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CN1412181A - Carboxylic acid derivatives inhibiting the binding of integrins to their receptors - Google Patents

Carboxylic acid derivatives inhibiting the binding of integrins to their receptors Download PDF

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CN1412181A
CN1412181A CN 01145182 CN01145182A CN1412181A CN 1412181 A CN1412181 A CN 1412181A CN 01145182 CN01145182 CN 01145182 CN 01145182 A CN01145182 A CN 01145182A CN 1412181 A CN1412181 A CN 1412181A
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amino
alkyl
dihydro
carbonyl
methyl
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CN100491353C (en
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R·J·比迪格
Q·陈
G·W·霍兰德
J·M·卡斯尔
W·李
R·V·马克特
I·L·斯科特
C·吴
E·R·戴克
J·李
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Texas Biotechnology Corp
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Abstract

The invention relates to a method for suppressingα4β1Methods of binding integrins to their receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit such binding; pharmaceutically active compositions comprising said compounds; the compounds are referred to in the above respect or in the control or prevention of alpha4β1The disease state of .

Description

抑制整联蛋白与其受体结合的羧酸衍生物Carboxylic acid derivatives that inhibit the binding of integrins to their receptors

本申请是2000年11月6日申请的美国专利申请序列号09/707,068的部分继续申请，美国专利申请序列号09/707,068是2000年5月5日申请的美国专利申请序列号09/565,920的部分继续申请，本申请要求1999年5月7日申请的美国临时专利申请序列号60/132,971的利益。This application is a continuation-in-part of U.S. Patent Application Serial No. 09/707,068, filed November 6, 2000, which is a continuation-in-part of U.S. Patent Application Serial No. 09/565,920, filed May 5, 2000 A continuation-in-part, this application claims the benefit of US Provisional Patent Application Serial No. 60/132,971 filed May 7, 1999.

                        技术领域 technical field

本发明一般涉及对α4β1整联蛋白与其受体例如VCAM-1(血管细胞粘附分子-1)和纤连蛋白结合的抑制作用。本发明还涉及抑制这种结合的化合物；含有这种化合物的药用活性组合物；以及涉及所述化合物在以上方面或在控制或预防涉及α4β1的疾病状态的制剂中的应用。The present invention generally relates to the inhibition of the binding of α4β1 integrin to its receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding; pharmaceutically active compositions containing such compounds; and to the use of said compounds in the above aspects or in preparations for the control or prevention of disease states involving α4β1 .

                        背景技术 Background technique

当组织受微生物侵袭或受损时，白细胞在炎症反应中起主要作用。炎症反应最重要方面之一涉及细胞粘附过程。一般来说，白细胞通过血流循环。然而，当组织感染或受损时，白细胞识别受侵袭组织或受损组织，结合到毛细血管壁，通过毛细血管迁移到受累组织中。这些过程由称为细胞粘附分子的蛋白家族介导。White blood cells play a major role in the inflammatory response when tissues are attacked or damaged by microorganisms. One of the most important aspects of the inflammatory response involves the process of cell adhesion. Generally, white blood cells circulate through the bloodstream. However, when tissue is infected or damaged, white blood cells recognize the invaded or damaged tissue, bind to capillary walls, and migrate through the capillaries into the affected tissue. These processes are mediated by a family of proteins known as cell adhesion molecules.

白细胞存在3种主要类型：粒细胞、单核细胞和淋巴细胞。整联蛋白α4β1(也称为极迟抗原-4，VLA-4)为单核细胞、淋巴细胞以及2种亚型粒细胞嗜酸性粒细胞和嗜碱性粒细胞表面表达的异源二聚体蛋白。该蛋白通过其识别并结合毛细血管内壁内皮细胞相关蛋白VCAM-1和纤连蛋白的能力在细胞粘附中起重要作用。There are 3 main types of white blood cells: granulocytes, monocytes, and lymphocytes. Integrin α 4 β 1 (also known as very late antigen-4, VLA-4) is a heterologous protein expressed on the surface of monocytes, lymphocytes, and two subtypes of granulocytes, eosinophils and basophils Dimeric protein. This protein plays an important role in cell adhesion through its ability to recognize and bind endothelial cell-associated proteins VCAM-1 and fibronectin in the capillary lining.

毛细血管周围组织感染或受损后，内皮细胞表达一系列粘附分子，包括VCAM-1，粘附分子对结合抵抗感染必需的白细胞很关键。结合VCAM-1或纤连蛋白之前，白细胞最初结合到某些粘附分子上，使其流动减慢并使白细胞沿活化内皮“滚动”。然后单核细胞、淋巴细胞、嗜碱性粒细胞和嗜酸性粒细胞能够通过α4β1整联蛋白牢固地与血管壁上的VCAM-1或纤连蛋白结合。有证据表明，这种相互作用还参与这些白细胞越过细胞壁迁移到受损组织中以及其最初的滚动过程。Following infection or injury in pericapillary tissue, endothelial cells express a series of adhesion molecules, including VCAM-1, which are critical for binding white blood cells necessary to fight infection. Before binding VCAM-1 or fibronectin, leukocytes initially bind to certain adhesion molecules, slowing their flow and allowing leukocytes to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the vessel wall through α4β1 integrin . Evidence suggests that this interaction is also involved in the migration and initial rolling of these white blood cells across the cell wall into damaged tissue.

尽管白细胞迁移到损伤部位有助于抵抗感染和破坏外源性物质，但是在许多情况下白细胞迁移可变得不可控制，白细胞大量涌入病变部位，引起广泛组织损伤。因此，能够阻断该过程的化合物可用作有益的治疗药物。所以，开发防止白细胞与VCAM-1和纤连蛋白结合的抑制剂应该是有用的。Although leukocyte migration to the site of injury helps to fight infection and destroy foreign material, in many cases leukocyte migration can become uncontrollable, with an influx of leukocytes into the lesion, causing extensive tissue damage. Therefore, compounds capable of blocking this process could be used as beneficial therapeutic agents. Therefore, it would be useful to develop inhibitors that prevent leukocyte binding to VCAM-1 and fibronectin.

可通过抑制α4β1结合治疗的部分疾病包括但不限于动脉硬化、类风湿性关节炎、哮喘、变态反应、多发性硬化、狼疮、炎症性肠病、移植排斥反应、接触性超敏反应和I型糖尿病。α4β1除了见于部分白细胞之外，还见于各种癌细胞，包括白血病细胞、黑素瘤细胞、淋巴瘤细胞和肉瘤细胞。已经提出涉及α4β1的细胞粘附可能参与某些癌症的转移。因此，α4β1结合抑制剂也可以用于治疗某些类型的癌症。Some diseases that can be treated by inhibiting α 4 β 1 binding include but are not limited to arteriosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, transplant rejection, contact hypersensitivity and type I diabetes. α 4 β 1 is not only found in some white blood cells, but also in various cancer cells, including leukemia cells, melanoma cells, lymphoma cells and sarcoma cells. It has been suggested that cell adhesion involving α4β1 may be involved in the metastasis of certain cancers. Therefore, inhibitors of α4β1 binding may also be useful in the treatment of certain types of cancer.

美国专利第5,510,332号公开了对抑制α4β1与蛋白结合的肽的分离纯化。WO 95/15973、EP 0 341 915、EP 0 422 938 A1、美国专利第5,192,746号和WO 96/06108公开了抑制结合的肽。WO 96/22966、WO98/04247和WO 98/04913公开了可用于抑制和防止细胞粘附和细胞粘附介导的病理的新型化合物。US Patent No. 5,510,332 discloses the separation and purification of peptides that inhibit the binding of α 4 β 1 to proteins. Peptides that inhibit binding are disclosed in WO 95/15973, EP 0 341 915, EP 0 422 938 A1, US Patent No. 5,192,746 and WO 96/06108. WO 96/22966, WO 98/04247 and WO 98/04913 disclose novel compounds useful for inhibiting and preventing cell adhesion and cell adhesion-mediated pathologies.

所以，本发明目的之一是提供为α4β1结合抑制剂的新型化合物以及包含这种新型化合物的药用组合物。Therefore, one of the objects of the present invention is to provide novel compounds which are inhibitors of α4β1 binding and pharmaceutical compositions comprising such novel compounds.

