mmol). The crude product was used in the next step without further purification. LCMS: m/z 196.0 [M+H] + .
中间体101和102.4-溴-6-甲氧基-1-甲基-1H-苯并[d]咪唑和7-溴-5-甲氧基-1-甲基-1H-苯并[d]咪唑Intermediates 101 and 102, 4-bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole and 7-bromo-5-methoxy-1-methyl-1H-benzo[d]imidazole
将7-溴-5-甲氧基-1H-苯并[d]咪唑(0.3g，1当量，1.32mmol)溶于DMF(5mL)中。将混合物冷却至5℃，并分批加入氢化钠(58.1mg，60w-％，1.1当量，1.45mmol)。将混合物在5℃下搅拌30min，并在相同温度下逐滴加入甲基碘(206mg，90.9μL，1.1当量，1.45mmol)。将所得混合物加热至20℃并搅拌12h，倒入冰冷的水(10mL)中，并用EtOAc(2×20mL)萃取。将合并的有机层用盐水(4×5mL)洗涤，干燥并浓缩，得到粗产物的混合物，将其通过HPLC(方法A)分离，得到两种区域异构体7-溴-5-甲氧基-1-甲基-1H-苯并[d]咪唑(0.0467g，194μmol)和4-溴-6-甲氧基-1-甲基-1H-苯并[d]咪唑(0.0868g，360μmol)。LCMS:m/z 243.0[M+H]+。7-Bromo-5-methoxy-1H-benzo[d]imidazole (0.3 g, 1 equivalent, 1.32 mmol) was dissolved in DMF (5 mL). The mixture was cooled to 5 °C, and sodium hydride (58.1 mg, 60 w-%, 1.1 equivalent, 1.45 mmol) was added in portions. The mixture was stirred at 5 °C for 30 min, and methyl iodine (206 mg, 90.9 μL, 1.1 equivalent, 1.45 mmol) was added dropwise at the same temperature. The resulting mixture was heated to 20 °C and stirred for 12 h, poured into ice-cold water (10 mL), and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (4 × 5 mL), dried, and concentrated to obtain a mixture of crude products. This mixture was separated by HPLC (Method A) to yield two regioisomers: 7-bromo-5-methoxy-1-methyl-1H-benzo[d]imidazole (0.0467 g, 194 μmol) and 4-bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole (0.0868 g, 360 μmol). LCMS: m/z 243.0 [M+H] + .
中间体103.4-溴-1-甲基-1H-苯并[d]咪唑-6-醇Intermediate 103,4-bromo-1-methyl-1H-benzo[d]imidazol-6-ol
将4-溴-6-甲氧基-1-甲基-1H-苯并[d]咪唑(80mg，1当量，0.33mmol)溶于DCM(2mL)中，并在4℃下向该混合物中滴加三溴硼烷(0.83g，0.32mL，10当量，3.3mmol)。将所得混合物在28℃搅拌18h，并在4℃下向该混合物中滴加MeOH(5mL)。在减压下浓缩该混合物，将残余物倒入饱和碳酸钠水溶液(10mL)中，用乙酸乙酯(3×50mL)萃取。将合并的有机层经硫酸钠干燥并浓缩，得到粗4-溴-1-甲基-1H-苯并[d]咪唑-6-醇(80mg，0.26mmol)，其未经进一步纯化即用于下一步。LCMS:m/z 227.0[M+H]+。4-Bromo-6-methoxy-1-methyl-1H-benzo[d]imidazole (80 mg, 1 equivalent, 0.33 mmol) was dissolved in DCM (2 mL), and tribromoborane (0.83 g, 0.32 mL, 10 equivalent, 3.3 mmol) was added dropwise to the mixture at 4 °C. The resulting mixture was stirred at 28 °C for 18 h, and MeOH (5 mL) was added dropwise to the mixture at 4 °C. The mixture was concentrated under reduced pressure, and the residue was poured into a saturated aqueous sodium carbonate solution (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give crude 4-bromo-1-methyl-1H-benzo[d]imidazole-6-ol (80 mg, 0.26 mmol), which was used in the next step without further purification. LCMS: m/z 227.0 [M+H] + .
中间体104.2-(5-溴-2-氟-4-甲氧基苯氧基)-5-(三氟甲基)吡啶Intermediate 104.2-(5-bromo-2-fluoro-4-methoxyphenoxy)-5-(trifluoromethyl)pyridine
将5-溴-2-氟-4-甲氧基苯酚(4.75g，1当量，21.49mmol)、2-氟-5-(三氟甲基)吡啶(3.548g，1当量，21.49mmol)和碳酸铯(14g，2当量，42.98mmol)在DMF(100mL)中的混合物在60℃下搅拌18h。向残余物中加入水(100mL)，并将所得混合物用乙酸乙酯(100×20mL)萃取。合并有机层，用盐水(4×100mL)洗涤，经硫酸钠干燥，过滤并蒸发，得到粗标题化合物(6.35g，14.8mmol)，其不经进一步纯化即可用于下一步。1H NMR(400MHz,氯仿-d)δ:8.38(s,1H),7.91(dd,1H),7.42(d,1H),7.07(d,1H),6.78(d,1H),3.88(s,3H)。A mixture of 5-bromo-2-fluoro-4-methoxyphenol (4.75 g, 1 equivalent, 21.49 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (3.548 g, 1 equivalent, 21.49 mmol), and cesium carbonate (14 g, 2 equivalent, 42.98 mmol) in DMF (100 mL) was stirred at 60 °C for 18 h. Water (100 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (100 × 20 mL). The combined organic layers were washed with brine (4 × 100 mL), dried over sodium sulfate, filtered, and evaporated to give the crude title compound (6.35 g, 14.8 mmol), which was ready for use in the next step without further purification. 1H NMR (400MHz, chloroform-d) δ: 8.38 (s, 1H), 7.91 (dd, 1H), 7.42 (d, 1H), 7.07 (d, 1H), 6.78 (d, 1H), 3.88 (s, 3H).
中间物105.4-(3,4-二氟苯氧基)-2-硝基苯甲酸甲酯Intermediate 105.4-(3,4-difluorophenoxy)-2-nitrobenzene methyl ester
将4-氟-2-硝基苯甲酸甲酯(5.0g，1当量，25.11mmol)、3,4-二氟苯酚(3.593g，1.1当量，27.62mmol)和碳酸钾(6.940g，2当量，50.22mmol)混合在乙腈(100mL)中，随后在回流温度下加热14h。冷却至RT后，将混合物在减压下浓缩，用EtOAc(100mL)萃取，用水(20mL)、K2CO3溶液(20mL，15％在水中)和盐水(20mL)洗涤。有机相经Na2SO4干燥，并在真空中浓缩，得到标题化合物(6.68g，19mmol，77％，90％纯度)。1H NMR(500MHz,DMSO-d6)δ:7.89(d,1H),7.63(d,1H),7.59–7.50(m,1H),7.47(dq,1H),7.33(dd,1H),7.12–7.03(m,1H),3.81(s,3H)。Methyl 4-fluoro-2-nitrobenzene (5.0 g, 1 equivalent, 25.11 mmol), 3,4-difluorophenol (3.593 g, 1.1 equivalent, 27.62 mmol), and potassium carbonate (6.940 g, 2 equivalent, 50.22 mmol) were mixed in acetonitrile (100 mL) and then heated at reflux for 14 h . After cooling to RT, the mixture was concentrated under reduced pressure, extracted with EtOAc (100 mL), and washed with water (20 mL), K₂CO₃ solution (20 mL, 15% in water) , and brine (20 mL). The organic phase was dried over Na₂SO₄ and concentrated under vacuum to give the title compound (6.68 g, 19 mmol, 77%, 90% purity). 1 H NMR(500MHz, DMSO-d6)δ:7.89(d,1H),7.63(d,1H),7.59–7.50(m,1H),7.47(dq,1H),7.33(dd,1H),7.12–7.03(m,1H),3.81(s,3H).
根据中间体105所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。According to the method described in intermediate 105, the following intermediates are prepared from the starting materials shown in the table. No data is displayed if there is no information in the LCMS/GCMS data.
中间体116.4-(3,4-二氟苯氧基)-2-硝基苯酰肼Intermediate 116.4-(3,4-difluorophenoxy)-2-nitrobenzoylhydrazine
向4-(3,4-二氟苯氧基)-2-硝基苯甲酸甲酯(2.000g，1当量，6.468mmol)在乙醇(20mL)中的溶液中加入水合肼(2.266g，7当量，45.28mmol)。将混合物在回流下加热过夜。然后在减压下蒸发溶剂，向残余物中加入水(20mL)。过滤所得固体，用水、己烷洗涤，并在真空中干燥，得到标题化合物(1.900g，5.5mmol，85％，90％纯度)。1H NMR(500MHz,DMSO-d6)δ:9.77(s,1H),7.59(d,1H),7.59–7.49(m,2H),7.47–7.42(m,1H),7.33(dd,1H),7.07–6.99(m,1H),4.32(s,1H)。Hydrazine hydrate (2.266 g, 7 equivalents, 45.28 mmol) was added to a solution of methyl 4-(3,4-difluorophenoxy)-2-nitrobenzene (2.000 g, 1 equivalent, 6.468 mmol) in ethanol (20 mL). The mixture was heated under reflux overnight. The solvent was then evaporated under reduced pressure, and water (20 mL) was added to the residue. The resulting solid was filtered, washed with water and hexane, and dried under vacuum to give the title compound (1.900 g, 5.5 mmol, 85%, 90% purity). 1 H NMR (500MHz, DMSO-d6) δ: 9.77 (s, 1H), 7.59 (d, 1H), 7.59–7.49 (m, 2H), 7.47–7.42 (m, 1H), 7.33 (dd, 1H), 7.07–6.99 (m, 1H), 4.32 (s, 1H).
根据中间体116所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 116, the following intermediates are prepared from the starting materials shown in the table.
中间体119.2-(4-(3,4-二氟苯氧基)-2-硝基苯基)-1,3,4-噁二唑Intermediate 119.2-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1,3,4-oxadiazole
将4-(3,4-二氟苯氧基)-2-硝基苯酰肼(1.000g，1当量，3.234mmol)、4-甲基苯磺酸(111.4mg，0.2当量，646.8μmol)和三乙氧基甲烷(20mL)在回流温度下加热14h。然后将混合物在真空中浓缩，得到标题化合物(1.00g，2.2mmol，69％，71％纯度)LCMS:m/z 320.0[M+H]+。4-(3,4-difluorophenoxy)-2-nitrobenzoylhydrazine (1.000 g, 1 equivalent, 3.234 mmol), 4-methylbenzenesulfonic acid (111.4 mg, 0.2 equivalent, 646.8 μmol), and triethoxymethane (20 mL) were heated at reflux for 14 h. The mixture was then concentrated under vacuum to give the title compound (1.00 g, 2.2 mmol, 69%, 71% purity) LCMS: m/z 320.0 [M+H] + .
根据中间体119所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 119, the following intermediates are prepared from the starting materials shown in the table.
中间体122.(E)-1-(4-(3,4-二氟苯氧基)-2-硝基苯基)-3-(二甲基氨基)丙-2-烯-1-酮Intermediate 122.(E)-1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one
在回流温度下，将1-(4-(3,4-二氟苯氧基)-2-硝基苯基)乙-1-酮(0.300g，1当量，1.02mmol)、DMF-DMA(244mg，272μL，2当量，2.05mmol)和甲苯(3mL)的溶液搅拌并加热16h，随后冷却至RT。过滤所得固体，用甲苯、己烷洗涤，并在真空中干燥，得到标题化合物(0.246g，706μmol，69.0％)，为黄色固体。LCMS:m/z 349.2[M+H]+。A solution of 1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)ethyl-1-one (0.300 g, 1 equivalent, 1.02 mmol), DMF-DMA (244 mg, 272 μL, 2 equivalent, 2.05 mmol), and toluene (3 mL) was stirred and heated for 16 h at reflux, followed by cooling to RT. The resulting solid was filtered, washed with toluene and hexane, and dried under vacuum to give the title compound (0.246 g, 706 μmol, 69.0%) as a yellow solid. LCMS: m/z 349.2 [M+H] + .
中间体123.5-(4-(3,4-二氟苯氧基)-2-硝基苯基)-1-甲基-1H-吡唑Intermediate 123.5-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-1-methyl-1H-pyrazole
将(E)-1-(4-(3,4-二氟苯氧基)-2-硝基苯基)-3-(二甲基氨基)丙-2-烯-1-酮(0.246g，1当量，706μmol)和甲基肼硫酸盐(112mg，1.1当量，777μmol)混合在2-丙醇(4mL)中，并在回流温度下加热18h。将混合物冷却至RT，在真空中浓缩，并通过方法C纯化，得到标题化合物(0.109g，329μmol，46.6％，100％纯度)。LCMS:m/z 325.0[M+H]+。(E)-1-(4-(3,4-difluorophenoxy)-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one (0.246 g, 1 equivalent, 706 μmol) and methylhydrazine sulfate (112 mg, 1.1 equivalent, 777 μmol) were mixed in 2-propanol (4 mL) and heated at reflux for 18 h. The mixture was cooled to RT, concentrated under vacuum, and purified by method C to give the title compound (0.109 g, 329 μmol, 46.6%, 100% purity). LCMS: m/z 325.0 [M+H] + .
中间体124.7-硝基-5-((5-(三氟甲基)吡啶-2-基)氧基)-1H-吲唑Intermediate 124,7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole
向搅拌的2-甲基-6-硝基-4-((5-(三氟甲基)吡啶-2-基)氧基)苯胺(1.524g，1当量，4.865mmol)在乙酸(70.5mL)中的溶液中加入亚硝酸钠(369.2mg，1.1当量，5.352mmol)在水(2.4mL)中的溶液，并将混合物搅拌1h。反应完全后，蒸馏出乙酸，并将所得残余物与冰水(200mL)混合，并用MTBE(3×30mL)萃取。将合并的有机相用水(2×10mL)洗涤，在硫酸钠下干燥并在减压下浓缩，得到标题化合物(1.5g，3.9mmol，80％，84％纯度)。LCMS:m/z325.0[M+H]+。A solution of sodium nitrite (369.2 mg, 1.1 equivalent, 5.352 mmol) in water (2.4 mL) was added to a stirred solution of 2-methyl-6-nitro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline (1.524 g, 1 equivalent, 4.865 mmol) in acetic acid (70.5 mL), and the mixture was stirred for 1 h. After the reaction was complete, the acetic acid was distilled off, and the resulting residue was mixed with ice water (200 mL) and extracted with MTBE (3 × 30 mL). The combined organic phases were washed with water (2 × 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.5 g, 3.9 mmol, 80%, 84% purity). LCMS: m/z 325.0 [M+H] + .
根据中间体124所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 124, the following intermediates are prepared from the starting materials shown in the table.
中间体126.5-(4-(三氟甲基)苯氧基)-1H-吲唑-7-胺Intermediate 126.5-(4-(trifluoromethyl)phenoxy)-1H-indazole-7-amine
将5-(2-氯-4-(三氟甲基)苯氧基)-7-硝基-1H-吲唑(0.093g，1当量，0.26mmol)溶于甲醇(15mL)中。加入甲酸铵盐(0.33g，20当量，5.2mmol)和钯(0.22g，10w-％，0.8当量，0.21mmol)。将所得混合物在65℃下搅拌16h，冷却至RT并过滤。在减压下浓缩滤液，并用EtOAc(10mL)处理。过滤沉淀物并在减压下干燥，得到标题化合物(0.044g，0.15mmol，58％，100％纯度)，其不经进一步纯化即可用于下一步。1H NMR(500MHz,DMSO-d6)δ:7.87(s,1H),7.65(d,2H),7.06(d,2H),6.62(s,1H),6.18(s,1H),5.69(s,2H)。5-(2-chloro-4-(trifluoromethyl)phenoxy)-7-nitro-1H-indazole (0.093 g, 1 equivalent, 0.26 mmol) was dissolved in methanol (15 mL). Ammonium formate (0.33 g, 20 equivalent, 5.2 mmol) and palladium (0.22 g, 10 w-%, 0.8 equivalent, 0.21 mmol) were added. The resulting mixture was stirred at 65 °C for 16 h, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure and treated with EtOAc (10 mL). The precipitate was filtered and dried under reduced pressure to give the title compound (0.044 g, 0.15 mmol, 58%, 100% purity), which was ready for use in the next step without further purification. 1 H NMR (500MHz, DMSO-d6) δ: 7.87 (s, 1H), 7.65 (d, 2H), 7.06 (d, 2H), 6.62 (s, 1H), 6.18 (s, 1H), 5.69 (s, 2H).
中间体127.1-甲基-7-硝基-5-((5-(三氟甲基)吡啶-2-基)氧基)-1H-吲唑Intermediate 127, 1-methyl-7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole
向冷却至0℃的7-硝基-5-((5-(三氟甲基)吡啶-2-基)氧基)-1H-吲唑(0.1g，1当量，308μmol)在THF(4mL)中的溶液中加入氢化钠(14.8mg，60w-％，1.2当量，370μmol)。在23℃搅拌1h后，在0℃下逐滴加入甲基碘(46.0mg，20.3μL，1.05当量，324μmol)。将该混合物在23℃下搅拌16h。加入水(1mL)，并将所得混合物在减压下浓缩。将粗产物溶于EtOAc(10mL)中，用水和盐水洗涤，用MgSOS干燥，并在减压下除去溶剂，得到标题化合物(0.129g，310μmol，100％，81.2％纯度)，其不经进一步纯化即可用于下一步。LCMS:m/z 339.2[M+H]+。Sodium hydride (14.8 mg, 60 w-%, 1.2 equivalence, 370 μmol) was added to a solution of 7-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)-1H-indazole (0.1 g, 1 equivalent, 308 μmol) in THF (4 mL) cooled to 0 °C. After stirring at 23 °C for 1 h, methyl iodine (46.0 mg, 20.3 μL, 1.05 equivalent, 324 μmol) was added dropwise at 0 °C. The mixture was stirred at 23 °C for 16 h. Water (1 mL) was added, and the resulting mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc (10 mL), washed with water and brine, dried over MgSO₄ , and the solvent was removed under reduced pressure to give the title compound (0.129 g, 310 μmol, 100%, 81.2% purity), which was ready for use in the next step without further purification. LCMS:m/z 339.2[M+H] + .
中间体128.1-(3,4-二氟苯氧基)-4-甲氧基-2-甲基-3-硝基苯Intermediate 128.1-(3,4-difluorophenoxy)-4-methoxy-2-methyl-3-nitrobenzene
将1-溴-4-甲氧基-2-甲基-3-硝基苯(0.384g，1.5mmol)、3,4-二氟苯酚(0.13g，1.0mmol)、Cs2CO3(0.652g，2.0mmol)、CuI(0.057g，0.3mmol)和N,N-二甲基甘氨酸(0.031g，0.3mmol)在二噁烷(5ml)中的混合物在130℃下加热24h。蒸发混合物并将残余物通过正相色谱纯化，得到0.175g标题化合物。1H NMR(400MHz,DMSO-d6)δ:2.07(3H,s),3.87(3H,s),6.71-6.79(1H,m),7.12-7.19(1H,m),7.19-7.27(2H,m),7.38-7.49(1H,m)。A mixture of 1-bromo-4-methoxy-2-methyl-3-nitrobenzene (0.384 g, 1.5 mmol), 3,4- difluorophenol (0.13 g, 1.0 mmol), Cs₂CO₃ (0.652 g, 2.0 mmol), CuI (0.057 g, 0.3 mmol), and N,N-dimethylglycine (0.031 g, 0.3 mmol) in dioxane (5 mL) was heated at 130 °C for 24 h. The mixture was evaporated, and the residue was purified by normal-phase chromatography to give 0.175 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 2.07(3H,s), 3.87(3H,s), 6.71-6.79(1H,m), 7.12-7.19(1H,m), 7.19-7.27(2H,m), 7.38-7.49(1H,m).
中间体129.2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺Intermediate 129,2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline
将1-甲氧基-2-硝基-4-(4-(三氟甲基)苯氧基)苯(558mg，1当量，1.78mmol)溶于甲醇(20mL)中，并用Pd/C(37.9mg，0.2当量，356μmol)处理。将所得混合物在1atm压力、RT下氢化过夜。滤出催化剂，并在减压下蒸发溶剂，得到粗标题产物，其不经进一步纯化即可用于下一步。LCMS:m/z 284.2[M+H]+。1-Methoxy-2-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (558 mg, 1 equivalent, 1.78 mmol) was dissolved in methanol (20 mL) and treated with Pd/C (37.9 mg, 0.2 equivalent, 356 μmol). The resulting mixture was hydrogenated overnight at 1 atm and RT. The catalyst was filtered off, and the solvent was evaporated under reduced pressure to give the crude title product, which could be used for the next step without further purification. LCMS: m/z 284.2 [M+H] + .
根据中间体129所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 129, the following intermediates are prepared from the starting materials shown in the table.
中间体158.2-(4-甲氧基-3-硝基苯氧基)-4-(三氟甲基)吡啶Intermediate 158.2-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)pyridine
将2-氯-4-(三氟甲基)吡啶(2.72g，15.0mmol)、4-甲氧基-3-硝基苯酚(2.80g，15.8mmol)和Cs2CO3(5.68g，17.3mmol)在DMF(20ml)中的混合物在100℃加热7h。加入水(50ml)，并将混合物用EtOAc(3×50ml)萃取。合并有机层并蒸发，得到4.71g粗标题化合物，其不经进一步纯化即可用于下一步反应。1H NMR(400MHz,DMSO-d6)δ:3.96(3H,s),7.44(1H,d),7.50-7.59(3H,m),7.84(1H,d),8.41(1H,d).LCMS:m/z 315.4[M+H]+。A mixture of 2-chloro-4-(trifluoromethyl)pyridine (2.72 g, 15.0 mmol), 4-methoxy-3- nitrophenol (2.80 g, 15.8 mmol), and Cs₂CO₃ (5.68 g, 17.3 mmol) in DMF (20 mL) was heated at 100 °C for 7 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (3 × 50 mL). The organic layers were combined and evaporated to give 4.71 g of the crude title compound, which could be used for the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ: 3.96 (3H, s), 7.44 (1H, d), 7.50–7.59 (3H, m), 7.84 (1H, d), 8.41 (1H, d). LCMS: m/z 315.4 [M+H] ⁺ .
根据中间体158所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 158, the following intermediates are prepared from the starting materials shown in the table.
中间体163.2-甲氧基-5-((3-(三氟甲基)苄基)氧基)苯胺盐酸盐Intermediate 163,2-methoxy-5-((3-(trifluoromethyl)benzyl)oxy)aniline hydrochloride
将1-甲氧基-2-硝基-4-((3-(三氟甲基)苄基)氧基)苯(8.70g，1当量，26.6mmol)、水(7.43g，7.4mL，15.5当量，412mmol)、盐酸氨(142mg，0.1当量，2.66mmol)和氯化氢(266mg，226μL，36.5％水溶液，0.1当量，2.66mmol)混合在1,4-二噁烷(200mL)中，随后加入铁(7.42g，5当量，133mmol)。将混合物在110℃下搅拌5h，并在RT下搅拌16h。将混合物通过二氧化硅薄层过滤，浓缩，并将残余物加入到用盐酸饱和的二噁烷(30mL)中。在减压下蒸发溶液。将所得残余物用乙酸乙酯洗涤并干燥，得到标题化合物。LCMS:m/z 334.2[M+H]+。1-Methoxy-2-nitro-4-((3-(trifluoromethyl)benzyl)oxy)benzene (8.70 g, 1 equivalent, 26.6 mmol), water (7.43 g, 7.4 mL, 15.5 equivalent, 412 mmol), ammonium hydrochloride (142 mg, 0.1 equivalent, 2.66 mmol), and hydrogen chloride (266 mg, 226 μL, 36.5% aqueous solution, 0.1 equivalent, 2.66 mmol) were mixed in 200 mL of 1,4-dioxane, followed by the addition of iron (7.42 g, 5 equivalent, 133 mmol). The mixture was stirred at 110 °C for 5 h and then at RT for 16 h. The mixture was filtered through a silica thin-layer filter, concentrated, and the residue was added to 30 mL of dioxane saturated with hydrochloric acid. The solution was evaporated under reduced pressure. The resulting residue was washed with ethyl acetate and dried to give the title compound. LCMS:m/z 334.2[M+H] + .
根据中间体163所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 163, the following intermediates are prepared from the starting materials shown in the table.
中间体182.5-((5-氯吡啶-2-基)氧基)-2-甲氧基苯胺Intermediate 182.5-((5-chloropyridin-2-yl)oxy)-2-methoxyaniline
将5-氯-2-(4-甲氧基-3-硝基苯氧基)吡啶(197mg，1当量，702μmol)溶于甲醇(5mL)中，并加入铂(20.5mg，0.15当量，105μmol)。将混合物脱气，并在氢气气氛中搅拌12h，然后过滤，并蒸发溶剂，得到标题化合物(175mg，0.66mmol，94％，95％纯度)，其不经进一步纯化即可用于下一步。LCMS:m/z 251.0[M+H]+。中间体183.1,1-二苯基-N-(6-(3-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)甲亚胺5-Chloro-2-(4-methoxy-3-nitrophenoxy)pyridine (197 mg, 1 equivalent, 702 μmol) was dissolved in methanol (5 mL), and platinum (20.5 mg, 0.15 equivalent, 105 μmol) was added. The mixture was degassed and stirred for 12 h under a hydrogen atmosphere, then filtered and the solvent was evaporated to give the title compound (175 mg, 0.66 mmol, 94%, 95% purity), which could be used for the next step without further purification. LCMS: m/z 251.0 [M+H] + . Intermediate 183.1,1-Diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxanepenten-4-yl)methylimine
将4-溴-6-(3-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯(1.20g，1当量，3.32mmol)、二苯基甲亚胺(663mg，1.1当量，3.66mmol)、2-甲基丙-2-醇钠(335mg，1.05当量，3.49mmol)和2,2'-双(二苯基膦基)-1,1'-联萘(207mg，0.1当量，332μmol)溶于甲苯(20mL)中。用氩气将溶液鼓泡1min，然后加入二乙酰氧基钯(37.3mg，0.05当量，166μmol)，并将混合物在氩气气氛中于110℃搅拌12h。过滤混合物，并将固体用乙酸乙酯(2×20mL)洗涤。然后用盐水(2×50mL)洗涤乙酸乙酯溶液。有机相经硫酸钠干燥并过滤。在减压下蒸发溶剂，得到标题化合物，其不经进一步纯化即可用于下一步。LCMS:m/z 462.0[M+H]+。4-Bromo-6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopentene (1.20 g, 1 equivalent, 3.32 mmol), diphenylmethyleneimine (663 mg, 1.1 equivalent, 3.66 mmol), sodium 2-methylprop-2-ol (335 mg, 1.05 equivalent, 3.49 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (207 mg, 0.1 equivalent, 332 μmol) were dissolved in toluene (20 mL). The solution was bubbled with argon for 1 min, then palladium diacetoxy (37.3 mg, 0.05 equivalent, 166 μmol) was added, and the mixture was stirred at 110 °C for 12 h under an argon atmosphere. The mixture was filtered, and the solid was washed with ethyl acetate (2 × 20 mL). The ethyl acetate solution was then washed with brine (2 × 50 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound, which could be used in the next step without further purification. LCMS: m/z 462.0 [M+H] + .
