TWI712600B - Biphenyl compounds as immunomodulator and use thereof - Google Patents

Biphenyl compounds as immunomodulator and use thereof Download PDF

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TWI712600B
TWI712600B TW108130887A TW108130887A TWI712600B TW I712600 B TWI712600 B TW I712600B TW 108130887 A TW108130887 A TW 108130887A TW 108130887 A TW108130887 A TW 108130887A TW I712600 B TWI712600 B TW I712600B
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金迪 余
辛利軍
山松
王曉亮
付超
李志斌
先平 魯
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大陸商深圳微芯生物科技股份有限公司
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Abstract

The present invention relates to biphenyl compounds of formula I, a process for its preparation and its pharmaceutical use. The definition of each group in formula I is as described in the specification. The compounds are capable of blocking the interaction between the PD-1/PD-L1 signaling pathways and are useful for treating or preventing diseases associated with the signaling pathways, such as cancer, autoimmune diseases or chronic infectious diseases.

Description

作為免疫調節劑的聯苯化合物及其用途 Biphenyl compound as immunomodulator and its use

本發明涉及能夠抑制PD-1/PD-L1蛋白/蛋白相互作用的聯苯類化合物、其製備方法及其在在製備用於治療或預防與該信號通路相關的疾病的藥物中的用途。 The present invention relates to a biphenyl compound capable of inhibiting the interaction of PD-1/PD-L1 protein/protein, a preparation method thereof, and use in preparing a medicine for treating or preventing diseases related to the signal pathway.

近年來，以PD-1/PD-L1抗體為代表的免疫檢查點抑制劑在腫瘤免疫治療(Cancer immunotherapy)領域取得了重大的臨床研究進展。與傳統基於細胞毒作用的化療不同，腫瘤免疫治療通過激發人體的免疫系統，增強自身的抗腫瘤免疫力，從而達到持久抑制或殺死腫瘤細胞的目的，這為抗擊癌症提供了新型武器(Sharma P.,Allison J.P.,2015,Science,348：56-61)。 In recent years, immune checkpoint inhibitors represented by PD-1/PD-L1 antibody have made significant clinical research progress in the field of cancer immunotherapy. Unlike traditional chemotherapy based on cytotoxicity, tumor immunotherapy stimulates the body’s immune system and enhances its own anti-tumor immunity, thereby achieving the purpose of lasting suppression or killing tumor cells, which provides a new weapon in the fight against cancer (Sharma P., Allison JP, 2015 , Science , 348: 56-61).

程式性死亡受體1(Programmed death receptor 1，PD-1)主要表達於啟動的T細胞、B細胞及骨髓細胞中，屬於CD28家族。與CD28、CD134(OX40)、糖皮質激素誘導的TNFR相關蛋白(Glucocorticoid-induced TNFR-related protein,GITR)、CD137、CD27、HVEM等傳遞啟動信號的活化性受體不同，PD-1與配體結合後通過活化胞內段的免疫受體酪氨酸抑制性基序(Immunoreceptor tyrosine-based inhibitory motif,ITIM)後啟動蛋白磷酸水解酶(SH-2 domain containing protein tyrosine phosphatase 1/2,SHP-1/2)等向胞內傳遞免疫抑制性信號，從而阻斷T細胞的持續活化(Cheng X.,Veverka V.,Radhakrishnan A.,et al.2013,J.Biol.Chem.,288：11771-11785)。 Programmed death receptor 1 (PD-1) is mainly expressed in activated T cells, B cells and bone marrow cells, and belongs to the CD28 family. Unlike CD28, CD134 (OX40), glucocorticoid-induced TNFR-related protein (Glucocorticoid-induced TNFR-related protein, GITR), CD137, CD27, HVEM and other activating receptors that transmit initiation signals, PD-1 and ligand After binding, the immunoreceptor tyrosine inhibitory motif (Immunoreceptor tyrosine-based inhibitory motif, ITIM) of the intracellular segment is activated and then the protein phosphohydrolase (SH-2 domain containing protein tyrosine phosphatase 1/2, SHP-1) is activated. /2) Transmit immunosuppressive signals into the cell, thereby blocking the continuous activation of T cells (Cheng X., Veverka V., Radhakrishnan A., et al. 2013, J. Biol. Chem., 288: 11771- 11785).

PD-1的配體包括程式性死亡配體1(Programmed death protein ligand 1,PD-L1)和程式性死亡配體2(Programmed death protein ligand 2,PD-L2)兩種，其中PD-L1可持續性表達於多種腫瘤細胞、T細胞、APC及多種非造血細胞；PD-L2只限制性地表達於樹突狀細胞和巨噬細胞中。在正常生理條件下， PD-1與PD-L2的相互作用會抑制T細胞啟動，這對於維持正常機體的免疫耐受至關重要；另一方面可避免免疫反應過度啟動導致組織損傷。然而，在腫瘤細胞中和病毒感染時，PD-L1的表達上調，同時T細胞上的PD-1被誘導性高表達，導致PD-1信號通路持續啟動而抑制T細胞增殖，造成腫瘤細胞和病原體的免疫逃逸(Fuller M.J.,Callendret B.,Zhu B.,et al. 2013,Proc.Natl.Acad.Sci.USA.,110：15001-15006；Dolan D.E.,Gupta S.,2014,CancerControl,21：231-237；Chen L.,Han X.,2015,J.Clin.Invest.,125：3384-3391；Postow M.A.,Callahan M.K.,Wolchok J.D.,2015,J.Clin.Oncol.,33：1974-1982)。因此，需要通過啟動共刺激信號(踩“油門”)並抑制共抑制信號(松“刹車”)而重新啟動T細胞攻擊腫瘤細胞，進而實現腫瘤免疫治療。臨床研究表明，免疫檢查點阻斷是T細胞啟動的關鍵策略之一，而幾個抗體藥物的成功上市和巨大的市場潛力無疑使免疫檢查點的研究成為了各大製藥公司的聚焦點(Pardoll D.M.,2012,Nat.Rev.Cancer.,12：252-264)。 The ligands of PD-1 include programmed death protein ligand 1 (PD-L1) and programmed death protein ligand 2 (PD-L2), of which PD-L1 can It is continuously expressed in a variety of tumor cells, T cells, APC and a variety of non-hematopoietic cells; PD-L2 is only restrictedly expressed in dendritic cells and macrophages. Under normal physiological conditions, the interaction of PD-1 and PD-L2 will inhibit the activation of T cells, which is essential for maintaining the normal body's immune tolerance; on the other hand, it can avoid excessive activation of the immune response and cause tissue damage. However, when tumor cells neutralize virus infection, the expression of PD-L1 is up-regulated, and PD-1 on T cells is induced to be highly expressed, leading to the continuous activation of the PD-1 signaling pathway and inhibiting T cell proliferation, resulting in tumor cells and Immune escape of pathogens (Fuller MJ, Callendret B., Zhu B., et al. 2013 , Proc.Natl.Acad.Sci.USA. , 110:15001-15006; Dolan DE, Gupta S., 2014 , CancerControl , 21 : 231-237; Chen L., Han X., 2015 , J. Clin. Invest. , 125: 3384-3391; Postow MA, Callahan MK, Wolchok JD, 2015 , J. Clin. Oncol. , 33: 1974- 1982). Therefore, it is necessary to restart T cells to attack tumor cells by activating the costimulatory signal (step on the accelerator pedal) and inhibit the co-suppressive signal (releasing the "brake") to realize tumor immunotherapy. Clinical studies have shown that immune checkpoint blockade is one of the key strategies for T cell activation, and the successful listing of several antibody drugs and the huge market potential undoubtedly make immune checkpoint research the focus of major pharmaceutical companies (Pardoll DM, 2012 , Nat. Rev. Cancer . , 12: 252-264).

目前，針對阻斷這一信號通路已有5個抗體藥物獲批上市，分別是MSD的Pembrolizumab(PD-1，2014)，BMS的Nivolumab(PD-1，2014)，羅氏的Atezolizumab(PD-L1，2016)，新基的Durvalumab(PD-L1，2017)和輝瑞的Avelumab(PD-L1，2017)。多項臨床研究證實這些抗體藥物在多種腫瘤中有效，如黑色素瘤、非小細胞肺癌、腎細胞癌、尿路上皮癌、宮頸癌、胃癌、頭頸癌、及霍奇金淋巴瘤等。 At present, five antibody drugs have been approved to block this signaling pathway, namely MSD's Pembrolizumab (PD-1, 2014), BMS's Nivolumab (PD-1, 2014), Roche's Atezolizumab (PD-L1). , 2016), Sunbase’s Durvalumab (PD-L1, 2017) and Pfizer’s Avelumab (PD-L1, 2017). A number of clinical studies have confirmed that these antibody drugs are effective in a variety of tumors, such as melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial cancer, cervical cancer, gastric cancer, head and neck cancer, and Hodgkin’s lymphoma.

與基於大分子的抗體的PD-1/PD-L1抑制劑相比，小分子的PD-1/PD-L1抑制劑目前還未得到人們的充分重視，還處於前期研發階段。Curis公司多肽類的PD-L1小分子抑制劑CA-170(WO2015033299)已進入臨床I期，BMS公開了多篇以苄基苯基醚類化合物為骨架的小分子PD-1/PD-L1抑制劑專利(WO2015034820，WO2017066227，WO2018009505)，廣州再極也公開了一篇芳香乙烯類小分子PD-1/PD-L1抑制劑專利(WO2018006795)。目前小分子PD-1/PD-L1抑制劑在效果、安全性、以及可選擇化合物等方面還遠未能滿足日益增加臨床的需要。 Compared with PD-1/PD-L1 inhibitors based on macromolecular antibodies, small-molecule PD-1/PD-L1 inhibitors have not yet received sufficient attention and are still in the early stage of development. Curis's polypeptide PD-L1 small molecule inhibitor CA-170 (WO2015033299) has entered clinical phase I. BMS has published many articles on small molecule PD-1/PD-L1 inhibition with benzyl phenyl ether compounds as the backbone Agent patents (WO2015034820, WO2017066227, WO2018009505), Guangzhou Zaiji also published a patent for aromatic vinyl small molecule PD-1/PD-L1 inhibitors (WO2018006795). At present, small molecule PD-1/PD-L1 inhibitors are far from meeting the increasing clinical needs in terms of efficacy, safety, and alternative compounds.

相較於生物大分子，小分子化合物具有可口服、給藥便利和明顯更低的價格等多種優勢，因此尋找小分子PD-1/PD-L1抑制劑具有重大的理論意義 和應用價值。 Compared with biological macromolecules, small molecule compounds have many advantages such as oral administration, convenient administration and significantly lower price, so it is of great theoretical significance to find small molecule PD-1/PD-L1 inhibitors And application value.

為了克服現有技術中的缺陷，本發明人進行了大量研究，通過大量篩選試驗後意外發現，具有以下式I的化合物具有出乎意料地好的PD-1和/或PD-L1抑制作用： In order to overcome the deficiencies in the prior art, the inventors conducted a lot of research and unexpectedly discovered through a large number of screening tests that the compound with the following formula I has unexpectedly good PD-1 and/or PD-L1 inhibitory effect:

Figure 108130887-A0202-12-0003-2
Figure 108130887-A0202-12-0003-2

本發明所述的式I化合物，可以選擇性地抑制PD-1和/或PD-L1，可用於治療和/或預防PD-1/PD-L1信號通路介導的疾病。這樣的疾病包括但不限於癌症、自身免疫性疾病、感染性疾病和敗血症。 The compound of formula I of the present invention can selectively inhibit PD-1 and/or PD-L1, and can be used to treat and/or prevent diseases mediated by PD-1/PD-L1 signaling pathway. Such diseases include but are not limited to cancer, autoimmune diseases, infectious diseases and sepsis.

基於上述發現，一方面，本發明提供了具有PD-1和/或PD-L1抑制活性的式I所示的聯苯類化合物。本發明所述的式I化合物包括其可藥用鹽。 Based on the above findings, in one aspect, the present invention provides a biphenyl compound represented by formula I having PD-1 and/or PD-L1 inhibitory activity. The compounds of formula I described in the present invention include their pharmaceutically acceptable salts.

在另一方面，本發明提供了製備本發明所述式I化合物的方法。 In another aspect, the present invention provides a method for preparing the compound of formula I of the present invention.

在另一方面，本發明還提供了本發明式I化合物在製備用作PD-1和/或PD-L1抑制劑的藥物中的應用。在又一方面，本發明還提供了本發明式I化合物在製備用於治療或預防癌症、自身免疫性疾病、感染性疾病等疾病的藥物中的應用。 In another aspect, the present invention also provides the use of the compound of formula I of the present invention in the preparation of drugs for PD-1 and/or PD-L1 inhibitors. In another aspect, the present invention also provides the application of the compound of formula I of the present invention in the preparation of medicines for treating or preventing cancer, autoimmune diseases, infectious diseases and other diseases.

在又一方面，本發明還提供了一種藥物組合物，其包含本發明所述的式I化合物(包括其可藥用鹽)以及任選的可藥用賦形劑或載體。 In another aspect, the present invention also provides a pharmaceutical composition comprising the compound of formula I (including pharmaceutically acceptable salts thereof) of the present invention and optional pharmaceutically acceptable excipients or carriers.

本發明所說的化合物，其化學結構如式I所示： The chemical structure of the compound of the present invention is shown in formula I:

Figure 108130887-A0202-12-0004-3
Figure 108130887-A0202-12-0004-3

包括其可藥用鹽， Including its pharmaceutically acceptable salts,

其中， among them,

R1選自氫、C1-C3烷基、CN、鹵素、C1-C3鹵代烷基； R 1 is selected from hydrogen, C 1 -C 3 alkyl, CN, halogen, C 1 -C 3 haloalkyl;

R2選自氫、C1-C3烷基、CN、鹵素、C1-C3烷氧基； R 2 is selected from hydrogen, C 1 -C 3 alkyl, CN, halogen, C 1 -C 3 alkoxy;

L為任選取代的C3-C6烯基，所述C3-C6烯基中的一個CH2任選地被-C(O)-、-S(O)-或-S(O)2-所替代； L is an optionally substituted C 3 -C 6 alkenyl group, one CH 2 of the C 3 -C 6 alkenyl group is optionally replaced by -C(O)-, -S(O)- or -S(O ) 2 -Replaced;

B為氫，或NR6R7，或任選取代的具有1到3個獨立地選自氮、氧或硫的雜原子的4元到7元飽和或部分不飽和雜環；其中 B is hydrogen, or NR 6 R 7 , or an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein

R6和R7獨立地為氫、C1-C3烷基、C1-C3鹵代烷基、羥基C1-C3烷基或羧基C1-C3烷基； R 6 and R 7 are independently hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxy C 1 -C 3 alkyl or carboxy C 1 -C 3 alkyl;

Z為氫、-CH3、-CH=CHAr或-OR8；其中 Z is hydrogen, -CH 3 , -CH=CHAr or -OR 8 ; where

R8選自氫、C3-C6烯基、鹵代C1-C4烷基、羥基C1-C4烷基、-(CH2)nX及-(CH2)nAr； R 8 is selected from hydrogen, C 3 -C 6 alkenyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, -(CH 2 ) n X and -(CH 2 ) n Ar;

n為1、2、3或4； n is 1, 2, 3 or 4;

X選自氫、-CH3、-CF3、C1-C4烷氧基、-N(CH3)2、任選經一個或兩個鹵素取代的C3-C6環烷基、-CN、-CO2Rg、-C(O)NH2、-C(O)N(CH3)2、

Figure 108130887-A0202-12-0004-4
、
Figure 108130887-A0202-12-0004-5
、
Figure 108130887-A0202-12-0004-6
、嗎啉基、四氫吡喃基、選經羥 基取代的吡咯烷酮基及任選經一個或兩個獨立選自以下的基團取代的呱啶基：C1-C4烷基、羧基、羥基及C1-C4烷氧基羰基； X is selected from hydrogen, -CH 3 , -CF 3 , C 1 -C 4 alkoxy, -N(CH 3 ) 2 , C 3 -C 6 cycloalkyl optionally substituted by one or two halogens,- CN, -CO 2 Rg, -C(O)NH 2 , -C(O)N(CH 3 ) 2 ,
Figure 108130887-A0202-12-0004-4
,
Figure 108130887-A0202-12-0004-5
,
Figure 108130887-A0202-12-0004-6
, Morpholinyl, tetrahydropyranyl, pyrrolidone optionally substituted by hydroxy and pyridinyl optionally substituted by one or two groups independently selected from the following: C 1 -C 4 alkyl, carboxy, hydroxy And C 1 -C 4 alkoxycarbonyl;

Rg選自氫及C1-C4烷基；及 Rg is selected from hydrogen and C 1 -C 4 alkyl; and

Ar選自苯並二噁烷基、吲唑基、異喹啉基、異噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基及喹啉基；其中各環任選經1、2、3或4個獨立選自以下的取代基取代：C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基氨基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷基磺醯基、甲醯氨基、甲醯氨基C1-C4烷基、-(CH2)qCO2-(C1-C4烷基)、-(CH2)qOH、羧基、氰基、甲醯基、鹵素、鹵代C1-C4烷基、鹵代C1-C4烷氧基、硝基、任選經一個氰基取代的苯基、任選經一個鹵素取代的苯基氧基、苯基羰基、吡咯、四氫吡喃及 Ar is selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridyl, pyrimidinyl and quinolinyl; wherein each ring is optional Substitution with 1, 2, 3 or 4 substituents independently selected from the following: C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkyl group, C 1 -C 4 alkylcarbonyl group, C 1 -C 4 alkyl sulfonyl group, formylamino group, formylamino group C 1 -C 4 alkyl group, -(CH 2 ) q CO 2- (C 1 -C 4 alkyl), -(CH 2 ) q OH, carboxyl, cyano, formyl, halogen, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, Nitro, phenyl optionally substituted with a cyano group, phenyloxy optionally substituted with a halogen, phenylcarbonyl, pyrrole, tetrahydropyran and

Figure 108130887-A0202-12-0005-7
Figure 108130887-A0202-12-0005-7

其中q為0、1、2、3或4且其中t、z及Rz如下定義： Where q is 0, 1, 2, 3 or 4 and where t, z and R z are defined as follows:

t為0、1、2、3或4； t is 0, 1, 2, 3 or 4;

z為1、2或3； z is 1, 2 or 3;

各Rz獨立選自C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基C1-C4烷基、C1-C4烷基、C1-C4烷基醯氨基、C1-C4烷基氨基、C1-C4烷基羰基、醯氨基、羧基、羧基C1-C4烷基、二(C1-C4烷基)醯氨基、二(C1-C4烷基)氨基、鹵素、鹵代C1-C4烷氧基、鹵代C1-C4烷基、羥基、羥基C1-C4烷基、嗎啉基、-NRcRd、(NRcRd)C1-C4烷基、-NReRf、(NReRf)C1-C4烷基、氧代、苯基及苯基C1-C4烷基，其中該苯基及該苯基C1-C4烷基的苯基部分任選經一個、兩個或三個獨立選自C1-C3烷基及鹵素的基團取代； Each R z is independently selected from C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 Alkylamino, C 1 -C 4 Alkylamino, C 1 -C 4 Alkylcarbonyl, Alkylamino, Carboxy, Carboxyl C 1 -C 4 Alkyl, Di (C 1 -C 4 Alkyl Yl)amino, di(C 1 -C 4 alkyl)amino, halogen, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkyl, hydroxy, hydroxy C 1 -C 4 alkyl , Morpholinyl, -NR c R d , (NR c R d )C 1 -C 4 alkyl, -NR e R f , (NR e R f )C 1 -C 4 alkyl, oxo, phenyl And a phenyl C 1 -C 4 alkyl group, wherein the phenyl group and the phenyl moiety of the phenyl C 1 -C 4 alkyl group are optionally selected from C 1 -C 3 alkyl groups via one, two or three And halogen group substitution;

Rc及Rd獨立選自氫、C2-C4烯基羰基、C1-C4烷氧基羰基、C1-C6烷基、C1-C4烷基羰基、醯氨基C1-C4烷基、氨基C1-C4烷基、芳基C1-C4烷基、C3-C10環烷基、(C3-C10環烷基)C1-C4烷基、鹵代C1-C4烷基羰基、雜環基C1-C4 烷基、雜環基C1-C4烷基羰基、羥基C1-C6烷基及羥基C1-C4烷基羰基，其中該醯氨基C1-C4烷基、該氨基C1-C4烷基、該芳基C1-C4烷基、該(C3-C10環烷基)C1-C4烷基、該雜環基C1-C4烷基及該雜環基C1-C4烷基羰基的烷基部分任選經一個或兩個獨立選自羧基及羥基的基團取代；其中該羥基C1-C4烷基及該羥基C1-C4烷基羰基的烷基部分任選經一個或兩個獨立選自羧基及羥基的基團取代；且其中該芳基C1-C4烷基的芳基部分、該C3-C10環烷基、該(C3-C10環烷基)C1-C4烷基的環烷基部分及該雜環基C1-C4烷基及該雜環基C1-C4烷基羰基的雜環基部分各任選經一個、兩個或三個獨立選自C1-C4烷氧基羰基、C1-C4烷基及鹵素的基團取代； R c and R d are independently selected from hydrogen, C 2 -C 4 alkenyl carbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl carbonyl, amino C 1 -C 4 alkyl, amino C 1 -C 4 alkyl, aryl C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, (C 3 -C 10 cycloalkyl) C 1 -C 4 alkane Group, halogenated C 1 -C 4 alkylcarbonyl, heterocyclic C 1 -C 4 alkyl, heterocyclic C 1 -C 4 alkylcarbonyl, hydroxy C 1 -C 6 alkyl and hydroxy C 1 -C 4 alkyl carbonyl group, wherein the acylamino C 1 -C 4 alkyl group, the amino C 1 -C 4 alkyl group, the aryl group C 1 -C 4 alkyl group, the (C 3 -C 10 cycloalkyl group) C The alkyl portion of the 1- C 4 alkyl group, the heterocyclic group C 1 -C 4 alkyl group, and the heterocyclic group C 1 -C 4 alkylcarbonyl group may optionally be through one or two groups independently selected from carboxy and hydroxy. Wherein the hydroxy C 1 -C 4 alkyl group and the alkyl portion of the hydroxy C 1 -C 4 alkylcarbonyl group are optionally substituted with one or two groups independently selected from carboxyl and hydroxy; and wherein the aryl The aryl part of the C 1 -C 4 alkyl group, the C 3 -C 10 cycloalkyl group, the cycloalkyl part of the (C 3 -C 10 cycloalkyl) C 1 -C 4 alkyl group, and the heterocyclic ring The C 1 -C 4 alkyl group and the heterocyclic moiety of the heterocyclic group C 1 -C 4 alkylcarbonyl group are each independently selected from C 1 -C 4 alkoxycarbonyl groups by one, two or three groups, C 1 -C 4 alkyl and halogen group substitution;

Re及Rf与其所连接的原子一起形成选自吗啉及

Figure 108130887-A0202-12-0006-8
的环； R e and R f together with the atoms to which they are connected are formed from morpholine and
Figure 108130887-A0202-12-0006-8
The ring

R3独立选自C2-C4烯基、C1-C4烷氧基、C1-C4烷基、氰基、卤素及卤代C1-C4烷基； R 3 is independently selected from C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyano, halogen and halogenated C 1 -C 4 alkyl;

m为0、1或2； m is 0, 1 or 2;

R4选自氢、C1-C4烷基、苄基、(C3-C6环烷基)C1-C3烷基、卤代C1-C4烷基、任选经第二个羟基取代的羟基C1-C6烷基及任选经氰基取代的吡啶基(C1-C3烷基)；及 R 4 is selected from hydrogen, C 1 -C 4 alkyl, benzyl, (C 3 -C 6 cycloalkyl) C 1 -C 3 alkyl, halogenated C 1 -C 4 alkyl, optionally with a second A hydroxy substituted hydroxy C1-C6 alkyl group and a pyridyl group (C 1 -C 3 alkyl group) optionally substituted with a cyano group; and

R5选自氢、C1-C4烷基、-(CH2)nN(CH3)2、羧基C2-C6烯基、羧基C1-C6烷基及羟基C1-C6烷基，其中该羧基C1-C6烷基及该羟基C1-C6烷基的烷基部分任选经一个羟基或苯基取代，其中该苯基进一步任选经羟基取代；或者，R5选自以下基团： R 5 is selected from hydrogen, C 1 -C 4 alkyl, -(CH 2 ) n N(CH 3 ) 2 , carboxy C 2 -C 6 alkenyl, carboxy C 1 -C 6 alkyl and hydroxyl C 1 -C 6 alkyl, wherein the carboxy C 1 -C 6 alkyl group and the alkyl portion of the hydroxy C 1 -C 6 alkyl group are optionally substituted with a hydroxy group or a phenyl group, wherein the phenyl group is further optionally substituted with a hydroxy group; or , R 5 is selected from the following groups:

Figure 108130887-A0202-12-0006-9
Figure 108130887-A0202-12-0006-9

Figure 108130887-A0202-12-0006-11
、
Figure 108130887-A0202-12-0006-12
、
Figure 108130887-A0202-12-0006-13
、
Figure 108130887-A0202-12-0006-15
、
Figure 108130887-A0202-12-0006-16
、
Figure 108130887-A0202-12-0006-17
，其中
Figure 108130887-A0202-12-0006-11
,
Figure 108130887-A0202-12-0006-12
,
Figure 108130887-A0202-12-0006-13
,
Figure 108130887-A0202-12-0006-15
,
Figure 108130887-A0202-12-0006-16
,
Figure 108130887-A0202-12-0006-17
,among them

Rw為-CONH2； R w is -CONH 2 ;

R10選自氫、苄基及甲基； R 10 is selected from hydrogen, benzyl and methyl;

各R10’獨立選自氫及C1-C3烷基； Each R 10' is independently selected from hydrogen and C 1 -C 3 alkyl;

R11選自氫、C1-C3烷基及苄基； R 11 is selected from hydrogen, C 1 -C 3 alkyl and benzyl;

R12選自C2-C4烯基及C1-C4烷基；及 R 12 is selected from C 2 -C 4 alkenyl and C 1 -C 4 alkyl; and

R50選自氫、C1-C6烷基及C1-C6烷氧基羰基； R 50 is selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxycarbonyl;

或 or

R4及R5與其所連接的氮原子一起形成選自以下的環： R 4 and R 5 together with the nitrogen atom to which they are attached form a ring selected from:

Figure 108130887-A0202-12-0007-18
和
Figure 108130887-A0202-12-0007-19
；其中
Figure 108130887-A0202-12-0007-18
with
Figure 108130887-A0202-12-0007-19
;among them

s為0、1或2； s is 0, 1 or 2;

z為1、2或3； z is 1, 2 or 3;

p為0，1或2； p is 0, 1 or 2;

R13及R13’獨立選自氫、羧基、羥基C1-C4烷基、氧代及- R 13 and R 13' are independently selected from hydrogen, carboxyl, hydroxy C 1 -C 4 alkyl, oxo and-

C(O)NHSO2R16； C(O)NHSO 2 R 16 ;

R14獨立選自氫、羥基C1-C4烷基、氧代及羧基； R 14 is independently selected from hydrogen, hydroxy C 1 -C 4 alkyl, oxo and carboxy;

各R15獨立選自C1-C4烷氧基羰基、C1-C6烷基、羧基、鹵素、羥基、羥基C1-C4烷基、-NRc’Rd’及苯基氧基羰基，其中該苯基任選經硝基取代，其中Rc’及Rd’獨立選自氫、C1-C4烷氧基羰基及C1-C4烷基羰基；及 Each R 15 is independently selected from C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, carboxy, halogen, hydroxy, hydroxy C 1 -C 4 alkyl, -NR c 'R d' and diphenyl oxide A carbonyl group, wherein the phenyl group is optionally substituted with a nitro group, wherein R c'and Rd' are independently selected from hydrogen, C 1 -C 4 alkoxycarbonyl and C 1 -C 4 alkylcarbonyl; and

R16選自三氟甲基、環丙基、C1-C4烷基、二甲基氨基及經甲基取代的咪唑基。 R 16 is selected from trifluoromethyl, cyclopropyl, C 1 -C 4 alkyl, dimethylamino and imidazolyl substituted by methyl.

對於上述式I所示化合物，優選地， For the compound represented by the above formula I, preferably,

R1和R2獨立地選自氫和C1-C3烷基； R 1 and R 2 are independently selected from hydrogen and C 1 -C 3 alkyl;

L為-CH2-CH=CH-或-CH2-CH2-CH=CH-，其中一個CH2任選地被-C(O)-、-S(O)-或-S(O)2-所替代，上述L定義中基團左側與式I結構中B基團相連； L is -CH 2 -CH=CH- or -CH 2 -CH 2 -CH=CH-, where one CH 2 is optionally -C(O)-, -S(O)- or -S(O) 2 -Instead, the left side of the group in the above definition of L is connected to the group B in the structure of formula I;

Z為甲基、-CH=CHAr或-O(CH2)nAr；其中 Z is methyl, -CH=CHAr or -O(CH 2 ) n Ar; where

n為1、2、3或4； n is 1, 2, 3 or 4;

Ar選自苯並二噁烷基、吲唑基、異喹啉基、異噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基及喹啉基；其中各環任選經1、2、3或4個獨立選自以下的取代基取代：C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基氨基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷基磺醯基、醯氨基、醯氨基C1-C4烷基、-(CH2)qCO2C1-C4烷基、-(CH2)qOH、羧基、氰基、甲醯基、鹵素、鹵代C1-C4烷基、鹵代C1-C4烷氧基、硝基、任選經一個氰基取代的苯基、任選經一個鹵素取代的苯基氧基、苯基羰基、吡咯、四氫吡喃，其中q為0、1、2、3或4； Ar is selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridyl, pyrimidinyl and quinolinyl; wherein each ring is optional Substitution with 1, 2, 3, or 4 substituents independently selected from the following: C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1- C 4 alkoxycarbonylamino, C 1 -C 4 alkyl group, C 1 -C 4 alkylcarbonyl group, C 1 -C 4 alkylsulfonyl group, acylamino group, acylamino group C 1 -C 4 alkyl group, -(CH 2 ) q CO 2 C 1- C 4 alkyl, -(CH 2 ) q OH, carboxyl, cyano, methanoyl, halogen, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, nitro, optional Phenyl substituted with a cyano group, phenyloxy optionally substituted with a halogen, phenylcarbonyl, pyrrole, tetrahydropyran, wherein q is 0, 1, 2, 3 or 4;

R3獨立選自C1-C4烷氧基和鹵素。對於上述式I所示化合物，較優選地， R 3 is independently selected from C 1 -C 4 alkoxy and halogen. For the compound represented by the above formula I, more preferably,

R1和R2獨立選自甲基及鹵素； R 1 and R 2 are independently selected from methyl and halogen;

Z為甲基、-CH=CHAr或-OCH2Ar；其中 Z is methyl, -CH=CHAr or -OCH 2 Ar;

Ar為任選經一個或兩個獨立選自以下的基團取代的吡啶基：C1-C4烷基、C1-C4烷基磺醯基、甲醯氨基、氰基及鹵素； Ar is pyridyl optionally substituted with one or two groups independently selected from: C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, methylamino, cyano and halogen;

R3為鹵素；且 R 3 is halogen; and

m為1。 m is 1.

本發明所述的“鹵素”為氟、氯、溴或碘。 The "halogen" in the present invention is fluorine, chlorine, bromine or iodine.