                    发明内容 Contents of the invention

本发明涉及式I化合物或其药学上可接受的盐：

Figure A0114518200371
式I其中Y在每次出现时独立选自C(O)、N、CR1、C(R2)(R3)、NR5、CH、O和S；q是3-10的整数；A选自O、S、C(R16)(R17)和NR6；E选自CH2、O、S和NR7；J选自O、S和NR8；T选自C(O)和(CH2)b，其中b是0-3的整数；M选自C(R9)(R10)和(CH2)u，其中u是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；X选自CO2B、PO3H2、SO3H、SO2NH2、SO2NHCOR12、OPO3H2、The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure A0114518200371
Formula I wherein Y at each occurrence is independently selected from C(O), N, CR 1 , C(R 2 )(R 3 ), NR 5 , CH, O and S; q is an integer from 3 to 10; A selected from O, S, C(R 16 )(R 17 ) and NR 6 ; E selected from CH 2 , O, S and NR 7 ; J selected from O, S and NR 8 ; T selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; M is selected from C(R 9 )(R 10 ) and (CH 2 ) u , wherein u is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; X is selected from CO 2 B, PO 3 H 2 , SO 3 H, SO 2 NH 2 , SO 2 NHCOR 12 , OPO 3 H 2 ,

C(O)NHC(O)R13、C(O)NHSO2R14、羟基、四唑基和氢；W选自C、CR15和N；以及B、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、C(O)NHC(O)R 13 , C(O)NHSO 2 R 14 , hydroxyl, tetrazolyl and hydrogen; W is selected from C, CR 15 and N; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 ,

R14、R15、R16和R17在每次出现时独立选自氢、卤素、烷基、R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, alkyl,

链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧Alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy

基、羟烷基、脂族酰基、-CF3、-CO2H、-SH、-CN、-NO2、group, hydroxyalkyl group, aliphatic acyl group, -CF 3 , -CO 2 H, -SH, -CN, -NO 2 ,

NH2、-OH、链炔基氨基、烷氧羰基、杂环酰基(heterocycloyl)、NH 2 , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl (heterocycloyl),

羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷Carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)

基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-Base) C (O) NH (C 1 -C 3 alkyl), -NHC (O) NH (C 1 -C 6 alkyl), -

NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino,

链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-Alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, -

C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH,

-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl

胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl

基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group,

杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle

基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene

磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl)

团；group;

其中B、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、Where B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 ,

    R12、R13、R14、R15、R16和R17为未取代的基团或被至R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are unsubstituted groups or are replaced by

    少一个给电子或吸电子基团取代的基团；One less group substituted by an electron-donating or electron-withdrawing group;

其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;

其中当M为C(R9)(R10)时，R9和R10一起可形成一个环；Wherein when M is C(R 9 )(R 10 ), R 9 and R 10 together can form a ring;

其中当A为NR6和至少一个Y为CR1时，R1和R6一起可形where when A is NR 6 and at least one Y is CR 1 , R 1 and R 6 together form

    成一个环；into a ring;

前提是当A是C(R16)(R17)时，E不是NR7。The premise is that when A is C(R 16 )(R 17 ), E is not NR 7 .

对于式I，本发明优选化合物可以是具有以下基团的化合物：A为NR6；E为NR7；J为O；M为C(R9)(R10)；q是4或5；T为(CH2)b，其中b是0；L为(CH2)n，其中n是0；X为CO2B；W为C或CR15；R4为芳基、烷基芳基、芳烷基、杂环基、烷基杂环基或杂环基烷基；R6、R7、R9、R10和R15独立为氢或低级烷基。For formula I, preferred compounds of the invention may be compounds having the following groups: A is NR 6 ; E is NR 7 ; J is O; M is C(R 9 )(R 10 ); q is 4 or 5; is (CH 2 ) b , where b is 0; L is (CH 2 ) n , where n is 0; X is CO 2 B; W is C or CR 15 ; R 4 is aryl, alkylaryl, aryl Alkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; R 6 , R 7 , R 9 , R 10 and R 15 are independently hydrogen or lower alkyl.

更具体地说，本发明的化合物可以用下式II或其药学上可接受的盐来描述

Figure A0114518200381
式IIMore specifically, the compounds of the present invention can be described by the following formula II or a pharmaceutically acceptable salt thereof
Figure A0114518200381
Formula II

其中Y在每次出现时独立选自C(O)、N、CR1、C(R2)(R3)、NR5、wherein Y is at each occurrence independently selected from C(O), N, CR 1 , C(R 2 )(R 3 ), NR 5 ,

CH、O和S；q是3-7的整数；T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；W选自C、CR15和N；B、R1、R2、R3、R4、R5、R6、R7、R9、R10、R11和R15独立选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、-SH、-CN、-NO2、-NH2、-OH、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3烷基)、-C(O)NH--(C1-C3烷基)、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基团；CH, O and S; q is an integer of 3-7; T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; W is selected from C, CR 15 and N; B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R R and R are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, -SH, -CN, -NO 2 , -NH 2 , -OH, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkane base)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC( O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH--(C 1 -C 3 alkyl), -C(O)N (C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formamido, cycloalkyl, cyclo Alkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl), -SO 3 -(C 1 -C 3 alkyl ), sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups;

   其中B、R1、R2、R3、R4、R5、R6、R7、R9、R10、R11和where B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 and

       R15为未取代基团或被至少一个给电子或吸电子基R 15 is an unsubstituted group or is replaced by at least one electron-donating or electron-withdrawing group

       团取代的基团；The group substituted by the group;

   其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;

   其中R9和R10一起可形成一个环；Wherein R 9 and R 10 together can form a ring;

   其中当至少一个Y为CR1时，R1和R6一起可形成一个wherein when at least one Y is CR 1 , R 1 and R 6 together form a

       环。Ring.

对于式II，本发明优选化合物可以是具有以下基团的化合物：q是4或5；W为C或CR15；T为(CH2)b，其中b是0；L为(CH2)n，其中n是0；R4为芳基、烷基芳基、芳烷基、杂环基、烷基杂环基或杂环基烷基；R6、R7、R9、R10和R15独立为氢或低级烷基。For formula II, preferred compounds of the invention may be compounds having the following groups: q is 4 or 5; W is C or CR 15 ; T is (CH 2 ) b where b is 0; L is (CH 2 ) n , wherein n is 0; R 4 is aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; R 6 , R 7 , R 9 , R 10 and R 15 is independently hydrogen or lower alkyl.

更具体地说，本发明的化合物可以用下式III或其药学上可接受的盐来描述 More specifically, the compounds of the present invention can be described by the following formula III or a pharmaceutically acceptable salt thereof

式III其中Y在每次出现时独立选自C(O)、N、CR1、C(R2)(R3)、NR5、Formula III wherein Y at each occurrence is independently selected from C(O), N, CR 1 , C(R 2 )(R 3 ), NR 5 ,

CH、O和S；q是2-5的整数；T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；及R5、R6、R7、R11和R18各自独立选自烷基、链烯基、链炔基、羟CH, O and S; q is an integer of 2-5; T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; and R 5 , R 6 , R 7 , R 11 and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl

烷基、脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、Alkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl,

-CH＝NOH、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、-CH=NOH, haloalkyl, alkoxyalkoxy, formaldehyde, formamide,

环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳Cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryl

氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、Oxygen, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,

烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、Alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,

氨基甲酸酯基、芳氧基烷基、氢和-C(O)NH(苄基)基团；B、R1、R2、R3、R4、R9和R10独立选自氢、卤素、烷基、链烯Carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; B, R 1 , R 2 , R 3 , R 4 , R 9 and R 10 are independently selected from hydrogen , halogen, alkyl, alkenes

基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、group, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy,

羟烷基、脂族酰基、-CF3、-CO2H、-SH、-CN、硝基、氨基、Hydroxyalkyl, Aliphatic Acyl, -CF 3 , -CO 2 H, -SH, -CN, Nitro, Amino,

羟基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3 Hydroxy, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3

烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-Alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -

C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -

NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )

氨基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3烷基)、-Amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 alkyl), -

C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkane

基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、group, alkoxyalkoxy group, formaldehyde group, formamide group, cycloalkyl group, cycloalkenyl group,

环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、Cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,

联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain

烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3 Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3

烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧Alkyl), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxy

基烷基和-C(O)NH(苄基)基团；Alkyl and -C(O)NH(benzyl) groups;

    其中B、R1、R2、R3、R4、R5、R6、R7、R9、R10、R11和where B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 and

        R18为未取代基团或被至少一个给电子或吸电子基团R 18 is an unsubstituted group or is replaced by at least one electron-donating or electron-withdrawing group

        取代的基团；Substituting groups;

    其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;

    而且其中R9和R10一起可形成一个环；And wherein R 9 and R 10 can form a ring together;

    以及其中当至少一个Y为CR1时，R1和R6一起可形成一and wherein when at least one Y is CR 1 , R 1 and R 6 together form a

        个环。rings.

对于式III，本发明优选化合物可以是具有以下基团的化合物：R18为氢、烷基、芳基、芳烷基、环烷基、烷基杂环基、杂环基烷基或杂环基；T为(CH2)b，其中b是0；L为(CH2)n，其中n是0；Y为CR1和C(R2)(R3)，而q是2或3。For formula III, preferred compounds of the invention may be compounds having the following groups: R is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, alkylheterocyclyl, heterocyclylalkyl or heterocycle T is (CH 2 ) b , where b is 0; L is (CH 2 ) n , where n is 0; Y is CR 1 and C(R 2 )(R 3 ), and q is 2 or 3.