根据中间体183所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 183, the following intermediates are prepared from the starting materials shown in the table.
中间体189.(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)氨基甲酸叔丁酯Intermediate 189. (7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl) tert-butyl carbamate
在氩气下，向5-溴-7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯(1.410g，1当量，3.759mmol)、氨基甲酸叔丁酯(660.5mg，1.5当量，5.638mmol)和碳酸铯(3.674g，3当量，11.28mmol)在甲苯(40mL)中的混合物中加入XantPhos(326.2mg，0.15当量，563.8μmol)和三(二亚苄基丙酮)二钯(172.1mg，0.05当量，187.9μmol)，并将该混合物在110℃下加热18h。冷却至RT后，将混合物过滤并浓缩。将残留物用乙酸乙酯(10mL)稀释，并用盐水(2×50mL)洗涤。有机相经Na2SO4干燥，过滤并在真空中浓缩。将残留物从乙腈中重结晶，得到标题化合物。LCMS:m/z 412.2[M+H]+。Under argon atmosphere, XantPhos (326.2 mg, 0.15 equivalent, 563.8 μmol) and tris(dibenzylacetone)dipalladium (172.1 mg, 0.05 equivalent, 187.9 μmol) were added to a mixture of 5-bromo-7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxene (1.410 g, 1 equivalent, 3.759 mmol), tert-butyl carbamate (660.5 mg, 1.5 equivalent, 5.638 mmol), and cesium carbonate (3.674 g, 3 equivalent, 11.28 mmol) in toluene (40 mL), and the mixture was heated at 110 °C for 18 h. After cooling to RT, the mixture was filtered and concentrated. The residue was diluted with ethyl acetate (10 mL) and washed with brine (2 × 50 mL). The organic phase was dried over Na₂SO₄ , filtered, and concentrated under vacuum. The residue was recrystallized from acetonitrile to give the title compound. LCMS : m/z 412.2 [M+H] ⁺ .
根据中间体189所述的方法，由表中所示的起始原料制备以下中间体。在LCMS/GCMS数据无信息时，则不显示数据。According to the method described in intermediate 189, the following intermediates are prepared from the starting materials shown in the table. No data is displayed if there is no information in the LCMS/GCMS data.
中间体202.7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-胺盐酸盐Intermediate 202.7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxene-5-amine hydrochloride
在0℃下，将三甲基氯硅烷(1.320g，1.54mL，5当量，12.15mmol)逐滴加入到甲醇(25mL)中。将混合物搅拌30min，并加入(7-(4-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)氨基甲酸叔丁酯(1g，1当量，2.431mmol)，并将该溶液在RT下搅拌48h。将混合物在真空中浓缩，得到粗标题化合物(808mg，2.11mmol，86.9％，90.93％纯度)。LCMS:m/z312.2[M+H]+。Trimethylchlorosilane (1.320 g, 1.54 mL, 5 equivalents, 12.15 mmol) was added dropwise to methanol (25 mL) at 0 °C. The mixture was stirred for 30 min, and (7-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)carbamate tert-butyl ester (1 g, 1 equivalent, 2.431 mmol) was added. The solution was stirred at RT for 48 h. The mixture was concentrated under vacuum to give the crude title compound (808 mg, 2.11 mmol, 86.9%, 90.93% purity). LCMS: m/z 312.2 [M+H] + .
根据中间体202所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 202, the following intermediates are prepared from the starting materials shown in the table.
中间体214.6-(3-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯-4-胺Intermediate 214,6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopentene-4-amine
将1,1-二苯基-N-(6-(3-(三氟甲基)苯氧基)苯并[d][1,3]间二氧杂环戊烯-4-基)甲亚胺(0.800g，1当量，1.73mmol)溶于THF(10mL)中，并在RT下加入HCl溶液(253mg，6.93mL，1摩尔，4当量，6.93mmol)。将混合物在RT下搅拌10min，然后在真空中蒸发，得到标题化合物(640mg，1.1mmol，62％，50％纯度)，其不经进一步纯化即可用于下一步。LCMS:m/z298.0[M+H]+。1,1-Diphenyl-N-(6-(3-(trifluoromethyl)phenoxy)benzo[d][1,3]m-dioxacyclopenten-4-yl)methylimine (0.800 g, 1 equivalent, 1.73 mmol) was dissolved in THF (10 mL), and HCl solution (253 mg, 6.93 mL, 1 mol, 4 equivalent, 6.93 mmol) was added under RT. The mixture was stirred under RT for 10 min and then evaporated under vacuum to give the title compound (640 mg, 1.1 mmol, 62%, 50% purity), which was ready for use in the next step without further purification. LCMS: m/z 298.0 [M+H] + .
根据中间体214所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 214, the following intermediates are prepared from the starting materials shown in the table.
中间体220.5-(2-氯-4-(三氟甲基)苯氧基)-4-氟-2-甲氧基苯胺盐酸盐Intermediate 220.5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyaniline hydrochloride
将(5-(2-氯-4-(三氟甲基)苯氧基)-4-氟-2-甲氧基苯基)氨基甲酸叔丁酯(0.185g，1当量，425μmol)溶于甲醇(5mL)中，并在25℃下逐滴加入HCl(155mg，104μL，10w-％，1当量，425μmol)在二噁烷中的溶液。将混合物在25℃下搅拌56h，然后在减压下浓缩，得到标题化合物(0.150g，0.32mmol，76％，80％纯度)，其不经进一步纯化即可用于下一步。1H NMR(500MHz,DMSO-d6)δ:8.00(s,1H),7.66(d,1H),7.21(d,1H),6.97(m,2H),3.85(s,3H).LCMS:m/z 336.0[M+H]+。0.185 g (1 equivalent, 425 μmol) of tert-butyl (5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)carbamate was dissolved in methanol (5 mL), and a solution of HCl (155 mg, 104 μL, 10 w-%, 1 equivalent, 425 μmol) in dioxane was added dropwise at 25 °C. The mixture was stirred at 25 °C for 56 h, and then concentrated under reduced pressure to give the title compound (0.150 g, 0.32 mmol, 76%, 80% purity), which could be used in the next step without further purification. 1 H NMR (500MHz, DMSO-d6) δ: 8.00 (s, 1H), 7.66 (d, 1H), 7.21 (d, 1H), 6.97 (m, 2H), 3.85 (s, 3H). LCMS: m/z 336.0 [M+H] + .
中间体221a.N-甲基丙氨酸甲酯1,1-二氧化物Intermediate 221a. N-methylalanine methyl ester 1,1-dioxide
将丙氨酸甲酯1,1-二氧化物(350mg，1当量，2.12mmol)和碳酸钾(879mg，3当量，6.36mmol)在无水DMF(5mL)中混合，随后一次性加入碘甲烷(1.50g，660μL，5当量，10.6mmol)。将混合物在27℃下搅拌18h。将混合物在真空中浓缩，残余物用水(5mL)处理，并将所得悬浮液用乙酸乙酯(2×20mL)萃取。将合并的有机相用盐水(2×15，6615mL)洗涤，经硫酸钠干燥，过滤并在真空中浓缩，得到标题化合物(116mg，0.39mmol，18％，60％纯度)，其不经进一步纯化即可用于下一步。1H NMR(500MHz,DMSO-d6)δ:4.56–4.46(m,1H),4.38(m,1H),3.95(m,1H),3.71(s,3H),2.67(s,3H)。Alanine methyl ester 1,1-dioxide (350 mg, 1 equivalent, 2.12 mmol) and potassium carbonate (879 mg, 3 equivalent, 6.36 mmol) were mixed in anhydrous DMF (5 mL), followed by the addition of iodomethane (1.50 g, 660 μL, 5 equivalent, 10.6 mmol) in a single batch. The mixture was stirred at 27 °C for 18 h. The mixture was concentrated under vacuum, the residue was treated with water (5 mL), and the resulting suspension was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 15, 6615 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound (116 mg, 0.39 mmol, 18%, 60% purity), which was ready for use in the next step without further purification. 1 H NMR (500MHz, DMSO-d6) δ: 4.56–4.46 (m, 1H), 4.38 (m, 1H), 3.95 (m, 1H), 3.71 (s, 3H), 2.67 (s, 3H).
中间体221b.N-甲基丙氨酸锂-1,1-二氧化物Intermediate 221b. Lithium N-methylalanine-1,1-dioxide
将N-甲基丙氨酸甲酯1,1-二氧化物(100mg，1当量，558μmol)和氢氧化锂水合物(23.4mg，1当量，558μmol)溶于甲醇(2mL)中，并在RT下搅拌16h。将该混合物浓缩，并将残余物用乙腈浓缩三次，得到标题化合物(77mg，0.43mmol，77％，95％纯度)，其不经进一步纯化即可用于下一步。1H NMR(400MHz,DMSO-d6)δ:4.10–3.96(m,2H),3.13(t,1H),2.61(s,3H)。N-methylalanine methyl ester 1,1-dioxide (100 mg, 1 equivalent, 558 μmol) and lithium hydroxide hydrate (23.4 mg, 1 equivalent, 558 μmol) were dissolved in methanol (2 mL) and stirred at RT for 16 h. The mixture was concentrated, and the residue was concentrated three times with acetonitrile to give the title compound (77 mg, 0.43 mmol, 77%, 95% purity), which could be used for the next step without further purification. ¹H NMR (400 MHz, DMSO-d6) δ: 4.10–3.96 (m, 2H), 3.13 (t, 1H), 2.61 (s, 3H).
中间体222a.1-甲基-5-硫代吡咯烷-2-甲酸叔丁酯Intermediate 222a, tert-butyl 1-methyl-5-thiopyrrolidine-2-carboxylate
向1-甲基-5-氧代吡咯烷-2-甲酸叔丁酯(470mg，1当量，2.36mmol)在THF(3mL)中的溶液中加入硫化磷(V)(262mg，0.5当量，1.18mmol)。将混合物回流搅拌24h。将溶液冷却并过滤。加入氯仿(20mL)，并将有机相用饱和碳酸氢钠(20mL)洗涤。将水相用氯仿(20mL)萃取。干燥合并的有机相，并在真空中浓缩，得到标题化合物(500mg，1.8mmol，76％，77％纯度)，其不经进一步纯化即可用于下一步。GCMS:m/z 216.1[M]+。Phosphorus sulfide (V) (262 mg, 0.5 equivalent, 1.18 mmol) was added to a solution of 1-methyl-5-oxopyrrolidine-2-carboxylic acid tert-butyl ester (470 mg, 1 equivalent, 2.36 mmol) in THF (3 mL). The mixture was refluxed and stirred for 24 h. The solution was cooled and filtered. Chloroform (20 mL) was added, and the organic phase was washed with saturated sodium bicarbonate (20 mL). The aqueous phase was extracted with chloroform (20 mL). The combined organic phases were dried and concentrated under vacuum to give the title compound (500 mg, 1.8 mmol, 76%, 77% purity), which was ready for use in the next step without further purification. GCMS: m/z 216.1 [M] + .
中间体222b.1-甲基-5-硫代吡咯烷-2-甲酸Intermediate 222b, 1-methyl-5-thiopyrrolidine-2-carboxylic acid
将1-甲基-5-硫代吡咯烷-2-甲酸叔丁酯(500mg，1当量，2.32mmol)溶于三氟乙酸(2.65g，1.79mL，10当量，23.2mmol)中，并将该溶液在RT下搅拌12h。然后蒸发溶剂，并将残余物溶于甲苯(5mL)中，并浓缩除去过量的TFA，得到标题化合物(370mg，1.2mmol，50％，50％纯度)，其不经进一步纯化即可用于下一步。中间体223.N-(5-羟基-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺1-Methyl-5-thiopyrrolidine-2-carboxylic acid tert-butyl ester (500 mg, 1 equivalent, 2.32 mmol) was dissolved in trifluoroacetic acid (2.65 g, 1.79 mL, 10 equivalent, 23.2 mmol), and the solution was stirred at RT for 12 h. The solvent was then evaporated, and the residue was dissolved in toluene (5 mL) and concentrated to remove excess TFA, yielding the title compound (370 mg, 1.2 mmol, 50%, 50% purity), which could be used in the next step without further purification. Intermediate 223,N-(5-hydroxy-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide
将1-甲基-5-氧代吡咯烷-2-甲酸(0.5g，1.2当量，3.49mmol)溶于N,N-二甲基甲酰胺(5mL)中，并加入HATU(1.33g，1.2当量，3.49mmol)。将溶液在RT下搅拌5min。向该溶液中加入3-氨基-4-甲氧基苯酚盐酸盐(511mg，1当量，2.91mmol)，随后加入DIPEA(1.05g，1.42mL，2.8当量，8.15mmol)。然后将混合物在RT下搅拌2h。在真空中除去溶剂。将粗产物溶于乙酸乙酯(10mL)中，用盐水(50mL)和水(50mL)洗涤，干燥并蒸发溶剂。残余物用方法B纯化，得到标题化合物(0.0667g)。1H NMR(400MHz,DMSO-d6)δ:9.34(s,1H),8.96(s,1H),7.54(s,1H),6.85(d,1H),6.45(d,1H),4.42(d,1H),3.32(s,2H),2.66(s,3H),2.37–2.11(m,3H),1.87(s,1H).LCMS:m/z 265.2[M+H]+。1-Methyl-5-oxopyrrolidine-2-carboxylic acid (0.5 g, 1.2 equivalents, 3.49 mmol) was dissolved in N,N-dimethylformamide (5 mL), and HATU (1.33 g, 1.2 equivalents, 3.49 mmol) was added. The solution was stirred at RT for 5 min. 3-Amino-4-methoxyphenol hydrochloride (511 mg, 1 equivalent, 2.91 mmol) was added to the solution, followed by DIPEA (1.05 g, 1.42 mL, 2.8 equivalents, 8.15 mmol). The mixture was then stirred at RT for 2 h. The solvent was removed under vacuum. The crude product was dissolved in ethyl acetate (10 mL), washed with brine (50 mL) and water (50 mL), dried, and the solvent was evaporated. The residue was purified by method B to give the title compound (0.0667 g). 1 H NMR(400MHz,DMSO-d6)δ:9.34(s,1H),8.96(s,1H),7.54(s,1H),6.85(d,1H),6.45(d, 1H),4.42(d,1H),3.32(s,2H),2.66(s,3H),2.37–2.11(m,3H),1.87(s,1H).LCMS:m/z 265.2[M+H] + .
根据中间体223所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 223, the following intermediates are prepared from the starting materials shown in the table.
中间体226.(3-氟苯基)(4-甲氧基-3-(5-氧代吡咯烷-2-甲酰胺基)苄基)氨基甲酸叔丁酯Intermediate 226. (3-Fluorophenyl)(4-methoxy-3-(5-oxopyrrolidine-2-carbamate)benzyl)tert-butyl carbamate
向(3-氨基-4-甲氧基苄基)(3-氟苯基)氨基甲酸叔丁酯(200mg，1当量，577μmol)、5-氧代吡咯烷-2-甲酸(74.5mg，1当量，577μmol)和1-甲基-1H-咪唑(237mg，5当量，2.89mmol)在乙腈(4mL)中的混合物中加入N-(氯(二甲基氨基)亚甲基)-N-甲基甲铵六氟磷酸盐(V)(243mg，1.5当量，866μmol)。将混合物在RT下搅拌18h，然后在真空中浓缩。向残余物中加入水(20mL)，并将所得混合物用乙酸乙酯(2×20mL)萃取。合并有机层，用盐水(20mL)洗涤，经硫酸钠干燥，过滤并蒸发，得到标题化合物(0.3g)，其不经进一步纯化即可用于下一步。LCMS:m/z 358.0[M+H]+。N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (243 mg, 1.5 equivalent, 866 μmol) was added to a mixture of (3-amino-4-methoxybenzyl)(3-fluorophenyl)carbamate (200 mg, 1 equivalent, 577 μmol), 5-oxopyrrolidine-2-carboxylic acid (74.5 mg, 1 equivalent, 577 μmol), and 1-methyl-1H-imidazolium (237 mg, 5 equivalent, 2.89 mmol) in acetonitrile (4 mL). The mixture was stirred at RT for 18 h and then concentrated under vacuum. Water (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (0.3 g), which was ready for use in the next step without further purification. LCMS:m/z 358.0[M+H] + .
中间体227a.4-(甲氧基甲氧基)-2,3-二氢苯并呋喃-6-甲酸甲酯Intermediate methyl 227a.4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-carboxylate
在0℃下，向4-羟基-2,3-二氢苯并呋喃-6-甲酸甲酯(2g，1当量，10.30mmol)和N-乙基-N-异丙基丙-2-胺(3.994g，5.38mL，3当量，30.90mmol)在DCM(80mL)中的溶液中加入氯(甲氧基)甲烷(1.309g，1.24mL，95w-％，1.5当量，15.45mmol)，然后在20℃下搅拌该混合物18h。将该混合物用盐水洗涤(3×10mL)，经硫酸钠干燥，过滤并蒸发，得到标题化合物(2.3g，8.834mmol，85.78％，90.75％纯度)，其不经进一步纯化即可用于下一步。1H NMR(500MHz,氯仿-d)δ:7.29(s,1H),7.13(s,1H),5.23(s,2H),4.63(t,2H),3.87(s,3H),3.49(s,3H),3.20(t,2H)。At 0 °C, methyl 4-hydroxy-2,3-dihydrobenzofuran-6-carboxylate (2 g, 1 equivalent, 10.30 mmol) and N-ethyl-N-isopropylpropyl-2-amine (3.994 g, 5.38 mL, 3 equivalent, 30.90 mmol) in DCM (80 mL) were added to a solution of chloro(methoxy)methane (1.309 g, 1.24 mL, 95 w-%, 1.5 equivalent, 15.45 mmol), and the mixture was stirred at 20 °C for 18 h. The mixture was washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (2.3 g, 8.834 mmol, 85.78%, 90.75% purity), which was ready for use in the next step without further purification. 1H NMR (500MHz, chloroform-d) δ: 7.29(s, 1H), 7.13(s, 1H), 5.23(s, 2H), 4.63(t, 2H), 3.87(s, 3H), 3.49(s, 3H), 3.20(t, 2H).
中间体227b.(4-(甲氧基甲氧基)-2,3-二氢苯并呋喃-6-基)甲醇Intermediate 227b. (4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-yl)methanol
将LiAlH4(127mg，2当量，3.36mmol)在THF(5mL)中的溶液冷却至0℃，并逐滴加入4-(甲氧基甲氧基)-2,3-二氢苯并呋喃-6-甲酸甲酯(400mg，1当量，1.68mmol)在THF(5mL)中的溶液。除去冷却浴，并将混合物在20℃下搅拌18h。将混合物冷却至0℃，并逐滴加入水(130μL)和30％的K2CO3溶液(4×130μL)。过滤混合物，并将残余物用THF(5mL)洗涤。分离有机层并浓缩，得到粗标题化合物(340mg，1.48mmol，88.0％，91.31％纯度)，为黄色油状物，其不经进一步纯化即可用于下一步。1H NMR(400MHz,氯仿-d)δ:6.59(s,1H),6.48(s,1H),5.17(s,2H),4.66–4.48(m,4H),3.47(s,3H),3.14(t,2H)。A solution of LiAlH₄ (127 mg, 2 equivalents, 3.36 mmol) in THF (5 mL) was cooled to 0 °C, and a solution of methyl 4-(methoxymethoxy)-2,3-dihydrobenzofuran-6-carboxylate (400 mg, 1 equivalent, 1.68 mmol) in THF (5 mL) was added dropwise. The cooling bath was removed, and the mixture was stirred at 20 °C for 18 h. The mixture was cooled to 0 °C, and water (130 μL) and 30% K₂CO₃ solution (4 × 130 μL) were added dropwise. The mixture was filtered, and the residue was washed with THF (5 mL). The organic layer was separated and concentrated to give the crude title compound (340 mg, 1.48 mmol, 88.0%, 91.31% purity) as a yellow oil, which could be used for the next step without further purification. 1H NMR (400MHz, chloroform-d) δ: 6.59 (s, 1H), 6.48 (s, 1H), 5.17 (s, 2H), 4.66–4.48 (m, 4H), 3.47 (s, 3H), 3.14 (t, 2H).
中间体227c.5-((3,4-二氟苯氧基)甲基)-4-(甲氧基甲氧基)-2,3-二氢苯并呋喃Intermediate 227c.5-((3,4-difluorophenoxy)methyl)-4-(methoxymethoxy)-2,3-dihydrobenzofuran
在0℃、Ar气氛下，向(7-(甲氧基甲氧基)-2,3-二氢苯并呋喃-5-基)甲醇(200mg，1当量，951μmol)和3,4-二氟苯酚(124mg，1当量，951μmol)在THF(40mL)中的混合物中加入三丁基膦(385mg，0.48mL，2当量，1.90mmol)，然后加入(E)-二氮烯-1,2-二基双(哌啶-1-基甲酮)(480mg，2当量，1.90mmol)。将混合物在20℃搅拌18h。在减压下蒸发混合物的溶剂。将残余物通过反相HPLC(水-乙腈)纯化，得到标题化合物(178mg，552μmol，58.1％)。1H NMR(500MHz,氯仿-d)δ:7.04(q,1H),6.83–6.71(m,1H),6.64(s,2H),6.54(s,1H),5.19(s,2H),4.92(s,2H),4.60(t,2H),3.49(s,3H),3.17(t,2H)。Tributylphosphine (385 mg, 0.48 mL, 2 equivalents, 1.90 mmol) was added to a mixture of (7-(methoxymethoxy)-2,3-dihydrobenzofuran-5-yl)methanol (200 mg, 1 equivalent, 951 μmol) and 3,4-difluorophenol (124 mg, 1 equivalent, 951 μmol) in THF (40 mL) under Ar atmosphere, followed by (E)-diazepine-1,2-diylbis(piperidin-1-yl ketone) (480 mg, 2 equivalents, 1.90 mmol). The mixture was stirred at 20 °C for 18 h. The solvent of the mixture was evaporated under reduced pressure. The residue was purified by reversed-phase HPLC (water-acetonitrile) to give the title compound (178 mg, 552 μmol, 58.1%). 1H NMR (500MHz, chloroform-d) δ: 7.04 (q, 1H), 6.83–6.71 (m, 1H), 6.64 (s, 2H), 6.54 (s, 1H), 5.19 (s, 2H), 4.92 (s, 2H), 4.60 (t, 2H), 3.49 (s, 3H), 3.17 (t, 2H).
中间体227d.5-((3,4-二氟苯氧基)甲基)-2,3-二氢苯并呋喃-4-醇Intermediate 227d.5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-ol
在0℃下，将三甲基氯硅烷(146mg，170μL，2当量，1.34mmol)逐滴加入到MeOH(4mL)中。将混合物搅拌30min，并加入5-((3,4-二氟苯氧基)甲基)-4-(甲氧基甲氧基)-2,3-二氢苯并呋喃(216mg，1当量，670μmol)的MeOH(1mL)溶液，随后在20℃下搅拌18h。将混合物在减压下浓缩，得到粗标题化合物(178mg，623μmol，92.9％，97.37％纯度)，为米色固体。1H NMR(500MHz,DMSO-d6)δ:9.50(s,1H),7.34–7.27(m,1H),7.14–7.01(m,1H),6.83–6.73(m,1H),6.34(s,1H),6.28(s,1H),4.92(s,2H),4.47(t,2H),2.99(t,2H)。At 0 °C, trimethylchlorosilane (146 mg, 170 μL, 2 equivalents, 1.34 mmol) was added dropwise to MeOH (4 mL). The mixture was stirred for 30 min, and a solution of 5-((3,4-difluorophenoxy)methyl)-4-(methoxymethoxy)-2,3-dihydrobenzofuran (216 mg, 1 equivalent, 670 μmol) in MeOH (1 mL) was added, followed by stirring at 20 °C for 18 h. The mixture was concentrated under reduced pressure to give the crude title compound (178 mg, 623 μmol, 92.9%, 97.37% purity) as a beige solid. 1 H NMR(500MHz,DMSO-d6)δ:9.50(s,1H),7.34–7.27(m,1H),7.14–7.01(m,1H),6.8 3–6.73(m,1H),6.34(s,1H),6.28(s,1H),4.92(s,2H),4.47(t,2H),2.99(t,2H).
中间体227e.6-((3,4-二氟苯氧基)甲基)-2,3-二氢苯并呋喃-4-基三氟甲磺酸酯Intermediate 227e., 6-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-yltrifluoromethanesulfonate
在0℃下，向5-((3,4-二氟苯氧基)甲基)-2,3-二氢苯并呋喃-4-醇(178mg，1当量，640μmol)和三乙胺(84.2mg，116μL，1.3当量，832μmol)在DCM(5mL)中的溶液中逐滴加入三氟甲磺酸酐(199mg，118μL，1.1当量，704μmol)，随后在20℃下搅拌该混合物18h。向混合物中加入DCM(10mL)，并将溶液用NaHSO4溶液(2×5mL)洗涤，经硫酸钠干燥，过滤并蒸发，得到标题化合物(238mg，0.52mmol，82％，90％纯度)，为棕色油状物，其无需进一步纯化即可用于下一步骤。1H NMR(500MHz,氯仿-d)δ:7.06(q,1H),6.84(s,1H),6.80(s,1H),6.79–6.72(m,1H),6.66–6.60(m,1H),4.96(s,2H),4.68(t,2H),3.34(t,2H)。At 0 °C, trifluoromethanesulfonic anhydride (199 mg, 118 μL, 1.1 equivalent, 704 μmol) was added dropwise to a solution of 5-((3,4-difluorophenoxy)methyl)-2,3-dihydrobenzofuran-4-ol (178 mg, 1 equivalent, 640 μmol) and triethylamine (84.2 mg, 116 μL, 1.3 equivalent, 832 μmol) in DCM (5 mL), and the mixture was stirred at 20 °C for 18 h. DCM (10 mL) was added to the mixture, and the solution was washed with NaHSO₄ solution (2 × 5 mL), dried over sodium sulfate, filtered, and evaporated to give the title compound (238 mg, 0.52 mmol, 82%, 90% purity) as a brown oil, which could be used in the next step without further purification. 1H NMR (500MHz, chloroform-d) δ: 7.06 (q, 1H), 6.84 (s, 1H), 6.80 (s, 1H), 6.79–6.72 (m, 1H), 6.66–6.60 (m, 1H), 4.96 (s, 2H), 4.68 (t, 2H), 3.34 (t, 2H).