本發明所述的“烷基”，是指具有1至約20個碳原子、通常為1至12個碳原子、優選為1至8個、1至6個甚至更優選為1至4個碳原子的直鏈或支鏈或環狀的烷基。直鏈烷基的實例包括具有1至8個碳原子的那些，比如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基；支鏈烷基的實例包括但不限於異丙基、異丁基、仲丁基、叔丁基、新戊基、異戊基、異己基和2,2-二甲基丙基；環烷基的實例包括但不限於環丙基、環丁基、環戊基、 環己基、環庚基和環辛基。 The "alkyl" in the present invention refers to having 1 to about 20 carbon atoms, usually 1 to 12 carbon atoms, preferably 1 to 8, 1 to 6, even more preferably 1 to 4 carbon atoms A linear or branched or cyclic alkyl group of atoms. Examples of straight chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl; branched alkyl groups Examples include but are not limited to isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, isohexyl, and 2,2-dimethylpropyl; examples of cycloalkyl include but Not limited to cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl and cyclooctyl.

本發明所述的“鹵代烷基”包括單鹵代烷基和多鹵代烷基(其中所有鹵原子可以相同或不同)。部分鹵代的烷基是本文含義內的“鹵代烷基”。鹵代烷基的實例包括三氟甲基、1,1-二氯乙基、1,2-二氯乙基、1,3-二溴-3,3-二氟丙基等。 The "haloalkyl" in the present invention includes monohaloalkyl and polyhaloalkyl (wherein all halogen atoms may be the same or different). Partially halogenated alkyl is "haloalkyl" within the meaning herein. Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, and the like.

本發明所述的“烷氧基”，是指上述烷基與氧原子相連所形成的基團，其中，氧原子具有自由成鍵能力，如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、異丙氧基、特丁氧基、環丙氧基、環己基氧基等。 The "alkoxy group" in the present invention refers to the group formed by connecting the above-mentioned alkyl group with an oxygen atom, wherein the oxygen atom has the ability to form bonds freely, such as methoxy, ethoxy, propoxy, butyl Oxy, pentoxy, isopropoxy, t-butoxy, cyclopropoxy, cyclohexyloxy, etc.

本發明所述的“藥學上可接受的鹽”或“可藥用鹽”是指藥學上可接受的酸和堿加成鹽和溶劑化物。這類藥學上可接受的鹽包括與酸形成的鹽，所述酸包括鹽酸、磷酸、氫溴酸、硫酸、亞磺酸、甲酸、對甲苯磺酸、甲磺酸、硝酸、苯甲酸、檸檬酸、酒石酸、馬來酸、氫碘酸、鏈狀羧酸如乙酸、HOOC-(CH2)n-COOH(n=0-4)等；也包括與堿形成的鹽，這些鹽的陽離子包括鈉、鉀、鈣、銨離子等。 The "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" as used in the present invention refers to pharmaceutically acceptable acid and salt addition salts and solvates. Such pharmaceutically acceptable salts include salts formed with acids including hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, lemon Acid, tartaric acid, maleic acid, hydroiodic acid, chain carboxylic acids such as acetic acid, HOOC-(CH 2 ) n -COOH (n=0-4), etc.; also include salts formed with spores. The cations of these salts include Sodium, potassium, calcium, ammonium ions, etc.

本發明中，“取代的”指本文中所定義的有機基團(其中包含有與氫原子鍵合的一個或多個鍵)被一個或多個與非氫原子或原子團鍵合的鍵取代，所述非氫原子或原子團即為取代基。 In the present invention, "substituted" means that the organic group defined herein (which contains one or more bonds to hydrogen atoms) is replaced by one or more bonds to non-hydrogen atoms or atomic groups, The non-hydrogen atom or atomic group is a substituent.

本發明化合物的取代基包括例如鹵素、烷基(優選C1-8烷基、C1-6烷基或C1-4烷基)、烷氧基(優選C1-8烷氧基、C1-6烷氧基或C1-4烷氧基)、鹵代烷基(優選C1-8鹵代烷基、C1-6鹵代烷基或C1-4鹵代烷基)、鹵代烷氧基(優選C1-8鹵代烷氧基、C1-6鹵代烷氧基或C1-4鹵代烷氧基)、羥基、羥基烷基(優選羥基C1-8烷基、羥基C1-6烷基或羥基C1-4烷基)。 The substituents of the compounds of the present invention include, for example, halogen, alkyl (preferably C 1-8 alkyl, C 1-6 alkyl or C 1-4 alkyl), alkoxy (preferably C 1-8 alkoxy, C 1-6 alkoxy or C 1-4 alkoxy), haloalkyl (preferably C 1-8 haloalkyl, C 1-6 haloalkyl or C 1-4 haloalkyl), haloalkoxy (preferably C 1- 8 halogenated alkoxy, C 1-6 halogenated alkoxy or C 1-4 halogenated alkoxy), hydroxy, hydroxyalkyl (preferably hydroxy C 1-8 alkyl, hydroxy C 1-6 alkyl or hydroxy C 1-4 alkyl).

在另一方面，本發明提供了製備本發明式I化合物的方法：

Figure 108130887-A0305-02-0011-1
In another aspect, the present invention provides a method for preparing the compound of formula I of the present invention:
Figure 108130887-A0305-02-0011-1

包括使式A化合物

Figure 108130887-A0305-02-0012-2
Including making compounds of formula A
Figure 108130887-A0305-02-0012-2

與式F化合物

Figure 108130887-A0305-02-0012-3
Compound with formula F
Figure 108130887-A0305-02-0012-3

在有機溶劑和還原劑的作用下經還原胺化形成式I化合物，其中R1、R2、R3、R4、R5、L、B、Z和m如前面所定義。式F化合物可以為氨基酸或氨基醇或氨基酸的酯。當式F化合物為氨基酸的酯時，式A與式F化合物經還原胺化得到式I化合物的酯，經水解得到式I化合物。 Under the action of an organic solvent and a reducing agent, the compound of formula I is formed by reductive amination, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L, B, Z and m are as defined above. The compound of formula F may be an amino acid or an amino alcohol or an ester of an amino acid. When the compound of formula F is an ester of an amino acid, the compound of formula A and formula F are reductively aminated to obtain the ester of the compound of formula I, and the compound of formula I is obtained by hydrolysis.

上述還原胺化反應所用的還原劑可為硼氫化鈉(NaBH4)、氰基硼氫化鈉(NaBH3CN)及醋酸硼氫化鈉(NaBH3OAc)等；所用酸性催化劑可為醋酸、鹽酸、三氟醋酸；所用的鹼性催化劑可為TEA和DIPEA等；所用的乾燥劑可為無水硫酸鎂(MgSO4)、無水硫酸鈉(Na2SO4)及分子篩等；所用的溶劑可為CH3OH、CH2Cl2及1,2-二氯乙烷等。 The reducing agent used in the above reductive amination reaction can be sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium acetate borohydride (NaBH 3 OAc), etc.; the acid catalyst used can be acetic acid, hydrochloric acid, Trifluoroacetic acid; the basic catalyst used can be TEA, DIPEA, etc.; the desiccant used can be anhydrous magnesium sulfate (MgSO 4 ), anhydrous sodium sulfate (Na 2 SO 4 ), molecular sieve, etc.; the solvent used can be CH 3 OH, CH 2 Cl 2 and 1,2-dichloroethane, etc.

特別地，本發明還提供了所述式A化合物作為用於製備本發明所述式I化合物的中間體的用途。 In particular, the present invention also provides the use of the compound of formula A as an intermediate for preparing the compound of formula I of the present invention.

式A化合物的製備 Preparation of compound of formula A

此外，本發明進一步提供了製備上述式A化合物的方法，包括兩種方案：方案一包括以下步驟(a)-(c)： In addition, the present invention further provides a method for preparing the compound of formula A, which includes two schemes: Scheme one includes the following steps (a)-(c):

(a)在堿的作用下，化合物1與化合物2進行親核取代反應得到化合物3； (a) Under the action of the compound, compound 1 and compound 2 undergo a nucleophilic substitution reaction to obtain compound 3;

Figure 108130887-A0202-12-0011-24
Figure 108130887-A0202-12-0011-24

(b)在鈀催化作用下，化合物3與化合物4進行鈴木交叉偶聯得到化合物5； (b) Suzuki cross-coupling compound 3 and compound 4 under palladium catalysis to obtain compound 5;

Figure 108130887-A0202-12-0011-25
Figure 108130887-A0202-12-0011-25

(c)化合物5在鹼性條件下轉變為化合物6，接下去與化合物7在鹼性條件下發生酚的O-烴化反應得到化合物A； (c) Compound 5 is transformed into compound 6 under alkaline conditions, and then undergoes O-alkylation of phenol with compound 7 under alkaline conditions to obtain compound A;

Figure 108130887-A0202-12-0011-26
Figure 108130887-A0202-12-0011-26

上述親核取代反應(a)以NaOH、Na2CO3、K2CO3等堿為去酸劑，反應溫度為25~140℃，反應時間為2~72小時。反應所用溶劑為常用溶劑，如水、甲醇、乙醇、乙腈、苯、二甲苯、丙酮、N,N'-二甲基甲醯胺、DMSO等。 The above-mentioned nucleophilic substitution reaction (a) uses NaOH, Na2CO 3 , K 2 CO 3 and the like as deacidification agents, the reaction temperature is 25-140°C, and the reaction time is 2-72 hours. The solvent used in the reaction is a common solvent, such as water, methanol, ethanol, acetonitrile, benzene, xylene, acetone, N,N'-dimethylformamide, DMSO, etc.

上述鈴木交叉偶聯反應(b)以鈀為催化劑，如Pd(PPh3)4、Pd(dffp)Cl2、Pd(OAc)2、Pd(dba)3/PCy3、PdCl2、Pd(PPh3)4Cl2等。或者以Ni為催化劑，如 NiCl2(dffp)、NiCl2(dffp)/Zn、NiCl2(dffp)/BuLi、NiCl2(PPh3)2/PPh3、NiCl2(NEt3)2、NiCl2(NEt3)2、NiCl(bipy)、Ni(TPPS)3、Ni(COD)2、NiCl2(PPh3)2/n-BuLi、Ni{P(OMe)3}2Cl2、NiCl2(PCy3)2等。反應優選在堿存在下進行，所述堿例如為KOAc、K3PO4、K2CO3、NaOH、Ba(OH)2、Na2CO3、CsF或NaHCO3等。反應溫度為25到140℃，反應時間為4~72小時。反應所用溶劑為常用溶劑，如乙醇、THF、異丙醇、DMSO、DMF、二氧六環、甲苯、水和DME等。 The above Suzuki cross-coupling reaction (b) uses palladium as a catalyst, such as Pd(PPh 3 ) 4 , Pd(dffp)Cl 2 , Pd(OAc) 2 , Pd(dba) 3 /PCy 3 , PdCl 2 , Pd(PPh 3 ) 4 Cl 2 etc. Or use Ni as a catalyst, such as NiCl 2 (dffp), NiCl 2 (dffp)/Zn, NiCl 2 (dffp)/BuLi, NiCl 2 (PPh 3 ) 2 /PPh 3 , NiCl 2 (NEt 3 ) 2 , NiCl 2 (NEt 3 ) 2 , NiCl(bipy), Ni(TPPS) 3 , Ni(COD) 2 , NiCl 2 (PPh 3 ) 2 /n-BuLi, Ni{P(OMe) 3 } 2 Cl 2 , NiCl 2 ( PCy 3 ) 2 etc. The reaction is preferably carried out in the presence of a salt, such as KOAc, K 3 PO 4 , K 2 CO 3 , NaOH, Ba(OH) 2 , Na 2 CO 3 , CsF, or NaHCO 3 . The reaction temperature is 25 to 140°C, and the reaction time is 4 to 72 hours. The solvent used in the reaction is a common solvent, such as ethanol, THF, isopropanol, DMSO, DMF, dioxane, toluene, water and DME.

上述反應(c)第一步將羥基轉變為好的離去基團，如-OMs、-OTs或溴，以三乙胺、DIPEA有機堿為去酸劑，反應溫度為0~90℃，反應時間為2~72小時。反應所用溶劑為常用溶劑，如水、甲醇、乙醇、異丙醇、四氫呋喃、二氯甲烷、丙酮等；第二步酚的O-烴化反應以NaOH、K2CO3、KOH等堿為去酸劑，反應溫度為0~90℃，反應時間為2~72小時。反應所用溶劑為常用溶劑，如水、甲醇、乙醇、異丙醇、丙酮、DMF、DMSO、苯或二甲苯等；【0048】式B化合物可由市場上直接購得。 The first step of the above reaction (c) converts the hydroxyl group into a good leaving group, such as -OMs, -OTs or bromine, using triethylamine and DIPEA as the deacidification agent, and the reaction temperature is 0~90℃. The time is 2 to 72 hours. The solvent used in the reaction is a common solvent, such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, acetone, etc.; in the second step of the O-alkylation reaction of phenol, NaOH, K 2 CO 3 , KOH, etc. are used as deacidification The reaction temperature is 0~90℃, and the reaction time is 2~72 hours. The solvent used in the reaction is a common solvent, such as water, methanol, ethanol, isopropanol, acetone, DMF, DMSO, benzene or xylene; [0048] The compound of formula B can be directly purchased on the market.

方案二包括以下步驟(d)-(e)： Scheme 2 includes the following steps (d)-(e):

(d)在PPh3和DIAD作用下，化合物4與化合物7通過Mitsunobu反應轉化為化合物8； (d) Under the action of PPh 3 and DIAD, compound 4 and compound 7 are converted into compound 8 by Mitsunobu reaction;

Figure 108130887-A0202-12-0012-27
Figure 108130887-A0202-12-0012-27

(e)在鈀催化作用下，化合物8與化合物3進行鈴木交叉偶聯得到化合 (e) Under the catalysis of palladium, compound 8 and compound 3 undergo Suzuki cross-coupling to obtain a compound

Figure 108130887-A0202-12-0012-29
物A；
Figure 108130887-A0202-12-0012-29
物A;

上述Mitsunobu反應(d)可以以nBu3P、PPh3、DIAD或DEAD作為活化試劑，反應溫度為-78℃到室溫，反應時間為2~72小時。反應所用溶劑可以為常用低極性溶劑，如THF、***、二氯甲烷、甲苯、乙酸乙酯、乙腈、 DMF等。 The Mitsunobu reaction (d) can use nBu 3 P, PPh 3 , DIAD or DEAD as an activating reagent, the reaction temperature is -78° C. to room temperature, and the reaction time is 2 to 72 hours. The solvent used in the reaction can be a common low-polarity solvent, such as THF, ether, dichloromethane, toluene, ethyl acetate, acetonitrile, DMF, and the like.

上述鈴木交叉偶聯反應(e)可以以鈀為催化劑，如Pd(PPh3)4、Pd(dffp)Cl2、Pd(OAc)2、Pd(dba)3/PCy3、PdCl2、Pd(PPh3)4Cl2等，或者以Ni為催化劑，如NiCl2(dffp)、NiCl2(dffp)/Zn、NiCl2(dffp)/BuLi、NiCl2(PPh3)2/PPh3、NiCl2(NEt3)2、NiCl2(NEt3)2、NiCl(bipy)、Ni(TPPS)3、Ni(COD)2、NiCl2(PPh3)2/n-BuLi、Ni{P(OMe)3}2Cl2、NiCl2(PCy3)2等。反應可以在堿存在下進行，所述堿例如KOAc、K3PO4、K2CO3、NaOH、Ba(OH)2、Na2CO3、CsF或NaHCO3等，反應溫度為25到140℃，反應時間為4~72小時。反應所用溶劑可以為常用溶劑，如乙醇、THF、異丙醇、DMSO、DMF、二氧六環、甲苯、水和DME等。 The above-mentioned Suzuki cross-coupling reaction (e) may use palladium as a catalyst, such as Pd(PPh 3 ) 4 , Pd(dffp)Cl 2 , Pd(OAc) 2 , Pd(dba) 3 /PCy 3 , PdCl 2 , Pd( PPh 3 ) 4 Cl 2 etc., or Ni as a catalyst, such as NiCl 2 (dffp), NiCl 2 (dffp)/Zn, NiCl 2 (dffp)/BuLi, NiCl 2 (PPh 3 ) 2 /PPh 3 , NiCl 2 (NEt 3 ) 2 , NiCl 2 (NEt 3 ) 2 , NiCl(bipy), Ni(TPPS) 3 , Ni(COD) 2 , NiCl 2 (PPh 3 ) 2 /n-BuLi, Ni(P(OMe) 3 } 2 Cl 2 , NiCl 2 (PCy 3 ) 2 and so on. The reaction can be carried out in the presence of a salt, such as KOAc, K 3 PO 4 , K 2 CO 3 , NaOH, Ba(OH) 2 , Na 2 CO 3 , CsF or NaHCO 3, etc. The reaction temperature is 25 to 140° C. The reaction time is 4~72 hours. The solvent used in the reaction can be a common solvent, such as ethanol, THF, isopropanol, DMSO, DMF, dioxane, toluene, water, DME and the like.

式I化合物可以採用常見的分離方法進行純化，如萃取、重結晶、柱層析等。按照上述說明方法，本發明製備了示例性的式I化合物(見表1)。 The compound of formula I can be purified by common separation methods, such as extraction, recrystallization, column chromatography and the like. According to the method described above, the present invention Exemplary compounds of formula I (see Table 1) were prepared.

Figure 108130887-A0202-12-0013-30
Figure 108130887-A0202-12-0013-30

Figure 108130887-A0202-12-0014-31
Figure 108130887-A0202-12-0014-31

Figure 108130887-A0202-12-0015-32
Figure 108130887-A0202-12-0015-32

Figure 108130887-A0202-12-0016-33
Figure 108130887-A0202-12-0016-33

Figure 108130887-A0202-12-0017-34
Figure 108130887-A0202-12-0017-34

Figure 108130887-A0202-12-0018-35
Figure 108130887-A0202-12-0018-35

下面結合具體實例進一步闡述本發明內容，但本發明的保護範圍並不僅僅局限於這些實例。本發明所述的百分比除特別注明外，均為重量百分比。說明書中所描述的數值範圍，如計量單位、反應條件、化合物物理狀態或百分比，均是為了提供明白無誤的書面參考。本領域技術人員在實施本發明時，使用在此範圍之外或有別於單個數值的溫度、濃度、數量、碳原子數等，仍然有可能得到預期結果。 The content of the present invention is further described below in conjunction with specific examples, but the protection scope of the present invention is not limited to these examples. Unless otherwise specified, the percentages in the present invention are all weight percentages. The numerical ranges described in the specification, such as the unit of measurement, reaction conditions, physical state of the compound, or percentage, are all intended to provide an unmistakable written reference. When those skilled in the art implement the present invention, it is still possible to obtain the expected result by using temperature, concentration, number, number of carbon atoms, etc. outside this range or different from a single value.

實施例中所使用的試劑縮寫所代表的完整名稱如下： The complete names of the reagent abbreviations used in the examples are as follows:

PdCl2(dppf) 1,1'-雙二苯基膦二茂鐵二氯化鈀 PdCl 2 (dppf) 1,1'-bisdiphenylphosphine ferrocene palladium dichloride

PdCl2(dppf)CH2Cl 1,1'-雙二苯基膦二茂鐵二氯化鈀二氯甲烷絡合物 PdCl 2 (dppf)CH 2 Cl 1,1'-bisdiphenylphosphinoferrocene dichloride palladium dichloromethane complex

DIAD 偶氮二甲酸二異丙酯 DIAD diisopropyl azodicarboxylate

Ph3P 三苯基膦 Ph 3 P Triphenylphosphine

B2(pin)2 雙聯頻哪醇硼酸酯 B 2 (pin) 2 double pinacol borate

DIBAL-H 二異丁基氫化鋁 DIBAL-H Diisobutyl aluminum hydride

TEA 三乙胺 TEA triethylamine

MsCl 甲基磺醯氯 MsCl Methanesulfonyl chloride

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

THF 四氫呋喃 THF Tetrahydrofuran

EA 乙酸乙酯 EA ethyl acetate

PE 石油醚 PE petroleum ether

DCM 二氯甲烷 DCM Dichloromethane

實施例1 Example 1

(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯的製備 (E) Preparation of 1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene

Figure 108130887-A0202-12-0019-36
Figure 108130887-A0202-12-0019-36

將環丙基溴化鎂(91mL,45.45mmol,0.5M/L in THF)在氮氣保護0℃條件下緩慢滴加進3-溴-2-甲基苯甲醛(3g,15.15mmol)的THF溶液(70mL)中。在室溫攪拌2h後，加入磷酸二乙酯(2.51g,18.18mmol)。混合物繼續在室溫下攪拌24h。然後用1N的HCl溶液(150mL)淬滅反應液。用乙酸乙酯(100mL)萃取三次，然後用無水Na2SO4乾燥有機相。去除溶劑，殘留物用矽膠柱(PE/EA=100/1)純化，得到淺黃色油狀物(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(1.585g,5.21mmol,35%收率)。 Cyclopropylmagnesium bromide (91mL, 45.45mmol, 0.5M/L in THF) was slowly added dropwise into the THF solution of 3-bromo-2-methylbenzaldehyde (3g, 15.15mmol) under nitrogen protection at 0°C (70mL). After stirring for 2 h at room temperature, diethyl phosphate (2.51 g, 18.18 mmol) was added. The mixture continued to stir at room temperature for 24h. Then the reaction solution was quenched with 1N HCl solution (150 mL). It was extracted three times with ethyl acetate (100 mL), and then the organic phase was dried with anhydrous Na 2 SO 4 . The solvent was removed, and the residue was purified with a silica gel column (PE/EA=100/1) to obtain a pale yellow oil (E)-1-bromo-3-(4-bromobut-1-en-1-yl)- 2-methylbenzene (1.585g, 5.21mmol, 35% yield).

1H NMR(400MHz,CDCl3)：δ 7.45(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.70(d,J=15.6Hz,1H),5.98(dt,J=15.6Hz,6.8Hz,1H),3.49(t,J=6.8Hz,2H),2.83-2.76(m,2H),2.42(s,3H). 1 H NMR(400MHz,CDCl 3 ): δ 7.45(d, J =8.0Hz,1H), 7.31(d, J =8.0Hz,1H), 7.00(t, J =7.6Hz,1H), 6.70(d , J =15.6Hz,1H), 5.98(dt, J =15.6Hz,6.8Hz,1H), 3.49(t, J =6.8Hz,2H), 2.83-2.76(m,2H),2.42(s,3H) ).

實施例2 Example 2

(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-3,3-二氟吡咯烷的制備 (E)-1-(4-(3-Bromo-2-methylphenyl)but-3-en-1-yl)-3,3-difluoropyrrolidine

Figure 108130887-A0202-12-0019-37
Figure 108130887-A0202-12-0019-37

將(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(1.48g,4.92mmol),3,3-二氟吡咯烷鹽酸鹽(1.41g,9.84mmol)和三乙胺(1.49g,14.76mmol)溶於1,4-二氧六環(20mL)，加熱至100℃，反應18h。將反應液濃縮得到粗品，用矽膠柱層析純化(PE/EA=100/1 to 20/1)，得到黃褐色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-3,3-二氟吡咯烷(810mg,2.46mmol,50%收率)。 (E)-1-Bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (1.48g, 4.92mmol), 3,3-difluoropyrrolidine hydrochloride (1.41g, 9.84mmol) and triethylamine (1.49g, 14.76mmol) were dissolved in 1,4-dioxane (20mL), heated to 100°C, and reacted for 18h. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=100/1 to 20/1) to obtain a yellow-brown oil (E)-1-(4-(3-bromo-2-methyl) (Phenyl)but-3-en-1-yl)-3,3-difluoropyrrolidine (810 mg, 2.46 mmol, 50% yield).

1H NMR(400MHz,CDCl3)：δ 7.42(d,J=8.0Hz,1H),7.29(d,J=7.6 Hz,1H),6.98(t,J=8.0Hz,1H),6.70(d,J=15.6Hz,1H),6.01(dt,J=15.2Hz,6.8Hz,1H),2.93(t,J=13.6Hz,2H),2.76(t,J=7.2Hz,2H),2.61(t,J=7.2Hz,2H),2.45-2.37(m,5H),2.33-2.21(m,2H)； 1H NMR(400MHz,CDCl 3 ): δ 7.42(d, J =8.0Hz,1H), 7.29(d, J =7.6 Hz,1H), 6.98(t, J =8.0Hz,1H), 6.70(d, J = 15.6Hz, 1H), 6.01(dt, J = 15.2Hz, 6.8Hz, 1H), 2.93(t, J = 13.6Hz, 2H), 2.76(t, J = 7.2Hz, 2H), 2.61(t , J =7.2Hz,2H),2.45-2.37(m,5H),2.33-2.21(m,2H);

MS Calcd：329；MS Found：329.9([M+H]+). MS Calcd: 329; MS Found: 329.9([M+H] + ).

實施例3 Example 3

(E)-(3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲醇的製備 (E)-(3'-(4-(3,3-Difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1' -Diphenyl]-3-yl)methanol

Figure 108130887-A0202-12-0020-38
Figure 108130887-A0202-12-0020-38

將(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-3,3-二氟吡咯烷(762mg,2.32mmol),(2-甲基-3-硼酸頻那醇酯苯基)甲醇(660mg,2.67mmol)，PdCl2(dppf)(189mg,0.23mmol)和K2CO3(640mg,4.64mmol)於氮氣保護下溶於1,4-二氧六環(9mL)和水(3mL)的混合溶劑，80℃下攪拌4h。將反應液濃縮得到粗品，用矽膠柱層析純化(PE/EA=20/1 to 10/1)，得到黃色油狀物(E)-(3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲醇(1.05g，粗品)。 (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)-3,3-difluoropyrrolidine (762mg, 2.32mmol), (2 -Methyl-3-boronic acid pinacol ester phenyl)methanol (660mg, 2.67mmol), PdCl 2 (dppf) (189mg, 0.23mmol) and K 2 CO 3 (640mg, 4.64mmol) dissolved in nitrogen The mixed solvent of 1,4-dioxane (9mL) and water (3mL) was stirred at 80°C for 4h. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=20/1 to 10/1) to obtain a yellow oil (E)-(3'-(4-(3,3-difluoro) Pyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methanol (1.05 g, crude).

1H NMR(400MHz,CDCl3)：δ 7.43-7.35(m,2H),7.25-7.15(m,2H),7.06(d,J=6.8Hz,1H),6.98(d,J=6.4Hz,1H),6.70(d,J=15.6Hz,1H),6.10(dt,J=15.6Hz,6.8Hz,1H),4.76(d,J=2.8Hz,2H),2.95(t,J=13.2Hz,2H),2.78(t,J=6.8Hz,2H),2.63(t,J=7.2Hz,2H),2.47-2.40(m,2H),2.33-2.22(m,2H),2.03(s,3H),1.99(s,3H)； 1H NMR (400MHz, CDCl 3 ): δ 7.43-7.35 (m, 2H), 7.25-7.15 (m, 2H), 7.06 (d, J = 6.8Hz, 1H), 6.98 (d, J = 6.4Hz, 1H ), 6.70(d, J =15.6Hz,1H), 6.10(dt, J =15.6Hz,6.8Hz,1H), 4.76(d, J =2.8Hz,2H), 2.95(t, J =13.2Hz, 2H), 2.78(t, J =6.8Hz,2H), 2.63(t, J =7.2Hz,2H), 2.47-2.40(m,2H),2.33-2.22(m,2H),2.03(s,3H) ),1.99(s,3H);

MS Calcd：371；MS Found：371.9([M+H]+). MS Calcd: 371; MS Found: 371.9([M+H] + ).

實施例4 Example 4

(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl -[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0021-39
Figure 108130887-A0202-12-0021-39

將甲磺醯氯(357mg,3.12mmol)在0℃下加入(E)-(3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲醇(580mg,1.56mmol)和三乙胺(473mg,4.68mmol)溶於10ml二氯甲烷的溶液中。反應液在室溫下攪拌4h，然後加入50mL飽和氯化銨水溶液。該溶液用二氯甲烷(50mL)萃取三遍，合併的有機相用無水Na2SO4乾燥，然後過濾。濾液減壓濃縮得到粗品(E)-(3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲磺酸甲酯，無需純化，直接用於下一步。 Add methanesulfonyl chloride (357mg, 3.12mmol) to (E)-(3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl) at 0℃ )-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methanol (580mg, 1.56mmol) and triethylamine (473mg, 4.68mmol) dissolved in 10ml of dichloromethane In solution. The reaction solution was stirred at room temperature for 4 hours, and then 50 mL of saturated aqueous ammonium chloride was added. The solution was extracted three times with dichloromethane (50 mL), and the combined organic phase was dried with anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure to obtain crude product (E)-(3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl -[1,1'-Diphenyl]-3-yl)methyl methanesulfonate, used directly in the next step without purification.

(E)-(3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲磺酸甲酯(700mg,1.56mmol)，5-氯-4-羥基-2-甲基苯甲醛(240mg,1.42mmol)和K2CO3(392mg,2.84mmol)溶於DMF(5mL)的混合溶液在60℃下攪拌16h。加入50mL飽和氯化銨水溶液。該溶液用EA(50mL)萃取三遍，合併的有機相用無水Na2SO4乾燥，然後過濾。濾液減壓濃縮，矽膠柱層析純化(PE/EA=15/1 to 10/1)得到黃色固體(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(480mg,0.91mmol，兩步收率59%)。 (E)-(3'-(4-(3,3-Difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1' -Diphenyl)-3-yl)methyl methanesulfonate (700mg, 1.56mmol), 5-chloro-4-hydroxy-2-methylbenzaldehyde (240mg, 1.42mmol) and K 2 CO 3 (392mg, A mixed solution of 2.84 mmol) dissolved in DMF (5 mL) was stirred at 60°C for 16 h. Add 50 mL of saturated aqueous ammonium chloride solution. The solution was extracted three times with EA (50 mL), and the combined organic phase was dried with anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=15/1 to 10/1) to obtain a yellow solid (E)-5-chloro-4-((3'-(4-(3,3-二) (Fluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2- Methylbenzaldehyde (480mg, 0.91mmol, two-step yield 59%).

1H NMR(400MHz,CDCl3)：δ 10.10(s,1H),7.84(s,1H),7.49(d,J=7.6Hz,1H),7.42(d,J=7.2Hz,1H),7.30-7.26(m,1H),7.22-7.12(m,2H),7.02(d,J=7.6Hz,1H),6.88(s,1H),6.72(d,J=15.6Hz,1H),6.11(dt,J=15.6Hz,6.8Hz,1H),5.23(s,2H),2.95(t,J=13.2Hz,2H),2.78(t,J=7.2Hz,2H),2.67-2.61(m,5H),2.48-2.41(m,2H),2.34-2.22(m,2H),2.07(s,3H),2.01(s,3H)；MS Calcd：323；MS Found：323.8([M+H]+). 1H NMR (400MHz, CDCl 3 ): δ 10.10 (s, 1H), 7.84 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.30- 7.26(m,1H),7.22-7.12(m,2H),7.02(d, J =7.6Hz,1H),6.88(s,1H),6.72(d, J =15.6Hz,1H),6.11(dt , J =15.6Hz,6.8Hz,1H),5.23(s,2H),2.95(t, J =13.2Hz,2H),2.78(t, J =7.2Hz,2H),2.67-2.61(m,5H ),2.48-2.41(m,2H),2.34-2.22(m,2H),2.07(s,3H),2.01(s,3H); MS Calcd: 323; MS Found: 323.8([M+H] + ).