在式III中，所述分子的组成部分

Figure A0114518200421
In formula III, the constituents of the molecule
Figure A0114518200421

可以是和

Figure A0114518200423
以及其药学上可接受的盐，其中R19、R20、R21和R28在每次出现时独立选自卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、羟基、-CO2H、巯基、氰基、硝基、氨基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3烷基)、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基团；R18选自烷基、链烯基、链炔基、羟烷基、脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二can be and
Figure A0114518200423
and pharmaceutically acceptable salts thereof, wherein R 19 , R 20 , R 21 and R 28 are independently selected from each occurrence of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy , alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , hydroxyl, -CO 2 H, mercapto, cyano, nitro, amino, alkynylamino, alkoxycarbonyl, Heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O )NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkyl Oxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy group, formaldehyde group, formamide group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, cycloalkylalkyl group, aryl group, aroyl group, aryloxy group, arylamino group, biaryl group, thioaryl group, Diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl ), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; R 18 is selected from Alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkyl, alkoxyalkoxy, formaldehyde, Formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, di

   芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂Arylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylhetero

   环基、杂环基烷基、氨基甲酸酯基、芳氧基烷基、氢和-Cyclic, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -

   C(O)NH(苄基)基团；C(O)NH(benzyl) group;

R22选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、R is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,

   链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、Alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H,

   -SH、-CN、硝基、氨基、羟基、链炔基氨基、烷氧羰基、杂-SH, -CN, nitro, amino, hydroxyl, alkynylamino, alkoxycarbonyl, hetero

   环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-Cycloacyl, carboxyl, -N(C 1 -C 3 alkyl) -C(O)(C 1 -C 3 alkyl), -

   NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -

   C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl,

   烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl,

   -C(O)NH-(C1-C3烷基)、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH,

   -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl

   胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl

   基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、Base, aryloxy, arylamino, biaryl, thioaryl, diarylamino,

   杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle

   基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene

   磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl)

   团；Group;

c为0-2的整数；c is an integer of 0-2;

d为0-3的整数；d is an integer of 0-3;

e为0-4的整数；及e is an integer from 0 to 4; and

i为0-2的整数。i is an integer of 0-2.

在一个实施方案中，R18为芳烷基；R4为芳基；T为(CH2)b，其中b是0；L为其中n是0的(CH2)n；而B、R6、R7、R9和R10各自独立为氢。In one embodiment, R 18 is aralkyl; R 4 is aryl; T is (CH 2 ) b , where b is 0; L is (CH 2 ) n where n is 0; and B, R 6 , R 7 , R 9 and R 10 are each independently hydrogen.

更具体来说，本发明化合物可用下式IV或其药学上可接受的盐来描述：

Figure A0114518200441
式IVMore specifically, the compounds of the present invention can be described by the following formula IV or a pharmaceutically acceptable salt thereof:
Figure A0114518200441
Formula IV

其中T选自C(O)和(CH2)b，其中b是0-3的整数；Wherein T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3;

L选自O、NR11、S和(CH2)n，其中n是0或1；L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1;

g为0-7的整数；g is an integer of 0-7;

B、R4、R9、R10和R23在每次出现时独立选自氢、卤素、烷基、B, R 4 , R 9 , R 10 and R 23 are each independently selected from hydrogen, halogen, alkyl,

   链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧Alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy

   基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、氰基、硝基、hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, mercapto, cyano, nitro,

   氨基、羟基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3 Amino, hydroxyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3

   烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-Alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -

   C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -

   NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )

   氨基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3)烷基、-Amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 )alkyl, -

   C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkane

   基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、 , alkoxyalkoxy, formaldehyde, formamide, cycloalkyl, cycloalkenyl,

   环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、Cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,

   联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链  Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain

   烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3 Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3

   烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧Alkyl), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxy

   基烷基和-C(O)NH(苄基)基团；ylalkyl and -C(O)NH(benzyl) groups;

R6、R7、R11和R18各自独立选自烷基、链烯基、链炔基、羟烷基、R 6 , R 7 , R 11 and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl,

   脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、  Aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH,

   卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环 Haloalkyl, alkoxyalkoxy, formaldehyde, formamide, cycloalkyl, cyclo

   烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基alkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, aryl

    氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、  Amino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,

    芳链烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯 Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate

    基、芳氧基烷基、氢和-C(O)NH(苄基)基团；radical, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups;

其中B、R4、R6、R7、R9、R10、R11、R18和R23为未取代基团或Wherein B, R 4 , R 6 , R 7 , R 9 , R 10 , R 11 , R 18 and R 23 are unsubstituted groups or

    被至少一个给电子或吸电子基团取代的基团；A group substituted with at least one electron-donating or electron-withdrawing group;

        其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;

        以及R9和R10一起可形成一个环。And R 9 and R 10 together may form a ring.

现在本发明的优选化合物也可以用下式V或其药学上可接受的盐来描述：式V其中h为0-5的整数；B、R9、R10、R24和R25各自独立选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、Now preferred compounds of the present invention can also be described by the following formula V or a pharmaceutically acceptable salt thereof: Formula V wherein h is an integer of 0-5; B, R 9 , R 10 , R 24 and R 25 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy radical, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxycarbonyl , heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C( O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), Alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-( C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkane Oxygen, formaldehyde, formamido, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,

联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain

烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3 Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3

烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧Alkyl), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxy

基烷基和-C(O)NH(苄基)基团；R27在每次出现时独立选自卤素、烷基、链烯基、链炔基、烷氧基、and -C(O)NH(benzyl) groups; R 27 at each occurrence is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy,

链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、Alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 ,

-CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧-CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxy

羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-Carbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl) -C(O)(C 1 -C 3 alkyl), -

NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -

C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、-N(C1-C3烷C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), -N(C 1 -C 3 alkane

基)SO2(C1-C3烷基)、-N(C1-C3烷基)SO2(芳基)、-烷氧基烷基、radical) SO 2 (C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)SO 2 (aryl), -alkoxyalkyl,

烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl,

-C(O)NH-(C1-C3烷基)、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH,

-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl

胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl

基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group,

杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle

基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene

磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl)

团；R6、R7和R18各自独立选自烷基、链烯基、链炔基、羟烷基、脂group; R 6 , R 7 and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, lipid

族酰基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、卤Family acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH, halogen

代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯Substituted alkyl, alkoxyalkoxy, formaldehyde, formamide, cycloalkyl, cycloalkene

基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨radical, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino

基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、Base, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,

芳链烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate

基、芳氧基烷基、氢和-C(O)NH(苄基)基团；R26选自氢、烷基、链烯基、链炔基、羟烷基、脂族酰基、-CF3、 R is selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, -CF 3 .

    烷氧羰基、杂环酰基、羧基、-C(O)O-(C1-C3)烷基、-Alkoxycarbonyl, heterocyclic acyl, carboxyl, -C(O)O-(C 1 -C 3 )alkyl, -

    C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-PO3H2、卤代烷C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -PO 3 H 2 , haloalkane

    基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳Base, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl

    基、芳酰基、联芳基、杂环基、烷基芳基、芳链烯基、芳烷yl, aroyl, biaryl, heterocyclyl, alkylaryl, arylalkenyl, aryl

    基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、group, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl),

    亚磺酰氨基、芳氧基烷基和-C(O)NH(苄基)基团；  Sulfonamido, aryloxyalkyl and -C(O)NH(benzyl) groups;

其中B、R6、R7、R9、R10、R18、R24、R25、R26和R27为未取代基Wherein B, R 6 , R 7 , R 9 , R 10 , R 18 , R 24 , R 25 , R 26 and R 27 are unsubstituted groups

    团或被至少一个给电子或吸电子基团取代的基团；group or a group substituted by at least one electron-donating or electron-withdrawing group;

        其中R18和R24一起可形成一个环；Wherein R 18 and R 24 together can form a ring;

        R24和R25一起可形成一个环；R 24 and R 25 together may form a ring;

        R25和R26一起可形成一个环；R 25 and R 26 together may form a ring;

        以及其中R9和R10一起可形成一个环。And wherein R 9 and R 10 together may form a ring.

现在式V的优选化合物为具有以下基团的化合物：B、R6、R7、R9、R10、R24、R25和R26各自独立为氢，而R18为取代芳烷基或未取代芳烷基。Now preferred compounds of formula V are those having the following groups: B, R 6 , R 7 , R 9 , R 10 , R 24 , R 25 and R 26 are each independently hydrogen, and R 18 is substituted aralkyl or Unsubstituted aralkyl.