中间体228.2-甲氧基-5-(4-(三氟甲基)苯氧基)苯甲酸Intermediate 228,2-methoxy-5-(4-(trifluoromethyl)phenoxy)benzoic acid
将氢氧化钾(51.6mg，1.5当量，919μmol)在水(0.6mL)中的溶液加入到2-甲氧基-5-(4-(三氟甲基)苯氧基)苯甲酸甲酯(0.200g，1当量，613μmol)在甲醇(5mL)中的溶液中。将混合物在25℃下搅拌16h，然后在减压下浓缩。将残余物溶于水(5mL)中，并用EtOAc(2×2mL)洗涤。用NaHSO4(5mL，15％在水中)酸化含水混合物。将所得混合物用EtOAc(2×8mL)萃取。合并的有机层在硫酸钠下干燥，并在减压下浓缩，得到标题化合物(0.08g，0.26mmol，42％)。LCMS:m/z 311.0[M-H]-。A solution of potassium hydroxide (51.6 mg, 1.5 equivalents, 919 μmol) in water (0.6 mL) was added to a solution of methyl 2-methoxy-5-(4-(trifluoromethyl)phenoxy)benzoate (0.200 g, 1 equivalent, 613 μmol) in methanol (5 mL). The mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure. The residue was dissolved in water (5 mL) and washed with EtOAc (2 × 2 mL). The aqueous mixture was acidified with NaHSO4 (5 mL, 15% in water). The resulting mixture was extracted with EtOAc (2 × 8 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.08 g, 0.26 mmol, 42%). LCMS: m/z 311.0 [MH] - .
中间体229.1-甲氧基-3-硝基-5-(4-(三氟甲基)苯氧基)苯Intermediate 229.1-Methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene
将3-甲氧基-5-硝基苯酚(0.5g，1当量，2.96mmol)、4-三氟苯基硼酸(0.7g，1.5当量，4.43mol)、吡啶(1.2g，1.2mL，5当量，14.8mol)、二乙酰氧基铜(0.54g，1当量，2.96mmol)和粉状分子筛(1g)悬浮于DCM(15mL)中。将空气通过所得溶液鼓泡30min，并将混合物在RT下搅拌过夜。过滤混合物，将滤液用水(2×30mL)洗涤，经硫酸钠干燥，过滤并在减压下除去溶剂。将残余物通过方法A纯化，得到标题化合物。LCMS:m/z 314.2[M+H]+。3-Methoxy-5-nitrophenol (0.5 g, 1 equivalent, 2.96 mmol), 4-trifluorophenylboronic acid (0.7 g, 1.5 equivalent, 4.43 mol), pyridine (1.2 g, 1.2 mL, 5 equivalent, 14.8 mol), copper diacetoxy (0.54 g, 1 equivalent, 2.96 mmol), and powdered molecular sieve (1 g) were suspended in DCM (15 mL). Air was bubbled through the resulting solution for 30 min, and the mixture was stirred overnight at RT. The mixture was filtered, the filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered again, and the solvent was removed under reduced pressure. The residue was purified by method A to give the title compound. LCMS: m/z 314.2 [M+H] + .
根据中间体229所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 229, the following intermediates are prepared from the starting materials shown in the table.
中间体240.1-甲氧基-2-硝基-4-((4-(三氟甲基)环己基)氧基)苯Intermediate 240.1-Methoxy-2-nitro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzene
在RT、氮气下，向4-甲氧基-3-硝基苯酚(0.25g，1.47mmol)、4-三氟甲基-1-羟基环己烷(0.20mL，1.47mmol)和三苯基膦(465mg，1.77mmol)在无水THF(10mL)中的混合物中逐滴加入DEAD(0.28mL，1.77mmol)，并将该混合物搅拌24h。用Et2O(30mL)稀释该混合物，用NaOH(2×10mL)、水(10mL)和盐水(10mL)洗涤。有机相经硫酸钠干燥，过滤并浓缩。粗残余物用纯化方法A进一步纯化，得到0.1g标题化合物。LCMS:m/z 320.28[M+H]+。Under RT and nitrogen atmosphere, DEAD (0.28 mL, 1.77 mmol) was added dropwise to a mixture of 4-methoxy-3-nitrophenol (0.25 g, 1.47 mmol), 4-trifluoromethyl-1-hydroxycyclohexane (0.20 mL, 1.47 mmol), and triphenylphosphine (465 mg, 1.77 mmol) in anhydrous THF (10 mL), and the mixture was stirred for 24 h. The mixture was diluted with Et₂O (30 mL) and washed with NaOH (2 × 10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude residue was further purified by purification method A to give 0.1 g of the title compound. LCMS: m/z 320.28 [M+H] ⁺ .
根据中间体240所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 240, the following intermediates are prepared from the starting materials shown in the table.
中间体248.(E)-4-(3-氟苯乙烯基)-1-甲氧基-2-硝基苯Intermediate 248.(E)-4-(3-fluorostyryl)-1-methoxy-2-nitrobenzene
在RT、N2下，将三乙基膦(5.6ml，32.6mmol)加入到3-氟苄基溴(2.0ml，16.3mmol)中。将所得混合物在150℃下加热2h。将混合物冷却并通过快速色谱法纯化，得到(3-氟苄基)膦酸二乙酯。在0-5℃下，向(3-氟苄基)膦酸二乙酯(0.82g，3.3mmol)在无水THF(10ml)中的混合物中加入NaH(0.27g，11.0mmol)。30min后，向混合物中逐滴加入在无水THF(10ml)中的4-甲氧基-3-硝基苯甲醛(0.5g，2.8mmol)，随后在RT下搅拌3h。冷却混合物，用冰水(20ml)淬灭，用2M HCl酸化，然后用乙酸乙酯(2×10ml)萃取。将合并的有机层用水洗涤，干燥，蒸发，然后通过快速色谱法纯化，得到标题化合物。LCMS m/z 274.2[M+H]+。1H NMR(氯仿-d,400MHz)δ:8.0-8.0(m,1H),7.6-7.7(m,1H),7.2-7.4(m,4H),6.9-7.1(m,3H),3.99(s,3H)。Triethylphosphine (5.6 mL, 32.6 mmol) was added to 3-fluorobenzyl bromide (2.0 mL, 16.3 mmol) at RT and N2 . The resulting mixture was heated at 150 °C for 2 h. The mixture was cooled and purified by rapid chromatography to give diethyl (3-fluorobenzyl)phosphonate. NaH (0.27 g, 11.0 mmol) was added to a mixture of diethyl (3-fluorobenzyl)phosphonate (0.82 g, 3.3 mmol) in anhydrous THF (10 mL) at 0–5 °C. After 30 min, 4-methoxy-3-nitrobenzaldehyde (0.5 g, 2.8 mmol) in anhydrous THF (10 mL) was added dropwise to the mixture, followed by stirring at RT for 3 h. The mixture was cooled, quenched with ice water (20 mL), acidified with 2 M HCl, and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dried, evaporated, and then purified by rapid chromatography to obtain the title compound. LCMS m/z 274.2 [M+H] + . 1H NMR (chloroform-d, 400MHz) δ: 8.0–8.0 (m, 1H), 7.6–7.7 (m, 1H), 7.2–7.4 (m, 4H), 6.9–7.1 (m, 3H), 3.99 (s, 3H).
中间体249.1-甲氧基-2-硝基-4-(3-(三氟甲基)苄基)苯Intermediate 249.1-Methoxy-2-nitro-4-(3-(trifluoromethyl)benzyl)benzene
将3-(三氟甲基)苯甲醛(0.20ml，1.4mmol)和甲苯磺酰肼(0.27g，1.4mmol)在1,4-二噁烷(10ml)中的混合物在60℃下加热90min。向所得(E)-4-甲基-N'-(3-(三氟甲基)亚苄基)苯磺酰肼(0.4g，1.168mmol)粗产物中加入K2CO3(0.24g，1.8mmol)和4-甲氧基-3-硝基苯基硼酸(0.23g，1.2mmol)。将混合物在氮气气氛下于110℃加热4h，随后冷却至RT。用2MNaHCO3(5ml)淬灭混合物，然后用乙酸乙酯(2×10ml)萃取。将合并的有机层用水洗涤，干燥，蒸发并通过快速色谱法纯化，得到标题化合物。LCMS m/z 312.3[M+H]+。1H NMR(400MHz,氯仿-d)δ:3.89-4.00(m,3H),4.02(s,2H),7.03(d,1H),7.27-7.35(m,3H),7.49-7.62(m,2H),7.65-7.70(m,1H)。A mixture of 3-(trifluoromethyl)benzaldehyde (0.20 mL, 1.4 mmol) and toluenesulfonyl hydrazine (0.27 g, 1.4 mmol) in 1,4-dioxane (10 mL) was heated at 60 °C for 90 min. K₂CO₃ (0.24 g, 1.8 mmol) and 4-methoxy- 3 - nitrophenylboronic acid (0.23 g, 1.2 mmol) were added to the resulting crude (E)-4-methyl-N'-(3-(trifluoromethyl)benzylene)benzenesulfonyl hydrazine (0.4 g, 1.168 mmol). The mixture was heated at 110 °C for 4 h under nitrogen atmosphere, followed by cooling to RT. The mixture was quenched with 2 M NaHCO₃ (5 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dried, evaporated, and purified by rapid chromatography to give the title compound. LCMS m/z 312.3 [M+H] ⁺ . 1H NMR (400MHz, chloroform-d) δ: 3.89-4.00 (m, 3H), 4.02 (s, 2H), 7.03 (d, 1H), 7.27-7.35 (m, 3H), 7.49-7.62 (m, 2H), 7.65-7.70 (m, 1H).
中间体250.1-甲氧基-2-硝基-4-(4-(三氟甲基)苄基)苯Intermediate 250.1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene
使用中间体234所述的方法，使用4-(三氟甲基)苯甲醛作为起始原料制备1-甲氧基-2-硝基-4-(4-(三氟甲基)苄基)苯。LCMS m/z 312.3[M+H]+。1H NMR(400MHz,氯仿-d)δ:3.90-4.04(m,5H),6.99-7.26(m,1H),7.32-7.34(m,1H),7.39-7.63(m,4H),7.69(d,1H)。Using the method described with intermediate 234, 1-methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene was prepared from 4-(trifluoromethyl)benzaldehyde as the starting material. LCMS m/z 312.3 [M+H] + . 1H NMR (400MHz, chloroform-d) δ: 3.90-4.04 (m, 5H), 6.99-7.26 (m, 1H), 7.32-7.34 (m, 1H), 7.39-7.63 (m, 4H), 7.69 (d, 1H).
中间体251.1-甲氧基-2-硝基-4-(4-(三氟甲基)苄基)苯Intermediate 251.1-Methoxy-2-nitro-4-(4-(trifluoromethyl)benzyl)benzene
将1-甲氧基-3-硝基-5-(4-(三氟甲基)苯氧基)苯(0.1g，1当量，0.32mmol)、锌(0.21g，10当量，3.2mmol)、氯化铵(0.17g，10当量，3.2mmol)在THF(5ml)、MeOH(2.5ml)和水(2.5ml)中的混合物在RT下搅拌4h。将混合物通过硅藻土过滤。将滤液用水洗涤(2×30mL)，经硫酸钠干燥，过滤并在减压下除去溶剂。将残余物通过快速色谱法纯化，得到标题化合物。LCMS m/z 284.1[M]+。A mixture of 1-methoxy-3-nitro-5-(4-(trifluoromethyl)phenoxy)benzene (0.1 g, 1 equivalent, 0.32 mmol), zinc (0.21 g, 10 equivalent, 3.2 mmol), and ammonium chloride (0.17 g, 10 equivalent, 3.2 mmol) in THF (5 mL), MeOH (2.5 mL), and water (2.5 mL) was stirred at RT for 4 h. The mixture was filtered through diatomaceous earth. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by rapid chromatography to give the title compound. LCMS m/z 284.1 [M] + .
根据中间体251所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 251, the following intermediates are prepared from the starting materials shown in the table.
中间体290.2-甲氧基-5-(3-(三氟甲氧基)苯氧基)苯胺Intermediate 290.2-Methoxy-5-(3-(trifluoromethoxy)phenoxy)aniline
将1-甲氧基-2-硝基-4-(3-(三氟甲氧基)苯氧基)苯(0.050g，0.152mol)、锌粉(0.050g，0.759mmol)、NH4Cl(0.041g，0.759mmol)、乙醇(1.5ml)和水(0.5ml)的混合物在50℃下搅拌，直至反应完全。将混合物通过硅藻土垫过滤。硅藻土层用乙醇进一步洗涤，并蒸发滤液，得到0.040g标题化合物。LCMS:m/z 299.8[M+H]+。A mixture of 1-methoxy-2-nitro-4-(3-(trifluoromethoxy)phenoxy)benzene (0.050 g, 0.152 mol), zinc powder (0.050 g, 0.759 mmol), NH₄Cl (0.041 g, 0.759 mmol), ethanol (1.5 mL), and water (0.5 mL) was stirred at 50 °C until the reaction was complete. The mixture was filtered through a diatomaceous earth mat. The diatomaceous earth layer was further washed with ethanol, and the filtrate was evaporated to give 0.040 g of the title compound. LCMS: m/z 299.8 [M+H] ⁺ .
中间体291.5-(4-异丙氧基苯氧基)-2-甲氧基苯胺Intermediate 291.5-(4-isopropoxyphenoxy)-2-methoxyaniline
根据中间体257的方法，由4-(4-异丙氧基苯氧基)-1-甲氧基-2-硝基苯(0.22g，0.725mmol)开始，使用4当量锌粉和4当量NH4Cl制备该化合物。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.044g。LCMS:m/z 273.9[M+H]+。The compound was prepared according to the method described in Intermediate 257, starting with 4-(4-isopropoxyphenoxy)-1-methoxy-2-nitrobenzene (0.22 g, 0.725 mmol), using 4 equivalents of zinc powder and 4 equivalents of NH₄Cl . The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.044 g. LCMS: m/z 273.9 [M+H] ⁺ .
中间体292.2-甲氧基-5-(4-(三氟甲氧基)苯氧基)苯胺Intermediate 292.2-methoxy-5-(4-(trifluoromethoxy)phenoxy)aniline
将1-甲氧基-2-硝基-4-(4-(三氟甲氧基)苯氧基)苯(0.12g，0.364mol)、铁粉(0.061g，1.093mmol)、无水CaCl2(0.040g，0.364mmol)、乙醇(1.0ml)和水(0.25ml)的混合物在60℃下搅拌，直至反应完全。将混合物通过硅藻土垫过滤。用EtOAc洗涤硅藻土层。将滤液用水(2x)洗涤，干燥并蒸发，得到0.090g标题化合物。LCMS:m/z 299.7[M]+。A mixture of 1-methoxy-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene (0.12 g, 0.364 mol), iron powder (0.061 g, 1.093 mmol), anhydrous CaCl₂ (0.040 g, 0.364 mmol), ethanol (1.0 mL), and water (0.25 mL) was stirred at 60 °C until the reaction was complete. The mixture was filtered through a diatomaceous earth mat. The diatomaceous earth layer was washed with EtOAc. The filtrate was washed with water (2x), dried, and evaporated to give 0.090 g of the title compound. LCMS: m/z 299.7 [M] + .
根据中间体292所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 292, the following intermediates are prepared from the starting materials shown in the table.
中间体297.2-氨基-4-(4-(三氟甲基)苯氧基)苯甲酰胺Intermediate 297.2-amino-4-(4-(trifluoromethyl)phenoxy)benzamide
根据中间体292的方法，由2-硝基-4-(4-(三氟甲基)苯氧基)苄腈(0.36g，1.168mmol)开始制备该化合物。将粗产物通过快速色谱法纯化，得到标题化合物。收率：0.21g。LCMS:m/z 296.8[M]+。The compound was prepared from 2-nitro-4-(4-(trifluoromethyl)phenoxy)benzyl nitrile (0.36 g, 1.168 mmol) according to the method described in intermediate 292. The crude product was purified by rapid chromatography to give the title compound. Yield: 0.21 g. LCMS: m/z 296.8 [M] + .
中间体298.5-(环己基甲氧基)-2-甲氧基苯胺Intermediate 298.5-(cyclohexylmethoxy)-2-methoxyaniline
将4-(环己基甲氧基)-1-甲氧基-2-硝基苯(0.26g，0.98mol)、锌粉(0.32g，4.90mmol，5.0当量)、NH4Cl(0.262g，4.90mmol，5.0当量)、THF(3.0ml)、甲醇(0.75ml)和水(0.75ml)的混合物在RT下搅拌，直至反应完全。将混合物通过硅藻土垫过滤。用EtOAc洗涤硅藻土层。将滤液用水(2×)洗涤，干燥并蒸发。将粗产物通过快速色谱法纯化，得到0.15g标题化合物。LCMS:m/z 235.4[M]+。A mixture of 4-(cyclohexylmethoxy)-1-methoxy-2-nitrobenzene (0.26 g, 0.98 mol), zinc powder (0.32 g, 4.90 mmol, 5.0 equivalent), NH₄Cl (0.262 g, 4.90 mmol, 5.0 equivalent), THF (3.0 mL), methanol (0.75 mL), and water (0.75 mL) was stirred at RT until the reaction was complete. The mixture was filtered through a diatomaceous earth filter. The diatomaceous earth layer was washed with EtOAc. The filtrate was washed with water (2×), dried, and evaporated. The crude product was purified by rapid chromatography to give 0.15 g of the title compound. LCMS: m/z 235.4 [M] + .
根据中间体298所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 298, the following intermediates are prepared from the starting materials shown in the table.
中间体306.5-(3-溴苯氧基)-2-甲氧基苯胺Intermediate 306.5-(3-bromophenoxy)-2-methoxyaniline
使用如中间体298所述的方法，由4-(3-溴苯氧基)-1-甲氧基-2-硝基苯(0.46g，1.419mmol)开始，使用7.5当量锌粉和7.5当量NH4Cl制备该化合物。收率：0.34g。LCMS:m/z294.2[M]+。The compound was prepared using the method described for intermediate 298, starting with 4-(3-bromophenoxy)-1-methoxy-2-nitrobenzene (0.46 g, 1.419 mmol), with 7.5 equivalents of zinc powder and 7.5 equivalents of NH₄Cl . Yield: 0.34 g. LCMS: m/z 294.2 [M] ⁺ .
根据中间体306所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 306, the following intermediates are prepared from the starting materials shown in the table.
中间体312.5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯胺Intermediate 312.5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyaniline
根据中间体298的方法，由3-氟-2-(4-甲氧基-3-硝基苯氧基)-5-(三氟甲基)吡啶(0.50g，1.505mmol)开始，使用10当量锌粉和10当量NH4Cl制备该化合物。收率：0.43g。LCMS:m/z 303.5[M+H]+。The compound was prepared according to the method described in Intermediate 298, starting with 3-fluoro-2-(4-methoxy-3-nitrophenoxy)-5-(trifluoromethyl)pyridine (0.50 g, 1.505 mmol), using 10 equivalents of zinc powder and 10 equivalents of NH₄Cl . Yield: 0.43 g. LCMS: m/z 303.5 [M+H] ⁺ .
根据中间体312所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 312, the following intermediates are prepared from the starting materials shown in the table.
中间体315.3-氨基-5-(4-(三氟甲基)苯氧基)苄腈Intermediate 315.3-Amino-5-(4-(trifluoromethyl)phenoxy)benzylnitrile
向3-硝基-5-(4-(三氟甲基)苯氧基)苄腈(0.22g，0.714mmol)在1,4-二噁烷(3.5ml)中的混合物中加入溶于37％ HCl水溶液(1.0ml)的氯化锡(II)二水合物(0.805g，3.57mmol)。将混合物在RT下搅拌，直至反应完全。用6M NaOH溶液使混合物呈碱性。加入DCM，并将混合物通过硅藻土短塞过滤。用DCM洗涤硅藻土。干燥滤液并蒸发溶剂，得到标题化合物。收率：0.14g。LCMS:m/z 279.3[M+H]+。To a mixture of 3-nitro-5-(4-(trifluoromethyl)phenoxy)benzyl nitrile (0.22 g, 0.714 mmol) in 1,4-dioxane (3.5 mL), 0.805 g (3.57 mmol) of stannous(II) dihydrate dissolved in 1.0 mL of 37% HCl aqueous solution was added. The mixture was stirred at RT until the reaction was complete. The mixture was made alkaline with 6 M NaOH solution. DCM was added, and the mixture was filtered through a diatomaceous earth stopper. The diatomaceous earth was washed with DCM. The filtrate was dried and the solvent was evaporated to give the title compound. Yield: 0.14 g. LCMS: m/z 279.3 [M+H] + .
根据中间体315所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 315, the following intermediates are prepared from the starting materials shown in the table.
中间体319.1-甲氧基-2-硝基-4-(3-(三氟甲氧基)苯氧基)苯Intermediate 319.1-Methoxy-2-nitro-4-(3-(trifluoromethoxy)phenoxy)benzene
向4-甲氧基-3-硝基苯酚(0.169g，1.00mmol)、3-(三氟甲氧基)苯基硼酸(0.448g，2.18mmol)、无水Cu(OAc)2(0.182g，1.00mmol)和粉状分子筛(0.25g)在无水DCM(7.5ml)中的混合物中加入DIPEA(0.871ml，5.00mmol)。将混合物在RT下搅拌直至获得最大转化率(48h)。将混合物通过硅藻土塞过滤，硅藻土层用EtOAc洗涤。滤液用5％NH4OH水溶液洗涤，干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到0.050g标题化合物。LCMS:m/z 330.2[M+H]+。DIPEA (0.871 ml, 5.00 mmol) was added to a mixture of 4-methoxy-3-nitrophenol (0.169 g, 1.00 mmol), 3-(trifluoromethoxy)phenylboronic acid (0.448 g, 2.18 mmol), anhydrous Cu(OAc) ₂ (0.182 g, 1.00 mmol), and powdered molecular sieve (0.25 g) in anhydrous DCM (7.5 ml). The mixture was stirred at RT until maximum conversion was achieved (48 h). The mixture was filtered through a diatomaceous earth plug, and the diatomaceous earth layer was washed with EtOAc. The filtrate was washed with 5% NH₄OH aqueous solution, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give 0.050 g of the title compound. LCMS: m/z 330.2 [M+H] ⁺ .
中间体320.1-甲氧基-2-硝基-4-(4-(三氟甲氧基)苯氧基)苯Intermediate 320: 1-Methoxy-2-nitro-4-(4-(trifluoromethoxy)phenoxy)benzene
向4-甲氧基-3-硝基苯酚(0.338g，2.00mmol)、4-(三氟甲氧基)苯基硼酸(0.618g，3.00mmol)、无水Cu(OAc)2(0.363g，2.00mmol)和粉状分子筛(0.25g)在无水DCM(15ml)中的混合物中加入吡啶(0.809ml，10.0mmol)。将混合物在RT下搅拌直至获得最大转化率(24-48h)。将混合物通过硅藻土塞过滤，并将硅藻土层用DCM洗涤。滤液用5％NH4OH水溶液洗涤，干燥并蒸发。将粗产物通过快速色谱法纯化，得到0.33g标题化合物。LCMS:m/z 330.2[M+H]+。Pyridine (0.809 mL, 10.0 mmol) was added to a mixture of 4-methoxy-3-nitrophenol (0.338 g, 2.00 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.618 g, 3.00 mmol), anhydrous Cu(OAc) ₂ (0.363 g, 2.00 mmol), and powdered molecular sieve (0.25 g) in anhydrous DCM (15 mL). The mixture was stirred at RT until maximum conversion was obtained (24–48 h). The mixture was filtered through a diatomaceous earth plug, and the diatomaceous earth layer was washed with DCM. The filtrate was washed with 5% NH₄OH aqueous solution, dried, and evaporated. The crude product was purified by rapid chromatography to give 0.33 g of the title compound. LCMS: m/z 330.2 [M+H] ⁺ .
根据中间体320所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 320, the following intermediates are prepared from the starting materials shown in the table.
中间体333.4-(环己基甲氧基)-1-甲氧基-2-硝基苯Intermediate 333,4-(cyclohexylmethoxy)-1-methoxy-2-nitrobenzene
向冷却(0-5℃)的环己基甲醇(0.285g，2.50mmol)、4-甲氧基-3-硝基苯酚(0.423g，2.50mmol)和三苯基膦(0.984g，3.75mmol)在无水THF(17ml)中的混合物中加入偶氮二甲酸二异丙酯(0.738ml，3.75mmol)。将混合物在RT下搅拌过夜。蒸发THF，并将残余物溶于DCM中。有机相用水和盐水洗涤，干燥并蒸发。将粗产物通过快速色谱法纯化，得到0.26g标题化合物。LCMS:m/z 266.2[M+H]+。Diisopropyl azodicarbonate (0.738 ml, 3.75 mmol) was added to a mixture of cooled (0–5 °C) cyclohexylethanol (0.285 g, 2.50 mmol), 4-methoxy-3-nitrophenol (0.423 g, 2.50 mmol), and triphenylphosphine (0.984 g, 3.75 mmol) in anhydrous THF (17 ml). The mixture was stirred overnight at RT. The THF was evaporated, and the residue was dissolved in DCM. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by rapid chromatography to give 0.26 g of the title compound. LCMS: m/z 266.2 [M+H] + .
根据中间体333所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 333, the following intermediates are prepared from the starting materials shown in the table.