實施例5 Example 5

(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 (S,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2, Preparation of 2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0022-40
Figure 108130887-A0202-12-0022-40

將(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(393mg,0.75mmol)和(S)-呱啶-2-羧酸(194mg,1.50mmol)溶於二氯甲烷(3mL)中於室溫下攪拌4h。然後在0℃下加入甲醇(5mL)和氰基硼氫化鈉(94mg,1.50mmol)。反應液在室溫下攪拌16h。將1N鹽酸水溶液緩慢加入反應液，調節反應液pH值到大約5，然後用二氯甲烷稀釋(40mL)。混合液用水(40mL)洗一次，有機相用無水Na2SO4乾燥，然後過濾。濾液減壓濃縮得到殘留物，用C18柱(with 10%-95% ACN in water)純化得到白色固體(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(167.9mg,0.26mmol,35%收率) (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (393mg, 0.75mmol) and (S)-piperidine-2-carboxylic acid (194mg, 1.50mmol) was dissolved in dichloromethane (3mL) and stirred at room temperature for 4h. Then methanol (5 mL) and sodium cyanoborohydride (94 mg, 1.50 mmol) were added at 0°C. The reaction solution was stirred at room temperature for 16h. A 1N aqueous hydrochloric acid solution was slowly added to the reaction solution, the pH of the reaction solution was adjusted to about 5, and then it was diluted with dichloromethane (40 mL). The mixed solution was washed once with water (40 mL), and the organic phase was dried over anhydrous Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified with a C18 column (with 10%-95% ACN in water) to obtain a white solid (S,E)-1-(5-chloro-4-((3'-(4-( 3,3-Difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy (Phenyl)-2-methylbenzyl)piperidine-2-carboxylic acid (167.9mg, 0.26mmol, 35% yield)

1H NMR(400MHz,CDCl3)：δ 7.49-7.38(m,3H),7.24-7.14(m,2H),7.08(d,J=7.6Hz,1H),6.98(d,J=7.2Hz,1H),6.76(s,1H),6.70(d,J=16.0Hz,1H),6.10(dt,J=15.2Hz,6.8Hz,1H),5.02(s,2H),4.36-4.20(m,1H),4.05-3.84(m,1H),3.74-3.59(m,1H),3.30-3.15(m,2H),2.94(t,J=13.2Hz,2H),2.78(t,J=6.8Hz,2H),2.63(t,J=7.2Hz,2H),2.47-2.391(m,2H),2.36-2.22(m,5H),2.11-1.85(m,8H),1.80-1.56(m,3H),1.40-1.28(m,1H)；MS Calcd：636；MS Found：637.0([M+H]+). 1 H NMR (400MHz, CDCl 3 ): δ 7.49-7.38 (m, 3H), 7.24-7.14 (m, 2H), 7.08 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.76(s, 1H), 6.70(d, J =16.0Hz,1H), 6.10(dt, J =15.2Hz,6.8Hz,1H),5.02(s,2H),4.36-4.20(m, 1H),4.05-3.84(m,1H),3.74-3.59(m,1H),3.30-3.15(m,2H),2.94(t, J =13.2Hz,2H),2.78(t, J =6.8Hz ,2H),2.63(t, J =7.2Hz,2H),2.47-2.391(m,2H),2.36-2.22(m,5H),2.11-1.85(m,8H),1.80-1.56(m,3H) ),1.40-1.28(m,1H); MS Calcd: 636; MS Found: 637.0([M+H] + ).

實施例6 Example 6

(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶的製備 (E)-1-(4-(3-Bromo-2-methylphenyl)but-3-en-1-yl)piperidine

Figure 108130887-A0202-12-0022-41
Figure 108130887-A0202-12-0022-41

將(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(300mg,0.993mmol)，呱啶 (255mg,3.000mmol)溶於DMF(10mL)中，加入K2CO3(556mg,4.000mmol)，在室溫下攪拌18h。反應用水淬滅，用乙酸乙酯萃取3次，合併有機相，用飽和食鹽水洗3次，無水Na2SO4乾燥，濃縮。粗品用矽膠柱層析純化(先用EA，再用DCM/MeOH=10/1洗脫)得黃色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶(167mg,54%收率)。 (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (300mg, 0.993mmol), piperidine (255mg, 3.000mmol) were dissolved in DMF( 10mL), K 2 CO 3 (556 mg, 4.000 mmol) was added, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water, extracted with ethyl acetate 3 times, the organic phases were combined, washed 3 times with saturated brine, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (first eluted with EA, then DCM/MeOH=10/1) to obtain a yellow oil (E)-1-(4-(3-bromo-2-methylphenyl) But-3-en-1-yl)piperidine (167 mg, 54% yield).

LC-MS(m/z)：308(M+1)。 LC-MS (m/z): 308 (M+1).

實施例7 Example 7

2-甲基-3-(羥甲基)苯硼酸頻哪醇酯的製備 Preparation of 2-methyl-3-(hydroxymethyl)phenylboronic acid pinacol ester

Figure 108130887-A0202-12-0023-42
Figure 108130887-A0202-12-0023-42

將3-溴-2-甲基苯甲醇(5.9g,29.500mmol)，雙聯頻哪醇硼酸酯(9.74g,38.346mmol),Pd(dppf)Cl2 CH2Cl2(1.68g,2.059mmol),KOAc(8.67g,88.469mmol)和1,4-二氧六環(70mL)的混合物在氮氣保護下加熱到80℃並攪拌5h。將反應液濃縮得到粗品，用矽膠柱層析純化(PE/EA=10/1 to 5/1)，再用石油醚打漿洗1次得到白色固體2-甲基-3-(羥甲基)苯硼酸頻哪醇酯(5.08g,20.484mmol,69%收率)。 Combine 3-bromo-2-methylbenzyl alcohol (5.9g, 29.500mmol), double pinacol borate (9.74g, 38.346mmol), Pd(dppf)Cl 2 CH 2 Cl 2 (1.68g, 2.059 mmol), a mixture of KOAc (8.67g, 88.469mmol) and 1,4-dioxane (70mL) was heated to 80°C and stirred for 5h under the protection of nitrogen. The reaction solution was concentrated to obtain a crude product, purified by silica gel column chromatography (PE/EA=10/1 to 5/1), and then beaten and washed with petroleum ether to obtain a white solid 2-methyl-3-(hydroxymethyl) Pinacol phenylboronic acid (5.08 g, 20.484 mmol, 69% yield).

LC-MS(m/z)：231(M-OH)。 LC-MS (m/z): 231 (M-OH).

實施例8 Example 8

5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛的製備 Preparation of 5-chloro-2-methyl-4-((2-methyl-3-boronic acid pinacol ester benzyl)oxy)benzaldehyde

Figure 108130887-A0202-12-0023-43
Figure 108130887-A0202-12-0023-43

將3-溴-2-甲基苯甲醇(10.450g,42.137mmol)，5-氯-4-羥基-2-甲基-苯甲醛(7.163g,42.137mmol)，PPh3(13.248g,50.564mmol)溶於超幹四氫呋喃(120mL)中，在氮氣保護下用冰/鹽浴冷卻至-7℃，緩慢滴加DIAD(10.214g,50.564mmol)。所得黃色溶液在室溫下攪拌3h，TLC(PE/EA=4/1)監控反應。反應用水淬滅，用乙酸乙酯萃取3次，合併有機相，濃縮，粗品用矽膠柱層析純化 (PE/EA=10/1 to 5/1)，再用石油醚打漿洗1次得到白色固體5-氯-2-甲基-4-[2-甲基-3-硼酸頻那醇酯苄氧基]-苯甲醛(16.38g,40.950mmol,97%)。 Combine 3-bromo-2-methylbenzyl alcohol (10.450g, 42.137mmol), 5-chloro-4-hydroxy-2-methyl-benzaldehyde (7.163g, 42.137mmol), PPh3 (13.248g, 50.564mmol) Dissolve in ultra-dry tetrahydrofuran (120mL), cool to -7°C with an ice/salt bath under nitrogen protection, and slowly add DIAD (10.214g, 50.564mmol) dropwise. The resulting yellow solution was stirred at room temperature for 3 h, and the reaction was monitored by TLC (PE/EA=4/1). The reaction was quenched with water, extracted with ethyl acetate 3 times, the organic phases were combined, concentrated, and the crude product was purified by silica gel column chromatography (PE/EA=10/1 to 5/1), then beating and washing with petroleum ether once to obtain white solid 5-chloro-2-methyl-4-[2-methyl-3-boronic acid pinacol ester benzyl Oxy]-benzaldehyde (16.38 g, 40.950 mmol, 97%).

LC-MS(m/z)：401(M+1)。 LC-MS (m/z): 401 (M+1).

實施例9 Example 9

(E)-5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((3'-(4-(pyridin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1 '-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0024-44
Figure 108130887-A0202-12-0024-44

將(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶(167mg,0.5440mmol)，5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(261mg,0.653mmol)，Pd(PPh3)4(94.3mg,0.0816mmol)，K2CO3(227mg,1.632mmol)，1,4-二氧六環(10.0mL)和H2O(2.0mL)的混合液在氮氣保護下加熱至100℃並攪拌3h，TLC(EA)監控反應。將反應液濃縮得到粗品，用矽膠柱層析純化(EA)得類白色固體(E)-5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(262mg,0.523mmol,96%)。 Add (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)piperidine (167mg, 0.5440mmol), 5-chloro-2-methyl- 4-((2-Methyl-3-boronic acid pinacol ester benzyl)oxy)benzaldehyde (261mg, 0.653mmol), Pd(PPh 3 ) 4 (94.3mg, 0.0816mmol), K 2 CO 3 (227mg , 1.632 mmol), 1,4-dioxane (10.0 mL) and H 2 O (2.0 mL) were heated to 100° C. and stirred for 3 h under the protection of nitrogen. The reaction was monitored by TLC (EA). The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (EA) to obtain an off-white solid (E)-5-chloro-4-((3'-(4-(piridin-1-yl)butan-1-yl) (En-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (262mg, 0.523mmol, 96% ).

LC-MS(m/z)：502(M+1)。 LC-MS (m/z): 502 (M+1).

實施例10 Example 10

(S,E)-1-(5-氯-4-((2,2’-二甲基-3’-(4-(呱啶-1-基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(4-(piridin-1-yl)but-1-en-1-yl) -[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0024-45
Figure 108130887-A0202-12-0024-45

將(E)-5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(262mg,0.523mmol)，L-呱啶-2-甲酸(236.1mg,1.831mmol)溶於DCM/MeOH(6mL/6mL)中，加入HOAc(10滴)，在室溫下攪拌18h，加入NaBH3CN(197.7mg,3.138mmol)，繼續攪拌2h。濃縮反應 液。粗品先用矽膠柱(DCM/MeOH=6/1,3/1)，再用製備薄層色譜版(DCM/MeOH=4/1)純化得白色固體(S,E)-1-(5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(21.0mg,0.0342mmol,6.5%)。 Put (E)-5-chloro-4-((3'-(4-(pyridin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1, 1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (262mg, 0.523mmol), L-piperidine-2-carboxylic acid (236.1mg, 1.831mmol) dissolved in DCM/MeOH (6mL/6mL), add HOAc (10 drops), stir at room temperature for 18h, add NaBH3CN (197.7mg, 3.138mmol), continue to stir for 2h. Concentration reaction liquid. The crude product was first purified with a silica gel column (DCM/MeOH=6/1,3/1) and then purified with a preparative thin layer chromatography (DCM/MeOH=4/1) to obtain a white solid (S,E)-1-(5- Chloro-4-((3'-(4-(pyridin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl] -3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (21.0 mg, 0.0342 mmol, 6.5%).

1H NMR(400MHz,DMSO-d 6)δ 7.51(d,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),7.33(s,1H),7.29(t,J=7.6Hz,1H),7.24(t,J=7.6Hz,1H),7.15(s,1H),7.07(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.82(d,J=16.0Hz,1H),6.12(dt,J=16.0,6.8Hz,1H),5.21(s,2H),3.75(d,J=13.2Hz,1H),3.40(d,J=13.2Hz,1H),3.15-2.92(m,4H),2.86-2.79(m,2H),2.59(d,J=7.6Hz,2H),2.31(s,3H),2.29-2.19(m,1H),2.01(s,3H),1.97(s,3H),1.72-1.69(m,7H),1.47-1.39(m,7H). 1 H NMR(400MHz,DMSO- d 6 )δ 7.51(d,J=7.6Hz,1H), 7.47(d,J=7.6Hz,1H), 7.33(s,1H), 7.29(t,J=7.6 Hz,1H), 7.24(t,J=7.6Hz,1H), 7.15(s,1H), 7.07(d,J=7.6Hz,1H), 7.00(d,J=7.6Hz,1H), 6.82( d,J=16.0Hz,1H),6.12(dt,J=16.0,6.8Hz,1H),5.21(s,2H),3.75(d,J=13.2Hz,1H), 3.40(d,J=13.2 Hz, 1H), 3.15-2.92 (m, 4H), 2.86-2.79 (m, 2H), 2.59 (d, J=7.6Hz, 2H), 2.31 (s, 3H), 2.29-2.19 (m, 1H) ,2.01(s,3H),1.97(s,3H),1.72-1.69(m,7H),1.47-1.39(m,7H).

LC-MS(m/z)：615(M+1)。 LC-MS (m/z): 615 (M+1).

實施例11 Example 11

(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)吡咯烷的製備 (E)-1-(4-(3-Bromo-2-methylphenyl)but-3-en-1-yl)pyrrolidine

Figure 108130887-A0202-12-0025-47
Figure 108130887-A0202-12-0025-47

黃色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)吡咯(172mg,0.587mmol,59%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(300mg,0.993mmol)和四氫吡咯烷(255mg,3.000mmol)按照實施例6中的類似步驟製備而成。 Yellow oil (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)pyrrole (172mg, 0.587mmol, 59%) is made of (E) -1-Bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (300mg, 0.993mmol) and tetrahydropyrrolidine (255mg, 3.000mmol) were in accordance with Example 6 Prepared by similar steps.

LC-MS(m/z)：294(M+1)。 LC-MS (m/z): 294 (M+1).

實施例12 Example 12

(E)-5-氯-4-((2,2’-二甲基-3’-(4-(吡咯-1-基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((2,2'-dimethyl-3'-(4-(pyrrol-1-yl)but-1-en-1-yl)-[1,1' -Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0025-49
Figure 108130887-A0202-12-0025-49

淺黃色固體(E)-5-氯-4-((3’-(4-(吡咯-1-基)丁-1-烯-1-基)-2,2’-二甲基- [1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(227mg,0.466mmol,79%)是由5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(235mg,0.587mmol)按照實施例9中的類似步驟製備而成。 Light yellow solid (E)-5-chloro-4-((3’-(4-(pyrrol-1-yl)but-1-en-1-yl)-2,2’-dimethyl- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (227mg, 0.466mmol, 79%) is composed of 5-chloro-2-methyl-4-(( 2-Methyl-3-boronic acid pinacol ester benzyl)oxy)benzaldehyde (235mg, 0.587mmol) was prepared according to the similar procedure in Example 9.

LC-MS(m/z)：488(M+1)。 LC-MS (m/z): 488 (M+1).

實施例13 Example 13

(S,E)-1-(5-氯-4-((2,2’-二甲基-3’-(4-(吡咯-1-基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(4-(pyrrol-1-yl)but-1-en-1-yl)- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0026-51
Figure 108130887-A0202-12-0026-51

(S,E)-1-(5-氯-4-((3’-(4-(吡咯-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(15.2mg,0.0253mmol,5.4%)是由(E)-5-氯-4-((3’-(4-(吡咯-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(227mg,0.466mmol)和L-呱啶-2-甲酸(210.4mg,1.631mmol)按照實施例10中的類似步驟製備而成。 (S,E)-1-(5-chloro-4-((3'-(4-(pyrrol-1-yl)but-1-en-1-yl)-2,2'-dimethyl- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (15.2mg, 0.0253mmol, 5.4%) is made of (E)- 5-chloro-4-((3'-(4-(pyrrol-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl ]-3-yl)methoxy)-2-methylbenzaldehyde (227mg, 0.466mmol) and L-piperidine-2-carboxylic acid (210.4mg, 1.631mmol) were prepared according to the similar steps in Example 10. .

1H NMR(400MHz,DMSO-d6)δ 7.50(dd,J=13.5,7.7Hz,2H),7.33(s,1H),7.29(t,J=7.5Hz,1H),7.23(t,J=7.6Hz,1H),7.15(s,1H),7.07(d,J=7.5Hz,1H),6.98(d,J=7.4Hz,1H),6.77(d,J=15.6Hz,1H),6.18(dt,J=14.9,6.8Hz,1H),5.21(s,2H),3.75(d,J=13.5Hz,1H),3.40(d,J=13.4Hz,1H),3.11(t,J=5.7Hz,1H),2.96(s,br,4H),2.87-2.79(m,1H),2.63-2.53(m,2H),2.32(s,3H),2.28-2.18(m,1H),2.01(s,3H),1.96(s,3H),1.91-1.80(m,4H),1.79-1.70(m,2H),1.57-1.33(m,4H),1.32-1.17(m,1H),0.90-0.79(m,1H).【0091】LC-MS(m/z)：601(M+1)。 1 H NMR(400MHz,DMSO-d6)δ 7.50(dd, J =13.5,7.7Hz,2H), 7.33(s,1H), 7.29(t, J =7.5Hz,1H), 7.23(t, J = 7.6Hz,1H), 7.15(s,1H), 7.07(d, J =7.5Hz,1H), 6.98(d, J =7.4Hz,1H), 6.77(d, J =15.6Hz,1H), 6.18 (dt, J =14.9,6.8Hz,1H),5.21(s,2H),3.75(d, J =13.5Hz,1H), 3.40(d, J =13.4Hz,1H),3.11(t, J = 5.7Hz, 1H), 2.96 (s, br, 4H), 2.87-2.79 (m, 1H), 2.63-2.53 (m, 2H), 2.32 (s, 3H), 2.28-2.18 (m, 1H), 2.01 (s,3H),1.96(s,3H),1.91-1.80(m,4H),1.79-1.70(m,2H),1.57-1.33(m,4H),1.32-1.17(m,1H),0.90 -0.79 (m, 1H). [0091] LC-MS (m/z): 601 (M+1).

實施例14 Example 14

(E)-4-(3-溴-2-甲基苯基)-N,N-二甲基丁-3-烯-1-胺的製備 Preparation of (E)-4-(3-bromo-2-methylphenyl) -N,N -dimethylbut-3-en-1-amine

Figure 108130887-A0202-12-0026-52
Figure 108130887-A0202-12-0026-52

黃色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)二甲胺(670mg,2.509mmol,76%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(1.0g,3.311mmol)和二甲胺鹽酸鹽(536.4mg,6.622mmol)按照實施例6中的類似步驟製備而成。 The yellow oil (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)dimethylamine (670mg, 2.509mmol, 76%) is made of ( E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (1.0g, 3.311mmol) and dimethylamine hydrochloride (536.4mg, 6.622mmol) Prepared according to the similar steps in Example 6.

LC-MS(m/z)：268(M+1)。 LC-MS (m/z): 268 (M+1).

實施例15 Example 15

(E)-5-氯-4-((3’-(4-(二甲胺)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((3'-(4-(dimethylamine)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-bis (Phenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0027-53
Figure 108130887-A0202-12-0027-53

淺黃色固體(E)-5-氯-4-((3’-(4-(二甲胺-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(1.12g,2.430mmol,97%)是由(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)二甲胺(670mg,2.509mmol)和5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(1.004g,2.509mmol)按照實施例9中的類似步驟製備而成。 Light yellow solid (E)-5-chloro-4-((3'-(4-(dimethylamino-1-yl)but-1-en-1-yl)-2,2'-dimethyl- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (1.12g, 2.430mmol, 97%) is composed of (E)-1-(4-(3- Bromo-2-methylphenyl)but-3-en-1-yl)dimethylamine (670mg, 2.509mmol) and 5-chloro-2-methyl-4-((2-methyl-3-boronic acid Pinacol ester benzyl)oxy)benzaldehyde (1.004g, 2.509mmol) was prepared according to the similar procedure in Example 9.

LC-MS(m/z)：462(M+1)。 LC-MS (m/z): 462 (M+1).

實施例16 Example 16

(S,E)-1-(5-氯-4-((3’-(4-(二甲胺)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((3'-(4-(dimethylamine)but-1-en-1-yl)-2,2'-dimethyl-[1 ,1'-Diphenyl)-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0027-55
Figure 108130887-A0202-12-0027-55

白色固體(S,E)-1-(5-氯-4-((3’-(4-(二甲胺-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(185.0mg,0.322mmol,13%yield)是由(E)-5-氯-4-((3’-(4-(二甲胺-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(1.12g,2.430mmol)和L-呱啶-2-甲酸(1.097g,8.505mmol)按照實施例10中的類似步驟製備而成。 White solid (S,E)-1-(5-chloro-4-((3'-(4-(dimethylamino-1-yl)but-1-en-1-yl)-2,2'- Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (185.0mg, 0.322mmol, 13% yield) is From (E)-5-chloro-4-((3'-(4-(dimethylamino-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1 ,1'-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde (1.12g, 2.430mmol) and L-piperidine-2-carboxylic acid (1.097g, 8.505mmol) according to the example Prepared by similar steps in 10.

1H NMR(400MHz,DMSO-d6)δ 7.50(d,J=7.6Hz,1H),7.44(d,J=7.8Hz,1H),7.32(s,1H),7.27(t,J=7.6Hz,1H),7.20(t,J=7.6Hz,1H),7.14(s,1H),7.10-7.03(m,1H),6.99-6.92(m,1H),6.72(d,J=15.7Hz,1H),6.15(dt,J=15.6,6.8Hz,1H),5.20(s,2H),3.74(d,J=13.4Hz,1H),3.09(t,J=5.8Hz,1H),2.83(dd,J=11.3,5.4Hz,1H),2.55-2.44(m,3H),2.44-2.34(m,2H),2.31(s,3H),2.28-2.13(m,6H),2.00(s,3H),1.95(s,3H),1.79-1.70(m,2H),1.58-1.29(m,5H). 1 H NMR(400MHz,DMSO-d6)δ 7.50(d, J =7.6Hz,1H), 7.44(d, J =7.8Hz,1H), 7.32(s,1H), 7.27(t, J =7.6Hz ,1H),7.20(t, J =7.6Hz,1H),7.14(s,1H),7.10-7.03(m,1H),6.99-6.92(m,1H),6.72(d, J =15.7Hz, 1H), 6.15(dt, J =15.6,6.8Hz,1H), 5.20(s,2H), 3.74(d, J =13.4Hz,1H), 3.09(t, J =5.8Hz,1H), 2.83( dd, J =11.3,5.4Hz,1H),2.55-2.44(m,3H),2.44-2.34(m,2H),2.31(s,3H),2.28-2.13(m,6H),2.00(s, 3H), 1.95 (s, 3H), 1.79-1.70 (m, 2H), 1.58-1.29 (m, 5H).

LC-MS(m/z)：575(M+1)。 LC-MS (m/z): 575 (M+1).

實施例17 Example 17

(E)-4-(3-溴-2-甲基苯基)-N,N-二乙基丁-3-烯-1-胺的製備 Preparation of (E)-4-(3-bromo-2-methylphenyl) -N,N -diethylbut-3-en-1-amine

Figure 108130887-A0202-12-0028-56
Figure 108130887-A0202-12-0028-56

黃色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)二乙胺(685.0mg,2.322mmol,70%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(1.0g,3.311mmol)和二乙胺(483.4mg,6.622mmol)按照實施例6中的類似步驟製備而成。 The yellow oil (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)diethylamine (685.0mg, 2.322mmol, 70%) is made of (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (1.0g, 3.311mmol) and diethylamine (483.4mg, 6.622mmol) as implemented Prepared in a similar procedure in Example 6.

LC-MS(m/z)：296(M+1)。 LC-MS (m/z): 296 (M+1).

實施例18 Example 18

(E)-5-氯-4-((3’-(4-(二乙胺)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((3'-(4-(diethylamine)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-bis (Phenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0028-57
Figure 108130887-A0202-12-0028-57

淺黃色固體(E)-5-氯-4-((3’-(4-(二乙胺-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(807mg,1.650mmol,71%)是由(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)二乙胺(685.0mg,2.322mmol)和5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(928.8mg,2.322mmol)按照實施例9中的類似步驟製備而成。 Light yellow solid (E)-5-chloro-4-((3'-(4-(diethylamine-1-yl)but-1-en-1-yl)-2,2'-dimethyl- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (807mg, 1.650mmol, 71%) is composed of (E)-1-(4-(3-bromo -2-methylphenyl)but-3-en-1-yl)diethylamine (685.0mg, 2.322mmol) and 5-chloro-2-methyl-4-((2-methyl-3-boronic acid Pinacol ester (benzyl)oxy)benzaldehyde (928.8mg, 2.322mmol) was prepared according to the similar procedure in Example 9.

LC-MS(m/z)：490(M+1)。 LC-MS (m/z): 490 (M+1).

實施例19 Example 19

(S,E)-1-(5-氯-4-((3’-(4-(二乙胺)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((3'-(4-(diethylamine)but-1-en-1-yl)-2,2'-dimethyl-[1 ,1'-Diphenyl)-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0029-58
Figure 108130887-A0202-12-0029-58

白色固體(S,E)-1-(5-氯-4-((3’-(4-(二乙胺-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(178.0mg,0.296mmol,36%yield)是由(E)-5-氯-4-((3’-(4-(二乙胺-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(400mg,0.818mmol)和L-呱啶-2-甲酸(369.3mg,2.863mmol)按照實施例10中的類似步驟製備而成。 White solid (S,E)-1-(5-chloro-4-((3'-(4-(diethylamine-1-yl)but-1-en-1-yl)-2,2'- Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (178.0mg, 0.296mmol, 36% yield) is From (E)-5-chloro-4-((3'-(4-(diethylamine-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1 ,1'-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde (400mg, 0.818mmol) and L-piperidine-2-carboxylic acid (369.3mg, 2.863mmol) according to Example 10. Prepared by similar steps in.

1H NMR(400MHz,DMSO-d 6)δ 7.49(dd,J=18.2,7.7Hz,2H),7.33(s,1H),7.29(t,J=7.6Hz,1H),7.24(t,J=7.6Hz,1H),7.15(s,1H),7.07(d,J=7.5Hz,1H),6.99(d,J=7.4Hz,1H),6.82(d,J=15.7Hz,1H),6.15(dt,J=14.9,6.9Hz,1H),5.21(s,2H),3.75(d,J=13.4Hz,1H),3.40(d,J=13.4Hz,1H),3.12(t,J=5.9Hz,1H),2.87-2.78(m,1H),2.59-2.52(m,4H),2.31(s,3H),2.27-2.19(m,1H),2.01(s,3H),1.97(s,3H),1.82-1.67(m,3H),1.56-1.33(m,6H),1.24(s,1H),1.16(t,J=7.2Hz,6H). 1 H NMR(400MHz,DMSO- d 6 )δ 7.49(dd, J =18.2,7.7Hz,2H),7.33(s,1H),7.29(t, J =7.6Hz,1H),7.24(t, J =7.6Hz,1H),7.15(s,1H),7.07(d, J =7.5Hz,1H), 6.99(d, J =7.4Hz,1H), 6.82(d, J =15.7Hz,1H), 6.15(dt, J =14.9,6.9Hz,1H), 5.21(s,2H), 3.75(d, J =13.4Hz,1H), 3.40(d, J =13.4Hz,1H), 3.12(t, J =5.9Hz, 1H), 2.87-2.78 (m, 1H), 2.59-2.52 (m, 4H), 2.31 (s, 3H), 2.27-2.19 (m, 1H), 2.01 (s, 3H), 1.97 ( s, 3H), 1.82-1.67 (m, 3H), 1.56-1.33 (m, 6H), 1.24 (s, 1H), 1.16 (t, J = 7.2Hz, 6H).

LC-MS(m/z)：603(M+1)。 LC-MS (m/z): 603 (M+1).

實施例20 Example 20

(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)嗎啉的製備 Preparation of (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)morpholine

Figure 108130887-A0202-12-0029-59
Figure 108130887-A0202-12-0029-59

黃色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)嗎啉(736mg,2.382mmol,72%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(1.0g,3.311mmol)和嗎啉(576.1mg,6.622mmol)按照實施例6中的類似步驟製備而成。 Yellow oil (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)morpholine (736mg, 2.382mmol, 72%) is made of (E )-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (1.0g, 3.311mmol) and morpholine (576.1mg, 6.622mmol) in accordance with Example 6 Prepared by similar steps.

LC-MS(m/z)：310(M+1)。 LC-MS (m/z): 310 (M+1).

實施例21 Example 21

(E)-5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-diphenyl] -3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0030-60
Figure 108130887-A0202-12-0030-60

淺黃色固體(E)-5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(1.114g,2.215mmol,93%)是由(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)嗎啉(736mg,2.382mmol)和5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(952.8mg,2.382mmol)按照實施例9中的類似步驟製備而成。 Light yellow solid (E)-5-chloro-4-((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[ 1,1'-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde (1.114g, 2.215mmol, 93%) is composed of (E)-1-(4-(3-bromo -2-methylphenyl)but-3-en-1-yl)morpholine (736mg, 2.382mmol) and 5-chloro-2-methyl-4-((2-methyl-3-boronic acid pina The alcohol ester benzyl)oxy)benzaldehyde (952.8mg, 2.382mmol) was prepared according to the similar procedure in Example 9.

LC-MS(m/z)：504(M+1)。 LC-MS (m/z): 504 (M+1).

實施例22 Example 22

(S,E)-1-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1' -Diphenyl)-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0030-61
Figure 108130887-A0202-12-0030-61

白色固體(S,E)-1-(5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(91.0mg,0.148mmol,6.7%yield)是由(E)-5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(1.114g,2.215mmol)和L-呱啶-2-甲酸(1.0g,7.752mmol)按照實施例10中的類似步驟製備而成。 White solid (S,E)-1-(5-chloro-4-((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (91.0mg, 0.148mmol, 6.7% yield) is made of (E)-5-chloro-4-((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1 '-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde (1.114g, 2.215mmol) and L-piperidine-2-carboxylic acid (1.0g, 7.752mmol) in accordance with Example 10 Prepared by similar steps.

1H NMR(400MHz,DMSO-d 6)δ 7.51(d,J=7.6Hz,1H),7.43(d,J=7.7Hz,1H),7.32(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.8Hz,1H),7.15(s,1H),7.07(d,J=7.4Hz,1H),6.96(d,J=7.6Hz,1H),6.72(d,J=15.7Hz,1H),6.16(dt,J=15.5,6.6Hz,1H),5.20(s,2H),3.88-3.81(m,1H),3.73(d,J=13.4Hz,1H),3.58(t,J=4.6Hz,3H),3.38(d,J=13.4Hz,1H),3.10(t,J=5.7Hz,1H),3.05(t,J=4.8Hz,1H),2.86-2.78(m,1H),2.48-2.35(m,7H),2.31(s,3H),2.27-2.14(m,1H),2.01(s,3H),1.95(s,3H),1.81-1.66(m,3H),1.55-1.32(m,5H). 1 H NMR(400MHz,DMSO- d 6 )δ 7.51(d, J =7.6Hz,1H), 7.43(d, J =7.7Hz,1H), 7.32(s,1H), 7.28(t, J =7.6 Hz,1H), 7.21(t, J =7.8Hz,1H), 7.15(s,1H), 7.07(d, J =7.4Hz,1H), 6.96(d, J =7.6Hz,1H), 6.72( d, J =15.7Hz,1H), 6.16(dt, J =15.5,6.6Hz,1H), 5.20(s,2H), 3.88-3.81(m,1H), 3.73(d, J =13.4Hz,1H) ),3.58(t, J =4.6Hz,3H),3.38(d, J =13.4Hz,1H),3.10(t, J =5.7Hz,1H),3.05(t, J =4.8Hz,1H), 2.86-2.78 (m, 1H), 2.48-2.35 (m, 7H), 2.31 (s, 3H), 2.27-2.14 (m, 1H), 2.01 (s, 3H), 1.95 (s, 3H), 1.81- 1.66 (m, 3H), 1.55-1.32 (m, 5H).

LC-MS(m/z)：617(M+1)。 LC-MS (m/z): 617 (M+1).