现在本发明的其它优选化合物可用下式VI或其药学上可接受的盐来描述：

Figure A0114518200471
Other preferred compounds of the present invention can now be described by the following formula VI or a pharmaceutically acceptable salt thereof:
Figure A0114518200471

式VI其中Z在每次出现时独立选自C(O)、N、CR30、C(R31)(R32)、NR33、Formula VI wherein at each occurrence Z is independently selected from C(O), N, CR 30 , C(R 31 )(R 32 ), NR 33 ,

CH、O和S；z是3-6的整数；k为0-5的整数；T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；R6、R7、R11、R18和R33各自独立选自烷基、链烯基、链炔基、CH, O and S; z is an integer of 3-6; k is an integer of 0-5; T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; R 6 , R 7 , R 11 , R 18 and R 33 are each independently selected from alkyl, alkenyl, alkynyl,

羟烷基、脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、Hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl,

-CH＝NOH、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、-CH=NOH, haloalkyl, alkoxyalkoxy, formaldehyde, formamide,

环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳Cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryl

氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、Oxygen, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,

烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、Alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,

氨基甲酸酯基、芳氧基烷基、氢和-C(O)NH(苄基)基团；B、R4、R9、R10、R30、R31和R32在每次出现时独立选自氢、卤Carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; B, R 4 , R 9 , R 10 , R 30 , R 31 and R 32 in each occurrence independently selected from hydrogen, halogen

素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、Element, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy,

硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、氰基、Thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, mercapto, cyano,

硝基、氨基、羟基、链炔基氨基、烷氧羰基、杂环酰基、羧Nitro, amino, hydroxyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxy

基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷group, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkane

基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-Base) C (O) NH (C 1 -C 3 alkyl), -NHC (O) NH (C 1 -C 6 alkyl), -

NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino,

链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-Alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, -

C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3-烷基)2、-CH＝NOH、C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 -alkyl) 2 , -CH=NOH,

-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl

胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl

基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group,

杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle

基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene

磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl)

团；R29在每次出现时独立选自卤素、烷基、链烯基、链炔基、烷氧基、group; R 29 at each occurrence is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy,

链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、Alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 ,

-CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧-CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxy

羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-Carbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl) -C(O)(C 1 -C 3 alkyl), -

NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -

C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl,

烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl,

-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH,

-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl

胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl

基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group,

杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle

基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene

磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl)

团；其中B、R4、R6、R7、R9、R10、R11、R18、R29、R30、R31、R32 group; wherein B, R 4 , R 6 , R 7 , R 9 , R 10 , R 11 , R 18 , R 29 , R 30 , R 31 , R 32

和R33为未取代基团或被至少一个给电子或吸电子基团取代and R 33 are unsubstituted or substituted with at least one electron-donating or electron-withdrawing group

的基团；group;

    当L为NR11时，R4和R11一起可形成一个环；When L is NR 11 , R 4 and R 11 together can form a ring;

    以及其中R9和R10一起可形成一个环。可用式VII和VIII的新型中间体制备部分式I-VI化合物， And wherein R 9 and R 10 together may form a ring. Some compounds of formulas I-VI can be prepared from novel intermediates of formulas VII and VIII,

式VII其中R24和R25各自独立选自氢、卤素、烷基、链烯基、链炔基、Formula VII wherein R 24 and R 25 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,

烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族Alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic

酰基、-CF3、巯基、羟基、-CO2H、氰基、硝基、氨基、链炔Acyl, -CF 3 , Mercapto, Hydroxyl, -CO 2 H, Cyano, Nitro, Amino, Alkyne

基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3 Amino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3

烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-Alkyl), -NHC(O)N(C 1 -C 3 Alkyl)C(O)NH(C 1 -C 3 Alkyl), -

    NHC(O)NH(C1-C6烷基)、烷基氨基、-NHSO2(C1-C3烷基)、-NHC(O)NH(C 1 -C 6 alkyl), alkylamino, -NHSO 2 (C 1 -C 3 alkyl), -

    NHSO2(芳基)、烷氧基烷基、链烯基氨基、二(C1-C3)氨基、-NHSO 2 (aryl), alkoxyalkyl, alkenylamino, di(C 1 -C 3 )amino, -

    C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkane

    基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧radical) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy

    基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基yl, formaldehyde, formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl

    烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳Alkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl

    基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、Base, diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl,

    烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-Alkyl heterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl), -

    SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl

    和-C(O)NH(苄基)基团；and -C(O)NH(benzyl) groups;

R18和R34各自独立选自烷基、链烯基、链炔基、羟烷基、脂族酰R and R are each independently selected from alkyl, alkenyl, alkynyl , hydroxyalkyl, aliphatic acyl

    基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、卤代烷Alkyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkane

    基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、 , alkoxyalkoxy, formaldehyde, formamide, cycloalkyl, cycloalkenyl,

    环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、  Cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,

    联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链  Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain

    烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯基、Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate,

    芳氧基烷基、氢和-C(O)NH(苄基)基团；Aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups;

        其中R18、R24、R25和R34为未取代基团或被至少一个给Wherein R 18 , R 24 , R 25 and R 34 are unsubstituted groups or are given by at least one

            电子或吸电子基团取代的基团；A group substituted with an electron or electron-withdrawing group;

        以及其中R24和R25一起可形成一个环；and wherein R 24 and R 25 together may form a ring;

前提是当R24和R25一起可形成一个环时，所形成的环不是苯。现在式VII的优选化合物为具有以下基团的化合物：R34为氢；R18为芳烷基；而R24和R25各自独立为氢、低级烷基或其中R24和R25一起可形成一个环的低级烷基。Provided that when R 24 and R 25 together can form a ring, the ring formed is not benzene. Now preferred compounds of formula VII are those having the following groups: R 34 is hydrogen; R 18 is aralkyl; and R 24 and R 25 are each independently hydrogen, lower alkyl or wherein R 24 and R 25 together may form A ring lower alkyl.

下式VIII为目前的优选新型中间体：

Figure A0114518200511
Following formula VIII is present preferred novel intermediate:
Figure A0114518200511

式VIII其中R24和R25各自独立选自氢、卤素、烷基、链烯基、链炔基、Formula VIII wherein R 24 and R 25 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,

烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族Alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic

酰基、-CF3、巯基、羟基、-CO2H、氰基、硝基、氨基、链炔Acyl, -CF 3 , Mercapto, Hydroxyl, -CO 2 H, Cyano, Nitro, Amino, Alkyne

基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3 Amino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3

烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-Alkyl), -NHC(O)N(C 1 -C 3 Alkyl)C(O)NH(C 1 -C 3 Alkyl), -

NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳NHC (O) NH (C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl

基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、group), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino,

-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3 -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3

烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷Alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkane

氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷Oxygen, Formaldehyde, Formamide, Cycloalkyl, Cycloalkenyl, Cycloalkynyl, Cycloalkane

基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代Alkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thio

芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、Aryl, diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl,

烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-Alkyl heterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl), -

SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl

和-C(O)NH(苄基)基团；R34选自烷基、链烯基、链炔基、羟烷基、脂族酰基、链炔基氨基、and -C(O)NH(benzyl) groups; R is selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino,

烷氧羰基、杂环酰基、-CH＝NOH、卤代烷基、烷氧基烷氧基、Alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkyl, alkoxyalkoxy,

甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、Formaldehyde, formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl,

芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二Aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, di

芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂Arylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylhetero

环基、杂环基烷基、氨基甲酸酯基、芳氧基烷基、氢和-Cyclic, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -

C(O)NH(苄基)基团；以及C(O)NH(benzyl) group; and

R35在每次出现时独立选自卤素、烷基、链烯基、链炔基、烷氧基、Each occurrence of R is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy,

   链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、Alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 ,

   -CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧-CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxy

   羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-Carbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl) -C(O)(C 1 -C 3 alkyl), -

   NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -

   C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl,

   烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl,

   -C(O)NH-(C1-C3烷基)、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 alkyl), -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH,

   -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl

   胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl

   基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、Base, aryloxy, arylamino, biaryl, thioaryl, diarylamino,

   杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle

   基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene

   磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl)

   团；Group;

       其中R24、R25、R34和R35为未取代基团或被至少一个给Wherein R 24 , R 25 , R 34 and R 35 are unsubstituted groups or are given by at least one

           电子或吸电子基团取代的基团；以及A group substituted with an electron or electron-withdrawing group; and

   m为0-5的整数。现在式VIII的优选化合物为具有以下基团的化合物：R34为氢；m为1-3的整数，而R35在每次出现时为烷基、卤素、烷氧基、卤代烷基、磺酰基、羟基或氰基。m is an integer of 0-5. Now preferred compounds of formula VIII are those having the following groups: R 34 is hydrogen; m is an integer from 1 to 3, and R 35 in each occurrence is alkyl, halogen, alkoxy, haloalkyl, sulfonyl , hydroxyl or cyano.