中间体336.4-(4-(二氟甲基)苯氧基)-1-甲氧基-2-硝基苯Intermediate 336,4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene
a)4-(4-甲氧基-3-硝基苯氧基)苯甲醛a) 4-(4-methoxy-3-nitrophenoxy)benzaldehyde
将4-氟苯甲醛(0.215ml，2.00mmol)、4-甲氧基-3-硝基苯酚(0.338g，2.00mmol)和碳酸钾(0.553g，4.00mmol)在无水DMA(4.0ml)中的混合物在120℃下搅拌，直至反应完全。向冷却的混合物中加入水，并将混合物用EtOAc萃取。将有机相用水洗涤，干燥并蒸发，得到0.49g标题化合物。LCMS:m/z 274.1[M+H]+。b)4-(4-(二氟甲基)苯氧基)-1-甲氧基-2-硝基苯A mixture of 4-fluorobenzaldehyde (0.215 mL, 2.00 mmol), 4-methoxy-3-nitrophenol (0.338 g, 2.00 mmol), and potassium carbonate (0.553 g, 4.00 mmol) in anhydrous DMA (4.0 mL) was stirred at 120 °C until the reaction was complete. Water was added to the cooled mixture, and the mixture was extracted with EtOAc. The organic phase was washed with water, dried, and evaporated to give 0.49 g of the title compound. LCMS: m/z 274.1 [M+H] + . b) 4-(4-(difluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene
将4-(4-甲氧基-3-硝基苯氧基)苯甲醛(0.49g，1.793mmol)溶于无水DCM(5.5ml)中并冷却至0-5℃。分小批加入二乙基氨基三氟化硫(0.521ml，3.95mmol)，并将该混合物在RT下搅拌24h。将混合物用DCM稀释，并分小批加入饱和NaHCO3溶液。分离各相，并用DCM萃取水相。将合并的有机相用水和盐水洗涤，干燥并蒸发。将粗产物通过快速色谱法纯化，得到0.37g标题化合物。LCMS:m/z 296.0[M+H]+。4-(4-methoxy-3-nitrophenoxy)benzaldehyde (0.49 g, 1.793 mmol) was dissolved in anhydrous DCM (5.5 mL) and cooled to 0–5 °C. Diethylaminosulfur trifluoride (0.521 mL, 3.95 mmol) was added in small batches, and the mixture was stirred at RT for 24 h. The mixture was diluted with DCM and added in small batches to a saturated NaHCO3 solution. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by rapid chromatography to give 0.37 g of the title compound. LCMS: m/z 296.0 [M+H] + .
中间337.(3,4-二氟苯基)(4-甲氧基-3-硝基苯基)硫烷337. (3,4-Difluorophenyl)(4-methoxy-3-nitrophenyl)thion
向3,4-二氟苯硫酚(0.155ml，1.40mmol)、4-甲氧基-3-硝基苯基硼酸(0.197g，1.00mmol)、硫酸铜(II)(8.0mg，0.05mmol)和1,10-菲咯啉(9.0mg，0.05mmol)在乙醇(1.0ml)(使用前用氧气鼓泡)中的混合物中加入40％的四丁基氢氧化铵水溶液(1.0ml，3.82mmol)。将混合物在RT下搅拌过夜。然后将混合物用EtOAc稀释，并通过硅藻土垫过滤。硅藻土层用EtOAc进一步洗涤。蒸发滤液，并将粗产物通过快速色谱法纯化，得到0.17g标题化合物。1H NMR(400MHz,CDCl3):δ7.88(d,1H),7.56(dd,1H),7.00-7.16(m,4H),3.98(s,3H)。To a mixture of 3,4-difluorothiophenol (0.155 mL, 1.40 mmol), 4-methoxy-3-nitrophenylboronic acid (0.197 g, 1.00 mmol), copper(II) sulfate (8.0 mg, 0.05 mmol), and 1,10-phenanthroline (9.0 mg, 0.05 mmol) in ethanol (1.0 mL) (bubbled with oxygen before use), 40% tetrabutylammonium hydroxide aqueous solution (1.0 mL, 3.82 mmol) was added. The mixture was stirred overnight at RT. The mixture was then diluted with EtOAc and filtered through a diatomaceous earth pad. The diatomaceous earth layer was further washed with EtOAc. The filtrate was evaporated, and the crude product was purified by rapid chromatography to give 0.17 g of the title compound. 1 H NMR (400MHz, CDCl 3 ): δ7.88 (d, 1H), 7.56 (dd, 1H), 7.00-7.16 (m, 4H), 3.98 (s, 3H).
中间体338.2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺Intermediate 338,2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline
a)2-氯-1-(4-甲氧基-3-硝基苯氧基)-4-(三氟甲基)苯a) 2-Chloro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene
将2-氯-1-氟-4-(三氟甲基)苯(0.397g，2.00mmol)、4-甲氧基-3-硝基苯酚(0.372g，2.20mmol)和碳酸钾(0.608g，4.40mmol)在无水DMF(4.0ml)中的混合物在120℃下搅拌，直至反应完全。向冷却的混合物中加入水，随后在RT下搅拌1h。过滤形成的沉淀物，用水洗涤，并在减压下干燥，得到0.62g标题化合物。LCMS:m/z 348.1[M+H]+。A mixture of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.397 g, 2.00 mmol), 4-methoxy-3-nitrophenol (0.372 g, 2.20 mmol), and potassium carbonate (0.608 g, 4.40 mmol) in anhydrous DMF (4.0 mL) was stirred at 120 °C until the reaction was complete. Water was added to the cooled mixture, followed by stirring at RT for 1 h. The precipitate formed was filtered, washed with water, and dried under reduced pressure to give 0.62 g of the title compound. LCMS: m/z 348.1 [M+H] + .
b)2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺b) 2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline
向2-氯-1-(4-甲氧基-3-硝基苯氧基)-4-(三氟甲基)苯(0.66g，1.898mmol)和甲酸铵(1.197g，18.98mmol)在无水甲醇(35ml)中的混合物中加入10wt-％钯碳(0.253g，0.237mmol)。在RT下剧烈搅拌混合物，直至反应完全。将混合物通过硅藻土塞过滤，并将硅藻土层用甲醇洗涤。蒸发滤液，将残余物溶于EtOAc中。将有机相用水洗涤，干燥并蒸发，得到0.52g标题化合物。LCMS:m/z 284.5[M+H]+。10 wt% palladium on carbon (0.253 g, 0.237 mmol) was added to a mixture of 2-chloro-1-(4-methoxy-3-nitrophenoxy)-4-(trifluoromethyl)benzene (0.66 g, 1.898 mmol) and ammonium formate (1.197 g, 18.98 mmol) in anhydrous methanol (35 mL). The mixture was stirred vigorously at RT until the reaction was complete. The mixture was filtered through a diatomaceous earth plug, and the diatomaceous earth layer was washed with methanol. The filtrate was evaporated, and the residue was dissolved in EtOAc. The organic phase was washed with water, dried, and evaporated to give 0.52 g of the title compound. LCMS: m/z 284.5 [M+H] + .
中间体339.2-氯-4-(4-甲氧基-3-硝基苯氧基)苄腈Intermediate 339.2-chloro-4-(4-methoxy-3-nitrophenoxy)benzyl nitrile
将4-甲氧基-3-硝基苯酚(0.677g，4.00mmol，1.0当量)、2-氯-4-氟苄腈(0.622g，4.00mmol，1.0当量)和碳酸钾(1.216g，8.80mmol，2.2当量)在无水DMF(5.5ml)中的混合物在100-120℃下搅拌，直至反应完全。将冷却的混合物用水处理，并过滤形成的沉淀物并干燥，得到标题化合物。收率：1.06g。LCMS:m/z 304.5[M+H]+。如果产物没有从水中沉淀，则用EtOAc萃取。将有机相用水洗涤，干燥并蒸发，得到标题化合物，其就此使用或通过快速色谱法纯化。A mixture of 4-methoxy-3-nitrophenol (0.677 g, 4.00 mmol, 1.0 equivalent), 2-chloro-4-fluorobenzyl nitrile (0.622 g, 4.00 mmol, 1.0 equivalent), and potassium carbonate (1.216 g, 8.80 mmol, 2.2 equivalent) in anhydrous DMF (5.5 mL) was stirred at 100–120 °C until the reaction was complete. The cooled mixture was treated with water, and the precipitate formed was filtered and dried to give the title compound. Yield: 1.06 g. LCMS: m/z 304.5 [M+H] + . If the product did not precipitate from water, it was extracted with EtOAc. The organic phase was washed with water, dried, and evaporated to give the title compound, which could be used therein or purified by rapid chromatography.
根据中间体339所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 339, the following intermediates are prepared from the starting materials shown in the table.
中间体348.2-硝基-4-(4-(三氟甲基)苯氧基)苄腈Intermediate 348.2-nitro-4-(4-(trifluoromethyl)phenoxy)benzyl nitrile
将4-(三氟甲基)苯酚(0.40g，2.467mmol)、4-氟-2-硝基苄腈(0.40g，2.408mmol)和碳酸钾(0.666g，4.82mmol)在无水DMA(5.0ml)中的混合物在100℃下搅拌，直至反应完全。将冷却的混合物用水稀释，并用EtOAc萃取。将有机相干燥并蒸发。将粗产物通过快速色谱法纯化，得到标题化合物。收率：0.40g。1H NMR(400MHz,CDCl3)δ:7.89(d,1H),7.87(d,1H),7.74-7.79(m,2H),7.36(dd,1H),7.20-7.25(m,2H)。A mixture of 4-(trifluoromethyl)phenol (0.40 g, 2.467 mmol), 4-fluoro-2-nitrobenzyl nitrile (0.40 g, 2.408 mmol), and potassium carbonate (0.666 g, 4.82 mmol) in anhydrous DMA (5.0 mL) was stirred at 100 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was dried and evaporated. The crude product was purified by rapid chromatography to give the title compound. Yield: 0.40 g. ¹H NMR (400 MHz, CDCl₃ ) δ: 7.89 (d, 1H), 7.87 (d, 1H), 7.74–7.79 (m, 2H), 7.36 (dd, 1H), 7.20–7.25 (m, 2H).
中间体349.3-硝基-5-(4-(三氟甲基)苯氧基)苄腈Intermediate 349.3-nitro-5-(4-(trifluoromethyl)phenoxy)benzyl nitrile
将4-(三氟甲基)苯酚(0.324g，2.00mmol)、3,5-二硝基苄腈(0.463g，2.40mmol)和磷酸钾(0.849g，4.00mmol)在无水DMA(3.0ml)中的混合物在100℃下搅拌，直至反应完全。将冷却的混合物用水稀释，并用EtOAc萃取。将有机相干燥并蒸发。将粗产物通过快速色谱法纯化，得到标题化合物。收率：0.42g。LCMS:m/z309.2[M+H]+。A mixture of 4-(trifluoromethyl)phenol (0.324 g, 2.00 mmol), 3,5-dinitrobenzyl nitrile (0.463 g, 2.40 mmol), and potassium phosphate (0.849 g, 4.00 mmol) in anhydrous DMA (3.0 mL) was stirred at 100 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was dried and evaporated. The crude product was purified by rapid chromatography to give the title compound. Yield: 0.42 g. LCMS: m/z 309.2 [M+H] + .
中间体350.4-(4-(氟甲基)苯氧基)-1-甲氧基-2-硝基苯Intermediate 350.4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene
a)(4-(4-甲氧基-3-硝基苯氧基)苯基)甲醇a)(4-(4-methoxy-3-nitrophenoxy)phenyl)methanol
向4-(4-甲氧基-3-硝基苯氧基)苯甲醛(0.98g，3.59mmol)在MeOH(15ml)中的混合物中，分小批加入NaBH4(0.204g，5.38mmol)，并在RT下搅拌，直至反应完全。蒸发溶剂，并将残余物用水和EtOAc处理。分离各相，并将水相用EtOAc萃取。将合并的有机相用水和盐水洗涤，干燥并蒸发，得到标题化合物。收率0.97g。LCMS:m/z 258.3[M-H2O+H]+。Add NaBH4 (0.204 g, 5.38 mmol) in small batches to a mixture of 4-(4-methoxy-3-nitrophenoxy)benzaldehyde (0.98 g, 3.59 mmol) in MeOH (15 mL) and stir at RT until the reaction is complete. Evaporate the solvent and treat the residue with water and EtOAc. Separate the phases and extract the aqueous phase with EtOAc. Wash the combined organic phases with water and brine, dry and evaporate to give the title compound. Yield: 0.97 g. LCMS: m/z 258.3 [M-H2O+H] + .
b)4-(4-(氟甲基)苯氧基)-1-甲氧基-2-硝基苯b) 4-(4-(fluoromethyl)phenoxy)-1-methoxy-2-nitrobenzene
向(4-(4-甲氧基-3-硝基苯氧基)苯基)甲醇(0.48g，1.744mmol)在无水DCM(5.0ml)中的冷却(-78℃)溶液中加入二乙基氨基三氟化硫(DAST)(0.25ml，1.892mmol)。除去冷却浴，并将混合物温热至RT并搅拌，直至反应完全。将混合物用DCM(15ml)稀释并冷却至0-5℃。加入饱和NaHCO3溶液(5ml)调节pH至7-8。分离各相，并将水相用DCM萃取。将合并的有机相用水和盐水洗涤，干燥并蒸发。将粗产物通过快速色谱法纯化，得到标题化合物。收率：0.26g。1H NMR(400MHz,CDCl3)δ:7.53(d,1H),7.36-7.41(m,2H),7.25(dd,1H),7.08(d,1H),6.98-7.03(m,2H),5.35(d,2H),3.96(s,3H)。Diethylaminosulfur trifluoride (DAST) (0.25 ml, 1.892 mmol) was added to a cooled (-78 °C) solution of (4-(4-methoxy-3-nitrophenoxy)phenyl)methanol (0.48 g, 1.744 mmol) in anhydrous DCM (5.0 ml) at a temperature of -78 °C. The cooling bath was removed, and the mixture was heated to RT and stirred until the reaction was complete. The mixture was diluted with DCM (15 ml) and cooled to 0–5 °C. The pH was adjusted to 7–8 by adding saturated NaHCO3 solution (5 ml). The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with water and brine, dried, and evaporated. The crude product was purified by rapid chromatography to give the title compound. Yield: 0.26 g. 1 H NMR (400MHz, CDCl 3 ) δ: 7.53 (d, 1H), 7.36-7.41 (m, 2H), 7.25 (dd, 1H), 7.08 (d, 1H), 6.98-7.03 (m, 2H), 5.35 (d, 2H), 3.96 (s, 3H).
中间体351.2,4-二氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯胺Intermediate 351,2,4-Difluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)aniline
将5-氨基-2,4-二氟苯酚(0.218g，1.50mmol)和叔丁醇钾(0.185g，1.65mmol)在无水DMSO(3.0ml)中的混合物在RT下搅拌1h。加入2-氯-5-(三氟甲基)吡啶(0.272g，1.50mmol)和K2CO3(0.104g，0.75mmol)，并在120℃下继续搅拌，直至反应完全。将冷却的混合物用水稀释，并用EtOAc萃取。将有机相用1M NaOH和水洗涤，干燥并蒸发。将粗产物通过用EtOAc-庚烷(4:1)洗脱的硅胶短塞过滤纯化。蒸发滤液，并将残余物在真空下干燥，得到标题化合物。收率：0.25g。LCMS:m/z 291.5[M+H]+。A mixture of 5-amino-2,4-difluorophenol (0.218 g, 1.50 mmol) and potassium tert-butoxide (0.185 g, 1.65 mmol) in anhydrous DMSO (3.0 mL) was stirred at RT for 1 h . 2-chloro-5-(trifluoromethyl)pyridine (0.272 g, 1.50 mmol) and K₂CO₃ (0.104 g, 0.75 mmol) were added, and stirring was continued at 120 °C until the reaction was complete. The cooled mixture was diluted with water and extracted with EtOAc. The organic phase was washed with 1 M NaOH and water, dried, and evaporated. The crude product was purified by filtration through a short-stoppered silica gel filter eluted with EtOAc-heptane (4:1). The filtrate was evaporated, and the residue was dried under vacuum to give the title compound. Yield: 0.25 g. LCMS: m/z 291.5 [M+H] ⁺ .
中间体352.(2S,4R)-4-羟基-2-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基甲酰基)吡咯烷-1-甲酸苄酯Intermediate 352.(2S,4R)-4-hydroxy-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester
向2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺(0.085g，0.30mmol)、(2S,4R)-1-((苄氧基)-羰基)-4-羟基吡咯烷-2-甲酸(0.080g，0.30mmol)在EtOAc(0.40ml)和吡啶(0.20ml)中的混合物中加入1-丙烷膦酸环酐，50wt-％在EtOAc(0.30ml，0.509mmol)中。将混合物在RT下搅拌过夜。用0.5％HCl溶液淬灭反应，并用水和EtOAc稀释。分离各相，并将有机相用0.5％HCl溶液、水和盐水洗涤，干燥并蒸发，得到标题化合物。收率：0.111g。LC-MS:m/z＝531.3[M+H]+。粗产物就此使用或通过反相快速色谱法纯化，得到纯化合物。To a mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.085 g, 0.30 mmol), (2S,4R)-1-((benzyloxy)-carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.080 g, 0.30 mmol) in EtOAc (0.40 mL) and pyridine (0.20 mL), 1-propanephosphonic anhydride, 50 wt% in EtOAc (0.30 mL, 0.509 mmol), was added. The mixture was stirred overnight at RT. The reaction was quenched with 0.5% HCl solution and diluted with water and EtOAc. The phases were separated, and the organic phase was washed with 0.5% HCl solution, water, and brine, dried, and evaporated to give the title compound. Yield: 0.111 g. LC-MS: m/z = 531.3 [M+H] + . The crude product is then used or purified by reversed-phase rapid chromatography to obtain the pure compound.
根据中间体352所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 352, the following intermediates are prepared from the starting materials shown in the table.
中间体357.1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酸叔丁酯Intermediate 357.1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid tert-butyl ester
向冷却(0-5℃)的5-氧代吡咯烷-2-甲酸叔丁酯(0.37g，2.00mmol)在无水THF(5.0ml)中的混合物中加入60w-％NaH的油状物(0.10g，2.50mmol)，随后在0-5℃下搅拌30min。加入溶于无水THF(2.5ml)中的2-甲氧基乙酰氯(0.26g，2.40mmol)，并在RT下继续搅拌过夜。蒸发溶剂，并将残余物用DCM和水处理。分离各相，并将有机相用水和盐水洗涤。将有机相干燥并蒸发，得到标题化合物。收率：0.51g。LCMS:m/z 258.0[M+H]+。粗产物就此使用或通过反相快速色谱法纯化，得到纯化合物。To a mixture of cooled (0–5 °C) tert-butyl 5-oxopyrrolidine-2-carboxylate (0.37 g, 2.00 mmol) in anhydrous THF (5.0 mL), an oily substance of 60 w-% NaH (0.10 g, 2.50 mmol) was added, followed by stirring at 0–5 °C for 30 min. 2-Methoxyacetyl chloride (0.26 g, 2.40 mmol) dissolved in anhydrous THF (2.5 mL) was added, and stirring continued overnight at RT. The solvent was evaporated, and the residue was treated with DCM and water. The phases were separated, and the organic phase was washed with water and brine. The organic phase was dried and evaporated to give the title compound. Yield: 0.51 g. LCMS: m/z 258.0 [M+H] + . The crude product was used as is or purified by reversed-phase rapid chromatography to give the pure compound.
根据中间体357所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 357, the following intermediates are prepared from the starting materials shown in the table.
中间体362.(2-甲氧基乙酰基)-L-脯氨酸叔丁酯Intermediate 362.(2-Methoxyacetyl)-L-proline tert-butyl ester
向冷却(0-5℃)的L-脯氨酸叔丁酯(0.342g，2.00mmol)和三乙胺(0.558ml，4.00mmol)在无水DCM(10ml)中的溶液中加入2-甲氧基乙酰氯(0.239g，2.20mmol)。将混合物在RT下搅拌过夜。过滤混合物，并将滤液用饱和NH4Cl溶液、饱和NaHCO3溶液和盐水洗涤，干燥并蒸发，得到标题化合物。收率：0.34g。LCMS:m/z 244.2[M+H]+。2-Methoxyacetyl chloride (0.239 g, 2.20 mmol) was added to a solution of L-proline tert-butyl ester (0.342 g, 2.00 mmol) and triethylamine (0.558 mL, 4.00 mmol) in anhydrous DCM (10 mL) cooled (0–5 °C). The mixture was stirred overnight at RT. The mixture was filtered, and the filtrate was washed with saturated NH₄Cl solution, saturated NaHCO₃ solution, and brine. The filtrate was dried and evaporated to give the title compound. Yield: 0.34 g. LCMS: m/z 244.2 [M+H] ⁺ .
中间体363.(2-甲氧基乙酰基)-L-脯氨酸叔丁酯Intermediate 363.(2-Methoxyacetyl)-L-proline tert-butyl ester
将L-脯氨酸叔丁酯(0.342g，2.00mmol)、2-溴乙酰胺(0.331g，2.40mmol)和碳酸氢钾(0.30g，3.00mmol)在无水乙腈(10ml)中的混合物在80℃下搅拌，直至反应完全。过滤冷却的混合物并蒸发滤液。将残余物用水和DCM处理。分离各相，并将水相用DCM萃取。将合并的有机相干燥并蒸发，得到标题化合物。收率：0.34g。LCMS:m/z 229.4[M+H]+。A mixture of L-proline tert-butyl ester (0.342 g, 2.00 mmol), 2-bromoacetamide (0.331 g, 2.40 mmol), and potassium bicarbonate (0.30 g, 3.00 mmol) in anhydrous acetonitrile (10 mL) was stirred at 80 °C until the reaction was complete. The cooled mixture was filtered and the filtrate was evaporated. The residue was treated with water and DCM. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried and evaporated to give the title compound. Yield: 0.34 g. LCMS: m/z 229.4 [M+H] + .
中间体364.(S)-1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酸Intermediate 364.(S)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid
向(S)-1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酸叔丁酯(0.77g，2.99mmol)在无水DCM(15ml)中的混合物中加入三氟乙酸(2.50ml，32.4mmol，10.8当量)，随后在RT搅拌过夜。蒸发溶剂，并将残余物用甲苯处理，并再次蒸发。重复该步骤，并将残余物在真空下干燥，得到标题化合物。粗产物是：(a)就此用于下一步骤或(b)用饱和Na2CO3溶液碱化后用DCM萃取，随后干燥并蒸发有机相。LCMS:m/z 201.9[M+H]+。Trifluoroacetic acid (2.50 mL, 32.4 mmol, 10.8 equivalence) was added to a mixture of (S)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid tert-butyl ester (0.77 g, 2.99 mmol) in anhydrous DCM (15 mL), followed by stirring at RT overnight. The solvent was evaporated, and the residue was treated with toluene and evaporated again. This step was repeated, and the residue was dried under vacuum to give the title compound. The crude product was: (a) used directly in the next step or (b) alkalized with saturated Na₂CO₃ solution , extracted with DCM, dried, and the organic phase was evaporated. LCMS: m/z 201.9 [M+H] ⁺ .
根据中间体364所述的方法，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 364, the following intermediates are prepared from the starting materials shown in the table.
中间体371.(E)-5-(2-(4,4-二氟环己基)乙烯基)-2,3-二氢苯并呋喃-7-胺Intermediate 371.(E)-5-(2-(4,4-difluorocyclohexyl)vinyl)-2,3-dihydrobenzofuran-7-amine
将5-溴-2,3-二氢苯并呋喃-7-胺(0.158g，0.738mmol)、2-[(E)-2-(4,4-二氟环己基)乙烯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.243g，1.15mmol)、K3PO4(0.313g，2.0mmol)和SPhos PdG2(0.040g，0.075mmol)在二噁烷(1ml)和水(1ml)中的混合物在氮气气氛下于85℃加热8h。将混合物用乙酸乙酯(2×4ml)萃取。将合并的有机层蒸发，然后通过正相色谱法纯化，得到0.144g标题化合物。1H NMR(400MHz,DMSO-d6)δ:1.34-1.46(2H,m),1.76-1.95(4H,m),1.97-2.09(2H,m),2.20-2.29(1H,m),3.08(2H,t),4.47(2H,t),4.57(2H,s),5.88-5.95(1H,m),6.21(1H,d),6.50(1H,d),6.53(1H,br s).LCMS:m/z 280.7[M+H]+。A mixture of 5-bromo-2,3-dihydrobenzofuran-7-amine (0.158 g, 0.738 mmol), 2-[(E)-2-(4,4-difluorocyclohexyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxane (0.243 g, 1.15 mmol), K₃PO₄ (0.313 g , 2.0 mmol), and SPhos PdG₂ (0.040 g, 0.075 mmol) in dioxane (1 mL) and water (1 mL) was heated at 85 °C for 8 h under a nitrogen atmosphere. The mixture was extracted with ethyl acetate (2 × 4 mL). The combined organic layers were evaporated and then purified by normal-phase chromatography to give 0.144 g of the title compound. 1 H NMR(400MHz,DMSO-d6)δ:1.34-1.46(2H,m),1.76-1.95(4H,m),1.97-2.09(2H,m),2.20-2.29(1H,m ),3.08(2H,t),4.47(2H,t),4.57(2H,s),5.88-5.95(1H,m),6.21(1H,d),6.50(1H,d),6.53(1H,br s).LCMS: m/z 280.7[M+H] + .
根据中间体371所述的方法，，由表中所示的起始原料制备以下中间体。According to the method described in intermediate 371, the following intermediates are prepared from the starting materials shown in the table.