實施例23 Example 23

(E)-((5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氮亞烷基)二甲醇的製備 (E)-((5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'- Preparation of dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)azaalkylene)dimethanol

Figure 108130887-A0202-12-0031-62
Figure 108130887-A0202-12-0031-62

將(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(105.0mg,0.201mmol)，絲氨醇(64.0mg,0.703mmol)，二氯甲烷(10.0mL)，甲醇(2.0mL)和三乙胺(1.0mL)的混合溶液於室溫下攪拌18h。然後加入NaBH3CN(76.0mg,1.206mmol)，繼續攪拌2h。用水淬滅反應，用二氯甲烷萃取2次，合併有機相，無水Na2SO4乾燥，濃縮。粗品用製備薄層色譜板純化(DCM/MeOH=12/1)得白色固體(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)絲氨醇(22.0mg,0.0368mmol,18%收率)。 (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (105.0mg, 0.201mmol), serinol (64.0mg, 0.703mmol), dichloro A mixed solution of methane (10.0 mL), methanol (2.0 mL) and triethylamine (1.0 mL) was stirred at room temperature for 18 h. Then NaBH 3 CN (76.0 mg, 1.206 mmol) was added, and stirring was continued for 2 h. The reaction was quenched with water, extracted with dichloromethane twice, the organic phases were combined, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified with preparative thin-layer chromatography (DCM/MeOH=12/1) to obtain a white solid (S, E)-1-(5-chloro-4-((3'-(4-(3,3-difluoro) (Pyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methyl Benzyl) serinol (22.0 mg, 0.0368 mmol, 18% yield).

1H NMR(400MHz,DMSO-d 6)δ 7.50(d,J=7.6Hz,1H),7.43(d,J=7.6Hz,1H),7.39(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.15(s,1H),7.07(d,J=7.6Hz,1H),6.96(d,J=7.6Hz,1H),6.73(d,J=15.6Hz,1H),6.15 (dt,J=15.6,6.8Hz,1H),5.20(s,2H),4.47(s,2H),3.69(s,2H),3.46-3.36(m,4H),2.91(t,J=13.6Hz,2H),2.73(t,J=6.8Hz,2H),2.59(t,J=7.2Hz,2H),2.39(q,J=7.2Hz,2H),2.30(s,3H),2.27-2.17(m,2H),2.01(s,3H),1.95(s,3H). 1 H NMR(400MHz,DMSO- d 6 )δ 7.50(d, J =7.6Hz,1H), 7.43(d, J =7.6Hz,1H), 7.39(s,1H), 7.28(t, J =7.6 Hz,1H), 7.21(t, J =7.6Hz,1H), 7.15(s,1H), 7.07(d, J =7.6Hz,1H), 6.96(d, J =7.6Hz,1H), 6.73( d, J =15.6Hz,1H),6.15 (dt, J =15.6,6.8Hz,1H),5.20(s,2H),4.47(s,2H),3.69(s,2H),3.46-3.36(m ,4H),2.91(t, J =13.6Hz,2H), 2.73(t, J =6.8Hz,2H), 2.59(t, J =7.2Hz,2H),2.39(q, J =7.2Hz,2H ), 2.30 (s, 3H), 2.27-2.17 (m, 2H), 2.01 (s, 3H), 1.95 (s, 3H).

LC-MS(m/z)：585(M+1)。 LC-MS (m/z): 585 (M+1).

實施例24 Example 24

(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸甲酯的製備 (S,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2, Preparation of 2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)glycine methyl ester

Figure 108130887-A0202-12-0032-63
Figure 108130887-A0202-12-0032-63

淺黃色固體(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸甲酯(166mg,0.278mmol,69%yield)是由(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(210.0mg,0.402mmol)和甘氨酸甲酯鹽酸鹽(175mg,1.400mmol)按照實施例23中的類似步驟製備而成。 Light yellow solid (S,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl) -2,2'-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)glycine methyl ester (166mg, 0.278mmol, 69% yield) It is composed of (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'- Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (210.0mg, 0.402mmol) and glycine methyl ester hydrochloride (175mg, 1.400mmol) Prepared according to the similar steps in Example 23.

LC-MS(m/z)：597(M+1)。 LC-MS (m/z): 597 (M+1).

實施例25 Example 25

(E)-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸的製備 (E)-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Preparation of methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)glycine

Figure 108130887-A0202-12-0032-65
Figure 108130887-A0202-12-0032-65

將(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸甲酯(166mg,0.278mmol)溶於四氫呋喃(10.0mL)和水(2.0mL)中，加入LiOH．H2O(200mg,4.762mmol)，在室溫下攪拌18h，TLC(EA)監控反應。濃縮反應液，加水(15.0mL)稀釋，用1N 稀鹽酸調pH至4-5，過濾收集固體，烘乾得白色固體(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸(85.0mg,0.146mmol,52%收率)。 (S,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2 ,2'-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)glycine methyl ester (166mg, 0.278mmol) dissolved in tetrahydrofuran (10.0mL ) And water (2.0mL), add LiOH. H 2 O (200 mg, 4.762 mmol) was stirred at room temperature for 18 h, and the reaction was monitored by TLC (EA). Concentrate the reaction solution, dilute with water (15.0mL), adjust the pH to 4-5 with 1N dilute hydrochloric acid, collect the solid by filtration, and dry to obtain a white solid (S,E)-1-(5-chloro-4-((3'-(4-(3,3-Difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3 -Yl)methoxy)-2-methylbenzyl)glycine (85.0 mg, 0.146 mmol, 52% yield).

1H NMR(400MHz,DMSO-d 6)δ 7.63(s,1H),7.51(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.32-7.20(m,3H),7.08(d,J=7.6Hz,1H),6.98(d,J=7.6Hz,1H),6.78(d,J=15.6Hz,1H),6.16(dt,J=15.6,6.8Hz,1H),5.26(s,2H),4.11(s,2H),3.90(s,2H),3.46-3.22(m,4H),3.03(s,2H),2.59-2.54(m,2H),2.46-2.42(m,2H),2.41(s,3H),2.01(s,3H),1.96(s,3H). 1 H NMR (400MHz, DMSO- d 6 ) δ 7.63 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.32-7.20 (m, 3H) ), 7.08(d, J =7.6Hz,1H), 6.98(d, J =7.6Hz,1H), 6.78(d, J =15.6Hz,1H), 6.16(dt, J =15.6,6.8Hz,1H ), 5.26 (s, 2H), 4.11 (s, 2H), 3.90 (s, 2H), 3.46-3.22 (m, 4H), 3.03 (s, 2H), 2.59-2.54 (m, 2H), 2.46 2.42(m, 2H), 2.41(s, 3H), 2.01(s, 3H), 1.96(s, 3H).

LC-MS(m/z)：583(M+1)。 LC-MS (m/z): 583 (M+1).

實施例26 Example 26

(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)L-絲氨酸苄酯的製備 (S,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2, Preparation of 2'-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)L-serine benzyl ester

Figure 108130887-A0202-12-0033-66
Figure 108130887-A0202-12-0033-66

淺黃色固體(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)L-絲氨酸苄酯(103mg,0.147mmol,70%yield)是由(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(110.0mg,0.210mmol)和L-絲氨酸苄酯鹽酸鹽(84.5mg,0.735mmol)按照實施例23中的類似步驟製備而成。 Light yellow solid (S,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl) -2,2'-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)L-serine benzyl ester (103mg, 0.147mmol, 70% yield) is composed of (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2 '-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (110.0mg, 0.210mmol) and L-serine benzyl ester hydrochloride (84.5 mg, 0.735mmol) was prepared according to the similar procedure in Example 23.

LC-MS(m/z)：703(M+1)。 LC-MS (m/z): 703 (M+1).

實施例27 Example 27

(E)-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-絲氨酸的製備 ( E )-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Preparation of methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -serine

Figure 108130887-A0202-12-0034-67
Figure 108130887-A0202-12-0034-67

白色固體(E)-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-絲氨酸(58mg,0.0948mmol,64%yield)是由(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)L-絲氨酸苄酯(103mg,0.147mmol)和LiOHH2O(200mg,4.762mmol)按照實施例25中的類似步驟製備而成。 White solid ( E )-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -serine (58mg, 0.0948mmol, 64% yield) is made of (S ,E)-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)L-serine benzyl ester (103mg, 0.147mmol) and LiOHH2O (200mg, 4.762mmol) ) Prepared according to the similar steps in Example 25.

1H NMR(400MHz,DMSO-d 6)δ 7.53-7.50(m,2H),7.43(d,J=7.6Hz,1H),7.28(t,J=7.6Hz,1H),7.23-7.16(m,2H),7.07(d,J=7.6Hz,1H),6.96(d,J=7.6Hz,1H),6.73(d,J=15.6Hz,1H),6.15(dt,J=15.6,6.8Hz,1H),5.22(s,2H),3.94-3.79(m,2H),3.74-3.62(m,2H),3.24(s,J=5.6Hz,1H),2.91(t,J=13.6Hz,2H),2.73(t,J=7.2Hz,2H),2.59(t,J=7.2Hz,2H),2.39(dd,J=13.6,7.2Hz,2H),2.33(s,3H),2.28-2.17(m,2H),2.01(s,3H),1.95(s,3H). 1 H NMR (400MHz, DMSO- d 6 ) δ 7.53-7.50 (m, 2H), 7.43 (d, J = 7.6Hz, 1H), 7.28 (t, J = 7.6Hz, 1H), 7.23-7.16 (m ,2H),7.07(d, J =7.6Hz,1H), 6.96(d, J =7.6Hz,1H), 6.73(d, J =15.6Hz,1H), 6.15(dt, J =15.6,6.8Hz ,1H),5.22(s,2H),3.94-3.79(m,2H),3.74-3.62(m,2H),3.24(s, J =5.6Hz,1H),2.91(t, J =13.6Hz, 2H), 2.73(t, J =7.2Hz,2H), 2.59(t, J =7.2Hz,2H), 2.39(dd, J =13.6,7.2Hz,2H),2.33(s,3H),2.28- 2.17 (m, 2H), 2.01 (s, 3H), 1.95 (s, 3H).

LC-MS(m/z)：613(M+1)。 LC-MS (m/z): 613 (M+1).

實施例28 Example 28

(5-氯-4-((3’-((E)-4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-蘇氨酸苄酯的製備 (5-Chloro-4-((3'-(( E )-4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Preparation of methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -threonine benzyl ester

Figure 108130887-A0202-12-0034-68
Figure 108130887-A0202-12-0034-68

淺黃色固體(5-氯-4-((3’-((E)-4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-蘇氨酸苄酯(57.0mg,0.0796mmol,42%yield)是由(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(100.0mg,0.191mmol) 和L-蘇氨酸苄酯半草酸鹽(149mg,0.668mmol)按照實施例23中的類似步驟製備而成。 Light yellow solid (5-chloro-4-((3'-(( E )-4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2 '-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -threonine benzyl ester (57.0mg, 0.0796mmol, 42% yield) is composed of (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2 '-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (100.0mg, 0.191mmol) and L-threonine benzyl ester hemioxalic acid The salt (149 mg, 0.668 mmol) was prepared following the similar procedure in Example 23.

LC-MS(m/z)：717(M+1)。 LC-MS (m/z): 717 (M+1).

實施例29 Example 29

(5-氯-4-((3’-((E)-4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-蘇氨酸的製備 (5-Chloro-4-((3'-(( E )-4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Preparation of methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -threonine

Figure 108130887-A0202-12-0035-69
Figure 108130887-A0202-12-0035-69

白色固體(5-氯-4-((3’-((E)-4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-蘇氨酸(43mg,0.0687mmol,86%yield)是由(5-氯-4-((3’-((E)-4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-蘇氨酸苄酯(57.0mg,0.0796mmol)和LiOH H2O(200mg,4.762mmol)按照實施例25中的類似步驟製備而成。 White solid (5-chloro-4-((3'-(( E )-4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -threonine (43mg, 0.0687mmol, 86% yield) is made of (5-Chloro-4-((3'-(( E )-4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl) -L -threonine benzyl ester (57.0mg, 0.0796mmol) and LiOH H 2 O (200mg, 4.762mmol) was prepared according to the similar procedure in Example 25.

1H NMR(400MHz,DMSO-d 6)δ 7.51(dd,J=7.6,1.6Hz,1H),7.45-7.40(m,2H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.18(s,1H),7.07(dd,J=7.6,1.6Hz,1H),6.96(dd,J=7.6,1.6Hz,1H),6.73(d,J=15.6Hz,1H),6.15(dt,J=15.6,6.8Hz,1H),5.22(s,2H),3.93-3.80(m,2H),3.65(d,J=13.6Hz,2H),2.97(s,1H),2.91(t,J=13.6Hz,2H),2.73(t,J=7.2Hz,2H),2.59(t,J=7.2Hz,2H),2.39(q,J=7.2Hz,2H),2.32(s,3H),2.29-2.15(m,2H),2.01(s,3H),1.95(s,3H),1.13(d,J=6.4Hz,3H). 1 H NMR(400MHz, DMSO- d 6 )δ 7.51(dd, J =7.6,1.6Hz,1H),7.45-7.40(m,2H),7.28(t, J =7.6Hz,1H), 7.21(t , J =7.6Hz,1H),7.18(s,1H),7.07(dd, J =7.6,1.6Hz,1H),6.96(dd, J =7.6,1.6Hz,1H),6.73(d, J = 15.6Hz, 1H), 6.15 (dt, J =15.6, 6.8 Hz, 1H), 5.22 (s, 2H), 3.93-3.80 (m, 2H), 3.65 (d, J =13.6 Hz, 2H), 2.97 ( s,1H), 2.91(t, J =13.6Hz,2H), 2.73(t, J =7.2Hz,2H), 2.59(t, J =7.2Hz,2H), 2.39(q, J =7.2Hz, 2H), 2.32 (s, 3H), 2.29-2.15 (m, 2H), 2.01 (s, 3H), 1.95 (s, 3H), 1.13 (d, J = 6.4Hz, 3H).

LC-MS(m/z)：627(M+1)。 LC-MS (m/z): 627 (M+1).

實施例30 Example 30

(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氮雜環丁烷-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2, Preparation of 2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)azetidine-2-carboxylic acid

Figure 108130887-A0202-12-0036-70
Figure 108130887-A0202-12-0036-70

將(E)-5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(100.0mg,0.191mmol)，S-氮雜環丁烷-2-羧酸(67.5mg,0.668mmol)，DMF(2.0mL)，MeOH(2.0mL)，HOAc(3滴)的混合液在室溫下攪拌18h，加入NaBH3CN(72.2mg，1.146mmol)，繼續攪拌2h。濃縮反應液除掉甲醇，加水(15.0mL)稀釋，過濾收集固體，烘乾。粗品用製備薄層色譜板(DCM/MeOH=4/1)純化得白色固體(S,E)-1-(5-氯-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氮雜環丁烷-2-羧酸(41.0mg,0.0675mmol,35%收率)。 (E)-5-chloro-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (100.0mg, 0.191mmol), S-azetidine-2-carboxylic acid ( A mixture of 67.5 mg, 0.668 mmol), DMF (2.0 mL), MeOH (2.0 mL), and HOAc (3 drops) was stirred at room temperature for 18 h, NaBH3CN (72.2 mg, 1.146 mmol) was added, and stirring was continued for 2 h. The reaction solution was concentrated to remove methanol, diluted with water (15.0 mL), and the solid was collected by filtration and dried. The crude product was purified by preparative thin-layer chromatography (DCM/MeOH=4/1) to obtain a white solid ( S , E )-1-(5-chloro-4-((3'-(4-(3,3-difluoro) (Pyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methyl Benzyl)azetidine-2-carboxylic acid (41.0 mg, 0.0675 mmol, 35% yield).

1H NMR(400MHz,DMSO-d 6)δ 7.50(d,J=7.6Hz,1H),7.43(d,J=7.6Hz,1H),7.35(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.17(s,1H),7.07(dd,J=7.6,1.4Hz,1H),6.96(d,J=7.6Hz,1H),6.73(d,J=15.6Hz,1H),6.15(dt,J=15.6,6.8Hz,1H),5.20(s,2H),3.91-3.81(m,2H),3.55(d,J=13.2Hz,1H),3.21(s,1H),3.08(q,J=8.0Hz,1H),2.91(t,J=13.2Hz,2H),2.73(t,J=7.2Hz,2H),2.59(t,J=7.2Hz,2H),2.39(q,J=7.2Hz,2H),2.34(s,3H),2.29-2.09(m,4H),2.01(s,3H),1.95(s,3H). 1 H NMR(400MHz,DMSO- d 6 )δ 7.50(d, J =7.6Hz,1H), 7.43(d, J =7.6Hz,1H), 7.35(s,1H), 7.28(t, J =7.6 Hz,1H), 7.21(t, J =7.6Hz,1H), 7.17(s,1H), 7.07(dd, J =7.6,1.4Hz,1H), 6.96(d, J =7.6Hz,1H), 6.73(d, J =15.6Hz,1H), 6.15(dt, J =15.6,6.8Hz,1H), 5.20(s,2H),3.91-3.81(m,2H),3.55(d, J =13.2Hz) ,1H),3.21(s,1H),3.08(q, J =8.0Hz,1H),2.91(t, J =13.2Hz,2H),2.73(t, J =7.2Hz,2H),2.59(t , J =7.2Hz,2H),2.39(q, J =7.2Hz,2H),2.34(s,3H),2.29-2.09(m,4H),2.01(s,3H),1.95(s,3H) .

LC-MS(m/z)：609(M+1)。 LC-MS (m/z): 609 (M+1).

實施例31 Example 31

(E)-4-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)硫代嗎啉-1,1-二氧化物的製備 Preparation of (E)-4-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)thiomorpholine-1,1-dioxide

Figure 108130887-A0202-12-0036-71
Figure 108130887-A0202-12-0036-71

黃色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)硫代嗎啉-1,1-二氧化物(815.0mg,2.283mmol,69%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯 Yellow oil (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)thiomorpholine-1,1-dioxide (815.0mg , 2.283mmol, 69%) is composed of (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene

(1.0g,3.311mmol)和硫代嗎啉-1,1-二氧化物(894.0mg,6.622mmol)按照實施例6中的類似步驟製備而成。 (1.0g, 3.311mmol) and thiomorpholine-1,1-dioxide (894.0mg, 6.622mmol) were prepared according to the similar procedure in Example 6.

LC-MS(m/z)：358(M+1)。 LC-MS (m/z): 358 (M+1).

實施例32 Example 32

(E)-5-氯-4-((3’-(4-(1,1-二氧化硫代嗎啉)丁-1-烯-1 基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((3'-(4-(1,1-thiomorpholine dioxide)but-1-en-1 yl)-2,2'-dimethyl-[1, Preparation of 1'-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0037-72
Figure 108130887-A0202-12-0037-72

淺黃色固體(E)-5-氯-4-((3’-(4-(1,1-二氧化硫代嗎啉)丁-1-烯-1 基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(1.120g,2.033mmol,89%)是由(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)硫代嗎啉-1,1 二氧化物(815.0mg,2.283mmol)和5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(913.2mg,2.283mmol)按照實施例9中的類似步驟製備而成。 Light yellow solid (E)-5-chloro-4-((3'-(4-(1,1-thiomorpholine dioxide)but-1-en-1 yl)-2,2'-dimethyl- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (1.120g, 2.033mmol, 89%) is composed of (E)-1-(4-(3- Bromo-2-methylphenyl)but-3-en-1-yl)thiomorpholine-1,1 dioxide (815.0mg, 2.283mmol) and 5-chloro-2-methyl-4-( (2-Methyl-3-boronic acid pinacol ester benzyl)oxy)benzaldehyde (913.2mg, 2.283mmol) was prepared according to the similar procedure in Example 9.

LC-MS(m/z)：552(M+1)。 LC-MS (m/z): 552 (M+1).

實施例33 Example 33

(S,E)-1-(5-氯-4-((3’-(4-(1,1-二氧化硫代嗎啉)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S , E )-1-(5-chloro-4-((3'-(4-(1,1-thiomorpholine dioxide)but-1-en-1-yl)-2,2'-di Preparation of methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0037-73
Figure 108130887-A0202-12-0037-73

將(E)-5-氯-4-((3’-(4-(1,1-二氧化硫代嗎啉)丁-1-烯-1 基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(160.0mg,0.290mmol)，L-呱啶-2-甲酸(131.0mg,1.016mmol)，DMF(2.0mL)，MeOH(2.0mL)，HOAc(3滴)的混合液在室溫下攪拌18h，然後用冰/鹽浴冷卻至-5℃，加入NaBH3CN(109.6mg,1.740mmol)，再將反應液升至室溫並繼續攪拌2h。濃縮反應液除掉甲醇，加水(15.0mL)稀釋，過濾收集固體，烘乾。粗品用製備薄層色譜板(DCM/MeOH= 6/1)純化得白色固體(S,E)-1-(5-氯-4-((3’-(4-(硫代嗎啉-1,1 二氧化物-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(32.2mg,0.0485mmol,16.7)。 Add (E)-5-chloro-4-((3'-(4-(1,1-dioxythiomorpholine)but-1-en-1 yl)-2,2'-dimethyl-(1 ,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (160.0mg, 0.290mmol), L-piperidine-2-carboxylic acid (131.0mg, 1.016mmol), DMF( 2.0mL), MeOH (2.0mL), HOAc (3 drops) mixture was stirred at room temperature for 18h, then cooled to -5°C with an ice/salt bath, NaBH3CN (109.6mg, 1.740mmol) was added, and the reaction The solution rose to room temperature and continued to stir for 2h. The reaction solution was concentrated to remove methanol, diluted with water (15.0 mL), and the solid was collected by filtration and dried. Preparative thin layer chromatography plate (DCM/MeOH= 6/1) Purified white solid (S, E)-1-(5-chloro-4-((3'-(4-(thiomorpholine-1,1 dioxide-1-yl)but- 1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2- Carboxylic acid (32.2 mg, 0.0485 mmol, 16.7).

1H NMR(400MHz,DMSO-d 6)δ 7.51(d,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.32(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.15(s,1H),7.07(d,J=7.6Hz,1H),6.96(d,J=7.6Hz,1H),6.73(d,J=15.6Hz,1H),6.16(dt,J=15.6,6.8Hz,1H),5.20(s,2H),3.73(d,J=13.6Hz,1H),3.38(d,J=13.6Hz,1H),3.12-3.06(m,5H),2.96-2.94(m,3H),2.89-2.77(m,2H),2.66(t,J=7.2Hz,2H),2.40(dd,J=14.4,7.2Hz,2H),2.31(s,3H),2.23-1.96(m,1H),2.01(s,3H),1.95(s,3H),1.76-1.73(m,2H),1.48-1.38(m,4H). 1 H NMR(400MHz,DMSO- d 6 )δ 7.51(d, J =7.6Hz,1H), 7.44(d, J =7.6Hz,1H), 7.32(s,1H), 7.28(t, J =7.6 Hz,1H), 7.21(t, J =7.6Hz,1H), 7.15(s,1H), 7.07(d, J =7.6Hz,1H), 6.96(d, J =7.6Hz,1H), 6.73( d, J =15.6Hz,1H), 6.16(dt, J =15.6,6.8Hz,1H), 5.20(s, 2H), 3.73(d, J =13.6Hz,1H), 3.38(d, J =13.6 Hz,1H),3.12-3.06(m,5H),2.96-2.94(m,3H),2.89-2.77(m,2H),2.66(t, J =7.2Hz,2H), 2.40(dd, J = 14.4, 7.2Hz, 2H), 2.31 (s, 3H), 2.23-1.96 (m, 1H), 2.01 (s, 3H), 1.95 (s, 3H), 1.76-1.73 (m, 2H), 1.48-1.38 (m,4H).

LC-MS(m/z)：665(M+1)。 LC-MS (m/z): 665 (M+1).

實施例34 Example 34

(R,E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶-3-醇的製備 Preparation of ( R , E )-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)piperidine-3-ol

Figure 108130887-A0202-12-0038-74
Figure 108130887-A0202-12-0038-74

白色固體(R,E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶-3-醇(475.0mg,1.471mmol,89%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(500.0mg,1.656mmol)和(R)-3羥基呱啶鹽酸鹽(400.0mg,2.907mmol)按照實施例6中的類似步驟製備而成。 White solid ( R , E )-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)piperidine-3-ol (475.0mg, 1.471mmol, 89% ) Is composed of (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (500.0mg, 1.656mmol) and (R)-3 hydroxypiperidine salt The acid salt (400.0 mg, 2.907 mmol) was prepared according to the similar procedure in Example 6.

LC-MS(m/z)：324(M+1)。 LC-MS (m/z): 324 (M+1).

實施例35 Example 35

(R,E)-5-氯-4-((3’-(4-(3-羥基呱啶-1-基)丁-1-烯-1 基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 ( R , E )-5-chloro-4-((3'-(4-(3-hydroxypiridin-1-yl)but-1-en-1 yl)-2,2'-dimethyl- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0039-75
Figure 108130887-A0202-12-0039-75

淺黃色固體(R,E)-5-氯-4-((3’-(4-(3-羥基呱啶-1-基)丁-1-烯-1 基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(300mg,0.580mmol,39%)是由(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-(R)-3-羥基呱啶(475.0mg,1.471mmol)和5-氯-2-甲基-4-((2-甲基-3-硼酸頻那醇酯苄基)氧)苯甲醛(588.4mg,1.471mmol)按照實施例9中的類似步驟製備而成。 Light yellow solid ( R , E )-5-chloro-4-((3'-(4-(3-hydroxypiridin-1-yl)but-1-en-1 yl)-2,2'-di Methyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (300mg, 0.580mmol, 39%) is made of (E)-1-(4-( 3-bromo-2-methylphenyl)but-3-en-1-yl)-(R)-3-hydroxypiperidine (475.0mg, 1.471mmol) and 5-chloro-2-methyl-4- ((2-Methyl-3-boronic acid pinacol ester benzyl)oxy)benzaldehyde (588.4 mg, 1.471 mmol) was prepared according to the similar procedure in Example 9.

LC-MS(m/z)：518(M+1)。 LC-MS (m/z): 518 (M+1).

實施例36 Example 36

(S)-1-(5-氯-4-((3’-((E)-4-((R)-3-羥基呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S )-1-(5-chloro-4-((3'-(( E )-4-(( R )-3-hydroxypiridin-1-yl)but-1-en-1-yl) Preparation of -2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0039-76
Figure 108130887-A0202-12-0039-76

白色固體(S)-1-(5-氯-4-((3’-((E)-4-((R)-3-羥基呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(30.0mg,0.0476mmol,16.4%)是由(R,E)-5-氯-4-((3’-(4-(3-羥基呱啶-1-基)丁-1-烯-1 基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(150mg,0.290mmol)和L-呱啶-2-甲酸(131.0mg,1.015mmol)按照實施例10中的類似步驟製備而成。 White solid ( S )-1-(5-chloro-4-((3'-(( E )-4-(( R )-3-hydroxypiridin-1-yl)but-1-ene-1- (Yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (30.0mg, 0.0476mmol, 16.4%) is composed of ( R , E )-5-chloro-4-((3'-(4-(3-hydroxypiridin-1-yl)but-1-en-1 yl)-2 ,2'-Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (150mg, 0.290mmol) and L-piperidine-2-carboxylic acid ( 131.0 mg, 1.015 mmol) was prepared according to the similar procedure in Example 10.

1H NMR(400MHz,DMSO-d6)δ 7.51(d,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),7.33(s,1H),7.29(t,J=7.6Hz,1H),7.24(t,J=7.6Hz,2H),7.15(s,1H),7.07(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.81(d,J=15.6Hz,1H),6.11(dt,J=15.6,6.8Hz,1H),5.21(s,2H),3.75(d,J=13.5Hz,1H),3.41(d,J=13.5Hz,1H),3.17-3.11(m,5H),2.87-2.79(m,2H),2.61(s,2H),2.31(s,3H),2.27-2.18 (m,1H),2.01(s,3H),1.97(s,3H),1.81-1.69(m,4H),1.65-1.56(m,2H),1.54-1.34(m,5H). 1 H NMR(400MHz,DMSO-d6)δ 7.51(d,J=7.6Hz,1H), 7.47(d,J=7.6Hz,1H), 7.33(s,1H), 7.29(t,J=7.6Hz ,1H),7.24(t,J=7.6Hz,2H),7.15(s,1H),7.07(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.81(d ,J=15.6Hz,1H),6.11(dt,J=15.6,6.8Hz,1H),5.21(s,2H),3.75(d,J=13.5Hz,1H),3.41(d,J=13.5Hz ,1H),3.17-3.11(m,5H),2.87-2.79(m,2H),2.61(s,2H),2.31(s,3H),2.27-2.18 (m,1H),2.01(s,3H) ), 1.97 (s, 3H), 1.81-1.69 (m, 4H), 1.65-1.56 (m, 2H), 1.54-1.34 (m, 5H).

LC-MS(m/z)：631(M+1)。 LC-MS (m/z): 631 (M+1).

實施例37 Example 37

4-((3-溴-2-甲基苄基)氧基)-5-氯-2-羥基苯甲醛的製備 Preparation of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde

Figure 108130887-A0202-12-0040-77
Figure 108130887-A0202-12-0040-77

0℃下將Ph3P(62.3g,237.8mmol)和DIAD(48.0g,237.8mmol)加入(3-溴-2-甲基苯基)甲醇(31.7g,158.5mmol)和5-氯-2,4-二羥基苯甲醛(30g,174.4mmol)的四氫呋喃溶液(200mL)中。反應液在氮氣保護下室溫攪拌過夜。然後將反應液濃縮，殘餘物用矽膠層析柱純化(PE/EA=30/1)。得到白色固體4-((3-溴-2-甲基苄基)氧基)-5-氯-2-羥基苯甲醛(12.6g,22% yield)。 Add Ph3P (62.3g, 237.8mmol) and DIAD (48.0g, 237.8mmol) to (3-bromo-2-methylphenyl) methanol (31.7g, 158.5mmol) and 5-chloro-2,4 at 0℃ -Dihydroxybenzaldehyde (30 g, 174.4 mmol) in tetrahydrofuran (200 mL). The reaction solution was stirred overnight at room temperature under nitrogen protection. Then the reaction solution was concentrated, and the residue was purified by silica gel chromatography (PE/EA=30/1). A white solid 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (12.6g, 22% yield) was obtained.

1H NMR(400MHz,CDCl3)：δ 11.42(s,1H),9.70(s,1H),7.58(d,J=8.0Hz,1H),7.54(s,1H),7.41(d,J=4Hz,1H),7.10(t,J=6.8Hz,1H),6.57(s,1H),5.15(s,2H),2.44(s,3H).。 1 H NMR (400MHz, CDCl 3 ): δ 11.42 (s, 1H), 9.70 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 4Hz, 1H), 7.10 (t, J =6.8Hz, 1H), 6.57 (s, 1H), 5.15 (s, 2H), 2.44 (s, 3H).

LC-MS(m/z)：631.4(M+1)。 LC-MS (m/z): 631.4 (M+1).

實施例38 Example 38

5-((5-((3-溴-2-甲基苄基)氧基)-4-氯-2-甲酸基苯氧基)甲基)煙腈的製備 Preparation of 5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-carboxyphenoxy)methyl)nicotinonitrile

Figure 108130887-A0202-12-0040-78
Figure 108130887-A0202-12-0040-78

將甲磺醯氯(8.07g,70.8mmol)在0℃下加入5-(羥基甲基)煙腈(7.16g,53mmol)和三乙胺(10.7g,106mmol)的二氯甲烷溶液中。混合溶液在室溫下攪 拌4小時，然後加入300mL飽和氯化銨水溶液。將該溶液用二氯甲烷(200mL)萃取三遍，合併有機相，無水Na2SO4乾燥並過濾。濾液減壓濃縮得到粗品，無需純化直接用於下一步。將該粗品、化合物4-((3-溴-2-甲基苄基)氧基)-5-氯-2-羥基苯甲醛(12.6g,35.4mmol)和碳酸鉀(14.6g,105.9mmol)溶於DMF(100ml)中，在60℃下加熱16個小時。然後加入50ml飽和氯化銨水溶液。該混合溶液用乙酸乙酯(300ml)萃取三次。合併有機相，無水Na2SO4乾燥並過濾。濾液減壓濃縮，得到的粗品用矽膠層析柱純化(PE/EA=2/1)。得到白色固體5-((5-((3-溴-2-甲基苄基)氧基)-4-氯-2-甲酸基苯氧基)甲基)煙腈(7.5g，兩步產率45% yield)。 Methanesulfonyl chloride (8.07g, 70.8mmol) was added to a dichloromethane solution of 5-(hydroxymethyl)nicotinonitrile (7.16g, 53mmol) and triethylamine (10.7g, 106mmol) at 0°C. The mixed solution was stirred at room temperature for 4 hours, and then 300 mL of saturated aqueous ammonium chloride was added. The solution was extracted three times with dichloromethane (200 mL), the organic phases were combined, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was directly used in the next step without purification. The crude product, compound 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (12.6g, 35.4mmol) and potassium carbonate (14.6g, 105.9mmol) Dissolve in DMF (100ml) and heat at 60°C for 16 hours. Then add 50 ml of saturated aqueous ammonium chloride solution. The mixed solution was extracted three times with ethyl acetate (300 ml). The organic phases were combined, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (PE/EA=2/1). A white solid 5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-carboxyphenoxy)methyl)nicotinonitrile (7.5g, produced in two steps 45% yield).