现在式I的优选化合物包括：(3S)-3-[({[2-甲基-4-(2-甲基丙基)-6-氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[2-氧代-1-(苯甲基)-4-丙基-1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-乙基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-丙基-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({6-甲基-2-氧代-1-(苯甲基)-4-[(苯甲基)氧基]-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-2，4-二甲基-6-氧代-1，6-二氢-5-嘧啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲基]-6-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[4-(甲氧基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3，4-二甲基苯基)丙酸，(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-(1，4-噁嗪烷(oxazinan)-4-基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-[(2-氯代苯基)甲基]-2-氧代-4-(丙基氨基)-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-溴代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-甲基-4-(甲氧基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-苯基-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[(2-{[2-(甲氧基)乙基]氧基}乙基)氧基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-6-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[(1，1-二甲基乙基)氨基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基)氨基}-3-苯基丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[4-甲基四氢-1(2H)-吡嗪基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{基)({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[4-(甲氧基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3，5-二甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-(甲氧基)苯基]丙酸，(3S)-3-[3，5-双(甲氧基)苯基]-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-喹啉基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-(三氟甲基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[({乙基[(乙基氨基)羰基]氨基}羰基)氨基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[0({4-(1-azetamyl)-1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-({2-[(2-{[2-(甲氧基)乙基]氧基}乙基)氧基]乙基}氧基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氟代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯-6-氟代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-5-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-((((2-氧代-1-((4-(三氟甲基)苯基)甲基)-1，2-二氢-3-吡啶基)氨基)羰基)氨基)丙酸，(3S)-3-((((1-((2-氯代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-氟代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-溴代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2，4-二氯苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-氯-6-氟代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-氯代苯基)甲基)-4-羟基-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-三氟甲基)氧基)苯基)丙酸(3S)-3-[({[1-[(2-氯-6-甲氧基苄基)-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，4-{[3-[({[(1S)-2-羧基-1-(4-甲基苯基)乙基]氨基}羰基)氨基]-1-(2-氯苄基)-2-氧代-1，2-二氢吡啶-4-基]氨基}苯甲酸(3S)-3-{[({1-[(2-氯代苄基)-4-[(2，2-二甲基丙酰基)氨基]-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[4-{{(叔丁基氨基)羰基]氨基}-1-(2-氯苄基)-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氰基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1，4-苯并二氧杂环己(benzodioxin)-6-基)丙酸，(3S)-3-[({{1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(7-甲氧基-1，3-苯并二氧杂环戊-5-基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基-4-甲氧基苯基)丙酸，(3S)-3-[({{1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲氧基苯基)丙酸，(3S)-3-[({[1-(4-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰-基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2，6-二氟苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲氧基-4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-5-乙基-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[2-氯-5-(三氟甲基)苄基]-4-羟基-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2，6-二甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-5-丙基-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-5-丙基-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-(3-丁氧基苯基)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基)丙酸，(3S)-3-{[({1-[2-氯-5-(甲基磺酰基)苄基]-4-羟基-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(2-甲氧基乙氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(二氟甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-氰基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2-萘基)丙酸和(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1-苯并呋喃-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二乙氧基苯基)丙酸，(3S)-3-[({{5-氯-1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-苯基丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(1，3-二乙基-2-氧代-2，3-二氢-1H-苯并咪唑-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(三氟甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-5-环丙基-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-5-环丙基-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-5-甲氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-6-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-6-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙氧基甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙基甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(二氟甲基)氧基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(1，1，2，2-四氟乙基)氧基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1-乙基-1H-吲哚-5-基)丙酸和(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-(二乙基氨基)苯基}丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(二乙基氨基)苯基]丙酸，和(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1-甲基-1H-吲哚-5-基)丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[甲基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[甲基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[乙基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[乙基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1H-吲哚-5-基)丙酸，以及它们的药学上可接受的盐。Now preferred compounds of formula I include: (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(benzyl)-1,6 -Dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5- Base)-3-[({[2-oxo-1-(phenylmethyl)-4-propyl-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]propanoic acid, (3S )-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino }-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-propyl- 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chloro Phenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, ( 3S)-3-{[({6-methyl-2-oxo-1-(benzyl)-4-[(benzyl)oxy]-1,2-dihydro-3-pyridyl }amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2,4- Dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[( {4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3 -(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2 -Dihydro-3-pyridyl}amino)carbonyl]amino}-3-[4-(methoxy)phenyl]propanoic acid, (3S)-3-{[({1-[(2-chloro Phenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(3,4-dimethylphenyl)propane Acid, (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl}amino) Carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo Substitute-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-[(2- Chlorophenyl)methyl]-4-(1,4-oxazinane (oxazinan)-4-yl)-2-oxo-1,2-dihydro-3-pyridyl]amino}carbonyl)amino ]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4-(propyl Amino)-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2 -Bromophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propane acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino) Carbonyl]amino}-3-[3-methyl-4-(methoxy)phenyl]propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{ [({1-[(2-chlorophenyl)methyl]-4-[(2-{[2-(methoxy)ethyl]oxy}ethyl)oxy]-2-oxo -1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chloro Substituted phenyl)methyl]-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl ) propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(1,1-dimethylethyl)amino]-2-oxo -1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chloro Substituted phenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl)amino}-3-phenylpropionic acid, (3S)-3-{ [({1-[(2-chlorophenyl)methyl]-4-[4-methyltetrahydro-1(2H)-pyrazinyl]-2-oxo-1,2-dihydro- 3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{yl)({1-[(2-chlorophenyl)methyl] -4-Hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[4-(methoxy)phenyl]propanoic acid, (3S)-3 -{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- (3,5-Dimethylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1, 2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(3-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chlorophenyl )methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3-(methoxy)phenyl]propionic acid, ( 3S)-3-[3,5-bis(methoxy)phenyl]-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy- 2-oxo-1,2-dihydro-3-quinolyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-{[({1-[ (2-Chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl )phenyl]propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]amino}carbonyl )amino]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[0 ({4-(1-azetamyl)-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3 -(4-methylphenyl)propionic acid, (3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-({2-[(2-{[2 -(methoxy)ethyl]oxy}ethyl)oxy]ethyl}oxy)-2-oxo-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]-3 -(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chloro-6-fluoro Phenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S )-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino }-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-((((2-oxo- 1-((4-(trifluoromethyl)phenyl)methyl)-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)propanoic acid, (3S)-3-(((( 1-((2-chlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl)propane Acid, (3S)-3-((((1-((2-fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino) -3-(4-methylphenyl)propanoic acid, (3S)-3-((((1-((2-bromophenyl)methyl)-2-oxo-1,2-dihydro -3-pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl)propionic acid, (3S)-3-((((1-((2,4-dichlorophenyl)methyl Base)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl)propionic acid, (3S)-3-(((( 1-((2-chloro-6-fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3-(4-methyl Phenyl)propionic acid, (3S)-3-((((1-((2-chlorophenyl)methyl)-4-hydroxy-2-oxo-1,2-dihydro-3-pyridine Base)amino)carbonyl)amino)-3-(4-trifluoromethyl)oxy)phenyl)propanoic acid (3S)-3-[({[1-[(2-chloro-6-methoxy Benzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, 4-{[3-[({ [(1S)-2-Carboxy-1-(4-methylphenyl)ethyl]amino}carbonyl)amino]-1-(2-chlorobenzyl)-2-oxo-1,2-dihydro Pyridin-4-yl]amino}benzoic acid (3S)-3-{[({1-[(2-chlorobenzyl)-4-[(2,2-dimethylpropionyl)amino]-2 -Oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-[({[4-{{ (tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4- Methylphenyl)propanoic acid, (3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1 , 2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid, (3S)-3-[({{1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- (7-methoxy-1,3-benzodioxol-5-yl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy- 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid, (3S)-3- [({{1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-di Methoxyphenyl) propionic acid, (3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] Amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy- 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-[({[1-( 2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl-yl)amino]-3-(4-methylbenzene base) propionic acid, (3S)-3-[({[1-(2,6-difluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxyl-2 -Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxyphenyl)propionic acid, (3S)-3-[({[ 1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxybenzene base) propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl) Amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxy-4-methylphenyl ) propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino ]-3-(3,4-Dimethylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-5-ethyl-4-hydroxyl-2-oxo Substitute-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[2-chloro -5-(trifluoromethyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl ) propionic acid, (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridin-3-yl ]amino}carbonyl)amino]-3-(3-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxyl- 5-Methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino} Carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2,6-dimethoxybenzyl)-4-hydroxyl-2-oxo Substitute-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid, (3S)- 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3 -(3-ethoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-(4-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)- 4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-(3-Butoxyphenyl)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3 -yl]amino}carbonyl)amino)propionic acid, (3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo- 1,2-Dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl )-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(2-methoxyethoxy)phenyl]propanoic acid , (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3 -(3,4-dipropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-di Hydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(difluoromethoxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl )-4-hydroxyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propane Acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxyl-5, 6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S) -3-[({[1-(2-chloro-6-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl]amino}carbonyl)amino]-3-(2-naphthyl)propionic acid and (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6- Dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3 -[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl )amino]-3-(3,4-diethoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methoxyphenyl)propionic acid , (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentyl Dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro- 6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid , (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-5-methyl-2-oxo-1,2-dihydropyridine-3 -yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl) -4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethane Oxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1, 2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propanoic acid, (3S)-3-[({[1-( 2-Chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2 , 3-dihydro-1-benzofuran-5-yl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-2 -Oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-diethoxybenzene base) propanoic acid, (3S)-3-[({{5-chloro-1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-2-oxo-1,2-dihydro Pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl Base) 4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, (3S)-3 -[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[b ]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxy Benzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-benzene Propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene [b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) Propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine -3-yl]amino}carbonyl)amino]-3-[3-(trifluoromethoxy)phenyl]propionic acid, (3S)-3-[({[1-(2-chloro-6-ethyl Oxybenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxy (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclo Pentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propanoic acid, (3S)-3-[({[ 1-(2-Chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy -2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-[({[1- (2-Chloro-5-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-( 4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6-methyl-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chloro -6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl -1H-indol-6-yl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-2-oxo-2, 5,6,7-tetrahydro-1H-cyclopentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropoxy)phenyl]propionic acid, ( 3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadieno[b]pyridine -3-yl]amino}carbonyl)amino]-3-[3-(cyclopropoxymethoxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chloro-6 -ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino] -3-[3-(cyclopropylmethoxy)phenyl]propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2 , 5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethylphenyl)propionic acid, ( 3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene [b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoic acid, (3S)-3-{[({1-[ (2-Chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl ]amino}-3-{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro Phenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}- 3-(1-Ethyl-1H-indol-5-yl)propanoic acid and (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- Oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-(diethylamino)phenyl }propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2 , 5,6,7-tetrahydro-1H-cyclopentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)- 3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-5- Methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid, (3S)-3-[({ [1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl )amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-5 -Methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid, (3S)-3 -[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl ]amino}carbonyl)amino]-3-(3-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5-methyl- 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(diethylamino)phenyl]propanoic acid, and (3S)-3-{[ ({1-[(2-Chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[b ]pyridin-3-yl}amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propionic acid, (3S)-3-{[({1-[(2- Chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino} -3-{3-[(Methylsulfonyl)amino]phenyl}propionic acid, (3S)-3-{[({1-[(2-Chloro-6-methylphenyl)methyl]- 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[( Methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5, 6,7-tetrahydro-1H-cyclopentadieno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propane Acid, (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro -1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)- 3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[b] Pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2 -Chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl} Amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro-6-methyl phenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino} -3-(1H-indol-5-yl)propionic acid, and their pharmaceutically acceptable salts.