中间体373.1-(((苄氧基)羰基)甘氨酰基)-5-氧代吡咯烷-2-甲酸Intermediate 373.1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylic acid
a)((苄氧基)羰基)甘氨酸4-硝基苯基酯a)((benzyloxy)carbonyl)glycine 4-nitrophenyl ester
将三乙胺(290mg，2.87mmol，1.2当量)加入到N-苄氧羰基甘氨酸(1当量)在无水CH2Cl2(12mL)的悬浮液中。将搅拌的混合物冷却至0℃，并加入4-硝基苯基氯甲酸酯(578mg，2.87mmol，1.2当量)。10min后，加入DMAP(29.2mg，0.239mmol，0.1当量)，并将混合物在0℃下搅拌1h。将混合物用CH2Cl2(20mL)进一步稀释，并用饱和NaHCO3溶液(10mL)、0.1M HCl溶液(10mL)、盐水(10mL)洗涤，然后干燥(Na2SO4)，过滤并在真空中蒸发，得到粗产物。将粗残余物用反相色谱法进一步纯化，得到标题化合物。LCMS:m/z 331.068(M+H)+。Triethylamine (290 mg, 2.87 mmol, 1.2 equivalents) was added to a suspension of N-benzyloxycarbonylglycine (1 equivalent) in anhydrous CH₂Cl₂ (12 mL ). The stirred mixture was cooled to 0 °C, and 4-nitrophenyl chloroformate (578 mg, 2.87 mmol, 1.2 equivalents) was added. After 10 min, DMAP (29.2 mg, 0.239 mmol, 0.1 equivalents) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was further diluted with CH₂Cl₂ ( 20 mL), washed with saturated NaHCO₃ solution (10 mL), 0.1 M HCl solution (10 mL), and brine (10 mL ), then dried ( Na₂SO₄ ), filtered, and evaporated under vacuum to give the crude product. The crude residue was further purified by reversed-phase chromatography to give the title compound. LCMS: m/z 331.068 (M+H) ⁺ .
b)1-(((苄氧基)羰基)甘氨酰基)-5-氧代吡咯烷-2-甲酸叔丁酯b) 1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylic acid tert-butyl ester
在-78℃、氮气下，将LiHMDS(896μL，0.896mmol，1.06当量)逐滴加入到5-氧代-2-吡咯烷甲酸叔丁酯(157mg，0.845mmol，1当量)在无水THF(3ml)中的溶液中。将混合物在RT下搅拌15min，随后在-78℃下加入((苄氧基)羰基)甘氨酸4-硝基苯基酯在无水THF(4ml)中的溶液。将混合物在该温度下搅拌1h。将混合物用乙酸乙酯(20ml)稀释，并用NH4Cl(10ml)、盐水(10ml)洗涤，然后干燥(Na2SO4)，过滤并在真空中蒸发溶剂，得到粗产物。将粗残余物用反相色谱法进一步纯化，得到标题化合物。LCMS:m/z 377.155(M+H)+。LiHMDS (896 μL, 0.896 mmol, 1.06 equivalents) was added dropwise to a solution of tert-butyl 5-oxo-2-pyrrolidinecarboxylate (157 mg, 0.845 mmol, 1 equivalent) in anhydrous THF (3 mL) at -78 °C under nitrogen. The mixture was stirred at RT for 15 min, followed by the addition of a solution of ((benzyloxy)carbonyl)glycine 4-nitrophenyl ester in anhydrous THF (4 mL) at -78 °C. The mixture was stirred at this temperature for 1 h. The mixture was diluted with ethyl acetate (20 mL), washed with NH₄Cl (10 mL) and brine (10 mL ), dried ( Na₂SO₄ ), filtered, and the solvent was evaporated under vacuum to give the crude product. The crude residue was further purified by reversed-phase chromatography to give the title compound. LCMS: m/z 377.155 (M+H) ⁺ .
c)1-(((苄氧基)羰基)甘氨酰基)-5-氧代吡咯烷-2-甲酸(中间体373)c) 1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylic acid (intermediate 373)
在氮气、0℃下，将三氟乙酸逐滴加入到1-(((苄氧基)羰基)甘氨酰基)-5-氧代吡咯烷-2-甲酸叔丁酯(285mg，0.76mmol，1当量)在无水DCM中的溶液中。将混合物在0℃下搅拌2h。在真空中除去DCM和三氟乙酸残余物，得到粗产物。将粗残余物用反相色谱法进一步纯化，得到标题化合物。LCMS:m/z 321.031(M+H)+。Trifluoroacetic acid was added dropwise to a solution of tert-butyl 1-(((benzyloxy)carbonyl)glycyl)-5-oxopyrrolidine-2-carboxylate (285 mg, 0.76 mmol, 1 equivalent) in anhydrous DCM under nitrogen atmosphere and at 0 °C. The mixture was stirred at 0 °C for 2 h. The DCM and trifluoroacetic acid residues were removed under vacuum to give the crude product. The crude residue was further purified by reversed-phase chromatography to give the title compound. LCMS: m/z 321.031 (M+H) + .
实施例1.N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物1)Example 1. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 1)
向2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺(215mg，1当量，759μmol)在无水乙腈(5mL)的溶液中加入5-氧代吡咯烷-2-甲酸(98.0mg，1当量，759μmol)和1-甲基-1H-咪唑(312mg，5当量，3.80mmol)。将混合物在RT下搅拌10min，并一次性加入N,N,N',N'-四甲基氯甲脒六氟磷酸盐(319mg，1.5eq，1.14mmol)。将所得溶液在RT下搅拌过夜，并将混合物通过方法A直接纯化，得到标题化合物(0.194g)。1H NMR(400MHz,DMSO-d6)δ:9.35(s,1H),7.91(d,2H),7.71(d,2H),7.14(d,1H),7.08(d,2H),6.91(dd,1H),4.38(dd,1H),3.88(s,3H),2.38–2.27(m,1H),2.26–2.07(m,2H),2.02–1.90(m,1H).LCMS:m/z 395.0[M+H]+。To a solution of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (215 mg, 1 equivalence, 759 μmol) in anhydrous acetonitrile (5 mL), 5-oxopyrrolidine-2-carboxylic acid (98.0 mg, 1 equivalence, 759 μmol) and 1-methyl-1H-imidazolium (312 mg, 5 equivalence, 3.80 mmol) were added. The mixture was stirred at RT for 10 min, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (319 mg, 1.5 eq, 1.14 mmol) was added in a single batch. The resulting solution was stirred at RT overnight, and the mixture was purified directly by method A to give the title compound (0.194 g). 1 H NMR(400MHz,DMSO-d6)δ:9.35(s,1H),7.91(d,2H),7.71(d,2H),7.14(d,1H),7.08(d,2H),6.91(dd ,1H),4.38(dd,1H),3.88(s,3H),2.38–2.27(m,1H),2.26–2.07(m,2H),2.02–1.90(m,1H).LCMS:m/z 395.0[M+H] + .
根据化合物1所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 1. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例2.N-(5-(3,4-二氟苯氧基)-2-(1,3,4-噁二唑-2-基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物224)Example 2. N-(5-(3,4-difluorophenoxy)-2-(1,3,4-oxadiazol-2-yl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 224)
向5-(3,4-二氟苯氧基)-2-(1,3,4-噁二唑-2-基)苯胺(0.122g，1当量，422μmol)在乙腈(3mL)中的溶液中加入1-甲基-5-氧代吡咯烷-2-甲酸(72.5mg，1.2当量，506μmol)和DIPEA(218mg，294μL，4当量，1.69mmol)。然后加入HATU(321mg，2当量，844μmol)，并将混合物于RT搅拌过夜。加入N-(氯(二甲基氨基)亚甲基)-N-甲基甲铵六氟磷酸盐(V)(237mg，2当量，844μmol)和1-甲基-1H-咪唑(208mg，202μL，6当量，2.53mmol)，并将混合物搅拌过夜。将混合物在真空中浓缩，用EtOAc(10mL)稀释，用NaHSO4(2mL，10％)、K2CO3(2mL，10％)和水(2mL)洗涤，随后经Na2SO4干燥。蒸发EtOAc。将残余物通过HPLC(2-10min0-55％MeCN，流速：30mL/min)纯化，得到标题化合物(0.0242g，58.4μmol，13.8％，100％纯度)。1H NMR(600MHz,DMSO-d6)δ:10.89(s,1H),9.38(s,1H),8.01–7.89(m,2H),7.57–7.50(m,1H),7.45–7.38(m,1H),7.04(dd,J＝8.0,4.8Hz,1H),6.96(dd,J＝8.8,2.5Hz,1H),4.26(dd,J＝9.1,3.9Hz,1H),2.70(s,3H),2.38–2.21(m,3H),2.01–1.93(m,1H).LCMS:m/z 415.0[M+H]+。To a solution of 5-(3,4-difluorophenoxy)-2-(1,3,4-oxadiazol-2-yl)aniline (0.122 g, 1 equivalent, 422 μmol) in acetonitrile (3 mL), 1-methyl-5-oxopyrrolidine-2-carboxylic acid (72.5 mg, 1.2 equivalent, 506 μmol) and DIPEA (218 mg, 294 μL, 4 equivalent, 1.69 mmol) were added. Then HATU (321 mg, 2 equivalent, 844 μmol) was added, and the mixture was stirred overnight at RT. N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (237 mg, 2 equivalent, 844 μmol) and 1-methyl-1H-imidazole (208 mg, 202 μL, 6 equivalent, 2.53 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with EtOAc (10 mL), washed with NaHSO4 (2 mL, 10%), K2CO3 ( 2 mL, 10%), and water (2 mL ), and then dried over Na2SO4 . EtOAc was evaporated. The residue was purified by HPLC (2–10 min, 0–55% MeCN, flow rate: 30 mL/min) to give the title compound (0.0242 g, 58.4 μmol, 13.8%, 100% purity). 1 H NMR(600MHz, DMSO-d6)δ:10.89(s,1H),9.38(s,1H),8.01–7.89(m,2H),7.57–7.50(m,1H),7.45–7.38(m,1H),7.04(dd,J＝8.0,4 .8Hz,1H),6.96(dd,J＝8.8,2.5Hz,1H),4.26(dd,J＝9.1,3.9Hz,1H),2.70(s,3H),2.38–2.21(m,3H),2.01–1.93(m,1H).LCMS:m/z 415.0[M+H] + .
根据化合物224所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 224. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例3.(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1,3-二甲基-2-氧代咪唑烷-4-甲酰胺(化合物226)Example 3. (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide (Compound 226)
将2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺(0.07g，1当量，0.25mmol)、(S)-1,3-二甲基-2-氧代咪唑烷-4-甲酸(39mg，1当量，0.25mmol)和三乙胺盐酸盐(34mg，1当量，0.25mmol)溶于DMF(3mL)中，随后搅拌10min。然后加入1-甲基-1H-咪唑(0.1g，99μL，5当量，1.2mmol)，随后搅拌10min。然后一次性加入N-(氯(二甲基氨基)亚甲基)-N-甲基甲胺六氟磷酸盐(V)(76mg，1.1当量，0.27mmol)，随后在20℃下搅拌10h。过滤混合物，并将滤液通过HPLC(方法A)纯化，得到标题化合物(0.0314g，74.2μmol，30％，100％纯度)。1H NMR(400MHz,DMSO-d6)δ:9.57(s,1H),7.88(t,1H),7.71(d,2H),7.15(d,1H),7.08(d,2H),7.00–6.88(m,1H),4.40–4.26(m,1H),3.88(s,3H),3.54(t,1H),3.26–3.16(m,1H),2.64(d,6H).LCMS:m/z 424.2[M+H]+。2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.07 g, 1 equivalent, 0.25 mmol), (S)-1,3-dimethyl-2-oxoimidazolidine-4-carboxylic acid (39 mg, 1 equivalent, 0.25 mmol), and triethylamine hydrochloride (34 mg, 1 equivalent, 0.25 mmol) were dissolved in DMF (3 mL) and stirred for 10 min. Then, 1-methyl-1H-imidazole (0.1 g, 99 μL, 5 equivalent, 1.2 mmol) was added and stirred for 10 min. Then, N-(chloro(dimethylamino)methylene)-N-methylmethylamine hexafluorophosphate (V) (76 mg, 1.1 equivalent, 0.27 mmol) was added in one batch, and the mixture was stirred at 20 °C for 10 h. The mixture was filtered, and the filtrate was purified by HPLC (Method A) to give the title compound (0.0314 g, 74.2 μmol, 30%, 100% purity). ¹H NMR (400 MHz, DMSO-d⁶) δ: 9.57 (s, 1H), 7.88 (t, 1H), 7.71 (d, 2H), 7.15 (d, 1H), 7.08 (d, 2H), 7.00–6.88 (m, 1H), 4.40–4.26 (m, 1H), 3.88 (s, 3H), 3.54 (t, 1H), 3.26–3.16 (m, 1H), 2.64 (d, 6H). LCMS: m/z 424.2 [M+H] ⁺ .
根据化合物226所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 226. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例4.4-羟基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-3-甲酰胺(化合物228)Example 4. 4-Hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (Compound 228)
将2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺(100mg，1当量，353μmol)、4-乙酰氧基-1-甲基-5-氧代吡咯烷-3-甲酸(92.3mg，1.3当量，459μmol)和1-甲基-1H-咪唑(174mg，169μL，6当量，2.12mmol)溶于乙腈(2mL)中，随后在22℃搅拌混合物10min。然后加入N-(氯(二甲基氨基)亚甲基)-N-甲基甲铵六氟磷酸盐(V)(198mg，2当量，706μmol)。将混合物在22℃下搅拌16h。将4-乙酰氧基-1-甲基-5-氧代吡咯烷-3-甲酸(92.3mg，1.3当量，459μmol)和N-(氯(二甲基氨基)亚甲基)-N-甲基甲铵六氟磷酸盐(V)(198mg，2当量，706μmol)加入到该混合物中，随后在22℃下搅拌16h。浓缩该混合物，并加入氨(60.1mg，10当量，3.53mmol)在甲醇中的溶液。将反应物料在22℃下搅拌16h。将溶液通过反相HPLC(纯化方法A)纯化，得到标题化合物(5mg，0.01mmol，3％，95％纯度)。1H NMR(400MHz,甲醇-d4)δ:8.03–8.00(m,1H),7.65–7.57(m,2H),7.10–7.03(m,3H),6.85(m,1H),4.54(dd,1H),3.93(d,3H),3.77–3.67(m,1H),3.58–3.47(m,2H),3.31–3.25(m,1H),2.88(s,3H).LCMS:m/z 425.1[M+H]+。2-Methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (100 mg, 1 equivalent, 353 μmol), 4-acetoxy-1-methyl-5-oxopyrrolidine-3-carboxylic acid (92.3 mg, 1.3 equivalent, 459 μmol), and 1-methyl-1H-imidazolium (174 mg, 169 μL, 6 equivalent, 2.12 mmol) were dissolved in acetonitrile (2 mL), and the mixture was stirred at 22 °C for 10 min. Then, N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (198 mg, 2 equivalent, 706 μmol) was added. The mixture was stirred at 22 °C for 16 h. 4-Acetoxy-1-methyl-5-oxopyrrolidine-3-carboxylic acid (92.3 mg, 1.3 equivalents, 459 μmol) and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (198 mg, 2 equivalents, 706 μmol) were added to the mixture, which was then stirred at 22 °C for 16 h. The mixture was concentrated, and a solution of ammonia (60.1 mg, 10 equivalents, 3.53 mmol) in methanol was added. The reaction mixture was stirred at 22 °C for 16 h. The solution was purified by reversed-phase HPLC (purification method A) to give the title compound (5 mg, 0.01 mmol, 3%, 95% purity). 1 H NMR(400MHz, methanol-d4)δ:8.03–8.00(m,1H),7.65–7.57(m,2H),7.10–7.03(m,3H),6.85(m,1H),4.54(d d,1H),3.93(d,3H),3.77–3.67(m,1H),3.58–3.47(m,2H),3.31–3.25(m,1H),2.88(s,3H).LCMS:m/z 425.1[M+H] + .
实施例5.N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(5-氧代吡咯烷-2-羰基)吡咯烷-2-甲酰胺(化合物229)Example 5. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (Compound 229)
向N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(0.047g，1当量，0.12mmol)在DMF(2mL)中的溶液中加入5-氧代吡咯烷-2-甲酸(15mg，1当量，0.12mmol)和二异丙基乙胺(46mg，62μL，3当量，0.36mmol)。将混合物在RT下搅拌15min，并一次性加入HATU(68mg，1.5当量，0.18mmol)。将所得溶液在RT下搅拌10h。将混合物在真空中浓缩，用乙酸乙酯(10mL)稀释，用NaHSO4(2mL，10％)、K2CO3(2mL，10％)和水(2mL)洗涤，随后经Na2SO4干燥。蒸发乙酸乙酯，残余物用方法A纯化，得到标题化合物(0.0117g)。1H NMR(400MHz,DMSO-d6)δ:9.78(s,1H),7.87(d,1H),7.77(s,1H),7.69(d,2H),7.14(d,1H),7.06(d,2H),6.90(dd,1H),5.16–5.07(m,1H),5.07–5.00(m,1H),3.90(s,3H),2.70–2.56(m,1H),2.46–2.30(m,3H),2.05–1.89(m,4H).LCMS:m/z506.0[M+H]+。To a solution of N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (0.047 g, 1 equivalent, 0.12 mmol) in DMF (2 mL), 5-oxopyrrolidine-2-carboxylic acid (15 mg, 1 equivalent, 0.12 mmol) and diisopropylethylamine (46 mg, 62 μL, 3 equivalent, 0.36 mmol) were added. The mixture was stirred at RT for 15 min, and HATU (68 mg, 1.5 equivalent, 0.18 mmol) was added in a single batch. The resulting solution was stirred at RT for 10 h. The mixture was concentrated under vacuum, diluted with ethyl acetate (10 mL), washed with NaHSO₄ (2 mL, 10%), K₂CO₃ (2 mL , 10%), and water ( 2 mL), and then dried over Na₂SO₄ . Ethyl acetate was evaporated, and the residue was purified by method A to give the title compound (0.0117 g). ¹H NMR (400 MHz, DMSO-d6) δ: 9.78 (s, 1H), 7.87 (d, 1H), 7.77 (s, 1H), 7.69 (d, 2H), 7.14 (d, 1H), 7.06 (d, 2H), 6.90 (dd, 1H), 5.16–5.07 (m, 1H), 5.07–5.00 (m, 1H), 3.90 (s, 3H), 2.70–2.56 (m, 1H), 2.46–2.30 (m, 3H), 2.05–1.89 (m, 4H). LCMS: m/z 506.0 [M+H] + .
根据化合物229所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 229. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例6.1-甲基-5-氧代-N-(7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯-5-基)吡咯烷-2-甲酰胺(化合物233)Example 6. 1-Methyl-5-oxo-N-(7-(3-(trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxen-5-yl)pyrrolidine-2-carboxamide (Compound 233)
在氩气下，向5-溴-7-(3-(三氟甲基)苯氧基)-2,3-二氢苯并[b][1,4]二噁烯(217.2mg，1当量，579.0μmol)、1-甲基-5-氧代吡咯烷-2-甲酰胺(123.5mg，1.5当量，868.5μmol)和碳酸铯(565.9mg，3当量，1.737mmol)在甲苯(4mL)中的溶液中加入Pd2(dba)3(26.51mg，0.05当量，28.95μmol)和4,5-双(二苯基膦基)-9,9-二甲基呫吨(50.25mg，0.15当量，86.85μmol)，并将混合物在110℃下加热18h。冷却至RT后，浓缩混合物，并将残余物通过方法A纯化，得到标题化合物(0.0286g)。1H NMR(600MHz,DMSO-d6)δ:9.68(s,1H),7.59–7.54(m,1H),7.42(d,1H),7.39(d,1H),7.25–7.19(m,2H),6.47(d,1H),4.44(dd,1H),4.35–4.27(m,4H),2.61(s,3H),2.27–2.12(m,3H),1.89–1.82(m,1H).LCMS:m/z 437.0[M+H]+。Under argon atmosphere, Pd₂(dba)₃ (26.51 mg, 0.05 equivalent, 28.95 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthone (50.25 mg, 0.15 equivalent, 86.85 μmol) were added to a solution of 5-bromo-7-( 3- (trifluoromethyl)phenoxy)-2,3-dihydrobenzo[b][1,4]dioxene (217.2 mg, 1 equivalent, 579.0 μmol), 1 -methyl-5-oxopyrrolidine-2-carboxamide (123.5 mg, 1.5 equivalent, 868.5 μmol) and cesium carbonate (565.9 mg, 3 equivalent, 1.737 mmol) in toluene (4 mL) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthone (50.25 mg, 0.15 equivalent, 86.85 μmol) and the mixture was heated at 110 °C for 18 h. After cooling to RT, the mixture was concentrated, and the residue was purified by method A to give the title compound (0.0286 g). ¹H NMR (600 MHz, DMSO-d⁶) δ: 9.68 (s, ¹H), 7.59–7.54 (m, ¹H), 7.42 (d, ¹H), 7.39 (d, ¹H), 7.25–7.19 (m, 2H), 6.47 (d, ¹H), 4.44 (dd, ¹H), 4.35–4.27 (m, 4H), 2.61 (s, 3H), 2.27–2.12 (m, 3H), 1.89–1.82 (m, 1H). LCMS: m/z 437.0 [M+H] ⁺ .
根据化合物233所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 233. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例7.N-(5-(((3-氟苯基)氨基)甲基)-2-甲氧基苯基)-5-氧代吡咯烷-2-甲酰胺(化合物246)Example 7. N-(5-(((3-fluorophenyl)amino)methyl)-2-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide (Compound 246)
在0℃下，将三甲基氯硅烷(210mg，245μL，5当量，1.93mmol)缓慢加入到甲醇(5mL)中，并将该混合物在0℃下搅拌30min。向所得溶液中加入(3-氟苯基)(4-甲氧基-3-(5-氧代吡咯烷-2-甲酰胺基)苄基)氨基甲酸叔丁酯(300mg，58.89％，1当量，386μmol)，并将混合物在RT下搅拌18h。将混合物用NaHCO3水溶液(10mL)处理，并用乙酸乙酯(2×20mL)萃取。将合并的有机相用盐水(2×15mL)洗涤，经硫酸钠干燥，过滤，浓缩，并将残余物用反相HPLC(水-乙腈)纯化，得到标题化合物(0.0201g)。1H NMR(400MHz,DMSO-d6)δ:9.17(s,1H),8.04–7.90(m,2H),7.12–6.96(m,3H),6.58–6.49(m,1H),6.39(dd,1H),6.32–6.18(m,2H),4.34(dd,1H),4.16(d,2H),3.82(s,3H),2.38–2.28(m,1H),2.28–2.02(m,2H),2.03–1.85(m,1H).LCMS:m/z 358.2[M+H]+。Trimethylchlorosilane (210 mg, 245 μL, 5 equivalents, 1.93 mmol) was slowly added to methanol (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Tert-butyl (3-fluorophenyl)(4-methoxy-3-(5-oxopyrrolidine-2-carbamate)benzyl)carbamate (300 mg, 58.89%, 1 equivalent, 386 μmol) was added to the resulting solution, and the mixture was stirred at RT for 18 h. The mixture was treated with an aqueous solution of NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 15 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified by reversed-phase HPLC (water-acetonitrile) to give the title compound (0.0201 g). 1 H NMR(400MHz, DMSO-d6)δ:9.17(s,1H),8.04–7.90(m,2H),7.12–6.96(m,3H),6.58–6.49(m,1H),6.39(dd,1H),6.32–6. 18(m,2H),4.34(dd,1H),4.16(d,2H),3.82(s,3H),2.38–2.28(m,1H),2.28–2.02(m,2H),2.03–1.85(m,1H).LCMS:m/z 358.2[M+H] + .
实施例8.N-(5-((4,4-二氟环己基)氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物247)Example 8. N-(5-((4,4-difluorocyclohexyl)oxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 247)
将N-(5-羟基-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.0667g，1当量，252μmol)、三苯基膦(86.1mg，1.3当量，328μmol)和DEAD(54.9mg，49.5μL，1.25当量，315μmol)溶于THF(5.5mL)中。将混合物在RT下搅拌30min。在RT下，将4,4-二氟环己烷-1-醇(48.1mg，1.4当量，353μmol)加入到混合物中并搅拌58h。将混合物通过柱色谱法纯化，得到标题化合物(0.0032g，7.9μmol，3.1％，95％纯度)。纯化方法C。1H NMR(400MHz,甲醇-d4)δ:7.75(d,1H),6.97(d,1H),6.77(dd,1H),4.48–4.40(m,2H),3.87(s,3H),2.85(s,3H),2.59–2.47(m,1H),2.47–2.34(m,2H),2.19–2.04(m,3H),1.99–1.84(m,6H).LCMS:m/z 383.2[M+H]+。N-(5-hydroxy-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.0667 g, 1 equivalent, 252 μmol), triphenylphosphine (86.1 mg, 1.3 equivalent, 328 μmol), and DEAD (54.9 mg, 49.5 μL, 1.25 equivalent, 315 μmol) were dissolved in THF (5.5 mL). The mixture was stirred at RT for 30 min. At RT, 4,4-difluorocyclohexane-1-ol (48.1 mg, 1.4 equivalent, 353 μmol) was added to the mixture and stirred for 58 h. The mixture was purified by column chromatography to give the title compound (0.0032 g, 7.9 μmol, 3.1%, 95% purity). Purification method C. 1 H NMR(400MHz, methanol-d4)δ:7.75(d,1H),6.97(d,1H),6.77(dd,1H),4.48–4.40(m,2H),3.87(s,3H),2 .85(s,3H),2.59–2.47(m,1H),2.47–2.34(m,2H),2.19–2.04(m,3H),1.99–1.84(m,6H).LCMS:m/z 383.2[M+H] + .
实施例9.N-(5-((3,4-二氟苄基)氧基)-2,3-二氢苯并呋喃-7-基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物248)Example 9. N-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran-7-yl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 248)
将7-溴-5-((3,4-二氟苄基)氧基)-2,3-二氢苯并呋喃(0.100g，1当量，293μmol)、1-甲基-5-氧代吡咯烷-2-甲酰胺(50.0mg，1.2当量，352μmol)、碳酸铯(95.5mg，1当量，293μmol)、碘化铜(I)(16.7mg，0.3当量，87.9μmol)和N1,N2-二甲基环己烷-1,2-二胺(25.0mg，0.6当量，176μmol)混合在N,N-二甲基甲酰胺(2mL)中。将混合物在氩气气氛下于100℃加热12h，然后蒸发N,N-二甲基甲酰胺，并将残余物用EtOAc(10mL)稀释，用水(2×2mL)洗涤，经Na2SO4干燥，并在真空中浓缩。通过LCMS分析反应混合物的样品。将残余物通过方法A纯化，得到标题化合物(0.0035g)。1H NMR(400MHz,乙腈-d3)δ:8.03(s,1H),7.59(d,1H),7.46–7.36(m,1H),7.36–7.24(m,2H),6.74(d,1H),5.01(s,2H),4.61(t,2H),4.23(dd,1H),3.24(t,2H),2.78(s,3H),2.45–2.24(m,3H).LCMS:m/z 403.0[M+H]+。7-Bromo-5-((3,4-difluorobenzyl)oxy)-2,3-dihydrobenzofuran (0.100 g, 1 equivalent, 293 μmol), 1-methyl-5-oxopyrrolidine-2-carboxamide (50.0 mg, 1.2 equivalent, 352 μmol), cesium carbonate (95.5 mg, 1 equivalent, 293 μmol), copper iodide (I) (16.7 mg, 0.3 equivalent, 87.9 μmol), and N1,N2-dimethylcyclohexane-1,2-diamine (25.0 mg, 0.6 equivalent, 176 μmol) were mixed in N,N-dimethylformamide (2 mL). The mixture was heated at 100 °C for 12 h under an argon atmosphere, then N,N-dimethylformamide was evaporated, and the residue was diluted with EtOAc (10 mL), washed with water (2 × 2 mL), dried over Na₂SO₄ , and concentrated under vacuum. A sample of the reaction mixture was analyzed by LCMS. The residue was purified by method A to give the title compound (0.0035 g). 1 H NMR(400MHz, acetonitrile-d3)δ:8.03(s,1H),7.59(d,1H),7.46–7.36(m,1H),7.36–7.24(m,2H),6.74(d,1H) ),5.01(s,2H),4.61(t,2H),4.23(dd,1H),3.24(t,2H),2.78(s,3H),2.45–2.24(m,3H).LCMS:m/z 403.0[M+H] + .