1H NMR(400MHz,CDCl3)：δ 10.27(s,1H),8.92-8.89(m,2H),8.08(s,1H),7.92(s,1H),7.60(d,J=7.2Hz,1H),7.35(d,J=7.6Hz,1H),7.10(t,J=7.6Hz,1H),6.56(s,1H),5.30-5.13(m,4H),2.43(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ 10.27 (s, 1H), 8.92-8.89 (m, 2H), 8.08 (s, 1H), 7.92 (s, 1H), 7.60 (d, J = 7.2Hz, 1H), 7.35(d, J =7.6Hz,1H), 7.10(t, J =7.6Hz,1H), 6.56(s,1H), 5.30-5.13(m,4H), 2.43(s,3H).

實施例39 Example 39

(E)-3,3-二氟-1-(4-(2-甲基-3-(-4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)苯基) 丁-3-烯-1-基)吡咯烷的製備 (E)-3,3-Difluoro-1-(4-(2-methyl-3-(-4,4,5,5-tetramethyl-[1,3,2]dioxaborole (Pentan-2-yl)phenyl) Preparation of but-3-en-1-yl)pyrrolidine

Figure 108130887-A0202-12-0041-79
Figure 108130887-A0202-12-0041-79

室溫下在化合物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-3,3-二氟吡咯烷(800mg,2.43mmol)的1,4-二氧六烷(10ml)溶液中中加入B2(pin)2(679mg,2.67mmol),KOAc(715mg,7.29mmol)and PdCl2(dppf)(178mg,0.24mmol)。該反應液在100℃下攪拌過夜。反應結束後將反應液濃縮，殘留物用矽膠層析柱純化(PE/EA=50/1)。得到黃色油狀物(E)-3,3-二氟-1-(4-(2-甲基-3-(-4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)苯基)丁-3-烯-1-基)吡咯烷(812mg,88% yield)。 At room temperature in compound (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)-3,3-difluoropyrrolidine (800mg, 2.43mmol B 2 (pin) 2 (679 mg, 2.67 mmol), KOAc (715 mg, 7.29 mmol) and PdCl 2 (dppf) (178 mg, 0.24 mmol) were added to the 1,4-dioxane (10 ml) solution of ). The reaction solution was stirred overnight at 100°C. After the reaction, the reaction solution was concentrated, and the residue was purified by silica gel chromatography (PE/EA=50/1). A yellow oil (E)-3,3-difluoro-1-(4-(2-methyl-3-(-4,4,5,5-tetramethyl-[1,3,2] Dioxaborolan-2-yl)phenyl)but-3-en-1-yl)pyrrolidine (812mg, 88% yield).

MS Calcd：377.2；MS Found：378.2([M+H]+). MS Calcd: 377.2; MS Found: 378.2([M+H] + ).

實施例40 Example 40

(E)-5-((4-氯-5-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)-2-甲酸基苯氧基)甲基)煙腈的製備 (E)-5-((4-chloro-5-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-carboxyphenoxy)methyl)nicotinonitrile

Figure 108130887-A0202-12-0042-80
Figure 108130887-A0202-12-0042-80

將化合物5-((5-((3-溴-2-甲基苄基)氧基)-4-氯-2-甲酸基苯氧基)甲基)煙腈(550mg,1.16mmol)和PdCl2(dppf)(85mg,0.13mmol)在室溫下加入化合物(E)-3,3-二氟-1-(4-(2-甲基-3-(-4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)苯基)丁-3-烯-1-基)吡咯烷(480mg，3.48mmol)的1,4-二氧六環(0.5ml)和K2CO3(480mg，3.48mmol)的水(0.5ml)混合溶液中。該反應液在80℃氮氣保護下加熱反應過夜。反應結束後將反應液濃縮，殘留物用矽膠層析柱純化(PE/EA=10/1)。得到黃色固體(E)-5-((4-氯-5-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)-2-甲酸基苯氧基)甲基)煙腈(417mg,54% yield)。 The compound 5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-carboxyphenoxy)methyl)nicotinonitrile (550mg, 1.16mmol) and PdCl 2 (dppf) (85mg, 0.13mmol) was added compound (E)-3,3-difluoro-1-(4-(2-methyl-3-(-4,4,5,5- Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl)but-3-en-1-yl)pyrrolidine (480mg, 3.48mmol) in 1,4-bis Oxane (0.5ml) and K 2 CO 3 (480mg, 3.48mmol) in a mixed solution of water (0.5ml). The reaction solution was heated and reacted overnight under the protection of nitrogen at 80°C. After the reaction, the reaction solution was concentrated, and the residue was purified with a silica gel column (PE/EA=10/1). A yellow solid (E)-5-((4-chloro-5-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)- 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-carboxyphenoxy)methyl)nicotinonitrile (417mg, 54% yield).

MS Calcd：642.1；MS Found：643.2([M+H]+). MS Calcd: 642.1; MS Found: 643.2([M+H] + ).

實施例41 Example 41

(S,E)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)卞基)呱啶-2-羧酸的製備 (S,E)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(4-(3,3-difluoropyrrole) Alk-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- Preparation of 2-carboxylic acid

Figure 108130887-A0202-12-0042-81
Figure 108130887-A0202-12-0042-81

將化合物(E)-5-((4-氯-5-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)-2-甲酸基苯氧基)甲基)煙腈(360mg,0.56mmol)和(S)-呱啶-2-羧酸(145mg,1.12mmol)溶於二氯甲烷(3mL)中在室溫下攪拌4小時。然後在0℃下加入甲醇(3mL)和氰基硼氫化鈉(72mg,1.12mmol)。該混合液在室溫攪拌16小時。反應結束後緩慢加入1N鹽酸溶液將pH值調至5，然後用二氯甲烷(40mL)稀釋。混合溶液用水(40mL)洗一次。有機相用無水Na2SO4乾燥並過濾。濾液減壓濃縮，得到的粗品用C18柱(with 10%-95% ACN in water)分離純化得到白色固體(S,E)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3’-(4-(3,3-二氟吡咯烷-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)卞基)呱啶-2-羧酸(130mg,31% yield)。 Compound (E)-5-((4-chloro-5-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2 ,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-carboxyphenoxy)methyl)nicotinonitrile (360mg, 0.56mmol) and (S) -Piperidine-2-carboxylic acid (145 mg, 1.12 mmol) was dissolved in dichloromethane (3 mL) and stirred at room temperature for 4 hours. Then methanol (3 mL) and sodium cyanoborohydride (72 mg, 1.12 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours. After the reaction, 1N hydrochloric acid solution was slowly added to adjust the pH to 5, and then diluted with dichloromethane (40 mL). The mixed solution was washed once with water (40 mL). The organic phase was dried with anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was separated and purified on a C18 column (with 10%-95% ACN in water) to obtain a white solid (S,E)-1-(5-chloro-2-((5-cyanopyridine- 3-yl)methoxy)-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)benyl)piperidine-2-carboxylic acid (130mg, 31% yield).

1H NMR(400MHz,CD3OD)：δ 8.96(d,J=11.2Hz,1H),8.41(s,1H),7.59(s,1H),7.50-7.47(m,2H),7.29-7.21(m,2H),7.11(s,1H),7.09(s,1H),7.25(d,J=7.2Hz,1H),6.96(d,J=15.6Hz,1H),6.12(t,J=8.0Hz,1H),5.39(s,2H),5.33(s,2H),4.48-4.43(m,2H),3.97(t,J=11.6Hz,3H),3.78(t,J=7.2Hz,2H),3.51-3.43(m,3H),3.01(s,1H),2.76-2.66(m,4H),2.30(s,1H),2.08(s,3H),2.03(s,3H),1.85(s,3H),1.60-1.61(m,2H)； 1H NMR (400MHz, CD 3 OD): δ 8.96 (d, J =11.2Hz, 1H), 8.41 (s, 1H), 7.59 (s, 1H), 7.50-7.47 (m, 2H), 7.29-7.21 ( m,2H),7.11(s,1H),7.09(s,1H),7.25(d, J =7.2Hz,1H),6.96(d, J =15.6Hz,1H),6.12(t, J =8.0 Hz,1H),5.39(s,2H),5.33(s,2H),4.48-4.43(m,2H),3.97(t, J =11.6Hz,3H),3.78(t, J =7.2Hz,2H ),3.51-3.43(m,3H),3.01(s,1H),2.76-2.66(m,4H),2.30(s,1H),2.08(s,3H),2.03(s,3H),1.85( s,3H),1.60-1.61(m,2H);

MS Calcd：754；MS Found：755.4([M+H]+). MS Calcd: 754; MS Found: 755.4([M+H] + ).

實施例42 Example 42

(E)-3-(3-溴-2-甲基苯基)丙烯酸乙酯的製備 Preparation of (E)-3-(3-bromo-2-methylphenyl) ethyl acrylate

Figure 108130887-A0202-12-0043-82
Figure 108130887-A0202-12-0043-82

0℃下將2-(二乙氧基磷醯基)乙酸乙酯(4.98g,22.2mmol)加入NaH(888mg,60%，22.2mmol)的DMF(50mL)溶液中。反應液在室溫攪拌2小時。然後加入3-溴-2-甲基苯甲醛(4.0g,20.2mmol)。反應液繼續在室溫攪拌過夜。加水終止反應，用石油醚(50ml)萃取兩次。無水Na2SO4乾燥並過濾。濾液減壓濃 縮，得到的黃色油狀物粗品(E)-3-(3-溴-2-甲基苯基)丙烯酸乙酯(5.83g，粗品)。粗品不經純化直接用於下一步。 At 0°C, ethyl 2-(diethoxyphosphoryl)acetate (4.98 g, 22.2 mmol) was added to a solution of NaH (888 mg, 60%, 22.2 mmol) in DMF (50 mL). The reaction solution was stirred at room temperature for 2 hours. Then 3-bromo-2-methylbenzaldehyde (4.0 g, 20.2 mmol) was added. The reaction solution continued to be stirred at room temperature overnight. The reaction was terminated by adding water, and extracted twice with petroleum ether (50ml). Dry and filter with anhydrous Na 2 SO 4 . The filtrate was concentrated under reduced pressure to obtain a crude yellow oil (E)-3-(3-bromo-2-methylphenyl)ethyl acrylate (5.83 g, crude product). The crude product was used directly in the next step without purification.

MS Calcd：268；MS Found：269.0([M+H]+) MS Calcd: 268; MS Found: 269.0([M+H] + )

實施例43 Example 43

(E)-3-(3-溴-2-甲基苯基)丙烯酸的製備 (E) Preparation of 3-(3-bromo-2-methylphenyl) acrylic acid

Figure 108130887-A0202-12-0044-83
Figure 108130887-A0202-12-0044-83

室溫下將LiOH.H2O(1.87g,44.61mmol)緩慢加入(E)-3-(3-溴-2-甲基苯基)丙烯酸乙酯(4.0g,14.87mmol)在乙醇(40mL)和水(10ml)的混合溶液中。反應液在氮氣保護下室溫攪拌6小時。反應結束後將反應液減壓蒸餾除去溶劑，殘留物溶于水(30mL)，用3N鹽酸將溶液pH值調節至5-6，過濾水洗得到白色固體(E)-3-(3-溴-2-甲基苯基)丙烯酸(3.30g,93% yield)。 At room temperature, LiOH.H 2 O (1.87g, 44.61mmol) was slowly added (E)-3-(3-bromo-2-methylphenyl) ethyl acrylate (4.0g, 14.87mmol) in ethanol (40mL ) And water (10ml) mixed solution. The reaction solution was stirred at room temperature for 6 hours under nitrogen protection. After the reaction, the reaction solution was distilled under reduced pressure to remove the solvent. The residue was dissolved in water (30 mL). The pH value of the solution was adjusted to 5-6 with 3N hydrochloric acid. The white solid (E)-3-(3-bromo- 2-Methylphenyl) acrylic acid (3.30 g, 93% yield).

1H NMR(400MHz,CDCl3)：δ 8.09(d,J=16.0Hz,1H),7.60(d,J=9.2Hz,1H),7.48(d,J=3.6Hz,1H),7.09(t,J=8.0Hz,1H),6.33(d,J=15.6Hz,1H),2.52(s,3H). 1 H NMR(400MHz,CDCl 3 ): δ 8.09(d, J =16.0Hz,1H), 7.60(d, J =9.2Hz,1H), 7.48(d, J =3.6Hz,1H), 7.09(t , J =8.0Hz,1H),6.33(d, J =15.6Hz,1H),2.52(s,3H).

實施例44 Example 44

(E)-3-(3-溴-2-甲基苯基)-1-(3,3-二氟吡咯烷-1-基)丙-2-烯-1-酮的製備 Preparation of (E)-3-(3-bromo-2-methylphenyl)-1-(3,3-difluoropyrrolidin-1-yl)prop-2-en-1-one

Figure 108130887-A0202-12-0044-84
Figure 108130887-A0202-12-0044-84

室溫下向(E)-3-(3-溴-2-甲基苯基)丙烯酸(2.0g,8.3mmol)和3,3-二氟吡咯烷(2.38g,16.6mmol)的二氯甲烷溶液(40mL)中加入HATU(4.73g,12.45mmol)和DIAD(2.14g,16.6mmol)。反應液在氮氣保護下室溫攪拌過夜。反應結束後將反應液濃縮，殘留物通過矽膠柱層析分離得到黃色油狀物(2.18g,75% yield)。 To (E)-3-(3-bromo-2-methylphenyl)acrylic acid (2.0g, 8.3mmol) and 3,3-difluoropyrrolidine (2.38g, 16.6mmol) in dichloromethane at room temperature HATU (4.73 g, 12.45 mmol) and DIAD (2.14 g, 16.6 mmol) were added to the solution (40 mL). The reaction solution was stirred overnight at room temperature under nitrogen protection. After the reaction, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain a yellow oil (2.18g, 75% yield).

MS Found：332.0([M+H]+). MS Found: 332.0([M+H] + ).

實施例45 Example 45

(E)-1-(3,3-二氟吡咯烷-1-基)-3-(2-甲基-3-(-4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)苯基)丙-2-烯-1-酮的製備 (E)-1-(3,3-Difluoropyrrolidin-1-yl)-3-(2-methyl-3-(-4,4,5,5-tetramethyl-[1,3, 2) Preparation of dioxaborolan-2-yl)phenyl)prop-2-en-1-one

Figure 108130887-A0202-12-0045-85
Figure 108130887-A0202-12-0045-85

室溫下在(E)-3-(3-溴-2-甲基苯基)-1-(3,3-二氟吡咯烷-1-基)丙-2-烯-1-酮(1.62g,4.9mmol)和B2(Pin)2(1.36g,5.39mmol)的1,4-二氧六烷(20ml)溶液中中加入KOAc(1.44g,14.7mmol)和PdCl2(dppf)(359mg,0.49mmol)。該反應液在氮氣保護下80℃下攪拌過夜。反應結束後將反應液濃縮，殘留物用矽膠層析柱純化(PE/EA=30/1)。得到黃色油狀物(E)-1-(3,3-二氟吡咯烷-1-基)-3-(2-甲基-3-(-4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)苯基)丙-2-烯-1-酮(1.7g,92% yield)。 (E)-3-(3-Bromo-2-methylphenyl)-1-(3,3-difluoropyrrolidin-1-yl)prop-2-en-1-one (1.62 g, 4.9mmol) and B 2 (Pin) 2 (1.36g, 5.39mmol) in 1,4-dioxane (20ml) solution was added KOAc (1.44g, 14.7mmol) and PdCl 2 (dppf) ( 359mg, 0.49mmol). The reaction solution was stirred overnight at 80°C under nitrogen protection. After the reaction, the reaction solution was concentrated, and the residue was purified by silica gel chromatography (PE/EA=30/1). A yellow oil (E)-1-(3,3-difluoropyrrolidin-1-yl)-3-(2-methyl-3-(-4,4,5,5-tetramethyl- [1,3,2]Dioxaborolan-2-yl)phenyl)prop-2-en-1-one (1.7g, 92% yield).

MS Calcd：377.2；MS Found：378.2([M+H]+) MS Calcd: 377.2; MS Found: 378.2([M+H] + )

實施例46 Example 46

(E)-5-((4-氯-5-((3’-(3-(3,3-二氟吡咯烷-1-基)-3-氧丙-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)-2-甲酸基苯氧基)甲基)煙腈的製備 (E)-5-((4-chloro-5-((3'-(3-(3,3-difluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl) -2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile

Figure 108130887-A0202-12-0045-86
Figure 108130887-A0202-12-0045-86

將K2CO3(600mg,4.35mmol)的水溶液(1ml)和PdCl2(dppf)(106mg,0.15mmol)在室溫下加入化合物(E)-1-(3,3-二氟吡咯烷-1-基)-3-(2-甲基-3-(-4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)苯基)丙-2-烯-1-酮(600mg,1.59mmol)和化合物5-((5-((3-溴-2-甲基苄基)氧基)-4-氯-2-甲酸基苯氧基)甲基)煙腈 (684mg,1.45mmol)的1,4-二氧六環溶液(8ml)中。該反應液在氮氣保護下80℃加熱反應過夜。反應結束後將反應液濃縮，殘留物用矽膠層析柱純化(PE/EA=2/1)。得到黃色固體(E)-5-((4-氯-5-((3’-(3-(3,3-二氟吡咯烷-1-基)-3-氧丙-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)-2-甲酸基苯氧基)甲基)煙腈(430mg,46% yield)。 An aqueous solution (1ml) of K 2 CO 3 (600 mg, 4.35 mmol) and PdCl 2 (dppf) (106 mg, 0.15 mmol) were added to compound (E)-1-(3,3-difluoropyrrolidine-) at room temperature 1-yl)-3-(2-methyl-3-(-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl )Prop-2-en-1-one (600mg, 1.59mmol) and the compound 5-((5-((3-bromo-2-methylbenzyl)oxy)-4-chloro-2-carboxylic acid benzene (Oxy)methyl)nicotinonitrile (684mg, 1.45mmol) in 1,4-dioxane solution (8ml). The reaction solution was heated at 80°C for overnight reaction under the protection of nitrogen. After the reaction, the reaction solution was concentrated, and the residue was purified with a silica gel chromatography column (PE/EA=2/1). A yellow solid (E)-5-((4-chloro-5-((3'-(3-(3,3-difluoropyrrolidin-1-yl)-3-oxoprop-1-ene-1 -Yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-carboxyphenoxy)methyl)nicotinonitrile (430mg, 46% yield).

MS Calcd：641；MS Found：642.2([M+H]+). MS Calcd: 641; MS Found: 642.2([M+H] + ).

實施例47 Example 47

(S,E)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3’-(4-(3,3-二氟吡咯烷-1-基)-3-氧丙-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)卞基)呱啶-2-羧酸的製備5193 (S,E)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(4-(3,3-difluoropyrrole) (Alk-1-yl)-3-oxoprop-1-en-1-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl ) Preparation of pyridine-2-carboxylic acid 5193

Figure 108130887-A0202-12-0046-87
Figure 108130887-A0202-12-0046-87

將化合物(E)-5-((4-氯-5-((3’-(3-(3,3-二氟吡咯烷-1-基)-3-氧丙-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)-2-甲酸基苯氧基)甲基)煙腈(430mg,0.67mmol)和(S)-呱啶-2-羧酸(173mg,1.34mmol)溶於二氯甲烷(3mL)中在室溫下攪拌4小時。然後在0℃下加入氰基硼氫化鈉(50mg,0.8mmol)。該混合液在室溫攪拌16小時。反應結束後緩慢加入1N鹽酸溶液將pH值調至5，然後用二氯甲烷(40mL)稀釋。混合溶液用水(40mL)洗一次。有機相用無水Na2SO4乾燥並過濾。濾液減壓濃縮，得到的粗品用C18柱(with 10%-95% ACN in water)分離純化得到白色固體(S,E)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3’-(4-(3,3-二氟吡咯烷-1-基)-3-氧丙-1-烯-1-基)-2,2’-二甲基-[1,1’-聯苯]-3-基)甲氧基)卞基)呱啶-2-羧酸(110mg,21% yield)。 Compound (E)-5-((4-chloro-5-((3'-(3-(3,3-difluoropyrrolidin-1-yl)-3-oxoprop-1-ene-1- (Base)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-carboxyphenoxy)methyl)nicotinonitrile (430mg, 0.67mmol) And (S)-piperidine-2-carboxylic acid (173 mg, 1.34 mmol) was dissolved in dichloromethane (3 mL) and stirred at room temperature for 4 hours. Then sodium cyanoborohydride (50 mg, 0.8 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. After the reaction, 1N hydrochloric acid solution was slowly added to adjust the pH to 5, and then diluted with dichloromethane (40 mL). The mixed solution was washed once with water (40 mL). The organic phase was dried with anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was separated and purified on a C18 column (with 10%-95% ACN in water) to obtain a white solid (S,E)-1-(5-chloro-2-((5-cyanopyridine- 3-yl)methoxy)-4-((3'-(4-(3,3-difluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (110mg, 21% yield).

1H NMR(400MHz,CD3OD)：δ 8.85-8.23(m,2H),8.29(s,1H),7.95(d,J=15.6Hz,1H),7.63(d,J=7.6Hz,1H),7.54(s,1H),7.38(d,J=7.2Hz,1H),7.22-7.15(m,2H),7.06-7.01(m,2H),6.74(dd,J=15.2Hz,J=39.2Hz,1H),5.26(s,2H),5.20(s,2H),4.31(d,J=13.2Hz,1H),4.18-4.03(m,2H),3.91(t,J=6.8Hz,1H), 3.79(t,J=13.2Hz,1H),3.69(t,J=7.2Hz,1H),3.38(s,1H),2.75(s,1H),2.47-2.36(m,2H),2.00-1.83(m,7H),1.68-1.40(m,6H)； 1H NMR(400MHz,CD 3 OD): δ 8.85-8.23(m,2H), 8.29(s,1H), 7.95(d, J =15.6Hz,1H), 7.63(d, J =7.6Hz,1H) ,7.54(s,1H),7.38(d, J =7.2Hz,1H),7.22-7.15(m,2H),7.06-7.01(m,2H),6.74(dd, J =15.2Hz, J =39.2 Hz, 1H), 5.26 (s, 2H), 5.20 (s, 2H), 4.31 (d, J =13.2 Hz, 1H), 4.18-4.03 (m, 2H), 3.91 (t, J = 6.8 Hz, 1H ), 3.79(t, J =13.2Hz,1H), 3.69(t, J =7.2Hz,1H), 3.38(s,1H), 2.75(s,1H), 2.47-2.36(m,2H),2.00 -1.83(m,7H),1.68-1.40(m,6H);

MS Calcd：754；MS Found：755.4([M+H]+). MS Calcd: 754; MS Found: 755.4([M+H] + ).

實施例48 Example 48

(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-(S)-3-羥基吡咯烷的製備 (E)-1-(4-(3-Bromo-2-methylphenyl)but-3-en-1-yl)-(S)-3-hydroxypyrrolidine

Figure 108130887-A0202-12-0047-88
Figure 108130887-A0202-12-0047-88

無色油狀物(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-(S)-3-羥基吡咯烷(240mg,0.77mmol,47.1%)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(500mg,1.64mmol)和(S)-3-羥基吡咯烷(400mg,4.60mmol)按照實施例14中的類似步驟製備而成。 Colorless oil (E)-1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)-(S)-3-hydroxypyrrolidine (240mg, 0.77mmol , 47.1%) is composed of (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (500mg, 1.64mmol) and (S)-3-hydroxyl Pyrrolidine (400 mg, 4.60 mmol) was prepared following the similar procedure in Example 14.

LC-MS(m/z)：311(M+1)。 LC-MS (m/z): 311 (M+1).

實施例49 Example 49

(S，E)-5-溴-4-((3'-(4-(3-羥基吡咯烷-1-基)丁-1-烯-1-基)-2,2'-二甲基-[1，1,1'-聯苯]-3-基)甲氧基)-2-甲基苯甲醛的製備 (S,E)-5-bromo-4-((3'-(4-(3-hydroxypyrrolidin-1-yl)but-1-en-1-yl)-2,2'-dimethyl -[1,1,1'-Biphenyl]-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0047-89
Figure 108130887-A0202-12-0047-89

灰白色固體(S，E)-5-氯-4-((3'-(4-(3-羥基吡咯烷-1-基)丁-1-烯-1-基)-2,2'-二甲基-[1，1,1'-聯苯]-3-基)甲氧基)-2-甲基苯甲醛(140mg,0.27mmol,35.9%)是由(E)-1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-(S)-3-羥基吡咯烷(240mg,0.77mmol,)和5-氯-2-甲基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛(310mg,0.77mmol)按照實施例17中的類似步驟製備而成。 Off-white solid (S, E)-5-chloro-4-((3'-(4-(3-hydroxypyrrolidin-1-yl)but-1-en-1-yl)-2,2'-di Methyl-[1,1,1'-biphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (140mg, 0.27mmol, 35.9%) is composed of (E)-1-(4- (3-Bromo-2-methylphenyl)but-3-en-1-yl)-(S)-3-hydroxypyrrolidine (240mg, 0.77mmol,) and 5-chloro-2-methyl-4 -[2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-benzaldehyde( 310 mg, 0.77 mmol) was prepared according to the similar procedure in Example 17.

LC-MS(m/z)：505(M+1)。 LC-MS (m/z): 505 (M+1).

實施例50 Example 50

(S)-1-(5-氯-4-((3'-((E)-4-((S)-3-羥基吡咯烷-1-基)丁-1-烯-1-基) -2-，2'-二甲基-[1,1'-聯苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 (S)-1-(5-chloro-4-((3'-((E)-4-((S)-3-hydroxypyrrolidin-1-yl)but-1-en-1-yl) -2-,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0048-90
Figure 108130887-A0202-12-0048-90

白色固體(S)-1-(5-氯-4-((3'-((E)-4-((S)-3-羥基吡咯烷-1-基)丁-1-烯-1-基)-2-，2'-二甲基-[1,1'-聯苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(18mg,0.029mmol,14.7%yield)是由(S,E)-5-氯-4-((3'-(4-(3-羥基吡咯烷-1-基)丁-1-烯-1-基)-2,2'-二甲基-[1，1,1'-聯苯]-3-基)甲氧基)-2-甲基苯甲醛(100mg,0.20mmol)和L-呱啶-2-甲酸(89mg,0.69mmol)按照實施例18中的類似步驟製備而成。 White solid (S)-1-(5-chloro-4-((3'-((E)-4-((S)-3-hydroxypyrrolidin-1-yl)but-1-ene-1- (Yl)-2-,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (18mg, 0.029mmol, 14.7% yield) is composed of (S,E)-5-chloro-4-((3'-(4-(3-hydroxypyrrolidin-1-yl)but-1-en-1-yl) -2,2'-Dimethyl-[1,1,1'-biphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (100mg, 0.20mmol) and L-piperidine-2 -Formic acid (89mg, 0.69mmol) was prepared according to the similar procedure in Example 18.

1H NMR(400MHz,DMSO-d6)δ 9.89(s,br,1H),7.50(dd,J=13.3,7.7Hz,2H),7.33(s,1H),7.27(dt,J=16.1,7.6Hz,2H),7.15(s,1H),7.07(d,J=7.6Hz,1H),7.00(d,J=7.4Hz,1H),6.83(d,J=15.6Hz,1H),6.13(dt,J=15.0,6.9Hz,1H),5.45(s,1H),5.21(s,2H),4.44(s,1H),3.77(d,J=13.4Hz,1H),3.42(d,J=13.4Hz,1H),3.36-3.07(m,5H),2.88-2.79(m,1H),2.62(q,J=7.4Hz,2H),2.32(s,3H),2.29-2.22(m,1H),2.18-2.13(m,1H),2.01(s,3H),1.97(s,3H),1.93-1.82(m,1H),1.78-1.73(m,2H),1.59-1.15(m,5H). 1H NMR(400MHz,DMSO-d6)δ 9.89(s,br,1H), 7.50(dd,J=13.3,7.7Hz,2H),7.33(s,1H), 7.27(dt,J=16.1,7.6Hz ,2H),7.15(s,1H),7.07(d,J=7.6Hz,1H),7.00(d,J=7.4Hz,1H),6.83(d,J=15.6Hz,1H),6.13(dt ,J=15.0,6.9Hz,1H),5.45(s,1H),5.21(s,2H),4.44(s,1H),3.77(d,J=13.4Hz,1H),3.42(d,J= 13.4Hz, 1H), 3.36-3.07 (m, 5H), 2.88-2.79 (m, 1H), 2.62 (q, J=7.4Hz, 2H), 2.32 (s, 3H), 2.29-2.22 (m, 1H) ), 2.18-2.13(m,1H),2.01(s,3H),1.97(s,3H),1.93-1.82(m,1H),1.78-1.73(m,2H),1.59-1.15(m,5H) ).

LC-MS(m/z)：618(M+1)。 LC-MS (m/z): 618 (M+1).

實施例51 Example 51

叔丁基-N-[2-(丙基-2-烯胺)乙基]氨基甲酸酯的製備 Preparation of tert-butyl-N-[2-(propyl-2-enamine) ethyl] carbamate

Figure 108130887-A0202-12-0048-91
Figure 108130887-A0202-12-0048-91

將N-叔丁氧基羰基-1,2-乙二胺(2.1g,13.125mmol)和TEA(3.977g,39.375mmol)溶於THF(30mL)中，用冰/鹽浴冷卻至0℃，滴加丙烯醯氯(2.376g,26.250mmol,2.0eq)，所得混合液在室溫下攪拌2h。將生成的固體過濾掉，濃縮濾液得黃色油狀叔丁基-N-[2-(丙基-2-烯胺)乙基]氨基甲酸酯粗產物(3.12g，13.125mmol，產率按100%計)，不經純化直接用於下一步。 Dissolve N-tert-butoxycarbonyl-1,2-ethylenediamine (2.1g, 13.125mmol) and TEA (3.977g, 39.375mmol) in THF (30mL) and cool to 0℃ with an ice/salt bath, Propylene chloride (2.376g, 26.250mmol, 2.0eq) was added dropwise, and the resulting mixture was stirred at room temperature for 2h. The resulting solid was filtered off, and the filtrate was concentrated to obtain a yellow oily tert-butyl-N-[2-(propyl-2-enamine)ethyl]carbamate crude product (3.12g, 13.125mmol, the yield was as per 100%), used directly in the next step without purification.

LC-MS(m/z)：215(M+1)。 LC-MS (m/z): 215 (M+1).