现在式VII的优选化合物包括：5-(2-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-苄基-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-苄基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，5-二甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，4-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，5-二氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(甲硫基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3，5-二(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-叔丁基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-溴苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3，4-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[4-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(吡啶-2-基甲基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，4-二氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(三氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[4-(三氟甲氧基)苄基基]3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(三氟甲基)苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，3-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3，5-二甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-戊基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，4-二氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-乙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-丁基-5-(2-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，7-甲基-5-[4-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，4-(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]-N，N-二甲基苯磺酰胺，5-(萮基甲基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-3，5，6，7，8，9-六氢[1，3]噁唑并[4，5-c]喹啉-2，4-二酮，5-(2-氯苄基)-7-乙基-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(甲硫基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]-N，N-二甲基苯磺酰胺，5-(2，6-二甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(三氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶2，4-二酮，5-(2-氯苄基)-6，7-二甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯-2-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-5，6，7，8，9，10-六氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-[2-(二氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-甲基-5-[(1R)-1-苯乙基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，3-氯-2-[(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]苄腈，5-(2-氯-6-甲基苄基)-6，7-二甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，2-[(2，4-二氧代-2，3二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]苄腈，5-(2-氯-6-甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(甲硫基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-环丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-甲基-5-(4-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3，5-二甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氟苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氟-6-甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲氧基苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(5-氯-2-氟苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-异丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(5-氟-2-甲基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-甲基-5-[(1S)-1-苯基乙基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-异丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(5-乙酰基-2-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氟-6-(三氟甲基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲基苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-(2-氯-6-乙氧基苄基)-7-乙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-异丁氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-(2-氯-6-异丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-6-(2，2，2-三氟乙氧基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-d]哒嗪-2，4-二酮，5-[2-氯-6-(2-甲氧基乙氧基)苄基]-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-(2-氯-6-乙氧基苄基)-6，7-二甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-乙基-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-乙基-3，5-二氢[1，3]噁唑并[4，5-d]哒嗪-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-环丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-乙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(哌啶-1-基磺酰基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(吡咯烷-1-基磺酰基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-6-(环戊基甲氧基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(苄氧基)-6-氯苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，3-二氯-6-乙氧基苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-[2-氯-5-(三氟甲基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮和5-(2-氯-5-氟苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮。Preferred compounds of formula VII now include: 5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5- (2-chlorobenzyl)-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-fluorobenzyl Base)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-fluorobenzyl)-3,5 -Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-benzyl-6-methyl-3,5-dihydro[1,3]oxazole And[4,5-c]pyridine-2,4-dione, 5-benzyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione Ketone, 5-(2,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2 -Methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4-dichlorobenzyl)- 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-methoxybenzyl)-3,5-dihydro[1 ,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,5-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[ 4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4, 5-c]pyridine-2,4-dione, 5-(4-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4- Diketone, 5-(2-chloro-5-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5 -[3,5-bis(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-( 4-tert-butylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl)-3 , 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-3,5-dihydro[1,3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4 , 5-c]pyridine-2,4-dione, 5-(2-bromobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4 -diketone, 5-(3,4-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-( 4-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methoxy Benzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(trifluoromethyl)benzyl]-3 , 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methylbenzyl)-3,5-dihydro[1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(pyridin-2-ylmethyl)-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine- 2,4-diketone, 5-(2,4-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(tri Fluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(trifluoromethoxy ) benzyl] 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(trifluoromethyl)benzyl)- 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methoxybenzyl)-3,5-dihydro[1 ,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,3-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[ 4,5-c]pyridine-2,4-dione, 5-(3,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c] Pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-pentyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4 -diketone, 5-(2,4-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-di Ketone, 5-(2-chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-butane Base-5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5 -(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dichloro Benzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-fluorobenzyl)-3, 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methylbenzyl)-7-methyl-3, 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-7-methyl-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-5,6,7,8-tetrahydro-2H-cyclopentadiene And[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 7-methyl-5-[4-(methylsulfonyl)benzyl] -3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-methoxybenzyl)-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxa Azolo[4,5-c]pyridine-2,4-dione, 4-(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c] Pyridin-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide, 5-(helicylmethyl)-3,5-dihydro[1,3]oxazolo[4, 5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-3,5,6,7,8,9-hexahydro[1,3]oxazolo[4,5- c] quinoline-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-[2-(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl ]-N,N-dimethylbenzenesulfonamide, 5-(2,6-dimethoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-[2-(trifluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine 2,4- Diketone, 5-(2-chlorobenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione , 5-[2-chloro-5-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chloro-2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2 -chlorobenzyl)-5,6,7,8,9,10-hexahydro-2H-cyclopentadieno[b][1,3]oxazolo[5,4-d]pyridine-2, 4(3H)-diketone, 5-[2-(difluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4 -Diketone, 7-methyl-5-[(1R)-1-phenylethyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4- Diketone, 5-(4-chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5- [2-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6- Dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 3-chloro-2-[(2,4-di Oxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2-chloro-6-methyl Benzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 2-[(2,4- Dioxo-2,3 dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2-chloro-6-methoxy benzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(methylthio) Benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-cyclopropyl- 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl)-7-methyl-3,5-di Hydrogen[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dichlorobenzyl)-7-methyl-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-5-(4-methylbenzyl)-3,5-dihydro[1,3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-(3,5-dimethoxybenzyl)-7-methyl-3,5-dihydro[1,3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-difluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazole And[4,5-c]pyridine-2,4-dione, 5-[3-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c] Pyridine-2,4-dione, 5-(2-fluoro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c ]pyridine-2,4-dione, 5-(2-chloro-6-methoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5- c] pyridine-2,4-dione, 5-(5-chloro-2-fluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c ]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-isopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-(5-fluoro-2-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 7-methyl-5-[(1S)-1-phenylethyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-(2-chloro-5-isopropoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-(5-acetyl-2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2, 4-diketone, 5-(2-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4 -diketone, 5-(2-chloro-6-methylbenzyl)-5,6,7,8-tetrahydro-2H-cyclopentadieno[b][1,3]oxazolo[5 ,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-6-ethoxybenzyl)-7-ethyl-3,5-dihydro[1,3]oxa Azolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-propoxybenzyl)-7-methyl-3,5-dihydro[1,3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-isobutoxybenzyl)-7-methyl-3,5-dihydro[1, 3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H- Cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-6-isopropoxybenzyl )-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-6-(2,2 , 2-trifluoroethoxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5- (2-Chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione, 5-[2-Chloro-6-(2-methoxyethoxy)benzyl]-5,6,7,8-tetrahydro-2H-cyclopentadieno[b][1,3]oxa Azolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-6-ethoxybenzyl)-6,7-dimethyl-3,5-di Hydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-ethyl-6-methyl -3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-3,5- Dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-propyl-3, 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-cyclopropyl- 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-propoxybenzyl)-7-methyl -3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-methoxybenzyl)-7-methyl Base-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-6- Methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-ethoxybenzyl)-7 -Methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(piperidin-1-yl Sulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5 -(pyrrolidin-1-ylsulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-Chloro-6-(cyclopentylmethoxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-[2-(benzyloxy)-6-chlorobenzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c] Pyridine-2,4-dione, 5-(2,3-dichloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopentadiene[b][ 1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-[2-chloro-5-(trifluoromethyl)benzyl]-7-methyl- 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione and 5-(2-chloro-5-fluorobenzyl)-7-methyl-3 , 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione.