根据化合物248所述的方法制备以下化合物。化合物编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 248. Compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例10.N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代四氢吡咯并[2,1-b]噻唑-7a(5H)-甲酰胺1,1-二氧化物(化合物252)Example 10. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formamide 1,1-dioxide (compound 252)
将N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代四氢吡咯并[2,1-b]噻唑-7a(5H)-甲酰胺(100mg，1当量，221μmol)溶于乙酸(3mL)中，并在RT下加入高锰酸钾(55.9mg，当量，354μmol)。将混合物在RT下搅拌24h，将混合物倒入碳酸氢钠饱和溶液(30mL)中，随后用乙酸乙酯(3×30mL)萃取。将合并的有机相用盐水(2×30mL)洗涤，经硫酸钠干燥，过滤，浓缩，并将残余物通过纯化方法A纯化，得到标题化合物(0.0079g)。1H NMR(400MHz,乙腈-d3)δ:8.77(s,1H),7.99(d,1H),7.70(d,2H),7.15–7.05(m,3H),6.96(dd,1H),4.52–4.38(m,1H),3.95(s,3H),3.73–3.64(m,1H),3.45–3.26(m,2H),2.87–2.66(m,3H),2.57–2.42(m,1H).LCMS:m/z 485.2[M+H]+。N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxotetrahydropyrrolo[2,1-b]thiazole-7a(5H)-formamide (100 mg, 1 equivalent, 221 μmol) was dissolved in acetic acid (3 mL), and potassium permanganate (55.9 mg, equivalent, 354 μmol) was added under RT. The mixture was stirred under RT for 24 h, poured into a saturated sodium bicarbonate solution (30 mL), and then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, concentrated, and the residue was purified by purification method A to give the title compound (0.0079 g). ¹H NMR (400MHz, acetonitrile-d³) δ: 8.77 (s, 1H), 7.99 (d, 1H), 7.70 (d, 2H), 7.15–7.05 (m, 3H), 6.96 (dd, 1H), 4.52–4.38 (m, 1H), 3.95 (s, 3H), 3.73–3.64 (m, 1H), 3.45–3.26 (m, 2H), 2.87–2.66 (m, 3H), 2.57–2.42 (m, 1H). LCMS: m/z 485.2 [M+H] + .
实施例11.N-(3-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物253)Example 11. N-(3-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 253)
向5-氧代吡咯烷-2-甲酸(51.1mg，0.40mmol)、3-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺(112mg，0.40mmol)、HATU(226mg，0.60mmol)和无水DMF(2ml)的溶液中加入DIPEA(0.34ml，2.0mmol)。将混合物在RT下搅拌过夜。将反应混合物用水(10ml)淬灭，随后用乙酸乙酯(2×10mL)萃取。将合并的有机层用水洗涤，干燥，蒸发，然后通过反相色谱法纯化，得到0.074g标题化合物。1H NMR(600MHz,DMSO-d6)δ:1.93-2.00(m,1H),2.08-2.22(m,2H),2.28-2.36(m,1H),3.75(s,3H),4.14(dd,1H),6.48(t,1H),6.97(t,1H),7.15-7.21(m,3H),7.76(d,2H),7.86(s,1H),10.14(s,1H).LCMS:m/z 395.2[M+H]+。DIPEA (0.34 mL, 2.0 mmol) was added to a solution of 5-oxopyrrolidine-2-carboxylic acid (51.1 mg, 0.40 mmol), 3-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (112 mg, 0.40 mmol), HATU (226 mg, 0.60 mmol), and anhydrous DMF (2 mL). The mixture was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dried, evaporated, and then purified by reversed-phase chromatography to give 0.074 g of the title compound. 1 H NMR(600MHz,DMSO-d6)δ:1.93-2.00(m,1H),2.08-2.22(m,2H),2.28-2.36(m,1H),3.75(s,3H),4.14(d d,1H),6.48(t,1H),6.97(t,1H),7.15-7.21(m,3H),7.76(d,2H),7.86(s,1H),10.14(s,1H).LCMS:m/z 395.2[M+H] + .
根据化合物253所述的方法制备以下化合物。化合物编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 253. Compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例12.(R)-N-(2-甲氧基-5-(4-(三氟甲氧基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物290)Example 12. (R)-N-(2-methoxy-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 290)
向2-甲氧基-5-(4-(三氟甲氧基)苯氧基)苯胺(0.060g，0.20mmol)、(2R)-1-甲基-5-氧代吡咯烷-2-甲酸(0.029g，0.20mmol)和HATU(0.114g，0.30mmol)在无水DMF(1.0ml)中的混合物中加入DIPEA(0.174ml，1.00mmol)。将混合物在RT下搅拌过夜。将混合物用EtOAc稀释，并用水和盐水洗涤。将有机相干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到0.056g标题化合物。1H NMR(400MHz,CDCl3)δ:8.17(d,1H),8.07(s,1H),7.11-7.18(m,2H),6.91-6.98(m,2H),6.87(d,1H),6.77(dd,1H),4.07-4.14(m,1H),3.90(s,3H),2.94(s,3H),2.37-2.63(m,3H),2.10-2.20(m,1H).LCMS:m/z 425.0[M+H]+。DIPEA (0.174 mL, 1.00 mmol) was added to a mixture of 2-methoxy-5-(4-(trifluoromethoxy)phenoxy)aniline (0.060 g, 0.20 mmol), (2R)-1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.029 g, 0.20 mmol), and HATU (0.114 g, 0.30 mmol) in anhydrous DMF (1.0 mL). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reversed-phase rapid chromatography to give 0.056 g of the title compound. 1 H NMR (400MHz, CDCl 3 )δ:8.17(d,1H),8.07(s,1H),7.11-7.18(m,2H),6.91-6.98(m,2H),6.87(d,1H),6.77(dd,1H) ,4.07-4.14(m,1H),3.90(s,3H),2.94(s,3H),2.37-2.63(m,3H),2.10-2.20(m,1H).LCMS:m/z 425.0[M+H] + .
根据化合物290所述的方法制备以下化合物。化合物编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 290. Compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例13.N-(2-氟-5-(4-(三氟甲氧基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物328)Example 13. N-(2-fluoro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 328)
向2-氟-5-(4-(三氟甲氧基)苯氧基)苯胺(0.069g，0.24mmol)、1-甲基-5-氧代吡咯烷-2-甲酸(0.034g，0.24mmol)和1-甲基咪唑(0.071ml，0.89mmol)在无水乙腈(1.0ml)中的混合物中加入N,N,N',N'-四甲基氯甲脒六氟磷酸盐(0.081g，0.288mmol)。将混合物在RT下搅拌过夜。将混合物用EtOAc稀释，用水和盐水洗涤。将有机相干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到0.028g标题化合物。1H NMR(400MHz,CDCl3)δ:8.05(dd,1H),7.81(s,1H),7.14-7.23(m,2H),7.05-7.14(m,1H),6.92-7.03(m,2H),6.71-6.80(m,1H),4.10-4.19(m,1H),2.93(s,3H),2.37-2.64(m,3H),2.10-2.21(m,1H).LCMS:m/z 413.0[M+H]+。N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (0.081 g, 0.288 mmol) was added to a mixture of 2-fluoro-5-(4-(trifluoromethoxy)phenoxy)aniline (0.069 g, 0.24 mmol), 1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.034 g, 0.24 mmol), and 1-methylimidazolium (0.071 mL, 0.89 mmol) in anhydrous acetonitrile (1.0 mL). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried and evaporated. The crude product was purified by reversed-phase rapid chromatography to give 0.028 g of the title compound. 1 H NMR (400MHz, CDCl 3 )δ:8.05(dd,1H),7.81(s,1H),7.14-7.23(m,2H),7.05-7.14(m,1H),6.92-7.03(m,2H),6.71 -6.80(m,1H),4.10-4.19(m,1H),2.93(s,3H),2.37-2.64(m,3H),2.10-2.21(m,1H).LCMS:m/z 413.0[M+H] + .
根据化合物328所述的方法制备以下化合物。化合物编号、结构、起始原料和表征数据示于表中。The following compounds were prepared according to the method described for compound 328. Compound numbers, structures, starting materials, and characterization data are shown in the table.
实施例14.N-(2-甲氧基-5-((4-(三氟甲基)-吡啶-2-基)氧基)苯基)-1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酰胺(化合物331)Example 14. N-(2-methoxy-5-((4-(trifluoromethyl)-pyridin-2-yl)oxy)phenyl)-1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxamide (Compound 331)
向2-甲氧基-5-((4-(三氟甲基)吡啶-2-基)氧基)苯胺(0.071g，0.25mmol)、1-(2-甲氧基乙酰基)-5-氧代吡咯烷-2-甲酸(0.053g，0.25mmol)在EtOAc(0.30ml)和吡啶(0.15ml)中的混合物中加入1-丙烷膦酸环酐，50wt-％在EtOAc(0.25ml，0.424mmol)中。将混合物在RT下搅拌过夜。用0.5％HCl溶液淬灭反应，并用水和EtOAc稀释。分离各相，并将有机相用0.5％HCl溶液、水和盐水洗涤，干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.046g。1H NMR(400MHz,CDCl3)δ:8.45(s,1H),8.30(d,1H),8.20(s,1H),7.04-7.22(m,2H),6.82-7.00(m,2H),4.88(d,1H),4.52-4.74(m,2H),3.93(s,3H),3.47(s,3H),2.84-3.03(m,1H),2.47-2.64(m,1H),2.22-2.47(m,2H).LCMS:m/z 468.5[M+H]+。To a mixture of 2-methoxy-5-((4-(trifluoromethyl)pyridin-2-yl)oxy)aniline (0.071 g, 0.25 mmol), 1-(2-methoxyacetyl)-5-oxopyrrolidine-2-carboxylic acid (0.053 g, 0.25 mmol) in EtOAc (0.30 mL) and pyridine (0.15 mL), 50 wt% of 1-propanephosphonic anhydride was added in EtOAc (0.25 mL, 0.424 mmol). The mixture was stirred overnight at RT. The reaction was quenched with 0.5% HCl solution and diluted with water and EtOAc. The phases were separated, and the organic phase was washed with 0.5% HCl solution, water, and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.046 g. 1 H NMR (400MHz, CDCl 3 )δ:8.45(s,1H),8.30(d,1H),8.20(s,1H),7.04-7.22(m,2H),6.82-7.00(m,2H),4.88(d,1H),4.52-4. 74(m,2H),3.93(s,3H),3.47(s,3H),2.84-3.03(m,1H),2.47-2.64(m,1H),2.22-2.47(m,2H).LCMS:m/z 468.5[M+H] + .
根据化合物331所述的方法制备以下化合物。化合物编号、结构、起始原料和表征数据示于表中。The following compounds were prepared according to the method described for compound 331. Compound numbers, structures, starting materials, and characterization data are shown in the table.
实施例15.N-(2-溴-5-(3-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物366)Example 15. N-(2-bromo-5-(3-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 366)
向冷却(0-5℃)的1-甲基-5-氧代吡咯烷-2-甲酸(0.067g，0.468mmol)在无水DCM(1.5ml)中的混合物中加入1-氯-N,N,2-三甲基-1-丙烯基胺(0.065ml，0.488mmol)，并将该混合物在0-5℃下搅拌1h。然后加入溶于无水DMF(0.5ml)中的2-溴-5-(3-(三氟甲基)苯氧基)苯胺(0.18g，0.390mmol)和DIPEA(0.34ml，1.951mmol)，并将该混合物在RT下搅拌过夜。蒸发DCM，并将混合物用EtOAc稀释。将有机相用水和盐水洗涤，干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.019g。1H NMR(600MHZ,d6-DMSO)δ:9.88(s,1H),7.72(d,1H),7.65(t,1H),7.51-7.55(m,1H),7.42(d,1H),7.36-7.39(m,1H),7.34(dd,1H),6.93(dd,1H),4.31-4.38(m,1H),2.70(s,3H),2.17-2.35(m,3H),1.94-2.02(m,1H).LCMS:m/z 457.1[M+H]+。To a mixture of cooled (0–5 °C) 1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.067 g, 0.468 mmol) in anhydrous DCM (1.5 mL), 1-chloro-N,N,2-trimethyl-1-propenylamine (0.065 mL, 0.488 mmol) was added, and the mixture was stirred at 0–5 °C for 1 h. Then, 2-bromo-5-(3-(trifluoromethyl)phenoxy)aniline (0.18 g, 0.390 mmol) and DIPEA (0.34 mL, 1.951 mmol) dissolved in anhydrous DMF (0.5 mL) were added, and the mixture was stirred overnight at RT. The DCM was evaporated, and the mixture was diluted with EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.019 g. 1H NMR(600MHZ,d6-DMSO)δ:9.88(s,1H),7.72(d,1H),7.65(t,1H),7.51-7.55(m,1H),7.42(d,1H),7.36-7.39(m,1 H),7.34(dd,1H),6.93(dd,1H),4.31-4.38(m,1H),2.70(s,3H),2.17-2.35(m,3H),1.94-2.02(m,1H).LCMS:m/z 457.1[M+H] + .
实施例16.N-(2-氰基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物367)Example 16. N-(2-cyano-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 367)
根据前述实施例的方法，由1-甲基-5-氧代吡咯烷-2-甲酸(0.051g，0.359mmol)、DCM(1.5ml)、1-氯-N,N,2-三甲基-1-丙烯基胺(0.057ml，0.431mmol)、2-氨基-4-(4-(三氟甲基)苯氧基)苄腈(0.10g，0.359mmol)和DMF(0.75ml)开始制备该化合物。收率：0.022g。1HNMR(600MHz,d6-DMSO)δ:10.5(s,1H),7.90(d,1H),7.81-7.86(m,2H),7-31-7.37(m,2H),7.30(d,1H),7.08(dd,1H),4.30(dd,1H),2.70(s,3H),2.19-2.36(m,3H),1.94-2.01(m,1H).LCMS:m/z 404.4[M+H]+。The compound was prepared according to the method described in the foregoing embodiments, starting with 1-methyl-5-oxopyrrolidine-2-carboxylic acid (0.051 g, 0.359 mmol), DCM (1.5 ml), 1-chloro-N,N,2-trimethyl-1-propenylamine (0.057 ml, 0.431 mmol), 2-amino-4-(4-(trifluoromethyl)phenoxy)benzyl nitrile (0.10 g, 0.359 mmol), and DMF (0.75 ml). Yield: 0.022 g. 1 HNMR(600MHz,d6-DMSO)δ:10.5(s,1H),7.90(d,1H),7.81-7.86(m,2H),7-31-7.37(m,2H),7.30( d,1H),7.08(dd,1H),4.30(dd,1H),2.70(s,3H),2.19-2.36(m,3H),1.94-2.01(m,1H).LCMS:m/z 404.4[M+H] + .
实施例17.N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物368)Example 17. N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 368)
采用中间体306的方法，由在无水DMF(1.0ml)中的N-(2-氟-5-羟基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.071g，0.28mmol)、2-氯-5-(三氟甲基)吡啶(0.051g，0.28mmol)和K2CO3(0.058g，0.42mmol)开始制备该化合物。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.078g。1H NMR(600MHz,CDCl3)δ:8.40-8.43(m,1H),8.21(dd,1H),7.92(dd,1H),7.79(s,1H),7.18(dd,1H),7.05(d,1H),6.91(dq,1H),4.15 8dd,1H),2.93(s,3H),2.54-2.62(m,1H),2.39-2.53(m,2H),2.11-2.18(m,1H).LCMS:m/z 398.6[M+H]+。The compound was prepared using the intermediate 306 method, starting with N-(2-fluoro-5-hydroxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.071 g, 0.28 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.051 g , 0.28 mmol), and K₂CO₃ (0.058 g, 0.42 mmol) in anhydrous DMF (1.0 mL). The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.078 g. 1 H NMR (600MHz, CDCl 3 )δ:8.40-8.43(m,1H),8.21(dd,1H),7.92(dd,1H),7.79(s,1H),7.18(dd,1H),7.05(d,1H),6.91(dq,1H),4.15 8dd,1H),2.93(s,3H),2.54-2.62(m,1H),2.39-2.53(m,2H),2.11-2.18(m,1H).LCMS: m/z 398.6[M+H] + .
实施例18.N-(2-氟-5-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物369)Example 18. N-(2-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 369)
采用中间体339的方法，由在无水DMF(1.0ml)中的N-(2-氟-5-羟基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.071g，0.28mmol)、2-氯-5-(三氟甲基)吡啶(0.051g，0.28mmol)和K2CO3(0.058g，0.42mmol)开始制备该化合物。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.078g。1H NMR(600MHz,CDCl3):δ8.40-8.43(m,1H),8.21(dd,1H),7.92(dd,1H),7.79(s,1H),7.18(dd,1H),7.05(d,1H),6.91(dq,1H),4.15 8dd,1H),2.93(s,3H),2.54-2.62(m,1H),2.39-2.53(m,2H),2.11-2.18(m,1H).LCMS:m/z 398.6[M+H]+。The compound was prepared using the method described in Intermediate 339, starting with N-(2-fluoro-5-hydroxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.071 g, 0.28 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.051 g , 0.28 mmol), and K₂CO₃ (0.058 g, 0.42 mmol) in anhydrous DMF (1.0 mL). The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.078 g. 1 H NMR (600MHz, CDCl 3 ): δ8.40-8.43(m,1H),8.21(dd,1H),7.92(dd,1H),7.79(s,1H),7.18(dd,1H),7.05(d,1H),6.91(dq,1H),4.15 8dd,1H),2.93(s,3H),2.54-2.62(m,1H),2.39-2.53(m,2H),2.11-2.18(m,1H).LCMS: m/z 398.6[M+H] + .
实施例19.(2S,4R)-4-羟基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-2-甲酰胺(化合物370)Example 19. (2S,4R)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (Compound 370)
向钯(碳上10w-％，0.045g，0.042mmol)在甲醇(15ml)中的混合物中加入溶于甲醇(2.0ml)的(2S,4R)-4-羟基-2-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基甲酰基)吡咯烷-1-甲酸苄酯(0.111g，0.209mmol)。剧烈搅拌混合物，同时加入甲酸铵(0.132mg，2.09mmol)。在50℃下继续搅拌直至反应完全。将冷却的混合物通过硅藻土短塞过滤。硅藻土用甲醇洗涤。蒸发滤液，并再溶于EtOAc中。将有机相用水和盐水洗涤，干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.041g。1H NMR(600MHz,d6-DMSO)δ:10.3(s,1H),8.13(d,1H),7.68-7.73(m,2H),7.13(d,1H),7.05-7.10(m,2H),6.85(dd,1H),4.71(d,1H),4.16-4.20(m,1H),3.89(s,3H),3.87-3.93(m,1H),3.48(bs,1H),2.88(d,1H),2.74(d,1H),1.99-2.06(m,1H),1.72-1.79(m,1H).LCMS:m/z 397.6[M+H]+。To a mixture of palladium (10 w-%, 0.045 g, 0.042 mmol on carbon) in methanol (15 mL), add benzyl (2S,4R)-4-hydroxy-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)pyrrolidine-1-carboxylate (0.111 g, 0.209 mmol) dissolved in methanol (2.0 mL). The mixture was vigorously stirred while ammonium formate (0.132 mg, 2.09 mmol) was added. Stirring was continued at 50 °C until the reaction was complete. The cooled mixture was filtered through a short diatomaceous earth stopper. The diatomaceous earth was washed with methanol. The filtrate was evaporated and redissolved in EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.041 g. 1 H NMR(600MHz,d6-DMSO)δ:10.3(s,1H),8.13(d,1H),7.68-7.73(m,2H),7.13(d,1H),7.05-7.10(m,2H),6.85(dd,1H),4.71(d,1H),4.16 -4.20(m,1H),3.89(s,3H),3.87-3.93(m,1H),3.48(bs,1H),2.88(d,1H),2.74(d,1H),1.99-2.06(m,1H),1.72-1.79(m,1H).LCMS:m/z 397.6[M+H] + .
实施例20.(S)-1-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物371)Example 20. (S)-1-acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 371)
向冷却(0-5℃)的(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(0.086g，0.225mmol)在无水DCM(2.0ml)中的溶液中加入溶于无水DCM(0.25ml)中的乙酰氯(0.018ml，0.248mmol)和三乙胺(0.039ml，0.281mmol)，并将混合物在RT下搅拌过夜。加入更多的乙酰氯(0.018ml，0.248mmol)和三乙胺(0.039ml，0.281mmol)，并继续搅拌直至反应完全。将混合物用DCM稀释，并用水、饱和NaHCO3溶液和盐水洗涤，干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.072g。1H NMR(400MHz,CDCl3)δ:9.44(s,1H),8.18(s,1H),7.43-7.60(m,2H),6.91-7.07(m,2H),6.86(d,1H),6.74(d,1H),4.75(d,1H),3.91(s,3H),3.59(t,1H),3.47(dd,1H),2.41-2.55(m,1H),2.15(s,3H),1.81-2.22.(m,3H).LCMS:m/z 423.6[M+H]+。To a solution of (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (0.086 g, 0.225 mmol) cooled (0–5 °C) in anhydrous DCM (2.0 mL), acetyl chloride (0.018 mL, 0.248 mmol) and triethylamine (0.039 mL, 0.281 mmol) dissolved in anhydrous DCM (0.25 mL) were added, and the mixture was stirred overnight at RT. More acetyl chloride (0.018 mL, 0.248 mmol) and triethylamine (0.039 mL, 0.281 mmol) were added, and stirring continued until the reaction was complete. The mixture was diluted with DCM, washed with water, saturated NaHCO3 solution, and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.072 g. 1 H NMR (400MHz, CDCl 3 )δ:9.44(s,1H),8.18(s,1H),7.43-7.60(m,2H),6.91-7.07(m,2H),6.86(d,1H),6.74(d,1H),4.75(d,1H ),3.91(s,3H),3.59(t,1H),3.47(dd,1H),2.41-2.55(m,1H),2.15(s,3H),1.81-2.22.(m,3H).LCMS:m/z 423.6[M+H] + .
实施例21.N-(2-羟基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物372)Example 21. N-(2-hydroxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 372)
在RT下，向化合物48(100mg，245μmol)在DCM(5ml)中的溶液中加入四丁基碘化铵(90mg，245μmol)。将溶液冷却至-50℃。然后逐滴加入在庚烷(1.469ml，1469μmol)中1M的BCl3。将混合物在-78℃搅拌10min，然后在RT下搅拌1h20min。将混合物用DCM(10ml)稀释并倒入冰冷的1N HCl(5ml)中。分离各相。将水相用DCM萃取两次。将合并的有机相在减压下浓缩。将粗产物通过柱色谱法纯化，得到标题化合物(0.055g)。1H NMR(400MHz,DMSO)δ:10.06(br s 1H),9.57(s,1H),7.79(d,1H),7.69(d,2H),7.05(d,2H),6.94(d,1H),6.80-6.75(m,1H),4.50-4.42(m,1H),2.65(s,3H),2.31-2.12(m,3H),1.95-1.84(m,1H).LCMS:m/z 395.4[M+H]+。At RT, tetrabutylammonium iodide (90 mg, 245 μmol) was added to a solution of compound 48 (100 mg, 245 μmol) in DCM (5 mL). The solution was cooled to -50 °C. Then, 1 M BCl3 in heptane (1.469 mL, 1469 μmol) was added dropwise. The mixture was stirred at -78 °C for 10 min, and then at RT for 1 h 20 min. The mixture was diluted with DCM (10 mL) and poured into ice-cold 1 N HCl (5 mL). The phases were separated. The aqueous phase was extracted twice with DCM. The combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound (0.055 g). 1 H NMR (400MHz, DMSO) δ: 10.06 (br s 1H),9.57(s,1H),7.79(d,1H),7.69(d,2H),7.05(d,2H),6.94(d,1H),6.80-6.75(m, 1H),4.50-4.42(m,1H),2.65(s,3H),2.31-2.12(m,3H),1.95-1.84(m,1H).LCMS:m/z 395.4[M+H] + .
根据化合物372所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 372. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例22.N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-6-氧代哌嗪-2-甲酰胺(化合物374)Example 22. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-6-oxopiperazin-2-carboxamide (Compound 374)
将3-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基甲酰基)-4-甲基-5-氧代哌嗪-1-甲酸叔丁酯(30.6mg，58.5μmol)溶于HCl(二噁烷溶液)(2.13g，1.43mL，10w-％，5.85mmol)中，并在RT下搅拌过夜。将混合物通过HPLC(方法D)纯化，得到12.9mg标题化合物(12.9mg，30.5μmol，52.1％，100％纯度)。1H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),7.92(d,1H),7.71(d,2H),7.10(dd,3H),6.91(dd,1H),4.20(s,1H),3.88(d,3H),3.26(s,2H),3.13(s,2H),2.77(s,3H).LCMS:m/z424.2[M+H]+。3-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-4-methyl-5-oxopiperazine-1-carboxylic acid tert-butyl ester (30.6 mg, 58.5 μmol) was dissolved in HCl (dioxane solution) (2.13 g, 1.43 mL, 10 w-%, 5.85 mmol) and stirred overnight at RT. The mixture was purified by HPLC (Method D) to give 12.9 mg of the title compound (12.9 mg, 30.5 μmol, 52.1%, 100% purity). 1 H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),7.92(d,1H),7.71(d,2H),7.10(dd,3H),6.91(dd,1 H),4.20(s,1H),3.88(d,3H),3.26(s,2H),3.13(s,2H),2.77(s,3H).LCMS:m/z424.2[M+H] + .