實施例52 Example 52

N-(2-氨基乙基)丙烯醯胺的製備 Preparation of N-(2-aminoethyl) acrylamide

Figure 108130887-A0202-12-0049-92
Figure 108130887-A0202-12-0049-92

將黃色油狀叔丁基-N-[2-(丙基-2-烯胺)乙基]氨基甲酸酯粗產物(3.12 g,13.125mmol)溶於DCM(30mL)中，加入TFA(30mL)，在室溫下攪拌1h。濃縮得N-(2-氨基乙基)丙烯醯胺(4.17g，13.125mmol，產率按100%計)粗產物，不經純化直接用於下一步。 The yellow oily tert-butyl-N-[2-(propyl-2-enamine)ethyl]carbamate crude product (3.12 g, 13.125 mmol) was dissolved in DCM (30 mL), TFA (30 mL) was added, and the mixture was stirred at room temperature for 1 h. Concentrated to obtain the crude product of N-(2-aminoethyl)acrylamide (4.17g, 13.125mmol, yield is 100%), which was directly used in the next step without purification.

LC-MS(m/z)：115(M+1)。 LC-MS (m/z): 115 (M+1).

實施例53 Example 53

(E)-N-(2-{5-氯-4-[2,2’-二甲基-3’-(4-嗎啉-4-基-丁基-1-烯基)-二苯基-3-基甲氧基]-2-甲基-苯並氨基}-乙基)-丙烯醯胺的製備 (E) -N-(2-{5-chloro-4-[2,2'-dimethyl-3'-(4-morpholin-4-yl-butyl-1-enyl)-diphenyl -3-ylmethoxy]-2-methyl-benzamino}-ethyl)-propenamide

Figure 108130887-A0202-12-0049-93
Figure 108130887-A0202-12-0049-93

將(E)-5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(300mg,0.596mmol)，N-(2-氨基乙基)丙烯醯胺(1.5g粗品，4.721mmol)溶於DCM/MeOH(20mL/2mL)中，加入TEA(2mL)，在室溫下攪拌18h，加入NaBH3CN(227.1mg,3.576mmol)，繼續攪拌2h。反應用水淬滅，用乙酸乙酯萃取3次，合併有機相，無水Na2SO4乾燥，濃縮。粗品用製備薄層色譜版(DCM/MeOH=6/1)純化一次，再用製備薄層色譜版(EA)純化一次得黃色固體(E)-N-(2-{5-氯-4-[2,2’-二甲基-3’-(4-嗎啉-4-基-丁基-1-烯基)-二苯基-3-基甲氧基]-2-甲基-苯並氨基}-乙基)-丙烯醯胺(37.0mg,0.0616mmol,10.3% yield)。 Add (E)-5-chloro-4-((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1, 1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (300mg, 0.596mmol), N-(2-aminoethyl)acrylamide (1.5g crude product, 4.721mmol) Dissolve in DCM/MeOH (20mL/2mL), add TEA (2mL), stir at room temperature for 18h, add NaBH3CN (227.1mg, 3.576mmol), continue stirring for 2h. The reaction was quenched with water, extracted 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified once by preparative thin layer chromatography (DCM/MeOH=6/1), and then purified by preparative thin layer chromatography (EA) once to obtain a yellow solid (E) -N-(2-{5-chloro-4- [2,2'-Dimethyl-3'-(4-morpholin-4-yl-butyl-1-enyl)-diphenyl-3-ylmethoxy]-2-methyl-benzene B-amino}-ethyl)-acrylamide (37.0 mg, 0.0616 mmol, 10.3% yield).

1H NMR(400MHz,DMSO-d 6)δ 7.50(dd,J=7.9,4.7Hz,2H),7.43(dd,J=7.8,3.3Hz,2H),7.40-7.09(m,6H),7.07(dp,J=12.0,4.3,3.6Hz,2H),6.96(dd,J=7.6,4.8Hz,2H),6.72(dd,J=15.7,4.6Hz,2H),6.29-6.01(m,4H),5.56 (td,J=10.2,2.3Hz,1H),5.23-5.13(m,4H),3.66-3.54(m,6H),3.46(d,J=7.5Hz,1H),3.31-3.09(m,3H),2.64(tq,J=19.9,7.0Hz,3H),2.42(dd,J=15.0,8.5Hz,19H),2.31(s,3H),2.01(s,3H),1.95(s,3H). 1 H NMR(400MHz, DMSO- d 6 )δ 7.50(dd, J =7.9,4.7Hz,2H), 7.43(dd, J =7.8,3.3Hz,2H), 7.40-7.09(m,6H), 7.07 (dp, J =12.0,4.3,3.6Hz,2H), 6.96(dd, J =7.6,4.8Hz,2H), 6.72(dd, J =15.7,4.6Hz,2H), 6.29-6.01(m,4H ),5.56 (td, J =10.2,2.3Hz,1H),5.23-5.13(m,4H),3.66-3.54(m,6H),3.46(d, J =7.5Hz,1H),3.31-3.09( m,3H), 2.64(tq, J =19.9,7.0Hz,3H), 2.42(dd, J =15.0,8.5Hz,19H), 2.31(s,3H),2.01(s,3H),1.95(s ,3H).

LC-MS(m/z)：602.3(M+1)。 LC-MS (m/z): 602.3 (M+1).

實施例54 Example 54

3-(3-溴-2-甲基-苯基)-丙烯酸乙酯的製備 Preparation of 3-(3-bromo-2-methyl-phenyl)-ethyl acrylate

Figure 108130887-A0202-12-0050-94
Figure 108130887-A0202-12-0050-94

將NaH(60%,484mg,12.120mmol)懸浮於超幹THF(30mL)中，用冰/鹽浴冷卻至0℃，加入膦醯基乙酸三乙酯(2.49g,11.116mmol)。在此溫度下攪拌30min後滴加3-溴-2-甲基苯甲醛(2.0g,10.102mmol)的THF(5mL)溶液，並繼續攪拌1h。反應用飽和NH4Cl溶液淬滅，用乙酸乙酯萃取2次。合併有機相，飽和食鹽水洗1次，無水Na2SO4乾燥，濃縮得黃色油狀3-(3-溴-2-甲基-苯基)-丙烯酸乙酯粗品(3.7g,10.102mmol，產率按100%計)，不經純化直接用於下一步。 NaH (60%, 484 mg, 12.120 mmol) was suspended in ultra-dry THF (30 mL), cooled to 0° C. with an ice/salt bath, and triethyl phosphinyl acetate (2.49 g, 11.116 mmol) was added. After stirring at this temperature for 30 min, a solution of 3-bromo-2-methylbenzaldehyde (2.0 g, 10.102 mmol) in THF (5 mL) was added dropwise, and stirring was continued for 1 h. The reaction was quenched with saturated NH 4 Cl solution and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine once, dried over anhydrous Na 2 SO 4 , and concentrated to obtain crude 3-(3-bromo-2-methyl-phenyl)-acrylic acid ethyl ester (3.7 g, 10.102 mmol, yield) as a yellow oil The rate is calculated as 100%) and used directly in the next step without purification.

LC-MS(m/z)：269(M+1)。 LC-MS (m/z): 269 (M+1).

實施例55 Example 55

3-(3-溴-2-甲基-苯基)-丙烯-2-1-醇的製備 Preparation of 3-(3-bromo-2-methyl-phenyl)-propene-2--1-ol

Figure 108130887-A0202-12-0050-95
Figure 108130887-A0202-12-0050-95

將3-(3-溴-2-甲基-苯基)-丙烯酸乙酯(3.7g,10.102mmol,1.0eq)溶於超幹DCM(30mL)中，氮氣球置換3次氮氣，用冰/鹽浴冷卻至0℃，滴加DIBAL-H(1mol/L的甲苯溶液，21.2mL,21.200mmol,2.1eq)，並繼續在此溫度下攪拌1h。反應用冰/水淬滅，用1N HCl(15mL)酸化。過濾除去固體，濾液用DCM萃取3次。合併有機相，濃縮。粗品用矽膠柱純化(PE/EA =4/1洗脫)得無色油狀3-(3-溴-2-甲基-苯基)-丙烯-2-1-醇(2.1g,9.292mmol,92.0% yield)。 Dissolve 3-(3-bromo-2-methyl-phenyl)-ethyl acrylate (3.7g, 10.102mmol, 1.0eq) in ultra-dry DCM (30mL), replace the nitrogen with a nitrogen balloon 3 times, and use ice/ The salt bath was cooled to 0°C, DIBAL-H (1mol/L toluene solution, 21.2mL, 21.200mmol, 2.1eq) was added dropwise, and stirring was continued at this temperature for 1h. The reaction was quenched with ice/water and acidified with 1N HCl (15 mL). The solid was removed by filtration, and the filtrate was extracted 3 times with DCM. Combine the organic phases and concentrate. The crude product is purified by silica gel column (PE/EA = 4/1 elution) to obtain a colorless oily 3-(3-bromo-2-methyl-phenyl)-propene-2-1-ol (2.1g, 9.292mmol, 92.0% yield).

LC-MS(m/z)：227(M+1)。 LC-MS (m/z): 227 (M+1).

實施例56 Example 56

甲磺酸3-(3-溴-2-甲基-苯基)-烯丙基酯的製備 Preparation of 3-(3-bromo-2-methyl-phenyl)-allyl methanesulfonate

Figure 108130887-A0202-12-0051-96
Figure 108130887-A0202-12-0051-96

將3-(3-溴-2-甲基-苯基)-丙烯-2-1-醇(452mg,2.000mmol,)溶於超幹DCM(10mL)中，用冰/鹽浴冷卻至0℃，加入TEA(606mg,6.000mmol)，滴加MsCl(456mg,4.000mmol)。所得混合液在室溫下攪拌4h。反應用DCM稀釋，用水洗3次。有機相用無水Na2SO4乾燥，濃縮得黃色油狀甲磺酸3-(3-溴-2-甲基-苯基)-烯丙基酯粗品(626mg,2.000mmol，產率按100%計)，不經純化直接用於下一步。 Dissolve 3-(3-bromo-2-methyl-phenyl)-propene-2-1-ol (452mg, 2.000mmol,) in ultra-dry DCM (10mL), and cool to 0℃ with ice/salt bath , TEA (606 mg, 6.000 mmol) was added, and MsCl (456 mg, 4.000 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 4h. The reaction was diluted with DCM and washed 3 times with water. The organic phase was dried with anhydrous Na 2 SO 4 and concentrated to obtain crude 3-(3-bromo-2-methyl-phenyl)-allyl methanesulfonate (626 mg, 2.000 mmol, 100% yield) as a yellow oil Calculated), used directly in the next step without purification.

LC-MS(m/z)：305(M+1)。 LC-MS (m/z): 305 (M+1).

實施例57 Example 57

4-[3-(3-溴-2-甲基-苯基)-烯基]嗎啉的製備 Preparation of 4-[3-(3-bromo-2-methyl-phenyl)-alkenyl]morpholine

Figure 108130887-A0202-12-0051-97
Figure 108130887-A0202-12-0051-97

將甲磺酸3-(3-溴-2-甲基-苯基)-烯丙基酯(626mg粗品，2.000mmol)溶於DMF(10mL)中，加入嗎啉(348mg,4.000mmol)和K2CO3(834mg,6.000mmol)，在室溫下攪拌18h。反應用水淬滅，用乙酸乙酯萃取3次。合併有機相，用飽和食鹽水洗3次，濃縮。粗品用矽膠柱純化(先用EA洗脫，再用DCM/MeOH=6/1)得4-[3-(3-溴-2-甲基-苯基)-烯基]嗎啉(530mg,1.797mmol,89.8% yield)。 3-(3-Bromo-2-methyl-phenyl)-allyl methanesulfonate (626mg crude product, 2.000mmol) was dissolved in DMF (10mL), morpholine (348mg, 4.000mmol) and K were added 2 CO 3 (834mg, 6.000mmol), stirred at room temperature for 18h. The reaction was quenched with water and extracted 3 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, and concentrated. The crude product was purified by silica gel column (first eluted with EA, then DCM/MeOH=6/1) to obtain 4-[3-(3-bromo-2-methyl-phenyl)-enyl]morpholine (530mg, 1.797mmol, 89.8% yield).

LC-MS(m/z)：296(M+1)。 LC-MS (m/z): 296 (M+1).

實施例58 Example 58

5-氯-2-羥基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛的製備 5-chloro-2-hydroxy-4-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -Benzyloxy]-benzaldehyde

Figure 108130887-A0202-12-0052-98
Figure 108130887-A0202-12-0052-98

淺黃色固體5-氯-2-羥基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛(1.33g,3.308mmol,33% yield)是由2-甲基-3-(羥甲基)苯硼酸頻哪醇酯(實施例15,2.48g,10.000mmol)和5-氯-2,4-二羥基-苯甲醛(1.72g,10.000mmol)按照實施例16中的類似步驟製備而成。 Light yellow solid 5-chloro-2-hydroxy-4-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 -Yl)-benzyloxy)-benzaldehyde (1.33g, 3.308mmol, 33% yield) is composed of 2-methyl-3-(hydroxymethyl)phenylboronic acid pinacol ester (Example 15, 2.48g, 10.000mmol) and 5-chloro-2,4-dihydroxy-benzaldehyde (1.72g, 10.000mmol) were prepared according to the similar procedure in Example 16.

LC-MS(m/z)：403(M+1)。 LC-MS (m/z): 403 (M+1).

實施例59 Example 59

5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-羥基苯甲醛的製備 5-chloro-4-((3'-(4-(pyridin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl (Yl)-3-yl)methoxy)-2-hydroxybenzaldehyde

Figure 108130887-A0202-12-0052-100
Figure 108130887-A0202-12-0052-100

橙色固體5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-羥基苯甲醛(422mg,0.859mmol,84.5% yield)是由5-氯-2-羥基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛(409mg,1.017mmol)和4-[3-(3-溴-2-甲基-苯基)-烯基]嗎啉(300mg,1.017mmol)按照實施例17中的類似步驟製備而成。 Orange solid 5-chloro-4-((3'-(4-(piridin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'- Diphenyl)-3-yl)methoxy)-2-hydroxybenzaldehyde (422mg, 0.859mmol, 84.5% yield) is composed of 5-chloro-2-hydroxy-4-[2-methyl-3-( 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-benzaldehyde (409mg, 1.017mmol) and 4-[3 -(3-Bromo-2-methyl-phenyl)-alkenyl]morpholine (300mg, 1.017mmol) was prepared according to the similar procedure in Example 17.

LC-MS(m/z)：492(M+1)。 LC-MS (m/z): 492 (M+1).

實施例60 Example 60

5-(氯甲基)煙腈的製備 Preparation of 5-(chloromethyl)nicotinonitrile

Figure 108130887-A0202-12-0053-101
Figure 108130887-A0202-12-0053-101

將(5-氰基吡啶-3-基)-甲醇(288mg,2.149mmol)溶於DCM(10mL)中，加入SOCl2(3.0mL)，在室溫下攪拌2h。濃縮得白色固體5-(氯甲基)煙腈粗品(422mg，產率按100%計)，不經純化直接用於下一步。 (5-Cyanopyridin-3-yl)-methanol (288 mg, 2.149 mmol) was dissolved in DCM (10 mL), SOCl 2 (3.0 mL) was added, and the mixture was stirred at room temperature for 2 h. It was concentrated to obtain crude 5-(chloromethyl)nicotinonitrile as a white solid (422 mg, 100% yield), which was directly used in the next step without purification.

LC-MS(m/z)：153(M+1)。 LC-MS (m/z): 153 (M+1).

實施例61 Example 61

5-{4-氯-5-[2,2’-二甲基-3’-(3-嗎啉-4-基-丙基)-雙苯-3-甲氧基]-2-甲基-苯氧甲基}-煙腈的製備 5-{4-chloro-5-[2,2'-dimethyl-3'-(3-morpholin-4-yl-propyl)-bisphenyl-3-methoxy]-2-methyl -Phenoxymethyl}-Nicotinonitrile Preparation

Figure 108130887-A0202-12-0053-102
Figure 108130887-A0202-12-0053-102

將5-(氯甲基)煙腈(422mg粗品，2.149mmol)溶於DMF(10mL)中，加入5-氯-4-((3’-(4-(呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-羥基苯甲醛(422mg,0.859mmol)和K2CO3(597mg,4.30mmol)，在室溫下攪拌18h。反應用水淬滅，用乙酸乙酯萃取3次。合併有機相，用飽和食鹽水洗3次，無水Na2SO4乾燥，濃縮。粗品用矽膠柱純化(DCM/MeOH=10/1洗脫)得橙色固體5-{4-氯-5-[2,2’-二甲基-3’-(3-嗎啉-4-基-丙基)-雙苯-3-甲氧基]-2-甲基-苯氧甲基}-煙腈(503mg,0.829mmol,96.5% yield)。 5-(Chloromethyl)nicotinonitrile (422mg crude product, 2.149mmol) was dissolved in DMF (10mL), and 5-chloro-4-((3'-(4-(piridin-1-yl)butyl- 1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (422mg, 0.859mmol) and K 2 CO 3 (597 mg, 4.30 mmol) was stirred at room temperature for 18 h. The reaction was quenched with water and extracted 3 times with ethyl acetate. The organic phases were combined, washed 3 times with saturated brine, dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified by silica gel column (DCM/MeOH=10/1 elution) to obtain an orange solid 5-{4-chloro-5-[2,2'-dimethyl-3'-(3-morpholin-4-yl -Propyl)-bisphenyl-3-methoxy]-2-methyl-phenoxymethyl}-nicotinonitrile (503 mg, 0.829 mmol, 96.5% yield).

LC-MS(m/z)：608(M+1)。 LC-MS (m/z): 608 (M+1).

實施例62 Example 62

(S)-1-{5-氯-2-(5-氰基吡啶-3-甲氧基)-4-[2,2’-二甲基-3’-(3-嗎啉-4-基-丙基)-二苯基-3-甲氧基]-苯基}-呱啶-2-羧酸的製備 (S) -1-{5-chloro-2-(5-cyanopyridine-3-methoxy)-4-[2,2'-dimethyl-3'-(3-morpholine-4- -Propyl)-diphenyl-3-methoxy]-phenyl}-piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0054-103
Figure 108130887-A0202-12-0054-103

淺黃色固體(S)-1-{5-氯-2-(5-氰基吡啶-3-甲氧基)-4-[2,2’-二甲基-3’-(3-嗎啉-4-基-丙基)-二苯基-3-甲氧基]-苯基}-呱啶-2-羧酸(10.4mg,0.0144mmol,3.2% yield)是由5-{4-氯-5-[2,2’-二甲基-3’-(3-嗎啉-4-基-丙基)-雙苯-3-甲氧基]-2-甲基-苯氧甲基}-煙腈(260mg,0.428mmol)和L-呱啶-2-甲酸(221mg,0.713mmol)按照實施例18中的類似步驟製備而成 Light yellow solid (S) -1-{5-chloro-2-(5-cyanopyridine-3-methoxy)-4-[2,2'-dimethyl-3'-(3-morpholine) -4-yl-propyl)-diphenyl-3-methoxy]-phenyl)-piperidine-2-carboxylic acid (10.4mg, 0.0144mmol, 3.2% yield) is made of 5-(4-chloro -5-[2,2'-Dimethyl-3'-(3-morpholin-4-yl-propyl)-bisphenyl-3-methoxy]-2-methyl-phenoxymethyl} -Nicotinonitrile (260mg, 0.428mmol) and L-piperidine-2-carboxylic acid (221mg, 0.713mmol) were prepared according to the similar steps in Example 18.

1H NMR(400MHz,CD3OD)：δ 9.01(dd,J=5.6,2.0Hz,2H),8.46(s,1H),7.50(d,J=7.7Hz,2H),7.42(s,1H),7.25(dt,J=19.0,7.5Hz,2H),7.12(s,1H),7.08(d,J=7.5Hz,1H),7.00(d,J=7.4Hz,1H),6.84(d,J=15.7Hz,1H),6.17(dt,J=15.6,6.6Hz,1H),5.39(s,2H),5.33(s,2H),5.27(s,2H),3.78(d,J=13.7Hz,1H),3.63(s,1H),3.13(d,J=6.5Hz,3H),2.88(d,J=8.5Hz,1H),2.42(t,J=4.5Hz,4H),2.28(m,1H),2.07-1.87(m,7H),1.82-1.77(m,2H),1.76-1.71(m,1H),1.51-1.46(m,4H),1.43-1.31(m,1H). 1H NMR(400MHz,CD 3 OD): δ 9.01(dd, J =5.6,2.0Hz,2H), 8.46(s,1H), 7.50(d, J =7.7Hz,2H), 7.42(s,1H) ,7.25(dt, J =19.0,7.5Hz,2H),7.12(s,1H),7.08(d, J =7.5Hz,1H),7.00(d, J =7.4Hz,1H),6.84(d, J =15.7Hz,1H), 6.17(dt, J =15.6,6.6Hz,1H), 5.39(s,2H), 5.33(s,2H), 5.27(s,2H), 3.78(d, J =13.7 Hz, 1H), 3.63 (s, 1H), 3.13 (d, J = 6.5 Hz, 3H), 2.88 (d, J = 8.5 Hz, 1H), 2.42 (t, J = 4.5 Hz, 4H), 2.28 ( m, 1H), 2.07-1.87 (m, 7H), 1.82-1.77 (m, 2H), 1.76-1.71 (m, 1H), 1.51-1.46 (m, 4H), 1.43-1.31 (m, 1H).

LC-MS(m/z)：721.3(M+1)。 LC-MS (m/z): 721.3 (M+1).

實施例63 Example 63

(E)-2-((5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氨基)丙烷-1,3-二醇的製備 ( E )-2-((5-Chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'- Preparation of diphenyl)-3-yl)methoxy)-2-methylbenzyl)amino)propane-1,3-diol

Figure 108130887-A0202-12-0054-104
Figure 108130887-A0202-12-0054-104

白色固體(E)-2-((5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氨基)丙烷-1,3-二醇(71mg，0.12mol，65.0%yield)由5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(95mg，0.19mmol)和2-氨基-1,3-丙二醇鹽酸鹽(127.5mg，1.0mmol)按照實施例6的類似步驟製備而成。 White solid ( E )-2-((5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1 '-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)amino)propane-1,3-diol (71mg, 0.12mol, 65.0% yield) is composed of 5-chloro-4- ((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl )Methoxy)-2-methylbenzaldehyde (95mg, 0.19mmol) and 2-amino-1,3-propanediol hydrochloride (127.5mg, 1.0mmol) were prepared according to the similar procedure of Example 6.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.50(d,J=7.7Hz,1H),7.43(d,J=8.0Hz,1H),7.38(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.14(s,1H),7.07(d,J=7.3Hz,1H),6.96(d,J=7.4Hz,1H),6.72(d,J=15.7Hz,1H),6.15(dt,J=15.5,6.5Hz,1H)，5.20(s,2H),4.44(s,2H),3.67(s,2H),3.58(t,J=4.6Hz,4H),3.47-3.35(m,4H),2.56(p,J=5.7Hz,1H),2.48-2.35(m,9H),2.29(s,3H),2.01(s,3H),1.95(s,3H)。 1 H-NMR(400MHz,DMSO- d 6 )δ ppm 7.50(d, J =7.7Hz,1H), 7.43(d, J =8.0Hz,1H), 7.38(s,1H), 7.28(t, J =7.6Hz,1H),7.21(t, J =7.6Hz,1H),7.14(s,1H),7.07(d, J =7.3Hz,1H), 6.96(d, J =7.4Hz,1H), 6.72(d, J =15.7Hz,1H), 6.15(dt, J =15.5,6.5Hz,1H), 5.20(s, 2H), 4.44(s, 2H), 3.67(s, 2H), 3.58(t , J =4.6Hz,4H),3.47-3.35(m,4H),2.56(p, J =5.7Hz,1H),2.48-2.35(m,9H),2.29(s,3H),2.01(s, 3H), 1.95(s, 3H).

MS Calcd：578.3 MS Found：579.4([M+H]+). MS Calcd: 578.3 MS Found: 579.4([M+H] + ).

實施例64 Example 64

(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸甲酯的製備 ( E )-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-diphenyl ]-3-yl)methoxy)-2-methylbenzyl)glycine methyl ester

Figure 108130887-A0202-12-0055-105
Figure 108130887-A0202-12-0055-105

淺黃色固體(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸甲酯 Light yellow solid ( E )-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'- (Diphenyl)-3-yl)methoxy)-2-methylbenzyl)glycine methyl ester

(55.0mg,0.095mmol,55.0%yield)由5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(88mg，0.17mmol)和甘氨酸甲酯鹽酸鹽(90.0mg,0.7mmol)按照實施例6的類似步驟製備而成。 (55.0mg, 0.095mmol, 55.0% yield) is composed of 5-chloro-4-((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'- Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (88mg, 0.17mmol) and glycine methyl ester hydrochloride (90.0mg, 0.7mmol) Prepared according to the similar steps of Example 6.

MS Calcd：576.2 MS Found：577.4([M+H]+). MS Calcd: 576.2 MS Found: 577.4([M+H] + ).

實施例65 Example 65

(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸 ( E )-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-diphenyl )-3-yl)methoxy)-2-methylbenzyl)glycine

Figure 108130887-A0202-12-0056-107
Figure 108130887-A0202-12-0056-107

(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸(12.5mg,0.022mmol,23.4%yield)由(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)甘氨酸甲酯(55.0mg，0.095mol)在LiOH/THF條件下按照實施例25中的類似步驟製備而成。 ( E )-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-diphenyl )-3-yl)methoxy)-2-methylbenzyl)glycine (12.5mg, 0.022mmol, 23.4% yield) is composed of ( E )-(5-chloro-4-((2,2'-二Methyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)glycine The methyl ester (55.0 mg, 0.095 mol) was prepared by following the similar procedure in Example 25 under LiOH/THF conditions.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.54-7.40(m,3H),7.28(t,J=7.6Hz,1H,),7.25-7.16(m,2H),7.07(d,J=7.5Hz,1H),6.96(d,J=7.5Hz,1H),6.72(d,J=15.6Hz,1H),6.15(dt,J=15.3,6.4Hz,1H),5.23(s,2H),3.84(s,2H),3.57(t,J=4.6Hz,4H),3.12(s,2H),2.48-2.36(m,8H),2.34(s,3H),2.01(s,3H),1.95(s,3H) 1 H-NMR (400MHz, DMSO- d 6 ) δ ppm 7.54-7.40 (m, 3H), 7.28 (t, J = 7.6Hz, 1H,), 7.25-7.16 (m, 2H), 7.07 (d, J =7.5Hz,1H), 6.96(d, J =7.5Hz,1H), 6.72(d, J =15.6Hz,1H), 6.15(dt, J =15.3,6.4Hz,1H), 5.23(s,2H ), 3.84(s, 2H), 3.57(t, J = 4.6Hz, 4H), 3.12(s, 2H), 2.48-2.36(m, 8H), 2.34(s, 3H), 2.01(s, 3H) ,1.95(s,3H)

MS Calcd：562.2 MS Found：563.3([M+H]+). MS Calcd: 562.2 MS Found: 563.3([M+H] + ).

實施例66 Example 66

(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧 ( E )-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-diphenyl ]-3-yl)methoxy

Figure 108130887-A0202-12-0056-108
Figure 108130887-A0202-12-0056-108

基)-2-甲基苄基)-L-脯氨酸的製備 (B)-2-methylbenzyl) -L -proline preparation

類白色固體(E)-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)-L-脯氨酸(11.0mg,0.018mmol,9.0%yield)由 5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(100mg,0.20mmol)和L-脯氨酸鹽酸鹽(151mg,1.0mmol)按照實施例18中的類似步驟製備而成。 Off-white solid ( E )-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'- Diphenyl)-3-yl)methoxy)-2-methylbenzyl) -L -proline (11.0mg, 0.018mmol, 9.0% yield) is composed of 5-chloro-4-((3'- (4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy) -2-Methylbenzaldehyde (100 mg, 0.20 mmol) and L-proline hydrochloride (151 mg, 1.0 mmol) were prepared according to the similar procedure in Example 18.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.51(d,J=7.6Hz,1H),7.43(d,J=7.7Hz,1H),7.39(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.16(s,1H),7.07(d,J=7.5Hz,1H),6.96(d,J=7.4Hz,1H),6.72(d,J=15.6Hz,1H),6.16(dt,J=15.6,6.4Hz,1H),5.21(s,2H),3.97(d,J=13.1Hz,1H),3.58(s,2H),3.61-3.49(m,5H)3.23(dd,J=8.9,5.9Hz,1H),3.01-2.88(m,1H),2.48-2.37(m,8H),2.35(s,3H),2.17-2.03(m,1H),2.01(s,3H),1.95(s,3H),1.91-1.80(m,1H),1.80-1.64(m,2H). 1 H-NMR(400MHz,DMSO- d 6 )δ ppm 7.51(d, J =7.6Hz,1H), 7.43(d, J =7.7Hz,1H), 7.39(s,1H), 7.28(t, J =7.6Hz,1H),7.21(t, J =7.6Hz,1H),7.16(s,1H),7.07(d, J =7.5Hz,1H),6.96(d, J =7.4Hz,1H), 6.72(d, J =15.6Hz,1H),6.16(dt, J =15.6,6.4Hz,1H),5.21(s,2H),3.97(d, J =13.1Hz,1H),3.58(s,2H ), 3.61-3.49 (m, 5H) 3.23 (dd, J = 8.9, 5.9 Hz, 1H), 3.01-2.88 (m, 1H), 2.48-2.37 (m, 8H), 2.35 (s, 3H), 2.17 -2.03(m,1H),2.01(s,3H),1.95(s,3H),1.91-1.80(m,1H),1.80-1.64(m,2H).

MS Calcd：602.3 MS Found：603.4([M+H]+). MS Calcd: 602.3 MS Found: 603.4([M+H] + ).

實施例67 Example 67

(E)-4-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-2,6-二甲基嗎啉的製備 Preparation of (E)-4-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)-2,6-dimethylmorpholine

Figure 108130887-A0202-12-0057-109
Figure 108130887-A0202-12-0057-109

中間體(E)-4-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-2,6-二甲基嗎啉(420mg，1.24mmol，62.3%yield)由2,6-二甲基嗎啉(345mg，3.0mmol)和(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(604.0mg，2.0mmol)按照實施例14中的類似步驟製備而成。 Intermediate (E)-4-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)-2,6-dimethylmorpholine (420mg, 1.24mmol, 62.3 %yield) is composed of 2,6-dimethylmorpholine (345mg, 3.0mmol) and (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (604.0 mg, 2.0 mmol) was prepared according to the similar procedure in Example 14.

MS Calcd：337.1，339.1 MS Found：338.0，340.2([M+H]+). MS Calcd: 337.1, 339.1 MS Found: 338.0, 340.2([M+H] + ).

實施例68 Example 68

(E)-5-氯-4-((3’-(4-(2,6-二甲基嗎啉)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 ( E )-5-chloro-4-((3'-(4-(2,6-dimethylmorpholine)but-1-en-1-yl)-2,2'-dimethyl-[ 1,1'-Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0057-110
Figure 108130887-A0202-12-0057-110

中間體(E)-5-氯-4-((3’-(4-(2,6-二甲基嗎啉基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(530mg，1.0mmol，83.3%yield)由中間體(E)-4-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)-2,6-二甲基嗎啉(420mg，1.24mmol)和5-氯-2-甲基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛(480mg，1.20mmol)按照實施例17中的類似步驟製備而成。 Intermediate (E)-5-chloro-4-((3'-(4-(2,6-dimethylmorpholinyl)but-1-en-1-yl)-2,2'-dimethyl -[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (530mg, 1.0mmol, 83.3% yield) was prepared from intermediate (E)-4-(4- (3-Bromo-2-methylphenyl)but-3-en-1-yl)-2,6-dimethylmorpholine (420mg, 1.24mmol) and 5-chloro-2-methyl-4- [2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-benzaldehyde (480mg , 1.20 mmol) was prepared according to the similar procedure in Example 17.