还设计了衍生物，例如酯、氨基甲酸酯、缩醛胺(aninal)、酰胺、旋光异构体和药物前体。Derivatives such as esters, carbamates, aninals, amides, optical isomers and prodrugs are also contemplated.

本发明还涉及包含生理学上可接受的稀释剂和至少一种本发明化合物的药用组合物。The invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the invention.

本发明还涉及抑制α4β1整联蛋白与VCAM-1结合的方法，包括在有效抑制量的本发明化合物存在下使表达α4β1整联蛋白的细胞与表达VCAM-1的细胞接触。VCAM-1可见于血管内皮细胞、抗原提呈细胞或其他细胞类型的表面。α4β1可见于白细胞如单核细胞、淋巴细胞、粒细胞；干细胞；或天然表达α4β1的任何其他细胞表面。The invention also relates to a method of inhibiting the binding of α4β1 integrin to VCAM-1 comprising contacting a cell expressing α4β1 integrin with a cell expressing VCAM - 1 in the presence of an effective inhibitory amount of a compound of the invention . VCAM-1 can be found on the surface of vascular endothelial cells, antigen-presenting cells, or other cell types. α4β1 can be found on the surface of leukocytes such as monocytes, lymphocytes, granulocytes; stem cells; or any other cell that naturally expresses α4β1 .

本发明还提供治疗α4β1整联蛋白结合介导的疾病状态的方法，该方法包括给予患者有效量的本发明化合物，该本发明化合物为单独的化合物或为其制剂。The invention also provides a method of treating a disease state mediated by α4β1 integrin binding, the method comprising administering to a patient an effective amount of a compound of the invention, either alone or in a formulation thereof.

本文单独或组合使用的术语“烷基”是指C1-C12直链或支链、饱和烃去除一个氢原子产生的取代或未取代的饱和链基，除非术语烷基前面有Cx-Cy标示。烷基的典型实例特别包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基。The term "alkyl" used herein, alone or in combination, refers to a C 1 -C 12 straight or branched chain, substituted or unsubstituted saturated chain radical produced by removal of a hydrogen atom from a saturated hydrocarbon, unless the term alkyl is preceded by C x - C y marked. Typical examples of alkyl groups include, inter alia, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

本文单独或组合使用的术语“链烯基”是指含2-10个碳原子的取代或未取代直链链烯基、或者取代或未取代支链链烯基。这种基团的实例包括但不限于乙烯基、E-和Z-戊烯基、癸烯基等。The term "alkenyl" used herein alone or in combination refers to a substituted or unsubstituted straight chain alkenyl group, or a substituted or unsubstituted branched chain alkenyl group containing 2 to 10 carbon atoms. Examples of such groups include, but are not limited to, vinyl, E- and Z-pentenyl, decenyl, and the like.

本文单独或组合使用的术语“链炔基”是指含2-10个碳原子的取代或未取代直链炔基、或取代或未取代支链炔基。这种基团的实例包括但不限于乙炔基、丙炔基、炔丙基、丁炔基、己炔基、癸炔基等。The term "alkynyl" used herein alone or in combination refers to a substituted or unsubstituted straight chain alkynyl group, or a substituted or unsubstituted branched chain alkynyl group containing 2 to 10 carbon atoms. Examples of such groups include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl, and the like.

术语“低级”修饰的“烷基”、“链烯基”、“链炔基”或“烷氧基”是指特定官能度的C1-C6单元。例如低级烷基是指C1-C6烷基。The term "lower" modified "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to C1 - C6 units of the specified functionality. For example, lower alkyl refers to C 1 -C 6 alkyl.

本文单独或组合使用的术语“脂族酰基”是指链烷羧酸、链烯羧酸或链炔羧酸产生的式：烷基-C(O)-、链烯基-C(O)-和链炔基-C(O)-的基团，其中术语“烷基”、“链烯基”和“链炔基”同以上定义。这种脂族酰基基团的实例特别包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、4-甲基戊酰基、丙烯酰基、巴豆基、丙炔酰基和甲基丙炔酰基。The term "aliphatic acyl" as used herein, alone or in combination, refers to an alkane, alkene, or alkynyl carboxylic acid produced by the formula: alkyl-C(O)-, alkenyl-C(O)- and alkynyl -C(O)-, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as defined above. Examples of such aliphatic acyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylpentanoyl, acryloyl, crotyl, propioloyl and methylpropioloyl, in particular, but not limited to.

本文使用的术语“环烷基”是指具有3-10个碳原子和1-3个环的脂族环系，特别包括但不限于环丙基、环戊基、环己基、降冰片烷基(norbornyl)和金刚烷基(adamantyl)。环烷基可未被取代或被独立选自以下的1、2或3个取代基取代：低级烷基、卤代烷基、烷氧基、硫代烷氧基、氨基、烷基氨基、二烷基氨基、羟基、卤基、巯基、硝基、甲醛基、羧基、烷氧羰基和甲酰胺基。The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3-10 carbon atoms and 1-3 rings, specifically including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl (norbornyl) and adamantyl (adamantyl). Cycloalkyl can be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkyl Amino, hydroxyl, halo, mercapto, nitro, formaldehyde, carboxyl, alkoxycarbonyl and formamide.

“环烷基”包括顺式或反式环烷基。此外，所述取代基可位于桥连双环体系的内位或外位。"Cycloalkyl" includes cis or trans cycloalkyl. Furthermore, the substituents may be located at the endo or exo position of the bridged bicyclic ring system.

本文单独或组合使用的术语“环烯基”是指含4-8个碳原子和一个或多个双键的环形碳环。这样的环烯基实例包括但不限于环戊烯基、环己烯基、环戊二烯基等。The term "cycloalkenyl" as used herein, alone or in combination, refers to a cyclic carbocyclic ring containing 4-8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

本文使用的术语“环烷基烷基”是指与低级烷基连接的环烷基，包括但不限于环己基甲基。As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group attached to a lower alkyl group, including but not limited to cyclohexylmethyl.

本文使用的术语“卤”或“卤素”是指碘、溴、氯或氟。As used herein, the term "halo" or "halogen" refers to iodine, bromine, chlorine or fluorine.

本文使用的术语“卤代烷基”是指附带至少一个卤素取代基的低级烷基，例如氯甲基、氟乙基、三氟甲基和五氟乙基等。The term "haloalkyl" as used herein refers to a lower alkyl group with at least one halogen substituent, such as chloromethyl, fluoroethyl, trifluoromethyl, pentafluoroethyl, and the like.

本文单独或组合使用的术语“烷氧基”是指烷基醚基团，其中的术语“烷基”同前定义。合适烷基醚基团的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。The term "alkoxy" as used herein alone or in combination refers to an alkyl ether group in which the term "alkyl" is as defined above. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like .

本文使用的术语“烷氧基烷基”是指Ry-O-Rz，其中Ry是以上定义的低级烷基，而Rz是亚烷基(-(CH2)W-)，其中w是1-6的整数。典型实例包括甲氧基甲基、甲氧基乙基和乙氧基乙基等。The term "alkoxyalkyl" as used herein refers to R y -OR z , where R y is lower alkyl as defined above, and R z is alkylene (-(CH 2 ) W -), where w is An integer of 1-6. Typical examples include methoxymethyl, methoxyethyl, ethoxyethyl and the like.

本文单独或组合使用的术语“链烯氧基”是指式：链烯基-O-的基团，前提是该基团不是烯醇醚，其中所述术语“链烯基”同前定义。合适链烯氧基的实例包括但不限于烯丙氧基、E-和Z-3-甲基-2-丙烯氧基等。The term "alkenyloxy" as used herein, alone or in combination, refers to a group of the formula: alkenyl-O-, provided that the group is not an enol ether, wherein the term "alkenyl" is as defined above. Examples of suitable alkenyloxy include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenyloxy, and the like.