根据化合物374所述方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 374. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例23.1-甲基-6-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)哌嗪-2-甲酰胺(化合物376)Example 23. 1-Methyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazin-2-carboxamide (Compound 376)
将4-甲基-3-氧代-5-((5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)氨基甲酰基)哌嗪-1-甲酸叔丁酯(0.0416g，1当量，77.7μmol)溶于甲醇(3mL)中。逐滴加入TMS-Cl(42.2mg，49.3μL，5当量，388μmol)。将混合物在25℃下搅拌16h，然后在减压下浓缩。将所得混合物进行HPLC(纯化方法D)，得到标题化合物(0.01g，0.02mmol，30％，95％纯度)。1HNMR(400MHz,DMSO-d6)δ:7.70(d,2H),7.60(s,1H),7.07(d,2H),6.86(s,1H),4.65(t,2H),4.20(t,1H),3.29–3.20(m,4H),3.18–3.02(m,2H),2.74(s,3H).LCMS:m/z 436.2[M+H]+。4-Methyl-3-oxo-5-((5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester (0.0416 g, 1 equivalent, 77.7 μmol) was dissolved in methanol (3 mL). TMS-Cl (42.2 mg, 49.3 μL, 5 equivalent, 388 μmol) was added dropwise. The mixture was stirred at 25 °C for 16 h, and then concentrated under reduced pressure. The resulting mixture was subjected to HPLC (purification method D) to give the title compound (0.01 g, 0.02 mmol, 30%, 95% purity). 1 HNMR(400MHz,DMSO-d6)δ:7.70(d,2H),7.60(s,1H),7.07(d,2H),6.86(s,1H),4.6 5(t,2H),4.20(t,1H),3.29–3.20(m,4H),3.18–3.02(m,2H),2.74(s,3H).LCMS:m/z 436.2[M+H] + .
实施例24.(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代-1-(1H-吡唑-4-基)吡咯烷-2-甲酰胺(化合物377)Example 24. (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxo-1-(1H-pyrazol-4-yl)pyrrolidine-2-carboxamide (Compound 377)
将TFA(335mg，226μL，50当量，2.94mmol)加入(R)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-(1-(4-甲氧基苄基)-1H-吡唑-4-基)-5-氧代吡咯烷-2-甲酰胺(0.0341g，1当量，58.7μmol)中，随后将混合物回流16h，然后蒸发溶剂，并将残余物通过HPLC(方法G)纯化，得到标题化合物(0.0057g，12μmol，21％，100％纯度)。1H NMR(400MHz,乙腈-d3)δ:8.62(s,1H),8.01(d,1H),7.79(s,2H),7.66(d,2H),7.07(dd,3H),6.88(dd,1H),4.75(dd,1H),3.92(s,3H),2.66–2.36(m,4H),2.23–2.13(m,2H).LCMS:m/z 459.1[M-H]-。TFA (335 mg, 226 μL, 50 equivalents, 2.94 mmol) was added to (R)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-oxopyrrolidine-2-carboxamide (0.0341 g, 1 equivalent, 58.7 μmol), the mixture was then refluxed for 16 h, the solvent was evaporated, and the residue was purified by HPLC (Method G) to give the title compound (0.0057 g, 12 μmol, 21%, 100% purity). 1 H NMR(400MHz, acetonitrile-d3)δ:8.62(s,1H),8.01(d,1H),7.79(s,2H),7.66(d,2H),7.07(dd,3H), 6.88(dd,1H),4.75(dd,1H),3.92(s,3H),2.66–2.36(m,4H),2.23–2.13(m,2H).LCMS:m/z 459.1[MH]-.
根据化合物377所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 377. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例25.1-(3-氨基-3-氧代丙基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(化合物379)Example 25. 1-(3-amino-3-oxopropyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (Compound 379)
向1-(2-氰乙基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺(158mg，1当量，353μmol)在DMSO(2mL)中的溶液中加入碳酸钾(97.6mg，2当量，706μmol)，随后加入过氧化氢(343mg，309μL，35w％，10当量，3.53mmol)。将混合物在40℃下搅拌36h。向残余物中加入水(20mL)，并将所得混合物用乙酸乙酯(2×20mL)萃取。合并有机层，用盐水(20mL)洗涤，经硫酸钠干燥，过滤并浓缩。将残余物通过反相HPLC(纯化方法B)纯化，得到标题化合物(13.4mg，28.8μmol，8.15％，100％纯度)。1H NMR(400MHz,DMSO-d6)δ:9.64(s,1H),7.89(s,1H),7.70(d,2H),7.36(s,1H),7.19–7.05(m,3H),6.92(d,1H),6.82(s,1H),4.63–4.55(m,1H),3.88(s,3H),3.64–3.51(m,1H),3.20–2.96(m,2H),2.31–2.12(m,4H),1.96–1.85(m,1H).LCMS:m/z 466.2[M+H]+。Potassium carbonate (97.6 mg, 2 equivalents, 706 μmol) was added to a solution of 1-(2-cyanoethyl)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (158 mg, 1 equivalent, 353 μmol) in DMSO (2 mL), followed by hydrogen peroxide (343 mg, 309 μL, 35 wt%, 10 equivalents, 3.53 mmol). The mixture was stirred at 40 °C for 36 h. Water (20 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase HPLC (purification method B) to give the title compound (13.4 mg, 28.8 μmol, 8.15%, 100% purity). 1 H NMR(400MHz,DMSO-d6)δ:9.64(s,1H),7.89(s,1H),7.70(d,2H),7.36(s,1H),7.19–7.05(m,3H),6.92(d,1H),6.82(s,1H ),4.63–4.55(m,1H),3.88(s,3H),3.64–3.51(m,1H),3.20–2.96(m,2H),2.31–2.12(m,4H),1.96–1.85(m,1H).LCMS:m/z 466.2[M+H] + .
实施例26.(2S,4S)-4-羟基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物380)Example 26. (2S,4S)-4-hydroxy-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 380)
将(2S,4S)-4-((叔丁基二甲基甲硅烷基)氧基)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.185g，1当量，343μmol)溶于THF(2mL)中。然后在0℃下将TBAF(89.8mg，343μL，1摩尔，1当量，343μmol)逐滴加入到该混合物中。将所得混合物搅拌20min并缓慢加热至20℃，在该温度搅拌10h，并通过HPLC(纯化方法A)纯化，得到标题化合物(0.0374g，88.1μmol，25.7％，100％纯度)。1H NMR(400MHz,DMSO-d6)δ:9.68(s,1H),7.87(s,1H),7.71(d,2H),7.14(d,1H),7.08(d,2H),6.96–6.88(m,1H),4.31(t,1H),4.12(t,1H),3.88(s,3H),2.67(s,3H),2.65–2.57(m,1H),1.74–1.57(m,1H).LCMS:m/z425.0[M+H]+。(2S,4S)-4-((tert-butyldimethylsilyl)oxy)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.185 g, 1 equivalent, 343 μmol) was dissolved in THF (2 mL). Then, TBAF (89.8 mg, 343 μL, 1 mol, 1 equivalent, 343 μmol) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred for 20 min and slowly heated to 20 °C, stirred at this temperature for 10 h, and purified by HPLC (purification method A) to give the title compound (0.0374 g, 88.1 μmol, 25.7%, 100% purity). 1 H NMR(400MHz,DMSO-d6)δ:9.68(s,1H),7.87(s,1H),7.71(d,2H),7.14(d,1H),7.08(d,2H),6.96–6.88(m,1H),4 .31(t,1H),4.12(t,1H),3.88(s,3H),2.67(s,3H),2.65–2.57(m,1H),1.74–1.57(m,1H).LCMS:m/z425.0[M+H] + .
实施例27.1-亚氨基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)六氢-1λ6-噻喃-4-甲酰胺1-氧化物(化合物381)Example 27.1-Imino-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)hexahydro- 1λ6 -thiaran-4-carboxamide 1-oxide (Compound 381)
将N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)四氢-2H-噻喃-4-甲酰胺1-氧化物(250mg，1当量，585μmol)、苯基-λ3-碘代二乙酸酯(565mg，3当量，1.75mmol)和氨基甲酸铵盐(183mg，4当量，2.34mmol)在甲醇(12mL)中的混合物在22℃下搅拌12h。浓缩该混合物，得到浅黄色淤浆和不混溶的无色液体的混合物。将混合物通过滗析用己烷(2×10mL)洗涤两次，并在真空下干燥。将残余物在乙酸乙酯中研磨并搅拌，过滤，并将收集的固体用另外的乙酸乙酯洗涤。浓缩滤液，得到顺式和反式异构体的混合物，并通过HPLC(纯化方法A)纯化，得到标题化合物(30.5mg，65μmol，11％，95％纯度)。1H NMR(400MHz,DMSO-d6)δ:9.34(d,1H),7.87(t,1H),7.70(d,2H),7.09(dd,3H),6.88(dd,1H),3.87(s,3H),3.70(s,0H),3.48(s,1H),3.16–2.79(m,4H),2.16–1.92(m,4H).LCMS:m/z 443.1[M+H]+。A mixture of N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)tetrahydro-2H-thiaran-4-carboxamide 1-oxide (250 mg, 1 equivalent, 585 μmol), phenyl-λ- 3 -iododiacetic acid ester (565 mg, 3 equivalent, 1.75 mmol), and ammonium carbamate salt (183 mg, 4 equivalent, 2.34 mmol) in methanol (12 mL) was stirred at 22 °C for 12 h. The mixture was concentrated to give a mixture of a pale yellow slurry and an immiscible colorless liquid. The mixture was washed twice with hexane (2 × 10 mL) by decanting and dried under vacuum. The residue was ground and stirred in ethyl acetate, filtered, and the collected solid was washed with another ethyl acetate. The filtrate was concentrated to give a mixture of cis and trans isomers, which was purified by HPLC (purification method A) to give the title compound (30.5 mg, 65 μmol, 11%, 95% purity). 1 H NMR(400MHz,DMSO-d6)δ:9.34(d,1H),7.87(t,1H),7.70(d,2H),7.09(dd,3H),6.88(dd,1 H),3.87(s,3H),3.70(s,0H),3.48(s,1H),3.16–2.79(m,4H),2.16–1.92(m,4H).LCMS:m/z 443.1[M+H] + .
实施例28.N-(4-氟-2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(化合物382)Example 28. N-(4-fluoro-2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (Compound 382)
将N-(5-(2-氯-4-(三氟甲基)苯氧基)-4-氟-2-甲氧基苯基)-3-甲基-2-氧代咪唑烷-4-甲酰胺(0.032g，1当量，69μmol)溶于甲醇(5mL)中。加入甲酸铵盐(26mg，6当量，0.42mmol)和钯(7.4mg，10w-％，0.1当量，6.9μmol)。将所得混合物在60℃下搅拌12h，冷却至RT并过滤。在减压下浓缩滤液。将残余物溶于DMSO(2mL)中，并向所得溶液中加入金属清除剂(SiliaMetSDimercaptotriazine，50mg)。将混合物在RT下搅拌3h并过滤。将澄清的滤液通过HPLC(纯化方法B)纯化，得到标题化合物(0.0038g，8.4μmol，12％，95％纯度)。1HNMR(400MHz,DMSO-d6)δ:9.55(s,1H),7.95(d,1H),7.72(d,2H),7.29(d,1H),7.10(d,2H),6.44(s,1H),4.49–4.26(m,1H),3.89(s,3H),3.52(t,1H),3.16(t,1H),2.61(s,3H).LCMS:m/z 428.0[M+H]+。N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-fluoro-2-methoxyphenyl)-3-methyl-2-oxoimidazolidine-4-carboxamide (0.032 g, 1 equivalent, 69 μmol) was dissolved in methanol (5 mL). Ammonium formate (26 mg, 6 equivalent, 0.42 mmol) and palladium (7.4 mg, 10 w-%, 0.1 equivalent, 6.9 μmol) were added. The resulting mixture was stirred at 60 °C for 12 h, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), and a metal scavenger (SiliaMetSDimercaptotriazine, 50 mg) was added to the resulting solution. The mixture was stirred at RT for 3 h and filtered. The clarified filtrate was purified by HPLC (purification method B) to give the title compound (0.0038 g, 8.4 μmol, 12%, 95% purity). 1 HNMR(400MHz,DMSO-d6)δ:9.55(s,1H),7.95(d,1H),7.72(d,2H),7.29(d,1H),7.10(d,2H),6 .44(s,1H),4.49–4.26(m,1H),3.89(s,3H),3.52(t,1H),3.16(t,1H),2.61(s,3H).LCMS:m/z 428.0[M+H] + .
实施例29.1,4-二甲基-6-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)哌嗪-2-甲酰胺(化合物383)Example 29.1, 4-Dimethyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazin-2-carboxamide (Compound 383)
向1-甲基-6-氧代-N-(5-(4-(三氟甲基)苯氧基)-2,3-二氢苯并呋喃-7-基)哌嗪-2-甲酰胺(0.022g，1当量，51μmol)在1,4-二噁烷(2mL)中的溶液中加入NaCNBH4(6.4mg，2当量，0.10mmol)和甲醛水溶液(8.2mg，7.5μL，37w-％，2当量，0.10mmol)。然后加入HOAc(0.01mL)，并将混合物在25℃下搅拌12h，并蒸发。将残余物溶于DMSO(2mL)中，并加入金属清除剂(SiliaMetSDimercaptotriazine，10mg)。将所得混合物在RT下搅拌3h，过滤，并将澄清溶液通过HPLC(纯化方法A)纯化，得到标题化合物(0.0052g，11μmol，22％，95％纯度)。1HNMR(500MHz,DMSO-d6)δ:9.97(s,1H),7.68(d,2H),7.57(s,1H),7.05(d,2H),6.84(s,1H),4.63(t,2H),4.20(t,1H),3.23(t,2H),3.12(d,1H),2.93(dd,1H),2.82–2.64(m,5H),2.17(s,3H).LCMS:m/z 450.2[M+H]+。To a solution of 1-methyl-6-oxo-N-(5-(4-(trifluoromethyl)phenoxy)-2,3-dihydrobenzofuran-7-yl)piperazin-2-carboxamide (0.022 g, 1 equivalent, 51 μmol) in 1,4-dioxane (2 mL), NaCNBH₄ (6.4 mg, 2 equivalent, 0.10 mmol) and an aqueous formaldehyde solution (8.2 mg, 7.5 μL, 37 w-%, 2 equivalent, 0.10 mmol) were added. HOAc (0.01 mL) was then added, and the mixture was stirred at 25 °C for 12 h and evaporated. The residue was dissolved in DMSO (2 mL), and a metal scavenging agent (SiliaMetSDimercaptotriazine, 10 mg) was added. The resulting mixture was stirred at RT for 3 h, filtered, and the clarified solution was purified by HPLC (purification method A) to give the title compound (0.0052 g, 11 μmol, 22%, 95% purity). ¹H NMR (500 MHz, DMSO-d⁶) δ: 9.97 (s, 1H), 7.68 (d, 2H), 7.57 (s, 1H), 7.05 (d, 2H), 6.84 (s, 1H), 4.63 (t, 2H), 4.20 (t, 1H), 3.23 (t, 2H), 3.12 (d, 1H), 2.93 (dd, 1H), 2.82–2.64 (m, 5H), 2.17 (s, 3H). LCMS: m/z 450.2 [M+H] ⁺ .
实施例30.N-(5-(4-氨基-2-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物384)Example 30. N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 384)
将N-(5-(2-氟-4-硝基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.080g，1当量，0.20mmol)溶于MeOH中，并加入二羟基钯(28mg，10w％，0.1当量，20μmol)。将所得混合物在氢气气氛下搅拌16h，过滤并浓缩，得到标题化合物(0.065g，0.16mmol，79％，90％纯度)。LCMS:m/z 393.0[M+H]+。N-(5-(2-fluoro-4-nitrophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.080 g, 1 equivalent, 0.20 mmol) was dissolved in MeOH, and dihydroxypalladium (28 mg, 10 wt%, 0.1 equivalent, 20 μmol) was added. The resulting mixture was stirred for 16 h under a hydrogen atmosphere, filtered, and concentrated to give the title compound (0.065 g, 0.16 mmol, 79%, 90% purity). LCMS: m/z 393.0 [M+H] + .
实施例31.N-(5-(4-氯-2-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物385)Example 31. N-(5-(4-chloro-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 385)
在0℃下，向N-(5-(4-氨基-2-氟苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.056g，1当量，0.15mmol)在盐酸中的溶液中加入22％(0.5mL)亚硝酸钠(12mg，1.2当量，0.18mmol)在水(0.1mL)中的溶液。将所得混合物在相同温度下搅拌15min，然后将混合物在0℃下倒入氯化铜(I)(21mg，1.4当量，0.21mmol)在37％盐酸(2mL)的溶液中。将所得混合物在22℃下搅拌10h。将混合物在减压下浓缩，并用HPLC(纯化方法A)纯化，得到标题化合物(0.0181g，46.1μmol，31％，100％纯度)。1H NMR(400MHz,DMSO-d6)δ:9.61(s,1H),7.83(d,1H),7.69–7.53(m,1H),7.26(d,1H),7.06(t,2H),6.88–6.70(m,1H),4.55–4.39(m,1H),3.85(s,3H),2.64(s,3H),2.41–2.11(m,3H),1.95–1.74(m,1H).LCMS:m/z393.0[M+H]+。At 0 °C, a solution of 22% (0.5 mL) sodium nitrite (12 mg, 1.2 equivalent, 0.18 mmol) in water (0.1 mL) was added to a solution of N-(5-(4-amino-2-fluorophenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.056 g, 1 equivalent, 0.15 mmol) in hydrochloric acid. The resulting mixture was stirred at the same temperature for 15 min, and then poured into a solution of copper chloride (I) (21 mg, 1.4 equivalent, 0.21 mmol) in 37% hydrochloric acid (2 mL) at 0 °C. The resulting mixture was stirred at 22 °C for 10 h. The mixture was concentrated under reduced pressure and purified by HPLC (purification method A) to give the title compound (0.0181 g, 46.1 μmol, 31%, 100% purity). 1 H NMR(400MHz,DMSO-d6)δ:9.61(s,1H),7.83(d,1H),7.69–7.53(m,1H),7.26(d,1H),7.06(t,2H),6.88–6.70(m ,1H),4.55–4.39(m,1H),3.85(s,3H),2.64(s,3H),2.41–2.11(m,3H),1.95–1.74(m,1H).LCMS:m/z393.0[M+H] + .
实施例32.N-(5-(3-乙酰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物386)Example 32. N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 386)
a)1-(4-(4-甲氧基-3-硝基苯氧基)苯基)乙-1-酮a) 1-(4-(4-methoxy-3-nitrophenoxy)phenyl)ethyl-1-one
将4-乙酰基苯基硼酸(0.33g，1.99mmol)、4-甲氧基-3-硝基苯酚(0.28g，1.66mmol)、Cu(OAc)2(0.451mg，2.48mmol)和新鲜活化的粉末状分子筛加入到无水DCM(20mL)中。然后将Et3N(1.15mL，8.28mmol)加入到该混合物中。在空气气氛下搅拌混合物。通过LCMS监测反应进程。24h后，将所得浆液通过硅藻土过滤并浓缩。将粗产物通过快速柱色谱法(庚烷：EtOAc)纯化，得到0.3g标题化合物。LCMS:m/z 288.21[M+H]+。4-Acetylphenylboronic acid (0.33 g, 1.99 mmol), 4-methoxy-3-nitrophenol (0.28 g, 1.66 mmol), Cu(OAc) ₂ (0.451 mg, 2.48 mmol), and freshly activated powdered molecular sieves were added to anhydrous DCM (20 mL). Then, Et₃N (1.15 mL, 8.28 mmol) was added to the mixture. The mixture was stirred under air. The reaction progress was monitored by LCMS. After 24 h, the resulting slurry was filtered through diatomaceous earth and concentrated. The crude product was purified by rapid column chromatography (heptane: EtOAc) to give 0.3 g of the title compound. LCMS: m/z 288.21 [M+H] ⁺ .
b)1-(4-(3-氨基-4-甲氧基苯氧基)苯基)乙-1-酮b) 1-(4-(3-amino-4-methoxyphenoxy)phenyl)ethyl-1-one
将1-(4-(4-甲氧基-3-硝基苯氧基)苯基)乙-1-酮(300mg，1.04mmol)、锌(0.68g，10当量，10.44mmol)、氯化铵(0.56g，10当量，10.44mmol)在THF(5ml)、MeOH(3ml)和水(3ml)中的混合物在RT下搅拌4h。将该混合物通过硅藻土过滤。滤液用水洗涤(2×30mL)，经硫酸钠干燥，过滤并在减压下除去溶剂。将残余物通过快速色谱法纯化，得到(0.19g)标题化合物。LCMS:m/z 258.65[M+H]+。A mixture of 1-(4-(4-methoxy-3-nitrophenoxy)phenyl)ethyl-1-one (300 mg, 1.04 mmol), zinc (0.68 g, 10 equivalents, 10.44 mmol), and ammonium chloride (0.56 g, 10 equivalents, 10.44 mmol) in THF (5 mL), MeOH (3 mL), and water (3 mL) was stirred at RT for 4 h. The mixture was filtered through diatomaceous earth. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by rapid chromatography to give (0.19 g) of the title compound. LCMS: m/z 258.65 [M+H] + .
c)N-(5-(4-乙酰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物386)c) N-(5-(4-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (compound 386)
在0℃下，向1-甲基-5-氧代吡咯烷-2-甲酸(22.25mg，0.15mmol)、1-(4-(3-氨基-4-甲氧基苯氧基)苯基)乙-1-酮(40mg，0.16mmol)和TEA(0.11，0.78mmol)在无水DMF(2ml)中的溶液中加入1-丙烷膦酸环酐(0.73ml，1.24mmol)。将混合物在RT下搅拌过夜。将反应混合物用水(10mL)淬灭，然后用乙酸乙酯(2×10mL)萃取。合并的有机层用2M NaHCO3洗涤，然后用水洗涤，经硫酸钠干燥，蒸发，然后通过反相色谱法纯化，得到标题化合物(40.5mg)。1HNMR(600MHz,DMSO-d6):δ:1.86-1.92(m,1H),2.16-2.30(m,3H),2.52-2.54(m,3H),2.61-2.65(m,3H),3.89(s,3H),4.47(dd,1H),6.91(dd,1H),6.98-7.01(m,2H),7.14(d,1H),7.87(d,1H),7.94-8.02(m,2H),9.65(s,1H).LCMS:m/z 383.28[M+H]+。At 0 °C, 1-propanephosphonic anhydride (0.73 mL, 1.24 mmol) was added to a solution of 1-methyl-5-oxopyrrolidone-2-carboxylic acid (22.25 mg, 0.15 mmol), 1-(4-(3-amino-4-methoxyphenoxy)phenyl)ethyl-1-one (40 mg, 0.16 mmol), and TEA (0.11 mL, 0.78 mmol) in anhydrous DMF (2 mL). The mixture was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with 2 M NaHCO3, then with water, dried over sodium sulfate, evaporated, and purified by reversed-phase chromatography to give the title compound (40.5 mg). 1 HNMR(600MHz,DMSO-d6): δ:1.86-1.92(m,1H),2.16-2.30(m,3H),2.52-2.54(m,3H),2.61-2.65(m,3H),3.89(s,3H) ,4.47(dd,1H),6.91(dd,1H),6.98-7.01(m,2H),7.14(d,1H),7.87(d,1H),7.94-8.02(m,2H),9.65(s,1H).LCMS:m/z 383.28[M+H] + .
实施例33.N-(5-(3-乙酰基苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物387)Example 33. N-(5-(3-acetylphenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 387)
a)1-甲氧基-4-硝基-2-(4-(三氟甲基)苄基)苯a) 1-Methoxy-4-nitro-2-(4-(trifluoromethyl)benzyl)benzene
将2-甲氧基-5-硝基苯甲醛(0.5g，2.8mmol)和甲苯磺酰肼(0.51g，2.8mmol)在1,4-二噁烷(5ml)中的混合物在60℃下加热90min。向粗产物(E)-N'-(2-甲氧基-5-硝基亚苄基)-4-甲基苯磺酰肼中加入K2CO3(0.53g，3.86mmol)和4-(三氟甲基)苯基硼酸(0.49g，2.6mmol)。将混合物在氮气气氛下于110℃加热4h。冷却至RT后，将混合物用2M NaHCO3(5ml)淬灭。将混合物用乙酸乙酯(2×10mL)萃取。将合并的有机层用水洗涤，干燥，蒸发，然后通过快速色谱法纯化，得到标题化合物(0.35g)。LCMS:m/z 312.2[M+H]+。A mixture of 2-methoxy-5-nitrobenzaldehyde (0.5 g, 2.8 mmol) and toluenesulfonyl hydrazine (0.51 g, 2.8 mmol) in 1,4-dioxane (5 mL) was heated at 60 °C for 90 min. K₂CO₃ (0.53 g, 3.86 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.49 g, 2.6 mmol) were added to the crude product (E)-N' - (2-methoxy-5-nitrobenzyl)-4-methylbenzenesulfonyl hydrazine. The mixture was heated at 110 °C for 4 h under a nitrogen atmosphere. After cooling to RT, the mixture was quenched with 2 M NaHCO₃ ( 5 mL). The mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water, dried, evaporated, and then purified by rapid chromatography to give the title compound (0.35 g). LCMS: m/z 312.2 [M+H] ⁺ .
b)4-甲氧基-3-(4-(三氟甲基)苄基)苯胺b) 4-Methoxy-3-(4-(trifluoromethyl)benzyl)aniline
将1-甲氧基-4-硝基-2-(4-(三氟甲基)苄基)苯(100mg，0.32mmol)、锌(0.21g，10当量，3.21mmol)和氯化铵(0.17g，10当量3.21mmol)在THF(10ml)、MeOH(3ml)和水(3ml)中的混合物在RT下搅拌4h。将该混合物通过硅藻土过滤。滤液用水(2×30mL)洗涤，经硫酸钠干燥，过滤并在减压下除去溶剂。将残余物通过快速色谱法纯化，得到(0.12g)标题化合物。LCMS:m/z 282.05[M+H]+。A mixture of 1-methoxy-4-nitro-2-(4-(trifluoromethyl)benzyl)benzene (100 mg, 0.32 mmol), zinc (0.21 g, 10 equivalents, 3.21 mmol), and ammonium chloride (0.17 g, 10 equivalents, 3.21 mmol) in THF (10 mL), MeOH (3 mL), and water (3 mL) was stirred at RT for 4 h. The mixture was filtered through diatomaceous earth. The filtrate was washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by rapid chromatography to give (0.12 g) of the title compound. LCMS: m/z 282.05 [M+H] + .
c)N-(4-甲氧基-3-(4-(三氟甲基)苄基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物387)c) N-(4-methoxy-3-(4-(trifluoromethyl)benzyl)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 387)
在0℃下，向1-甲基-5-氧代吡咯烷-2-甲酸(45.8mg，0.32mmol)、4-甲氧基-3-(4-(三氟甲基)苄基)苯胺(90mg，0.32mmol)和TEA(0.22，1.60mmol)在无水DMF(2ml)中的溶液中加入1-丙烷膦酸环酐(1.51ml，2.56mmol)。将混合物在RT下搅拌过夜。将反应混合物用水(10mL)淬灭，然后用乙酸乙酯(2×10ml)萃取。合并的有机层用2M NaHCO3洗涤，然后用水洗涤，经硫酸钠干燥，蒸发，然后通过反相色谱法纯化，得到标题化合物(5mg)。1H NMR(400MHz,氯仿-d)δ:1.75-2.02(m,1H),2.06-2.22(m,1H),2.31-2.59(m,3H),2.81-2.91(m,3H),3.79-3.93(m,3H),3.96-4.10(m,3H),6.85(d,1H),7.25-7.33(m,4H),7.44-7.57(m,3H),7.84(br s,1H).LCMS:m/z 282.05[M+H]+。At 0 °C, 1-propanephosphonic anhydride (1.51 mL, 2.56 mmol) was added to a solution of 1-methyl-5-oxopyrrolidine-2-carboxylic acid (45.8 mg, 0.32 mmol), 4-methoxy-3-(4-(trifluoromethyl)benzyl)aniline (90 mg, 0.32 mmol), and TEA (0.22, 1.60 mmol) in anhydrous DMF (2 mL). The mixture was stirred overnight at RT. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with 2 M NaHCO3 , then with water, dried over sodium sulfate, evaporated, and purified by reversed-phase chromatography to give the title compound (5 mg). 1 H NMR(400MHz, chloroform-d)δ:1.75-2.02(m,1H),2.06-2.22(m,1H),2.31-2.59(m,3H),2.81-2.91(m,3H), 3.79-3.93(m,3H),3.96-4.10(m,3H),6.85(d,1H),7.25-7.33(m,4H),7.44-7.57(m,3H),7.84(br s,1H).LCMS: m/z 282.05[M+H] + .