MS Calcd：513.2 MS Found：514.4([M+H]+) MS Calcd: 513.2 MS Found: 514.4([M+H] + )

實施例69 Example 69

(2S)-1-(5-氯-4-((3’-((E)-4-(2,6-二甲基嗎啉基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( 2S )-1-(5-chloro-4-((3'-(( E )-4-(2,6-dimethylmorpholinyl)but-1-en-1-yl)-2, Preparation of 2'-dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0058-111
Figure 108130887-A0202-12-0058-111

淺黃色固體(2S)-1-(5-氯-4-((3’-((E)-4-(2,6-二甲基嗎啉基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(14.0mg,0.021mmol,10.8%yield)由中間體(E)-5-氯-4-((3’-(4-(2,6-二甲基嗎啉)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(105mg，0.20mmol)和L-呱啶-2-甲酸(118.0mg,0.92mmol)按照實施例18似步驟製備而成。 Light yellow solid ( 2S )-1-(5-chloro-4-((3'-(( E )-4-(2,6-dimethylmorpholinyl)but-1-en-1-yl) -2,2'-Dimethyl-[1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (14.0mg, 0.021mmol , 10.8% yield) from the intermediate ( E )-5-chloro-4-((3'-(4-(2,6-dimethylmorpholine)but-1-en-1-yl)-2, 2'-Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (105mg, 0.20mmol) and L-piperidine-2-carboxylic acid (118.0 mg, 0.92mmol) was prepared according to the same procedure as in Example 18.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.50(d,J=7.6Hz,1H),7.42(d,J=7.7Hz,1H),7.37(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.09(s,1H),7.06(d,J=7.6Hz,1H),6.96(d,J=7.4Hz,1H),6.72(d,J=15.6Hz,1H),6.14(dt,J=12.8,6.0Hz,1H)，5.18(s,2H),3.81(d,J=13.5Hz,1H,),3.59-3.49(m,2H),2.82-2.72(m,2H),2.46-2.36(m,4H),2.30(s,3H),2.00(s,3H),1.94(s,3H),1.78(s,3H),1.69-1.57(m,4H),1.55-1.50(m,2H),1.42-1.37(m,2H),1.29-1.20(m,2H),1.05(s,3H),1.04(s,3H). 1 H-NMR(400MHz,DMSO- d 6 )δ ppm 7.50(d, J =7.6Hz,1H), 7.42(d, J =7.7Hz,1H), 7.37(s,1H), 7.28(t, J =7.6Hz,1H),7.21(t, J =7.6Hz,1H),7.09(s,1H),7.06(d, J =7.6Hz,1H),6.96(d, J =7.4Hz,1H), 6.72(d, J =15.6Hz,1H),6.14(dt, J =12.8,6.0Hz,1H), 5.18(s,2H), 3.81(d, J =13.5Hz,1H,),3.59-3.49( m, 2H), 2.82-2.72 (m, 2H), 2.46-2.36 (m, 4H), 2.30 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H), 1.78 (s, 3H) ,1.69-1.57(m,4H),1.55-1.50(m,2H),1.42-1.37(m,2H),1.29-1.20(m,2H),1.05(s,3H),1.04(s,3H) .

MS Calcd：644.3 MS Found：645.5([M+H]+). MS Calcd: 644.3 MS Found: 645.5([M+H] + ).

實施例70 Example 70

3-羥基呱啶-2-甲酸甲酯的製備 Preparation of methyl 3-hydroxypiperidine-2-carboxylate

Figure 108130887-A0202-12-0059-112
Figure 108130887-A0202-12-0059-112

將3-羥基吡啶-2-甲酸(695.0mg,5.0mmol)溶解於甲醇(25mL)，冰浴下滴加SOCl2(3.6mL，50.0mmol)，滴畢，加熱至70℃反應18h，反應完畢，旋幹溶劑，得到3-羥基吡啶-2-甲酸甲酯粗品810mg；取粗品120mg溶解於甲醇(15mL)，加入Pt2O(100mg)氫氣條件下催化加氫反應24h，抽濾，濾液加Pd/C(5%,100mg)，氫氣條件下繼續催化加氫反應16h，抽濾，旋幹濾液，得到油狀物110mg，直接用於下一步反應。 Dissolve 3-hydroxypyridine-2-carboxylic acid (695.0mg, 5.0mmol) in methanol (25mL), add SOCl 2 (3.6mL, 50.0mmol) dropwise under ice bath, after dripping, heat to 70℃ and react for 18h, the reaction is complete , Spin off the solvent to obtain 810 mg crude 3-hydroxypyridine-2-carboxylate methyl ester; dissolve 120 mg of the crude product in methanol (15 mL), add Pt 2 O (100 mg), and catalyze the hydrogenation reaction for 24 hours under hydrogen conditions, filter with suction, and add the filtrate Pd/C (5%, 100mg), continued catalytic hydrogenation under hydrogen for 16h, filtered with suction and spin-dried the filtrate to obtain 110mg of oil, which was directly used in the next reaction.

MS Calcd：159.0MS Found：160.0([M+H]+). MS Calcd: 159.0 MS Found: 160.0([M+H] + ).

實施例71 Example 71

(E)-4-(4-(3’-((2-氯-4-(氯甲基)-5-甲基苯氧基)甲基)-2,2’-二甲基-[1,1’-二苯基]-3-基)丁-3-烯-1-基)嗎啉的製備 (E)-4-(4-(3'-((2-chloro-4-(chloromethyl)-5-methylphenoxy)methyl)-2,2'-dimethyl-[1 ,1'-Diphenyl]-3-yl)but-3-en-1-yl)morpholine

Figure 108130887-A0202-12-0059-113
Figure 108130887-A0202-12-0059-113

淺黃色固體(E)-5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(200mg，0.4mol)溶解於甲醇(20mL)，加入NaBH4(75.6mg，2.0mmol)，室溫反應2h，反應完畢，加水(50mL)稀釋，二氯甲烷萃取(60mL)，旋幹溶劑，得到粗品中間體醇，溶解於SOCl2(7mL)，加熱至70℃，反應1h，反應完畢，旋幹SOCl2，得到淺黃固體(E)-4-(4-(3’-((2-氯-4-(氯甲基)-5-甲基苯氧基)甲基)-2,2’-二甲基-[1,1’-二苯基]-3-基)丁-3-烯-1-基)嗎啉，130mg，直接用於下一步反應。 Light yellow solid (E)-5-chloro-4-((3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[ 1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (200mg, 0.4mol) was dissolved in methanol (20mL), NaBH 4 (75.6mg, 2.0mmol) was added to the room Warm the reaction for 2h. After the reaction is complete, add water (50mL) to dilute, extract with dichloromethane (60mL), spin-dry the solvent to obtain the crude intermediate alcohol, dissolve in SOCl 2 (7mL), heat to 70℃, react for 1h, and complete the reaction. Spin the SOCl 2 to dryness to obtain a pale yellow solid (E)-4-(4-(3'-((2-chloro-4-(chloromethyl)-5-methylphenoxy)methyl)-2, 2'-Dimethyl-[1,1'-diphenyl]-3-yl)but-3-en-1-yl)morpholine, 130mg, directly used in the next reaction.

MS Calcd：523.2MS Found：524.1([M+H]+). MS Calcd: 523.2 MS Found: 524.1([M+H] + ).

實施例72 Example 72

(E)-1-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)3-羥基呱啶-2-羧酸 ( E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'-二(Phenyl)-3-yl)methoxy)-2-methylbenzyl)3-hydroxypiperidine-2-carboxylic acid

Figure 108130887-A0202-12-0060-114
Figure 108130887-A0202-12-0060-114

以上淺黃固體(130mg)溶解於乙腈(15mL)，加入碳酸鉀(415mg，3.0mmol)，3-羥基呱啶-2-甲酸甲酯(粗品100mg)，反應加熱至80℃，攪拌5小時，反應完畢，二氯甲烷：甲醇(5：1，60mL)萃取，水洗，乾燥旋幹，刮大板純化，展開劑(二氯甲烷：甲醇=5：1)，得到中間體45mg，溶解於四氫呋喃(6mL)加入氫氧化鋰溶液(1.0mol/L，3.0mL)，反應16h，反應完畢，旋去四氫呋喃，加水稀釋(5mL)，調節pH至弱酸性，析出白色固體，抽濾，烘乾，得到(E)-1-(5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)3-羥基呱啶-2-羧酸(35mg，收率22.2%)。 The above pale yellow solid (130mg) was dissolved in acetonitrile (15mL), potassium carbonate (415mg, 3.0mmol) and methyl 3-hydroxypiperidine-2-carboxylate (crude 100mg) were added, the reaction was heated to 80°C and stirred for 5 hours. After the reaction is complete, extract with dichloromethane: methanol (5:1, 60mL), wash with water, spin dry, and purify by scraping. The developing solvent (dichloromethane: methanol=5:1) gives the intermediate 45mg, which is dissolved in tetrahydrofuran (6mL) add lithium hydroxide solution (1.0mol/L, 3.0mL), react for 16h, after the reaction is complete, spin off the tetrahydrofuran, dilute with water (5mL), adjust the pH to weak acidity, precipitate a white solid, filter with suction, and dry. ( E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'- Diphenyl]-3-yl)methoxy)-2-methylbenzyl)3-hydroxypiperidine-2-carboxylic acid (35 mg, yield 22.2%).

1H NMR(400MHz,CDCl3)：δ 7.51(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.37(s,1H),7.26(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.15(s,1H),7.01(d,J=7.6Hz,1H),6.95(d,J=7.6Hz,1H),6.70(d,J=16.0Hz,1H),6.10-6.17(m,1H),5.20(s,2H),3.72(d,J=13.6Hz,1H),3.50-3.62(m,8H),3.23-3.29(m,2H),2.99(s,1H),2.95(m,1H),2.40-2.47(m,6H),2.39(s,3H),2.05(s,3H),1.95(s,3H),1.65-1.75(m,2H),1.23-1.41(m,2H). 1H NMR (400MHz, CDCl 3 ): δ 7.51(d, J =7.6Hz,1H), 7.41(d, J =7.6Hz,1H), 7.37(s,1H), 7.26(t, J =7.6Hz, 1H), 7.21(t, J =7.6Hz,1H), 7.15(s,1H), 7.01(d, J =7.6Hz,1H), 6.95(d, J =7.6Hz,1H), 6.70(d, J =16.0Hz, 1H), 6.10-6.17 (m, 1H), 5.20 (s, 2H), 3.72 (d, J =13.6 Hz, 1H), 3.50-3.62 (m, 8H), 3.23-3.29 (m ,2H),2.99(s,1H),2.95(m,1H),2.40-2.47(m,6H),2.39(s,3H),2.05(s,3H),1.95(s,3H),1.65- 1.75 (m, 2H), 1.23-1.41 (m, 2H).

MS Calcd：632.3MS Found：633.4([M+H]+). MS Calcd: 632.3 MS Found: 633.4([M+H] + ).

實施例73 Example 73

(E)-1-溴-2-甲基-3-(4-(甲基磺醯基)丁-1-烯-1-基)苯的製備 ( E ) Preparation of 1-bromo-2-methyl-3-(4-(methylsulfonyl)but-1-en-1-yl)benzene

Figure 108130887-A0202-12-0061-115
Figure 108130887-A0202-12-0061-115

將(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(602mg，2.0mmol)，甲烷亞磺酸鈉(408.0mg,4.0mmol)和KI(342.0mg,2.0mmol)溶於N,N-二甲基甲醯胺(20mL)，加熱至120℃，反應6h。加水(60mL)稀釋，乙酸乙酯(60mL)萃取，水洗兩遍，再飽和食鹽水洗，有機相乾燥旋幹，用矽膠柱層析純化(PE/EA=30/1至10/1)，得到淺黃色油狀物即中間體(E)-1-溴-2-甲基-3-(4-(甲基磺醯基)丁-1-烯-1-基)苯(450mg,1.49mmol,74.7% yield)。 Add (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (602mg, 2.0mmol), sodium methanesulfinate (408.0mg, 4.0mmol) And KI (342.0mg, 2.0mmol) were dissolved in N,N-dimethylformamide (20mL), heated to 120°C, and reacted for 6h. Dilute with water (60mL), extract with ethyl acetate (60mL), wash twice with water, then wash with saturated brine, dry the organic phase by spin-drying, and purify with silica gel column chromatography (PE/EA=30/1 to 10/1) to obtain Light yellow oily substance is intermediate ( E )-1-bromo-2-methyl-3-(4-(methylsulfonyl)but-1-en-1-yl)benzene (450mg, 1.49mmol, 74.7% yield).

MS Calcd：302.0，304.0 MS Found：302.9，305.0([M+H]+). MS Calcd: 302.0, 304.0 MS Found: 302.9, 305.0([M+H] + ).

實施例74 Example 74

(E)-5-氯-4-((2,2’-二甲基-3’-(4-(甲基磺醯基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛的製備 (E)-5-chloro-4-((2,2'-dimethyl-3'-(4-(methylsulfonyl)but-1-en-1-yl)-[1,1' -Diphenyl)-3-yl)methoxy)-2-methylbenzaldehyde

Figure 108130887-A0202-12-0061-116
Figure 108130887-A0202-12-0061-116

(E)-5-氯-4-((2,2’-二甲基-3’-(4-(甲基磺醯基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(310mg，0.62mmol，41.9%yield)由中間體(E)-1-溴-2-甲基-3-(4-(甲基磺醯基)丁-1-烯-1-基)苯(450mg，1.49mmol)和5-氯-2-甲基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛(800mg，2.0mmol)按照實施例17中的類似步驟製備而成。 (E)-5-chloro-4-((2,2'-dimethyl-3'-(4-(methylsulfonyl)but-1-en-1-yl)-[1,1' -Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (310mg, 0.62mmol, 41.9% yield) was prepared from the intermediate ( E )-1-bromo-2-methyl-3-( 4-(Methylsulfonyl)but-1-en-1-yl)benzene (450mg, 1.49mmol) and 5-chloro-2-methyl-4-[2-methyl-3-(4,4 ,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-benzaldehyde (800mg, 2.0mmol) Follow the similar procedure in Example 17 Prepared.

MS Calcd：496.1 MS Found：497.2([M+H]+) MS Calcd: 496.1 MS Found: 497.2([M+H] + )

實施例75 Example 75

(S,E)-1-(5-氯-4-((2,2’-二甲基-3’-((E)-4-(甲基磺醯基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸的製備 ( S,E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(( E )-4-(methylsulfonyl)but-1-ene-1 -Yl)-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0062-117
Figure 108130887-A0202-12-0062-117

淺黃色固體(S,E)-1-(5-氯-4-((2,2’-二甲基-3’-((E)-4-(甲基磺醯基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)呱啶-2-羧酸(17.0mg,0.028mmol,13.9%yield)由中間體(E)-5-氯-4-((2,2’-二甲基-3’-(4-(甲基磺醯基)丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(100mg，0.20mmol)和L-呱啶-2-甲酸(118.0mg,0.92mmol)按照實施例18似步驟製備而成。 Light yellow solid ( S, E )-1-(5-chloro-4-((2,2'-dimethyl-3'-(( E )-4-(methylsulfonyl)butan-1- En-1-yl)-[1,1'-diphenyl]-3-yl)methoxy)-2-methylbenzyl)piperidine-2-carboxylic acid (17.0mg, 0.028mmol, 13.9% yield) from the intermediate (E)-5-chloro-4-((2,2'-dimethyl-3'-(4-(methylsulfonyl)but-1-en-1-yl)- [1,1'-Diphenyl]-3-yl)methoxy)-2-methylbenzaldehyde (100mg, 0.20mmol) and L-piperidine-2-carboxylic acid (118.0mg, 0.92mmol) as implemented Example 18 was prepared by similar steps.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.51(d,J=7.5Hz,1H),7.45(d,J=7.8Hz,1H),7.34(s,1H),7.29(t,J=7.5Hz,1H),7.23(t,J=7.6Hz,1H),7.13(s,1H),7.07(d,J=7.6Hz,1H),6.99(d,J=7.3Hz,1H),6.81(d,J=15.7Hz,1H),6.19(dt,J=14.8,6.8Hz,1H),5.20(s,2H),3.75(d,J=13.4Hz,1H,),3.50-3.45(m,2H),3.01(s,3H),2.86-2.78(m,2H),2.73-2.61(m,2H),2.31(s,3H),2.19-2.09(m,2H),2.01(s,3H),1.97(s,3H),1.75-1.69(m,2H),1.46-1.41(m,4H). 1 H-NMR(400MHz,DMSO- d 6 )δ ppm 7.51(d, J =7.5Hz,1H), 7.45(d, J =7.8Hz,1H), 7.34(s,1H), 7.29(t, J =7.5Hz,1H),7.23(t, J =7.6Hz,1H),7.13(s,1H),7.07(d, J =7.6Hz,1H),6.99(d, J =7.3Hz,1H), 6.81(d, J =15.7Hz,1H), 6.19(dt, J =14.8,6.8Hz,1H), 5.20(s, 2H), 3.75(d, J =13.4Hz, 1H,), 3.50-3.45( m,2H),3.01(s,3H),2.86-2.78(m,2H),2.73-2.61(m,2H),2.31(s,3H),2.19-2.09(m,2H),2.01(s, 3H), 1.97 (s, 3H), 1.75-1.69 (m, 2H), 1.46-1.41 (m, 4H).

MS Calcd：609.2 MS Found：610.4([M+H]+). MS Calcd: 609.2 MS Found: 610.4([M+H] + ).

實施例76 Example 76

(E)-N-(1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶-4-基)乙醯胺的製備 Preparation of ( E )-N-(1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)piridin-4-yl)acetamide

Figure 108130887-A0202-12-0062-118
Figure 108130887-A0202-12-0062-118

白色固體中間體(E)-N-(1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶-4-基)乙醯胺(220mg,0.60mmol,60% yield)是由(E)-1-溴-3-(4-溴丁-1-烯-1-基)-2-甲基苯(302mg,1.0mmol)和N-呱啶-4-基-乙醯胺(284mg,2.0mmol)按照實施例14中的類似步驟製備而成。 White solid intermediate ( E )-N-(1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)pyridin-4-yl)acetamide (220mg , 0.60mmol, 60% yield) is composed of (E)-1-bromo-3-(4-bromobut-1-en-1-yl)-2-methylbenzene (302mg, 1.0mmol) and N-gua Pyridin-4-yl-acetamide (284 mg, 2.0 mmol) was prepared according to the similar procedure in Example 14.

MS Calcd：364.1，366.1 MS Found：365.0，367.2([M+H]+). MS Calcd: 364.1, 366.1 MS Found: 365.0, 367.2([M+H] + ).

實施例77 Example 77

(E)-N-(1-(4-(3’-((2-氯-4-甲醯基-5-甲基苯氧基)甲基)-2,2’-二甲基-[1,1’-二苯基]-3-基)丁-3-烯-1-基)呱啶-4-基)乙醯胺的製備 ( E )- N -(1-(4-(3'-((2-Chloro-4-methyl-5-methylphenoxy)methyl)-2,2'-dimethyl-[ Preparation of 1,1'-diphenyl)-3-yl)but-3-en-1-yl)pyridin-4-yl)acetamide

Figure 108130887-A0202-12-0063-119
Figure 108130887-A0202-12-0063-119

中間體(E)-N-(1-(4-(3’-((2-氯-4-甲醯基-5-甲基苯氧基)甲基)-2,2’-二甲基-[1,1’-二苯基]-3-基)丁-3-烯-1-基)呱啶-4-基)乙醯胺(235mg，0.42mmol，70.1%yield)由中間體(E)-N-(1-(4-(3-溴-2-甲基苯基)丁-3-烯-1-基)呱啶-4-基)乙醯胺(450mg，1.49mmol)和5-氯-2-甲基-4-[2-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧硼雜環戊烷-2-基)-苄氧基]-苯甲醛(400mg，1.0mmol)按照實施例17中的類似步驟製備而成。 Intermediate ( E ) -N -(1-(4-(3'-((2-chloro-4-methanyl-5-methylphenoxy)methyl)-2,2'-dimethyl -[1,1'-Diphenyl]-3-yl)but-3-en-1-yl)pyridin-4-yl)acetamide (235mg, 0.42mmol, 70.1% yield) from the intermediate ( E )-N-(1-(4-(3-bromo-2-methylphenyl)but-3-en-1-yl)pyridin-4-yl)acetamide (450mg, 1.49mmol) and 5-chloro-2-methyl-4-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl )-Benzyloxy]-benzaldehyde (400 mg, 1.0 mmol) was prepared according to the similar procedure in Example 17.

MS Calcd：558.2 MS Found：559.3([M+H]+) MS Calcd: 558.2 MS Found: 559.3([M+H] + )

實施例78 Example 78

(S,E)-1-(4-((3’-(4-(4-乙醯胺基呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-5-氯-2-甲基苄基)呱啶-2-羧酸的製備 ( S,E )-1-(4-((3'-(4-(4-acetamidopyridin-1-yl)but-1-en-1-yl)-2,2'-di Preparation of methyl-[1,1'-diphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)piperidine-2-carboxylic acid

Figure 108130887-A0202-12-0063-120
Figure 108130887-A0202-12-0063-120

白色固體(S,E)-1-(4-((3’-(4-(4-乙醯胺基呱啶-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-5-氯-2-甲基苄基)呱啶-2-羧酸(15.0mg，0.022mol，12.4%yield)由中間體(E)-N-(1-(4-(3’-((2-氯-4-甲醯基-5-甲基苯氧基)甲基)-2,2’-二甲基-[1,1’-二苯基]-3-基)丁-3-烯-1-基)呱啶-4-基)乙醯胺(100mg，0.18mmol)和L-呱啶-2-甲酸(118.0mg,0.92mmol)按照實施例18似步驟製備而成。 White solid ( S , E )-1-(4-((3'-(4-(4-acetamidopyridine-1-yl)but-1-en-1-yl)-2,2'-Dimethyl-[1,1'-diphenyl]-3-yl)methoxy)-5-chloro-2-methylbenzyl)piperidine-2-carboxylic acid (15.0mg, 0.022mol, 12.4% yield) from the intermediate ( E ) -N -(1-(4-(3'-((2-chloro-4-methanyl-5-methylphenoxy)methyl)-2,2 '-Dimethyl-[1,1'-Diphenyl]-3-yl)but-3-en-1-yl)pyridin-4-yl)acetamide (100mg, 0.18mmol) and L- Piperidine-2-carboxylic acid (118.0 mg, 0.92 mmol) was prepared according to the same procedure as in Example 18.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.73(d,J=7.7Hz,1H),7.51(d,J=7.6Hz,1H),7.43(d,J=7.8Hz,1H),7.35(s,1H),7.28(t,J=7.6Hz,1H),7.21(t,J=7.6Hz,1H),7.12(s,1H),7.07(d,J=7.5Hz,1H),6.96(d,J=7.4Hz,1H),6.71(d,J=15.7Hz,1H),6.14(dt,J=14.6,6.4Hz,1H),5.19(s,2H),3.77(d,J=13.5Hz,1H),3.58(s,2H),3.26(d,J=13.2Hz,1H),2.97-2.71(m,3H),2.42(d,J=6.2Hz,1H),2.41-2.34(m,2H)2.30(s,3H),2.01(s,3H),1.95(s,3H),1.86(s,2H),1.77(s,3H),1.74-1.64(m,4H),1.53-1.48(m,1H),1.44-1.39(m,3H),1.38-1.28(m,4H)。 1 H-NMR(400MHz,DMSO- d 6 )δ ppm 7.73(d, J =7.7Hz,1H), 7.51(d, J =7.6Hz,1H), 7.43(d, J =7.8Hz,1H), 7.35(s,1H),7.28(t, J =7.6Hz,1H),7.21(t, J =7.6Hz,1H),7.12(s,1H),7.07(d, J =7.5Hz,1H), 6.96(d, J =7.4Hz,1H), 6.71(d, J =15.7Hz,1H), 6.14(dt, J =14.6,6.4Hz,1H), 5.19(s,2H),3.77(d, J =13.5Hz,1H),3.58(s,2H), 3.26(d, J =13.2Hz,1H), 2.97-2.71(m,3H),2.42(d, J =6.2Hz,1H),2.41-2.34 (m,2H)2.30(s,3H),2.01(s,3H),1.95(s,3H),1.86(s,2H),1.77(s,3H),1.74-1.64(m,4H),1.53 -1.48 (m, 1H), 1.44-1.39 (m, 3H), 1.38-1.28 (m, 4H).

MS Calcd：671.3 MS Found：672.4([M+H]+). MS Calcd: 671.3 MS Found: 672.4([M+H] + ).

實施例79 Example 79

(E)-2-((5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氨基)乙基-1-醇的製備 ( E )-2-((5-Chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1'- (Diphenyl)-3-yl)methoxy)-2-methylbenzyl)amino)ethyl-1-ol

Figure 108130887-A0202-12-0064-121
Figure 108130887-A0202-12-0064-121

白色固體(E)-2-((5-氯-4-((2,2’-二甲基-3’-(4-嗎啉丁-1-烯-1-基)-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苄基)氨基)乙基-1-醇(24.0mg，0.043mol，23.0%yield)由5-氯-4-((3’-(4-(嗎啉-1-基)丁-1-烯-1-基)-2,2’-二甲基-[1,1’-二苯基]-3-基)甲氧基)-2-甲基苯甲醛(95mg，0.19mmol)和乙醇胺(122.0mg，2.0mmol)按照實施例6的類似步驟製備而成。 White solid ( E )-2-((5-chloro-4-((2,2'-dimethyl-3'-(4-morpholin-1-en-1-yl)-[1,1 '-Diphenyl]-3-yl)methoxy)-2-methylbenzyl)amino)ethyl-1-ol (24.0mg, 0.043mol, 23.0% yield) is composed of 5-chloro-4-( (3'-(4-(morpholin-1-yl)but-1-en-1-yl)-2,2'-dimethyl-[1,1'-diphenyl]-3-yl) Methoxy)-2-methylbenzaldehyde (95mg, 0.19mmol) and ethanolamine (122.0mg, 2.0mmol) were prepared according to the similar procedure of Example 6.

1H-NMR(400MHz,DMSO-d 6 )δ ppm 7.67(s,1H),7.51(d,J=7.8Hz,2H),7.34-7.20(m,3H),7.08(d,J=7.7Hz,1H),7.00(d,J=7.4Hz,1H),6.82(d,J=15.7Hz,1H),6.16(dt,J=15.5,6.8Hz,1H),5.27(s,1H),5.26(s,2H),4.10(s,2H),3.96(d,J=12.4Hz,2H),3.86(t,J=12.1Hz,2H),3.73(t,J=5.4Hz,2H),3.45(d,J=12.5Hz,2H),3.27-3.22(m,2H),3.13-3.01(m,5H),2.79-2.68(m,2H),2.41(s,3H),2.01(s,3H),1.97(s,3H). 1 H-NMR(400MHz, DMSO- d 6 ) δ ppm 7.67(s,1H), 7.51(d, J =7.8Hz,2H), 7.34-7.20(m,3H), 7.08(d, J =7.7Hz ,1H),7.00(d, J =7.4Hz,1H), 6.82(d, J =15.7Hz,1H), 6.16(dt, J =15.5,6.8Hz,1H), 5.27(s,1H), 5.26 (s, 2H), 4.10 (s, 2H), 3.96 (d, J =12.4 Hz, 2H), 3.86 (t, J =12.1 Hz, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.45 (d, J =12.5Hz,2H), 3.27-3.22(m,2H),3.13-3.01(m,5H),2.79-2.68(m,2H),2.41(s,3H),2.01(s,3H) ), 1.97(s, 3H).

MS Calcd：548.2 MS Found：549.3[M+H]+). MS Calcd: 548.2 MS Found: 549.3[M+H] + ).

體外生物學評價In vitro biological evaluation

本檢測方法用於本發明所述化合物的體外活性評價，包括體外蛋白水準結合抑制活性評價方法和細胞水準生物學功能活性評價方法。 The detection method is used to evaluate the in vitro activity of the compound of the present invention, including an in vitro protein-level binding inhibitory activity evaluation method and a cell-level biological function activity evaluation method.

本檢測的目的在於綜合評價不同化合物對PD-1/PD-L1結合抑制活性特點和對細胞模型的生物學活性影響，包括對特定模型細胞的生長活性以及對原代T細胞的生物活性影響。 The purpose of this test is to comprehensively evaluate the characteristics of the inhibitory activity of different compounds on PD-1/PD-L1 binding and the effect on the biological activity of cell models, including the growth activity of specific model cells and the biological activity of primary T cells.

實施例A 體外PD-1/PD-L1結合抑制篩選方法 Example A In vitro PD-1/PD-L1 binding inhibition screening method

實驗主要原理(HTRF)The main principle of the experiment (HTRF)

均相時間分辨螢光法(HTRF)：PD-1蛋白帶His標籤，其配體PD-L1的Fc融合蛋白帶hFc標籤。分別用Eu元素的鼇合標記物標記的抗hFc抗體和XL665標記的抗His抗體與兩個對應標籤結合，鐳射激發(320nm)後，能量能夠從供體Eu上，轉移到受體XL665，使得XL665發光(665nm)。當加入小分子化合物抑制劑後，阻斷PD-1與PD-L1的結合，使得Eu和XL665距離較遠，能量不能轉移，XL665不會發光。 Homogeneous time-resolved fluorescence method (HTRF): The PD-1 protein has a His tag, and the Fc fusion protein of its ligand PD-L1 has an hFc tag. The anti-hFc antibody and XL665-labeled anti-His antibody labeled with the chelating label of Eu element respectively bind to the two corresponding tags. After laser excitation (320nm), energy can be transferred from the donor Eu to the acceptor XL665, making XL665 emits light (665nm). When a small molecule compound inhibitor is added, the binding of PD-1 and PD-L1 is blocked, so that Eu and XL665 are far away, energy cannot be transferred, and XL665 will not emit light.

實驗材料與設備Experimental materials and equipment

帶His標籤的人重組PD-1蛋白(Cat#：80448-R08H-100)、人重組PD-L1-Fc融合蛋白(Cat#：90251-C02H-100)購自義翹神州(Sino Biological Inc.)公司，抗hFc-Eu3+、抗His-XL665抗體購自Cisbio公司，其它相關試劑如稀釋緩衝液、檢測緩衝液等均從Cisbio公司購買。螢光檢測儀器Tecan(Spark 10M)從瑞士Tecan公司購買。 Human recombinant PD-1 protein (Cat#: 80448-R08H-100) and human recombinant PD-L1-Fc fusion protein (Cat#: 90251-C02H-100) with His tag were purchased from Sino Biological Inc. ) Company, anti-hFc-Eu 3+ and anti-His-XL665 antibodies were purchased from Cisbio, and other related reagents such as dilution buffer, detection buffer, etc. were purchased from Cisbio. The fluorescence detection instrument Tecan (Spark 10M) was purchased from Tecan, Switzerland.

實驗主要過程The main process of the experiment

實驗過程按照檢測試劑使用說明書要求的流程進行(Invitrogen)。流程如下： The experimental process was carried out in accordance with the procedure required by the instruction manual of the detection reagent (Invitrogen). The process is as follows:

(1)實驗準備：用稀釋緩衝液將測試化合物稀釋成不同濃度梯度(在20μL最終反應體系中最高終濃度為10μM)，將His-PD-1蛋白稀釋成800nM(在20μL最終反應體系中終濃度100nM)，PD-L1-Fc融合蛋白稀釋成16nM(終濃度為2nM)；用檢測稀釋液分別按試劑要求將抗His-XL665抗體和抗hFc-Eu3+抗體稀釋20倍和100倍。 (1) Experimental preparation: Use dilution buffer to dilute the test compound into different concentration gradients (the highest final concentration is 10 μM in the 20 μL final reaction system), and dilute the His-PD-1 protein to 800 nM (in the final reaction system of 20 μL) Concentration 100nM), PD-L1-Fc fusion protein was diluted to 16nM (final concentration is 2nM); the anti-His-XL665 antibody and anti-hFc-Eu 3+ antibody were diluted 20 times and 100 times with the detection diluent according to the reagent requirements.