实施例34.N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-2-氧代-2,3-二氢噁唑-4-甲酰胺(化合物388)Example 34. N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxo-2,3-dihydrooxazol-4-carboxamide (Compound 388)
将TMA(2M，397μL，0.794mmol在氯苯中)加入到2-甲氧基-5-(4-(三氟甲基)苯氧基)苯胺(0.075g，0.265mmol)和2-氧代-2,3-二氢噁唑-4-甲酸乙酯(0.064g，0.397mmol)在甲苯(2ml)中的混合物中，随后在90℃下加热混合物3h。将反应混合物用冰冷的水淬灭。水层用EtOAc(2×5ml)萃取。蒸发合并的有机层，然后通过反相色谱法纯化，得到0.029g标题化合物。1H NMR(400MHz,DMSO-d6)δ:3.87(3H,s),7.00(1H,m),7.11(2H,d),7.17(1H,d),7.59(1H,d),7.72(2H,d),7.98(1H,s),9.46(1H,s),11.44(1H,br s).LCMS:m/z 395.2[M+H]+。TMA (2 M, 397 μL, 0.794 mmol in chlorobenzene) was added to a mixture of 2-methoxy-5-(4-(trifluoromethyl)phenoxy)aniline (0.075 g, 0.265 mmol) and ethyl 2-oxo-2,3-dihydrooxazol-4-carboxylate (0.064 g, 0.397 mmol) in toluene (2 mL), and the mixture was then heated at 90 °C for 3 h. The reaction mixture was quenched with ice-cold water. The aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were evaporated and then purified by reversed-phase chromatography to give 0.029 g of the title compound. 1 H NMR(400MHz,DMSO-d6)δ:3.87(3H,s),7.00(1H,m),7.11(2H,d),7.17(1H,d),7.59(1H,d),7.72(2H,d),7.98(1H,s),9.46(1H,s),11.44(1H,br s).LCMS: m/z 395.2[M+H] + .
实施例35.N-(3-(3,4-二氟苯氧基)-6-甲氧基-2-甲基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物389)Example 35. N-(3-(3,4-difluorophenoxy)-6-methoxy-2-methylphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 389)
向1-甲基-5-氧代吡咯烷-2-甲酸(15mg，0.10mmol)、3-(3,4-二氟苯氧基)-6-甲氧基-2-甲基苯胺(24mg，0.09mmol)、T3P(50％，80μl，0.14mmol在EtOAc中)和DCM(2ml)的溶液中加入DIPEA(47μl，0.27mmol)。回流3h后，加入另外的起始原料和试剂(1-甲基-5-氧代吡咯烷-2-甲酸1.15当量，T3P 1.5当量，DIPEA3.0当量)，随后在密闭容器中于80℃下搅拌7h。将反应混合物用2N NaOH(2ml)淬灭。分离有机层，并将水层用EtOAc(1×4ml)萃取。蒸发合并的有机层，然后通过反相色谱法纯化，得到0.016g标题化合物。1H NMR(400MHz,DMSO-d6)δ:1.94(3H,s),1.94-2.03(1H,m),2.19-2.37(3H,m),2.71(3H,s),3.79(3H,s),4.26-4.33(1H,m),6.61(1H,m),6.90-7.02(3H,m),7.36-7.45(1H,m),9.66(1H,s).LCMS:m/z 391.1[M+H]+。DIPEA ( 47 μl, 0.27 mmol) was added to a solution of 1-methyl-5-oxopyrrolidine-2-carboxylic acid (15 mg, 0.10 mmol), 3-(3,4-difluorophenoxy)-6-methoxy-2-methylaniline (24 mg, 0.09 mmol), T3P (50%, 80 μl, 0.14 mmol in EtOAc), and DCM (2 mL). After reflux for 3 h, additional starting materials and reagents (1.15 equivalents of 1-methyl-5-oxopyrrolidine-2-carboxylic acid, 1.5 equivalents of T3P , and 3.0 equivalents of DIPEA) were added, followed by stirring at 80 °C for 7 h in a sealed container. The reaction mixture was quenched with 2N NaOH (2 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1 × 4 mL). The combined organic layers were evaporated and then purified by reversed-phase chromatography to give 0.016 g of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ: 1.94 (3H, s), 1.94–2.03 (1H, m), 2.19–2.37 (3H, m), 2.71 (3H, s), 3.79 (3H, s), 4.26–4.33 (1H, m), 6.61 (1H, m), 6.90–7.02 (3H, m), 7.36–7.45 (1H, m), 9.66 (1H, s). LCMS: m/z 391.1 [M+H] + .
根据化合物389所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 389. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例36.N-(2-羟基-5-(3-甲氧基-4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物410)Example 36. N-(2-hydroxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 410)
在-50℃下将BCl3(1M在庚烷中，798μL，0.798mmol)逐滴加入到冷却的N-(2-甲氧基-5-(3-甲氧基-4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.100g，0.228mmol)在DCM(9ml)中的溶液中，随后在RT下搅拌50min。将反应混合物用1N HCl(5ml)淬灭。分离有机层并蒸发。将残余物通过反相色谱法纯化，得到0.066g标题化合物。1H NMR(400MHz,DMSO-d6)δ:1.85-1.95(1H,m),2.13-2.35(3H,m),2.65(3H,s),3.84(3H,s),4.43-4.50(1H,m),6.42(1H,m),6.78(1H,m),6.86(1H,d),6.94(1H,d),7.53(1H,d),7.79(1H,d),9.57(1H,s),10.07(1H,s).LCMS:m/z 425.2[M+H]+。 BCl₃ (1M in heptane, 798 μL, 0.798 mmol) was added dropwise at -50 °C to a cooled solution of N-(2-methoxy-5-(3-methoxy-4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.100 g, 0.228 mmol) in DCM (9 mL), followed by stirring at RT for 50 min. The reaction mixture was quenched with 1N HCl (5 mL). The organic layer was separated and evaporated. The residue was purified by reversed-phase chromatography to give 0.066 g of the title compound. 1 H NMR(400MHz,DMSO-d6)δ:1.85-1.95(1H,m),2.13-2.35(3H,m),2.65(3H,s),3.84(3H,s),4.43-4.50(1H,m),6.4 2(1H,m),6.78(1H,m),6.86(1H,d),6.94(1H,d),7.53(1H,d),7.79(1H,d),9.57(1H,s),10.07(1H,s).LCMS:m/z 425.2[M+H] + .
实施例37.N-(5-(2-羟基-4-(三氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(化合物411)Example 37. N-(5-(2-hydroxy-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (Compound 411)
在0℃下，将NaH(60％在油中，0.028g，0.704mmol)加入到冷却的N-(5-(2-氟-4-(三氟甲基)苯氧基)-2-甲氧基苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.100g，0.235mmol)在DMF(2ml)中的溶液中，随后在RT下搅拌15min。然后加入2-(甲基磺酰基)乙醇，并将混合物在50℃下加热2.5h。然后加入另外的NaH(60％在油中，5当量)和2-(甲基磺酰基)乙醇两次，并分别在80℃下加热5h和在100℃下加热5.5h。将反应混合物用2N HCl(2ml)淬灭，并用EtOAc(3×3ml)萃取。分离有机层并蒸发。将残余物通过反相色谱法纯化，得到0.012g标题化合物。1H NMR(600MHz,DMSO-d6)δ:1.85-1.92(1H,m),2.16-2.31(3H,m),2.64(3H,s),3.85(3H,s),4.46(1H,m),6.76(1H,m),6.92(1H,d),7.07(1H,d),7.11(1H,m),7.20(1H,d),7.80(1H,d),9.58(1H,s),10.17(1H,s).LCMS:m/z 425.2[M+H]+。At 0 °C, NaH (60% in oil, 0.028 g, 0.704 mmol) was added to a cooled solution of N-(5-(2-fluoro-4-(trifluoromethyl)phenoxy)-2-methoxyphenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.100 g, 0.235 mmol) in DMF (2 mL), followed by stirring at RT for 15 min. Then, 2-(methanesulfonyl)ethanol was added, and the mixture was heated at 50 °C for 2.5 h. Then, additional NaH (60% in oil, 5 equivalents) and 2-(methanesulfonyl)ethanol were added twice, and the mixture was heated at 80 °C for 5 h and at 100 °C for 5.5 h, respectively. The reaction mixture was quenched with 2N HCl (2 mL) and extracted with EtOAc (3 × 3 mL). The organic layer was separated and evaporated. The residue was purified by reversed-phase chromatography to give 0.012 g of the title compound. 1 H NMR(600MHz,DMSO-d6)δ:1.85-1.92(1H,m),2.16-2.31(3H,m),2.64(3H,s),3.85(3H,s),4.46(1H,m),6.76( 1H,m),6.92(1H,d),7.07(1H,d),7.11(1H,m),7.20(1H,d),7.80(1H,d),9.58(1H,s),10.17(1H,s).LCMS:m/z 425.2[M+H] + .
实施例38.1-乙酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-3-甲酰胺(化合物412)Example 38. 1-Acetyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-3-carboxamide (Compound 412)
在氮气下，将N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-3-甲酰胺(74mg，1当量，1.321mmol)和Et3N(271μL，10当量，1.945mmol)溶解于DCM(5mL)中。在0℃下逐滴加入乙酰氯，并搅拌混合物，并逐渐升至RT。反应完全后，将混合物用EtOAc(20ml)稀释，并用盐水(2×10ml)洗涤。将有机相经硫酸钠干燥，过滤并浓缩。将粗残余物用反相色谱法进一步纯化，得到36mg标题化合物。1H NMR(400MHz，CDCl3，～1.0:1.2比例的旋转异构体的混合物)δ:8.19(m,1H),7.93(br s,0.45H),7.88(br s,0.52H),7.57-7.50(m,2.1H),7.02-6.94(m,2.1H),6.90(m,1.1H),6.78(m,1H),3.93(s,1.54H),3.92(s,1.72H),3.91-3.84(m,0.59H),3.81-3.65(m,2.7H),3.55-3.42(m,1.12H),3.16(m,0.5H),3.06(quin,0.58H)2.45-2.34(m,0.67H),2.31-2.16(m,1.8H),2.08(s,1.44H),2.07(s,1.63H).LCMS:m/z 423.2[M+H]+。Under nitrogen atmosphere, N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-3-carboxamide (74 mg, 1 equivalent, 1.321 mmol) and Et3N (271 μL, 10 equivalent, 1.945 mmol) were dissolved in DCM (5 mL). Acetyl chloride was added dropwise at 0 °C with stirring and gradually increased to RT. After the reaction was complete, the mixture was diluted with EtOAc (20 mL) and washed with brine (2 × 10 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude residue was further purified by reversed-phase chromatography to give 36 mg of the title compound. ¹H NMR (400 MHz, CDCl3, a mixture of ~1.0:1.2 rotational isomers) δ: 8.19 (m, 1H), 7.93 (br s, 0.45H), 7.88 (br s,0.52H),7.57-7.50(m,2.1H),7.02-6.94(m,2.1H),6.90(m,1.1H),6.78( m,1H),3.93(s,1.54H),3.92(s,1.72H),3.91-3.84(m,0.59H),3.81-3.65(m ,2.7H),3.55-3.42(m,1.12H),3.16(m,0.5H),3.06(quin,0.58H)2.45-2.34 (m,0.67H),2.31-2.16(m,1.8H),2.08(s,1.44H),2.07(s,1.63H).LCMS:m/z 423.2[M+H] + .
根据化合物412所述的方法制备以下化合物。化合物的编号、结构、起始原料、纯化方法和表征数据示于表中。The following compounds were prepared according to the method described for compound 412. The compound numbers, structures, starting materials, purification methods, and characterization data are shown in the table.
实施例39.1-甘氨酰基-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-5-氧代吡咯烷-2-甲酰胺，HCl(化合物414)Example 39. 1-Glycyl-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, HCl (Compound 414)
在布氏烧瓶中，将(2-(2-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基甲酰基)-5-氧代吡咯烷-1-基)-2-氧代乙基)氨基甲酸苄酯(168mg，0.287mmol，1当量)溶于EtOH(10ml)中，并加入钯(24.4mg，0.023mmol，0.08当量)和HCl(37％，0.120ml，1.435mmol，5当量)。将烧瓶连接到H2/N2/真空管线，并在用氮气置换空气后，将混合物在氢气下搅拌2.5h。将混合物通过垫过滤，并用乙腈/H2O的1:1混合物洗涤。将产物在-78℃下冷冻，并在冷冻干燥器上除去溶剂，得到标题化合物。1H NMR(400MHz,DMSO-d6)δ:9.91(s,1H),8.17(br.s,1H),7.85(d,1H),7.70(d,2H),7.15(d,1H),7.06(d,2H),6.93(dd,1H),5.15(m,1H),4.20(d,1H),4.17(d,1H),3.91(s,3H),2.71-2.30(m,3H),2.04(m,1H).LCMS:m/z452.598[M+H]+。In a Buchner flask, benzyl (2-(2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidine-1-yl)-2-oxoethyl)carbamate (168 mg, 0.287 mmol, 1 equivalent) was dissolved in EtOH (10 mL), and palladium (24.4 mg, 0.023 mmol, 0.08 equivalent) and HCl (37%, 0.120 mL, 1.435 mmol, 5 equivalent) were added. The flask was connected to an H₂ / N₂ /vacuum line, and after purging the air with nitrogen, the mixture was stirred under hydrogen for 2.5 h. The mixture was filtered through a pad and washed with a 1:1 mixture of acetonitrile/ H₂O . The product was frozen at -78 °C and the solvent was removed on a freeze dryer to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ:9.91(s,1H),8.17(br.s,1H),7.85(d,1H),7.70(d,2H),7.15(d,1H),7.06(d,2H),6.93(d d,1H),5.15(m,1H),4.20(d,1H),4.17(d,1H),3.91(s,3H),2.71-2.30(m,3H),2.04(m,1H).LCMS:m/z452.598[M+H] + .
实施例40.(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)吡咯烷-2-甲酰胺(化合物415)Example 40. (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)pyrrolidine-2-carboxamide (Compound 415)
根据中间体364所述的方法，由(S)-2-((2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)氨基甲酰基)-5-氧代吡咯烷-1-甲酸叔丁酯开始制备该化合物。将粗终产物用饱和Na2CO3溶液处理，然后用DCM萃取。将有机相干燥并蒸发，得到标题化合物。1H NMR(400MHz,CDCl3)δ:10.2(s,1H),8.27(d,1H),7.48-7.56(m,2H),6.96-7.03(m,2H),6.87(d,1H),6.74(dd,1H),3.91(s,3H),3.85-3.92(m,1H),2.98-3.15(m,2H),2.14-2.26(m,1H),1.97-2.08(m,1H),1.68-1.85(m,2H).LCMS:m/z 381.7[M+H]+。The compound was prepared from (S)-2-((2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)carbamoyl)-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester, according to the method described in intermediate 364. The crude final product was treated with a saturated Na₂CO₃ solution and then extracted with DCM. The organic phase was dried and evaporated to give the title compound. 1 H NMR (400MHz, CDCl 3 )δ:10.2(s,1H),8.27(d,1H),7.48-7.56(m,2H),6.96-7.03(m,2H),6.87(d,1H),6.74(dd,1H),3.91(s,3H ),3.85-3.92(m,1H),2.98-3.15(m,2H),2.14-2.26(m,1H),1.97-2.08(m,1H),1.68-1.85(m,2H).LCMS:m/z 381.7[M+H] + .
实施例41.(S)-N-(5-((3-氟-5-(三氟甲基)吡啶-2-基)氧基)-2-甲氧基苯基)吡咯烷-2-甲酰胺(化合物416)Example 41. (S)-N-(5-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2-methoxyphenyl)pyrrolidine-2-carboxamide (Compound 416)
根据中间体364所述的方法，由(2S)-2-((5-((3-氟-5-(三氟甲基)-吡啶-2-基)氧基)-2-甲氧基苯基)氨基甲酰基)-1l4-吡咯烷-1-甲酸叔丁酯开始制备该化合物。将粗终产物用饱和Na2CO3溶液处理，然后用DCM萃取。将有机相干燥并蒸发，得到标题化合物。1H NMR(400MHz,CDCl3)δ:10.2(s,1H),8.37(d,1H),8.14-8.19(m,1H),7.64(dd,1H),6.91(d,1H),6.86(dd,1H),3.92(s,3H),3.86(dd,1H),2.96-3.14(m,2H),2.13(br,1H),2.12-2.24(m,1H),1.96-2.07(m,1H),1.67-1.84(m,2H).LCMS:m/z 400.6[M+H]+。The compound was prepared from (2S)-2-((5-((3-fluoro-5-(trifluoromethyl)-pyridin-2-yl)oxy)-2-methoxyphenyl)carbamoyl)-1l4-pyrrolidine-1-carboxylic acid tert-butyl ester, according to the method described in intermediate 364. The crude final product was treated with a saturated Na₂CO₃ solution and then extracted with DCM. The organic phase was dried and evaporated to give the title compound. 1 H NMR (400MHz, CDCl 3 )δ:10.2(s,1H),8.37(d,1H),8.14-8.19(m,1H),7.64(dd,1H),6.91(d,1H),6.86(dd,1H),3.92(s,3H),3.86 (dd,1H),2.96-3.14(m,2H),2.13(br,1H),2.12-2.24(m,1H),1.96-2.07(m,1H),1.67-1.84(m,2H).LCMS:m/z 400.6[M+H] + .
实施例42.(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-N,1-二甲基-5-氧代吡咯烷-2-甲酰胺(化合物417)Example 42. (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-N,1-dimethyl-5-oxopyrrolidine-2-carboxamide (Compound 417)
向冷却(0-5℃)的(S)-N-(2-甲氧基-5-(4-(三氟甲基)苯氧基)苯基)-1-甲基-5-氧代吡咯烷-2-甲酰胺(0.204g，0.50mmol)在无水DMF(2.0mmol)中的溶液中加入60w-％在油中的氢化钠(0.025g，0.625mmol)，随后在0-5℃下搅拌该混合物15min。加入碘甲烷(0.062ml，1.00mmol)，并在RT下继续搅拌直至反应完全。将混合物用水稀释，并用EtOAc萃取。将有机相用水和盐水洗涤，干燥并蒸发。将粗产物通过反相快速色谱法纯化，得到标题化合物。收率：0.152g。1H NMR(400MHz,CDCl3),旋转异构体的混合物。主旋转异构体的化学位移：δ:7.56-7.64(m,2H),7.07-7.14(m,1H),6.98-7.06(m,3H),6.96(dd,1H),3.93(dd,1H),3.90(s,3H),3.21(s,3H),2.76(s,3H),2.43-2.62(m,1H),2.18-2.31(m,1H),1.77-2.08(m,2H).LCMS:m/z 423.4[M+H]+。To a cooled (0–5 °C) solution of (S)-N-(2-methoxy-5-(4-(trifluoromethyl)phenoxy)phenyl)-1-methyl-5-oxopyrrolidine-2-carboxamide (0.204 g, 0.50 mmol) in anhydrous DMF (2.0 mmol), 60 w-% sodium hydride in oil (0.025 g, 0.625 mmol) was added, followed by stirring at 0–5 °C for 15 min. Iodimethane (0.062 mL, 1.00 mmol) was added, and stirring was continued at RT until the reaction was complete. The mixture was diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried, and evaporated. The crude product was purified by reversed-phase rapid chromatography to give the title compound. Yield: 0.152 g. ¹H NMR (400 MHz, CDCl₃), mixture of rotational isomers. Chemical shifts of the main rotational isomer: δ: 7.56–7.64 (m, 2H), 7.07–7.14 (m, 1H), 6.98–7.06 (m, 3H), 6.96 (dd, 1H), 3.93 (dd, 1H), 3.90 (s, 3H), 3.21 (s, 3H), 2.76 (s, 3H), 2.43–2.62 (m, 1H), 2.18–2.31 (m, 1H), 1.77–2.08 (m, 2H). LCMS: m/z 423.4 [M+H] + .
缩写abbreviation
DCM-二氯甲烷DCM-dichloromethane
DEAD-偶氮二甲酸二乙酯DEAD-Diethyl azodicarbonate
DIPEA-N,N-二异丙基乙胺DIPEA-N,N-Diisopropylethylamine
DMA-二甲基乙酰胺DMA-dimethylacetamide
DMAP-4-二甲氨基吡啶DMAP-4-Dimethylaminopyridine
DMF-N,N-二甲基甲酰胺DMF-N,N-dimethylformamide
DMSO-二甲亚砜DMSO-dimethyl sulfoxide
ee-对映异构体过量ee-enantiomer excess
eq.-摩尔当量eq. - molar equivalent
GCMS-气相色谱-质谱法GCMS (Gas Chromatography-Mass Spectrometry)
HATU-2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐HATU-2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate
HPLC-高效液相色谱法HPLC-High Performance Liquid Chromatography
LCMS-液相色谱-质谱法LCMS (Liquid Chromatography-Mass Spectrometry)
LiHMDS-双(三甲基甲硅烷基)氨基锂LiHMDS-bis(trimethylsilyl)aminolithium
MTBE-甲基叔丁基醚MTBE (methyl tert-butyl ether)
Pd2(dba)3-三(二亚苄基丙酮)二钯 Pd2 (dba) 3 -tris(dibenzylacetone)dipalladium
PdCl2(dppf)-[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II) PdCl₂ (dppf)-[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
RT-室温RT - room temperature
rt-保留时间rt - retention time
SPhos Pd G2-氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)SPhos Pd G2-chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)
T3P-1-丙烷膦酸环酐T 3 P-1-propanephosphonic anhydride
TBAF-氟化四正丁基铵TBAF - Tetrabutylammonium Fluoride
TEA-三乙胺TEA-Triethylamine
TFA-三氟乙酸TFA-trifluoroacetic acid
THF-四氢呋喃THF-Tetrahydrofuran
TMA-三甲基铝TMA-Trimethylaluminum
TMS-Cl-三甲基甲硅烷基氯化物TMS-Cl-trimethylsilyl chloride
XantPhos-4,5-双(二苯基膦基)-9,9-二甲基呫吨XantPhos-4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium
实验experiment
实验1.TEAD抑制Experiment 1. TEAD inhibition
使用Hippo通路TEAD报道基因–MCF-7细胞系(BPS Bioscience，货号：#60618)来测定TEAD抑制，所述细胞系含有在TEAD响应元件控制下的萤火虫荧光素酶基因。在该细胞系中，YAP1保留在细胞核中，诱导萤光素酶报告基因的组成型表达。使用ONE-Glo萤光素酶测定系统(Promega)并使用Enspire多模式读板器(PerkinElmer)测量板来检测表达的萤光素酶的量。TEAD inhibition was measured using the Hippo pathway TEAD reporter gene – MCF-7 cell line (BPS Bioscience, catalog number: #60618), which contains the firefly luciferase gene under the control of TEAD response elements. In this cell line, YAP1 is retained in the nucleus and induces constitutive expression of the luciferase reporter gene. The amount of expressed luciferase was detected using the ONE-Glo luciferase assay system (Promega) and an Enspire multimode plate reader (PerkinElmer) plate.
将Hippo通路TEAD报道基因-MCF-7细胞以8500个细胞/孔的密度铺板于白色/透明的聚-D-赖氨酸涂覆的384孔板(Corning#356660)上。次日将试验化合物(11个浓度，4次重复)和DMSO对照(0.1％)加入板中。24h后裂解细胞并测量荧光素酶活性。测定试验化合物对YAP-TEAD抑制的半数最大抑制浓度(IC50)。Hippo pathway TEAD reporter gene-MCF-7 cells were seeded at a density of 8500 cells/well in white/clear poly-D-lysine-coated 384-well plates (Corning #356660). The following day, the test compounds (11 concentrations, 4 replicates) and a DMSO control (0.1%) were added to the plates. Cells were lysed after 24 hours, and luciferase activity was measured. The half-maximal inhibitory concentration ( IC50 ) of the test compounds against YAP-TEAD was determined.
在上述试验中筛选本发明的化合物，化合物的IC50值列于下表1中，其中“A”是指一组IC50值小于50nM的化合物，“B”是指一组IC50值在50-300nM范围内的化合物，“C”是指一组IC50值在301nM-2000nM范围内的化合物。The compounds of the present invention were screened in the above experiments, and the IC 50 values of the compounds are listed in Table 1 below, where “A” refers to a group of compounds with IC 50 values less than 50 nM, “B” refers to a group of compounds with IC 50 values in the range of 50-300 nM, and “C” refers to a group of compounds with IC 50 values in the range of 301 nM-2000 nM.
表1.Table 1.
Claims (42)
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