(2)先將5μL測試化合物、2.5μLPD-L1蛋白和2.5μL PD-1蛋白溶液混勻後，室溫反應15min；隨後向該體系加入5μL anti-His-XL665抗體和5μL anti-hFc-Eu3+抗體，繼續孵育3h後檢測。 (2) First mix 5μL test compound, 2.5μLPD-L1 protein and 2.5μL PD-1 protein solution, and react at room temperature for 15min; then add 5μL anti-His-XL665 antibody and 5μL anti-hFc-Eu to the system 3+ antibody, continue to incubate for 3 hours and then detect.

(3)檢測反應同時設置有對照組，包括未添加測試化合物的0抑制陽性對照、未添加PD-1蛋白的陰性對照。所有檢測採用複孔進行。 (3) The detection reaction is also provided with a control group, including a positive control for 0 inhibition without adding a test compound, and a negative control without adding PD-1 protein. All inspections are carried out using multiple holes.

(4)使用螢光檢測儀Tecan(Spark 10M)檢測每孔的螢光信號，激發波長為320nm，檢測的發射波長分別為620nm和665nm。PD-1/PD-L1相互結合的強度參照螢光信號比值Em665/Em620。 (4) Detect the fluorescence signal of each hole with a fluorescence detector Tecan (Spark 10M), the excitation wavelength is 320nm, and the detected emission wavelengths are 620nm and 665nm, respectively. The intensity of the binding of PD-1/PD-L1 refers to the ratio of the fluorescent signal Em665/Em620.

(5)測試化合物的結合抑制率計算公式：抑制率(%)=[1-(檢測孔螢光信號比值-陰性對照)/(0抑制陽性對照螢光信號比值-陰性對照)×100%。不同濃度梯度的測試化合物分別計算結合抑制率後，進-步計算50%抑制濃度(IC50)。數據見下表2。 (5) Calculating formula for the binding inhibition rate of the test compound: inhibition rate (%)=[1-(fluorescence signal ratio of detection hole-negative control)/(0 inhibition ratio of fluorescence signal of positive control-negative control)×100%. After calculating the binding inhibition rate of test compounds with different concentration gradients, the 50% inhibition concentration (IC 50 ) was further calculated. Data in Table 2 below.

Figure 108130887-A0305-02-0068-4
Figure 108130887-A0305-02-0068-4

由上述結果可見，本發明化合物具有良好的體外PD-1/PD-L1結合抑制活性。 It can be seen from the above results that the compound of the present invention has good in vitro PD-1/PD-L1 binding inhibitory activity.

Figure 108130887-A0202-11-0002-1
Figure 108130887-A0202-11-0002-1

Claims (29)

式I化合物或其可藥用鹽，
Figure 108130887-A0305-02-0069-5
 其中，R1選自氫、C1-C3烷基、CN、鹵素、C1-C3鹵代烷基；R2選自氫、C1-C3烷基、CN、鹵素、C1-C3烷氧基；L為任選取代的C3-C6烯基，所述C3-C6烯基中的一個CH2任選地被-C(O)-、-S(O)-或-S(O)2-所替代；B為氫，或NR6R7，或任選取代的具有1到3個獨立地選自氮、氧或硫的雜原子的4元到7元飽和或部分不飽和雜環；其中R6和R7獨立地為氫、C1-C3烷基、C1-C3鹵代烷基、羥基C1-C3烷基或羧基C1-C3烷基；Z為氫、-CH3、-CH=CHAr或-OR8；其中R8選自氫、C3-C6烯基、鹵代C1-C4烷基、羥基C1-C4烷基、-(CH2)nX及-(CH2)nAr；n為1、2、3或4；X選自氫、-CH3、-CF3、C1-C4烷氧基、-N(CH3)2、任選經一個或兩個鹵素取代的C3-C6環烷基、-CN、-CO2Rg、-C(O)NH2、-C(O)N(CH3)2、
Figure 108130887-A0305-02-0069-6
、
Figure 108130887-A0305-02-0069-7
、
Figure 108130887-A0305-02-0069-8
嗎啉基、四氫吡喃基、任選經羥基取代的吡咯烷酮基及任選經一個或兩個獨立選自以下的基團取代的呱啶基：C1-C4烷基、羧基、羥基及C1-C4烷氧基羰基；Rg選自氫及C1-C4烷基；及 Ar選自苯並二噁烷基、吲唑基、異喹啉基、異噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基及喹啉基；其中各環任選經1、2、3或4個獨立選自以下的取代基取代：C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基氨基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷基磺醯基、甲醯氨基、甲醯氨基C1-C4烷基、-(CH2)qCO2-(C1-C4烷基)、-(CH2)qOH、羧基、氰基、甲醯基、鹵素、鹵代C1-C4烷基、鹵代C1-C4烷氧基、硝基、任選經一個氰基取代的苯基、任選經一個鹵素取代的苯基氧基、苯基羰基、吡咯、四氫吡喃及
Figure 108130887-A0305-02-0070-9
 其中q為0、1、2、3或4且其中t、z及Rz如下定義：t為0、1、2、3或4；z為1、2或3；各Rz獨立選自C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基C1-C4烷基、C1-C4烷基、C1-C4烷基醯氨基、C1-C4烷基氨基、C1-C4烷基羰基、醯氨基、羧基、羧基C1-C4烷基、二(C1-C4烷基)醯氨基、二(C1-C4烷基)氨基、鹵素、鹵代C1-C4烷氧基、鹵代C1-C4烷基、羥基、羥基C1-C4烷基、嗎啉基、-NRcRd、(NRcRd)C1-C4烷基、-NReRf、(NReRf)C1-C4烷基、氧代、苯基及苯基C1-C4烷基，其中該苯基及該苯基C1-C4烷基的苯基部分任選經一個、兩個或三個獨立選自C1-C3烷基及鹵素的基團取代；Rc及Rd獨立選自氫、C2-C4烯基羰基、C1-C4烷氧基羰基、C1-C6烷基、C1-C4烷基羰基、醯氨基C1-C4烷基、氨基C1-C4烷基、芳基C1-C4烷基、C3-C10環烷基、(C3-C10環烷基)C1-C4烷基、鹵代C1-C4烷基羰基、雜環基C1-C4烷基、雜環基C1-C4烷基羰基、羥基C1-C6烷基及羥基C1-C4烷基羰基，其中該醯氨基C1-C4烷基、該氨基C1-C4烷基、該芳基C1-C4烷基、該(C3-C10環烷基)C1-C4烷基、該雜環基C1-C4烷基及該雜環基C1-C4烷基羰基的烷基部分任選經一個或兩個獨立選自羧基及羥基的基團取代；其中該羥 基C1-C4烷基及該羥基C1-C4烷基羰基的烷基部分任選經一個或兩個獨立選自羧基及羥基的基團取代；且其中該芳基C1-C4烷基的芳基部分、該C3-C10環烷基、該(C3-C10環烷基)C1-C4烷基的環烷基部分及該雜環基C1-C4烷基及該雜環基C1-C4烷基羰基的雜環基部分各任選經一個、兩個或三個獨立選自C1-C4烷氧基羰基、C1-C4烷基及鹵素的基團取代； Re及Rf與其所連接的原子一起形成選自嗎啉及
Figure 108130887-A0305-02-0071-10
的 環； R3獨立選自C2-C4烯基、C1-C4烷氧基、C1-C4烷基、氰基、鹵素及鹵代C1-C4烷基；m為0、1或2；R4選自氫、C1-C4烷基、苄基、(C3-C6環烷基)C1-C3烷基、鹵代C1-C4烷基、任選經第二個羥基取代的羥基C1-C6烷基及任選經氰基取代的吡啶基(C1-C3烷基)；及R5選自氫、C1-C4烷基、-(CH2)nN(CH3)2、羧基C2-C6烯基、羧基C1-C6烷基及羥基C1-C6烷基，其中該羧基C1-C6烷基及該羥基C1-C6烷基的烷基部分任選經一個羥基或苯基取代，其中該苯基進一步任選經羥基取代；或者，R5選自以下基團：
Figure 108130887-A0305-02-0071-11
Figure 108130887-A0305-02-0071-12
、
Figure 108130887-A0305-02-0071-31
、
Figure 108130887-A0305-02-0071-33
、
Figure 108130887-A0305-02-0071-32
、
Figure 108130887-A0305-02-0071-17
、
Figure 108130887-A0305-02-0071-18
，其中 Rw為-CONH2； R10選自氫、苄基及甲基；各R10’獨立選自氫及C1-C3烷基；R11選自氫、C1-C3烷基及苄基；R12選自C2-C4烯基及C1-C4烷基；及 R50選自氫、C1-C6烷基及C1-C6烷氧基羰基；或R4及R5與其所連接的氮原子一起形成選自以下的環：
Figure 108130887-A0305-02-0072-19
和
Figure 108130887-A0305-02-0072-34
；其中 s為0、1或2；z為1、2或3；p為0，1或2；R13及R13’獨立選自氫、羧基、羥基C1-C4烷基、氧代及-C(O)NHSO2R16；R14獨立選自氫、羥基C1-C4烷基、氧代及羧基；各R15獨立選自C1-C4烷氧基羰基、C1-C6烷基、羧基、鹵素、羥基、羥基C1-C4烷基、-NRc’Rd’及苯基氧基羰基，其中該苯基任選經硝基取代，其中Rc’及Rd’獨立選自氫、C1-C4烷氧基羰基及C1-C4烷基羰基；及R16選自三氟甲基、環丙基、C1-C4烷基、二甲基氨基及經甲基取代的咪唑基。 The compound of formula I or a pharmaceutically acceptable salt thereof,
Figure 108130887-A0305-02-0069-5
 Wherein, R 1 is selected from hydrogen, C 1 -C 3 alkyl, CN, halogen, C 1 -C 3 haloalkyl; R 2 is selected from hydrogen, C 1 -C 3 alkyl, CN, halogen, C 1 -C 3 Alkoxy; L is an optionally substituted C 3 -C 6 alkenyl group, one of the C 3 -C 6 alkenyl groups CH 2 is optionally replaced by -C(O)-, -S(O)- Or -S(O) 2 -replaced; B is hydrogen, or NR 6 R 7 , or optionally substituted 4- to 7-membered saturated with 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur Or partially unsaturated heterocyclic ring; wherein R 6 and R 7 are independently hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxy C 1 -C 3 alkyl or carboxy C 1 -C 3 alkane Z is hydrogen, -CH 3 , -CH=CHAr or -OR 8 ; wherein R 8 is selected from hydrogen, C 3 -C 6 alkenyl, halogenated C 1 -C 4 alkyl, hydroxy C 1 -C 4 Alkyl, -(CH 2 ) n X and -(CH 2 ) n Ar; n is 1, 2, 3 or 4; X is selected from hydrogen, -CH 3 , -CF 3 , C 1 -C 4 alkoxy , -N(CH 3 ) 2 , C 3 -C 6 cycloalkyl optionally substituted by one or two halogens, -CN, -CO 2 R g , -C(O)NH 2 , -C(O) N(CH 3 ) 2 ,
Figure 108130887-A0305-02-0069-6
,
Figure 108130887-A0305-02-0069-7
,
Figure 108130887-A0305-02-0069-8
Morpholinyl, tetrahydropyranyl, pyrrolidone optionally substituted with hydroxy, and pyridinyl optionally substituted with one or two groups independently selected from: C 1 -C 4 alkyl, carboxy, hydroxy And C 1 -C 4 alkoxycarbonyl; R g is selected from hydrogen and C 1 -C 4 alkyl; and Ar is selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, Naphthyl, oxadiazolyl, phenyl, pyridyl, pyrimidinyl and quinolinyl; wherein each ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from: C 1 -C 4 alkane Oxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl Group, carboxamido, carboxamido C 1 -C 4 alkyl, -(CH 2 ) q CO 2 -(C 1 -C 4 alkyl), -(CH 2 ) q OH, carboxyl, cyano, methyl Acetyl, halogen, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, nitro, phenyl optionally substituted with a cyano group, phenyloxy optionally substituted with a halogen Group, phenylcarbonyl, pyrrole, tetrahydropyran and
Figure 108130887-A0305-02-0070-9
 Where q is 0, 1, 2, 3 or 4 and where t, z and R z are defined as follows: t is 0, 1, 2, 3 or 4; z is 1, 2 or 3; each R z is independently selected from C 1 -C 4 alkoxy, C 1 -C4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkyl Amino, C 1 -C 4 alkylamino, C 1 -C 4 alkylcarbonyl, acylamino, carboxyl, carboxyl C 1 -C 4 alkyl, two (C 1 -C 4 alkyl) acylamino, two (C 1- C 4 alkyl) amino, halogen, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkyl, hydroxy, hydroxy C 1 -C 4 alkyl, morpholinyl, -NR c R d , (NR c R d )C 1 -C 4 alkyl, -NR e R f , (NR e R f )C 1 -C 4 alkyl, oxo, phenyl and phenyl C 1 -C 4 An alkyl group, wherein the phenyl group and the phenyl portion of the phenyl C 1 -C 4 alkyl group are optionally substituted with one, two or three groups independently selected from C 1 -C 3 alkyl groups and halogen; R c and R d are independently selected from hydrogen, C 2 -C 4 alkenyl carbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl carbonyl, acylamino C 1- C 4 alkyl, amino C 1 -C 4 alkyl, aryl C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, (C 3 -C 10 cycloalkyl) C 1 -C 4 alkyl , Halogenated C 1 -C 4 alkylcarbonyl, heterocyclic C 1 -C 4 alkyl, heterocyclic C 1 -C 4 alkylcarbonyl, hydroxy C 1 -C 6 alkyl, and hydroxy C 1 -C 4 An alkylcarbonyl group, wherein the acylamino C 1 -C 4 alkyl group, the amino C 1 -C 4 alkyl group, the aryl group C 1 -C 4 alkyl group, the (C 3 -C 10 cycloalkyl group) C 1 -C 4 alkyl group, the heterocyclic group C 1 -C 4 alkyl group, and the alkyl part of the heterocyclic group C 1 -C 4 alkylcarbonyl group are optionally selected via one or two groups independently selected from carboxyl and hydroxy Substitution; wherein the hydroxy C 1 -C 4 alkyl group and the alkyl portion of the hydroxy C 1 -C 4 alkylcarbonyl group are optionally substituted with one or two groups independently selected from carboxyl and hydroxy; and wherein the aryl group The aryl part of the C 1 -C 4 alkyl group, the C 3 -C 10 cycloalkyl group, the cycloalkyl part of the (C 3 -C 10 cycloalkyl) C 1 -C 4 alkyl group, and the heterocyclic group The C 1 -C 4 alkyl group and the heterocyclic group portion of the heterocyclic group C 1 -C 4 alkylcarbonyl group are each optionally selected from C 1 -C 4 alkoxycarbonyl group, C 1 -C 4 alkyl and halogen group substitution; R e and R f together with the atoms to which they are attached form a group selected from morpholine and
Figure 108130887-A0305-02-0071-10
R 3 is independently selected from C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyano, halogen and halogenated C 1 -C 4 alkyl; m is 0, 1 or 2; R 4 is selected from hydrogen, C 1 -C 4 alkyl, benzyl, (C 3 -C 6 cycloalkyl) C 1 -C 3 alkyl, halogenated C 1 -C 4 alkyl , A hydroxy C1-C6 alkyl group optionally substituted by a second hydroxy group and a pyridyl group optionally substituted by a cyano group (C 1 -C 3 alkyl group); and R 5 is selected from hydrogen, C 1 -C 4 alkyl group , -(CH 2 ) n N(CH 3 ) 2 , carboxy C 2 -C 6 alkenyl, carboxy C 1 -C 6 alkyl and hydroxy C 1 -C 6 alkyl, wherein the carboxy C 1 -C 6 alkane And the alkyl portion of the hydroxy C 1 -C 6 alkyl group are optionally substituted with a hydroxy group or a phenyl group, wherein the phenyl group is further optionally substituted with a hydroxy group; or, R 5 is selected from the following groups:
Figure 108130887-A0305-02-0071-11
Figure 108130887-A0305-02-0071-12
,
Figure 108130887-A0305-02-0071-31
,
Figure 108130887-A0305-02-0071-33
,
Figure 108130887-A0305-02-0071-32
,
Figure 108130887-A0305-02-0071-17
,
Figure 108130887-A0305-02-0071-18
, Wherein R w is -CONH 2 ; R 10 is selected from hydrogen, benzyl and methyl; each R 10' is independently selected from hydrogen and C 1 -C 3 alkyl; R 11 is selected from hydrogen, C 1 -C 3 alkane R 12 is selected from C 2 -C 4 alkenyl and C 1 -C 4 alkyl; and R 50 is selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxycarbonyl; Or R 4 and R 5 together with the nitrogen atom to which they are attached form a ring selected from:
Figure 108130887-A0305-02-0072-19
with
Figure 108130887-A0305-02-0072-34
; Wherein s is 0, 1 or 2; z is 1, 2 or 3; p is 0, 1 or 2; R 13 and R 13' are independently selected from hydrogen, carboxyl, hydroxy C 1 -C 4 alkyl, oxo And -C(O)NHSO 2 R 16 ; R 14 is independently selected from hydrogen, hydroxy C 1 -C 4 alkyl, oxo and carboxy; each R 15 is independently selected from C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, carboxy, halogen, hydroxy, hydroxy C 1 -C 4 alkyl, -NR c 'R d' and phenyloxy carbonyl group, wherein the phenyl is optionally substituted with nitro, wherein R c ' And R d'are independently selected from hydrogen, C 1 -C 4 alkoxycarbonyl and C 1 -C 4 alkylcarbonyl; and R 16 is selected from trifluoromethyl, cyclopropyl, C 1 -C 4 alkyl, Dimethylamino and imidazolyl substituted by methyl. 如申請專利範圍第1項所述的式I化合物或其可藥用鹽，其中，R1和R2獨立地選自氫和C1-C3烷基；L為-CH2-CH=CH-或-CH2-CH2-CH=CH-，其中一個CH2任選地被-C(O)-、-S(O)-或-S(O)2-所替代，上述L定義中基團左側與式I結構中B基團相連；Z為甲基、-CH=CHAr或-O(CH2)nAr；其中n為1、2、3或4；Ar選自苯並二噁烷基、吲唑基、異喹啉基、異噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基及喹啉基；其中各環任選經1、2、3或4個獨立選自以下的取代基取代：C1-C4烷氧基、C1-C4烷氧基羰基、C1-C4烷氧基羰基氨基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷基磺醯基、醯氨基、醯氨基C1-C4烷基、-(CH2)qCO2C1-C4烷基、-(CH2)qOH、羧基、氰基、甲醯基、鹵素、鹵代C1-C4烷基、鹵代C1-C4烷氧基、硝基、任選經一個氰基取代的 苯基、任選經一個鹵素取代的苯基氧基、苯基羰基、吡咯、四氫吡喃，其中q為0、1、2、3或4；R3獨立選自C1-C4烷氧基和鹵素。 The compound of formula I or its pharmaceutically acceptable salt as described in item 1 of the patent application, wherein R 1 and R 2 are independently selected from hydrogen and C 1 -C 3 alkyl; L is -CH 2 -CH=CH -Or -CH 2 -CH 2 -CH=CH-, where one CH 2 is optionally replaced by -C(O)-, -S(O)- or -S(O) 2 -, in the above definition of L The left side of the group is connected to the group B in the structure of formula I; Z is methyl, -CH=CHAr or -O(CH 2 ) n Ar; where n is 1, 2, 3 or 4; Ar is selected from benzodioxin Alkyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridyl, pyrimidinyl and quinolinyl; wherein each ring is optionally connected by 1, 2, 3 or 4 substituents independently selected from substituents: C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1- C 4 alkoxycarbonyl group, C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, alkanoylamino, acylamino C 1 -C 4 alkyl, -(CH 2 ) q CO 2 C 1 -C 4 alkyl, -( CH 2 ) q OH, carboxyl, cyano, methanoyl, halogen, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, nitro, benzene optionally substituted with a cyano group Group, phenyloxy group optionally substituted by one halogen, phenylcarbonyl group, pyrrole, tetrahydropyran, wherein q is 0, 1, 2, 3 or 4; R 3 is independently selected from C 1 -C 4 alkoxy Radical and halogen. 如申請專利範圍第2項所述的式I化合物或其可藥用鹽，其中R1和R2獨立選自甲基及鹵素；Z為甲基、-CH=CHAr或-OCH2Ar；其中Ar為任選經一個或兩個獨立選自以下的基團取代的吡啶基：C1-C4烷基、C1-C4烷基磺醯基、甲醯氨基、氰基及鹵素；R3為鹵素；且m為1。 The compound of formula I or its pharmaceutically acceptable salt as described in item 2 of the scope of the patent application, wherein R 1 and R 2 are independently selected from methyl and halogen; Z is methyl, -CH=CHAr or -OCH 2 Ar; wherein Ar is a pyridyl group optionally substituted with one or two groups independently selected from: C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, methylamino, cyano and halogen; R 3 is halogen; and m is 1. 如申請專利範圍第1項所述的式I化合物或其可藥用鹽，其選自
Figure 108130887-A0305-02-0074-21
Figure 108130887-A0305-02-0075-22
 The compound of formula I or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, which is selected from
Figure 108130887-A0305-02-0074-21
Figure 108130887-A0305-02-0075-22
 一種製備如申請專利範圍第1至4項中任一項所述的式I化合物或其可藥用鹽的製備方法，
Figure 108130887-A0305-02-0076-23
 包括使式A化合物
Figure 108130887-A0305-02-0076-24
 與式F化合物
Figure 108130887-A0305-02-0076-25
 在有機溶劑和還原劑的作用下經還原胺化形成式I化合物，其中R1、R2、R3、R4、R5、L、B、Z和m如申請專利範圍第1項中所定義。 A method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4 in the scope of the patent application,
Figure 108130887-A0305-02-0076-23
 Including making compounds of formula A
Figure 108130887-A0305-02-0076-24
 Compound with formula F
Figure 108130887-A0305-02-0076-25
 Under the action of an organic solvent and a reducing agent, a compound of formula I is formed by reductive amination, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L, B, Z and m are as described in item 1 of the scope of patent application definition. 如申請專利範圍第5項所述的製備方法，其中所述還原劑選自NaBH4、NaBH3CN及NaBH3OAc。 The preparation method as described in item 5 of the scope of patent application, wherein the reducing agent is selected from NaBH 4 , NaBH 3 CN and NaBH 3 OAc. 如申請專利範圍第5或6項所述的製備方法，其中所述還原胺化反應在鹼性催化劑存在下進行，並且所述鹼性催化劑選自TEA和DIPEA。 The preparation method according to item 5 or 6 of the scope of patent application, wherein the reductive amination reaction is carried out in the presence of a basic catalyst, and the basic catalyst is selected from TEA and DIPEA. 如申請專利範圍第5或6項所述的製備方法，其中所述還原胺化反應在酸性催化劑存在下進行，並且所述酸性催化劑選自醋酸、鹽酸和三氟醋酸。 The preparation method according to item 5 or 6 of the scope of the patent application, wherein the reductive amination reaction is carried out in the presence of an acidic catalyst, and the acidic catalyst is selected from acetic acid, hydrochloric acid and trifluoroacetic acid. 如申請專利範圍第5或6項所述的製備方法，其中所述製備方法在乾燥劑存在下進行，並且所述乾燥劑選自無水MgSO4、無水Na2SO4和分子篩。 The preparation method according to item 5 or 6 of the scope of patent application, wherein the preparation method is carried out in the presence of a desiccant, and the desiccant is selected from anhydrous MgSO 4 , anhydrous Na 2 SO 4 and molecular sieves. 如申請專利範圍第5或6項所述的製備方法，其中所述還原胺化反應在溶劑中進行，並且所述溶劑選自CH3OH、CH2Cl2和1,2-二氯乙烷。 The preparation method according to item 5 or 6 of the scope of patent application, wherein the reductive amination reaction is carried out in a solvent, and the solvent is selected from CH 3 OH, CH 2 Cl 2 and 1,2-dichloroethane . 藥物組合物，其包含有效量的申請專利範圍第1至4項中任一項所述的式I化合物或其可藥用鹽，以及任選的可藥用賦形劑或載體。 A pharmaceutical composition comprising an effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of items 1 to 4 in the scope of patent application, and optionally a pharmaceutically acceptable excipient or carrier. 一種如申請專利範圍第1至4項中任一項所述的化合物或其可藥用鹽在製備用於提高、刺激、調節和/或增加免疫應答的藥物中的用途。 A use of the compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4 in the scope of the patent application in the preparation of a medicament for improving, stimulating, regulating and/or increasing immune response. 一種如申請專利範圍第1至4項中任一項所述的化合物或其可藥用鹽在製備用於抑制癌細胞生長、增殖或轉移的藥物中的用途。 A use of the compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4 in the scope of the patent application in the preparation of a medicine for inhibiting the growth, proliferation or metastasis of cancer cells. 如申請專利範圍第13項的用途，其中所述癌症選自鱗狀非小細胞肺癌(NSCLC)、非鱗狀NSCLC。 The use as in item 13 of the scope of patent application, wherein the cancer is selected from squamous non-small cell lung cancer (NSCLC) and non-squamous NSCLC. 一種如申請專利範圍第1至4項中任一項所述的化合物或其可藥用鹽在製備用於治療或預防感染性疾病的藥物中的用途。 A use of the compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4 in the scope of the patent application in the preparation of a medicament for the treatment or prevention of infectious diseases. 如申請專利範圍第15項的用途，其中所述感染性疾病是由病毒引起的感染性疾病。 Such as the use of item 15 of the scope of patent application, wherein the infectious disease is an infectious disease caused by a virus. 一種如申請專利範圍第1至4項中任一項所述的化合物或其可藥用鹽在製備用於治療或預防自身免疫性疾病的藥物中的用途。 A use of the compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4 in the scope of the patent application in the preparation of a medicament for the treatment or prevention of autoimmune diseases. 一種如申請專利範圍第1至4項中任一項所述的化合物或其可藥用鹽在製備用於治療或預防敗血性休克的藥物中的用途。 A use of the compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4 in the scope of the patent application in the preparation of a medicament for the treatment or prevention of septic shock. 式A化合物
Figure 108130887-A0305-02-0078-26
 其中R1、R2、R3、L、B、Z和m如申請專利範圍第1項中所定義。 Compound of formula A
Figure 108130887-A0305-02-0078-26
 Wherein R 1 , R 2 , R 3 , L, B, Z and m are as defined in item 1 of the scope of patent application. 一種製備如申請專利範圍第19項所述的式A化合物的製備方法，包括使式5化合物
Figure 108130887-A0305-02-0078-28
 在將羥基轉變為好的離去基團以後與式7化合物
Figure 108130887-A0305-02-0078-27
 反應得到式A化合物。 A method for preparing the compound of formula A as described in item 19 of the scope of patent application, including making the compound of formula 5
Figure 108130887-A0305-02-0078-28
 After converting the hydroxyl group into a good leaving group, the compound of formula 7
Figure 108130887-A0305-02-0078-27
 The reaction yields the compound of formula A. 如申請專利範圍第20項所述的製備方法，其中所述好的離去基團為-OMs、-OTs或溴。 The preparation method as described in item 20 of the scope of patent application, wherein the good leaving group is -OMs, -OTs or bromine. 如申請專利範圍第20項所述的製備方法，其中羥基已轉變為好的離去基團之後的式5化合物與式7化合物的反應在去酸劑存在下進行，並且所述去酸劑選自NaOH、K2CO3和KOH。 The preparation method as described in item 20 of the scope of patent application, wherein the reaction between the compound of formula 5 and the compound of formula 7 after the hydroxyl group has been converted into a good leaving group is carried out in the presence of an acid removing agent, and the acid removing agent is selected From NaOH, K 2 CO 3 and KOH. 如申請專利範圍第20至22項中任一項所述的製備方法，其中羥基已轉變為好的離去基團之後的式5化合物與式7化合物的反應在鹼性條件下發生酚的O-烴化反應，並且所述酚的O-烴化反應在選自水、甲醇、乙醇、異丙醇、丙酮、DMP、DMSO、苯和二甲苯的溶劑中進行。 The preparation method according to any one of items 20 to 22 in the scope of the patent application, wherein the reaction between the compound of formula 5 and the compound of formula 7 after the hydroxyl group has been converted into a good leaving group occurs under alkaline conditions. -Alkylation reaction, and the O-alkylation reaction of phenol is carried out in a solvent selected from water, methanol, ethanol, isopropanol, acetone, DMP, DMSO, benzene and xylene. 一種製備如申請專利範圍第19項所述的式A化合物的製備方法，包括使式3化合物
Figure 108130887-A0305-02-0079-29
 與式8化合物
Figure 108130887-A0305-02-0079-30
 在金屬催化作用下進行鈴木交叉偶聯反應。 A method for preparing the compound of formula A as described in item 19 of the scope of patent application, including making the compound of formula 3
Figure 108130887-A0305-02-0079-29
 With the compound of formula 8
Figure 108130887-A0305-02-0079-30
 Suzuki cross-coupling reaction is carried out under metal catalysis. 如申請專利範圍第24項所述的製備方法，其中所述金屬催化劑選自鈀催化劑或者Ni催化劑。 The preparation method according to item 24 of the scope of patent application, wherein the metal catalyst is selected from a palladium catalyst or a Ni catalyst. 如申請專利範圍第25項所述的製備方法，其中所述鈀催化劑選自Pd(PPh3)4、Pd(dffp)Cl2、Pd(OAc)2、Pd(dba)3/PCy3、PdCl2、Pd(PPh3)4Cl2，或者所述Ni催化劑選自NiCl2(dffp)、NiCl2(dffp)/Zn、NiCl2(dffp)/BuLi、NiCl2(PPh3)2/PPh3、NiCl2(NEt3)2、NiCl2(NEt3)2、NiCl(bipy)、Ni(TPPS)3、Ni(COD)2、NiCl2(PPh3)2/n-BuLi、Ni{P(OMe)3}2Cl2、NiCl2(PCy3)2。 The preparation method according to item 25 of the scope of patent application, wherein the palladium catalyst is selected from Pd(PPh 3 ) 4 , Pd(dffp)Cl 2 , Pd(OAc) 2 , Pd(dba) 3 /PCy 3 , PdCl 2. Pd(PPh 3 ) 4 Cl 2 , or the Ni catalyst is selected from NiCl 2 (dffp), NiCl 2 (dffp)/Zn, NiCl 2 (dffp)/BuLi, NiCl 2 (PPh 3 ) 2 /PPh 3 , NiCl 2 (NEt 3 ) 2 , NiCl 2 (NEt 3 ) 2 , NiCl(bipy), Ni(TPPS) 3 , Ni(COD) 2 , NiCl 2 (PPh 3 ) 2 /n-BuLi, Ni(P( OMe) 3 } 2 Cl 2 , NiCl 2 (PCy 3 ) 2 . 如申請專利範圍第24至25項中任一項的製備方法，其中所述鈴木交叉偶聯反應在鹼存在下進行，並且所述鹼為KOAc、K3PO4、K2CO3、NaOH、Ba(OH)2、Na2CO3、CsF或NaHCO3。 The preparation method according to any one of items 24 to 25 in the scope of patent application, wherein the Suzuki cross-coupling reaction is carried out in the presence of a base, and the base is KOAc, K 3 PO 4 , K 2 CO 3 , NaOH, Ba(OH) 2 , Na 2 CO 3 , CsF or NaHCO 3 . 如申請專利範圍第24至26項中任一項的製備方法，其中所述鈴木交叉偶聯反應在溶劑中進行，並且所述溶劑選自乙醇、THF、異丙醇、DMSO、DMF、二氧六環、甲苯、水和DME。 The preparation method according to any one of items 24 to 26 in the scope of the patent application, wherein the Suzuki cross-coupling reaction is carried out in a solvent, and the solvent is selected from ethanol, THF, isopropanol, DMSO, DMF, dioxane Six rings, toluene, water and DME. 一種如申請專利範圍第19項所述的式A化合物用作製備申請專利範圍第1項所述式I化合物的中間體的用途。 A use of the compound of formula A described in item 19 of the scope of patent application as an intermediate for preparing the compound of formula I described in item 1 of the scope of patent application.
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