本文单独或组合使用的术语“链炔氧基”是指式：链炔基-O-的基团，前提是该基团不能是-炔醇醚(-ynol ether)。合适链炔氧基的实例包括但不限于炔丙氧基、2-丁炔氧基等。The term "alkynyloxy" as used herein, alone or in combination, refers to a group of formula: alkynyl-O-, provided that the group is not -ynol ether. Examples of suitable alkynyloxy groups include, but are not limited to, propargyloxy, 2-butynyloxy, and the like.

本文使用的术语“羧基”是指-C(O)O-。As used herein, the term "carboxy" refers to -C(O)O-.

术语“硫代烷氧基”是指式：烷基-S-的硫醚基，其中“烷基”定义同前。The term "thioalkoxy" refers to a thioether group of the formula: alkyl-S-, wherein "alkyl" is as defined above.

本文使用的术语“亚磺酰氨基”是指-SO2NH2。 As used herein, the term "sulfonamido" refers to -SO2NH2 .

本文使用的术语“甲醛基”是指其中R为氢的-C(O)R。As used herein, the term "carbaldehyde" refers to -C(O)R wherein R is hydrogen.

本文使用的术语“甲酰胺基”或“酰胺基”是指其中Ra和Rb各自独立为氢、烷基或任何其他合适取代基的-C(O)NRaRb。As used herein, the term "carboxamido" or "amido" refers to -C(O) NRaRb , wherein Ra and Rb are each independently hydrogen, alkyl , or any other suitable substituent.

本文使用的术语“烷氧基烷氧基”是指RCO-RdO-，其中Rc为定义同上的低级烷基而Rd为亚烷基，其中亚烷基为-(CH2)n’-，其中n’为1-6的整数。烷氧基烷氧基的典型实例包括甲氧基甲氧基、乙氧基甲氧基、叔丁氧基甲氧基等。As used herein, the term "alkoxyalkoxy" refers to R C OR d O-, where R c is lower alkyl as defined above and R d is alkylene, where alkylene is -(CH 2 ) n ' -, wherein n' is an integer of 1-6. Typical examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.

本文使用的术语“烷基氨基”是指ReNH-，其中Re为低级烷基，例如乙基氨基、丁基氨基等。The term "alkylamino" as used herein refers to Re NH-, wherein Re is lower alkyl, such as ethylamino, butylamino and the like.

本文单独或组合使用的术语“链烯基氨基”是指式：链烯基-NH-或(链烯基)2N-的基团，其中术语“链烯基”定义同上，前提是该基团不是烯胺基。这种链烯基氨基基团的一个实例是烯丙基氨基基团。The term "alkenylamino" as used herein, alone or in combination, refers to a group of the formula: alkenyl-NH- or (alkenyl) 2N- , wherein the term "alkenyl" is as defined above, provided that the group The group is not an enamino group. An example of such an alkenylamino group is an allylamino group.

本文单独或组合使用的术语“链炔基氨基”是指式：链炔基-NH-或(链炔基)2N-的基团，其中术语“链炔基”定义同上，前提是该基团不是胺基。这种链炔基氨基基团的一个实例是炔丙基氨基基团。The term "alkynylamino" as used herein, alone or in combination, refers to a group of the formula: alkynyl-NH- or (alkynyl) 2N- , wherein the term "alkynyl" is as defined above, provided that the group group is not an amine group. An example of such an alkynylamino group is a propargylamino group.

本文使用的术语“二烷基氨基”是指RfRgN-，其中Rf和Rg独立选自低级烷基，例如二乙基氨基和甲基丙基氨基等。The term "dialkylamino" as used herein refers to R f R g N-, wherein R f and R g are independently selected from lower alkyl groups, such as diethylamino, methylpropylamino and the like.

本文使用的术语“烷氧羰基”是指通过羰基与母体分子部分连接的前面定义的烷氧基。烷氧羰基实例包括甲氧基羰基、乙氧基羰基和异丙氧基羰基等。The term "alkoxycarbonyl" as used herein means an alkoxy group, as defined above, attached to the parent molecular moiety through a carbonyl group. Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.

本文单独或组合使用的术语“芳基”或“芳香基”是指具有约6-12个碳原子的取代或未取代碳环芳香基，例如苯基、萘基、茚基、2，3-二氢茚基、薁基(azulenyl)、芴基和蒽基；或者是指含有至少一个桥环氮、氧或硫原子的杂环芳香基，例如呋喃基、噻吩基、吡啶基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、2-吡唑啉基、吡唑烷基、异噁唑基、异噻唑基、1，2，3-噁二唑基、1，2，3-三唑基、1，3，4-噻二唑基、哒嗪基、嘧啶基、吡嗪基、1，3，5-三嗪基、1，3，5-三噻烷基、中氮茚基、吲哚基、异吲哚基、3H-吲哚基、二氢吲哚基、苯并[b]呋喃基、2，3-二氢苯并呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并咪唑基、苯并噻唑基、嘌呤基、4H-喹嗪基、异喹啉基、噌啉基、2，3-二氮杂萘基、喹唑啉基、喹喔啉基、1，8-二氮萘基(naphthridinyl)、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、苯氧基吖嗪基、吡唑并[1，5-c]三嗪基等。“芳烷基”和“烷基芳基”应用上述定义的术语“烷基”。环可以是多取代的环。The term "aryl" or "aryl" as used herein alone or in combination refers to a substituted or unsubstituted carbocyclic aromatic group having about 6-12 carbon atoms, such as phenyl, naphthyl, indenyl, 2,3- Dihydroindenyl, azulenyl (azulenyl), fluorenyl and anthracenyl; or a heterocyclic aromatic group containing at least one bridging ring nitrogen, oxygen or sulfur atom, such as furyl, thienyl, pyridyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2, 3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, medium Indolyl, Indolyl, Isoindolyl, 3H-Indolyl, Indolinyl, Benzo[b]furyl, 2,3-Dihydrobenzofuryl, Benzo[b]thiophene Base, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinazinyl, isoquinolyl, cinnolinyl, 2,3-naphthyridine, quinazolinyl , quinoxalinyl, 1,8-naphthridinyl (naphthridinyl), pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[ 1,5-c] Triazinyl, etc. "Aralkyl" and "alkylaryl" apply the term "alkyl" as defined above. A ring may be a polysubstituted ring.

本文单独或组合使用的术语“芳烷基”是指芳基取代的烷基，其中术语“烷基”和“芳基”同前定义。合适芳烷基的实例包括但不限于苯甲基、苯乙基、苯基己基、二苯基甲基、吡啶基甲基、四唑基甲基、呋喃基甲基、咪唑基甲基、吲哚基甲基、噻吩基丙基等。The term "aralkyl" as used herein, alone or in combination, refers to an aryl-substituted alkyl group, wherein the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl groups include, but are not limited to, benzyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolylmethyl, furylmethyl, imidazolylmethyl, indolyl Indolylmethyl, thienylpropyl, etc.

本文单独或组合使用的术语“芳链烯基”是指芳基取代的链烯基，其中术语“芳基”和“链烯基”同前定义。The term "arylalkenyl" as used herein, alone or in combination, refers to an aryl-substituted alkenyl group, wherein the terms "aryl" and "alkenyl" are as defined above.

本文单独或组合使用的术语“芳基氨基”是指式：芳基-NH-的基团，其中“芳基”同前定义。芳基氨基基团的实例包括但不限于苯基氨基、萘基氨基、2-、3-和4-吡啶基氨基等。The term "arylamino" used herein alone or in combination refers to a group of formula: aryl-NH-, wherein "aryl" is as defined above. Examples of arylamino groups include, but are not limited to, phenylamino, naphthylamino, 2-, 3-, and 4-pyridylamino, and the like.

本文使用的术语“苄基”是指C6H5-CH2-。The term "benzyl" as used herein refers to C6H5 - CH2- .

本文单独或组合使用的术语“联芳基”是指式：芳基-芳基的基团，其中术语“芳基”同前定义。The term "biaryl" as used herein, alone or in combination, refers to a group of formula: aryl-aryl, wherein the term "aryl" is as defined above.

本文单独或组合使用的术语“硫代芳基”是指式：芳基-S-的基团，其中术语“芳基”同前定义。硫代芳基的一个实例是硫代苯基。The term "thioaryl" used herein alone or in combination refers to a group of formula: aryl-S-, wherein the term "aryl" is as defined above. An example of thioaryl is thiophenyl.

本文单独或组合使用的术语“芳酰基”是指式：芳基-CO-的基团，其中术语“芳基”同前定义。合适芳酰基的实例包括但不限于苯酰基、4-卤代苯酰基、4-羧基苯酰基、萘酰基、吡啶基羰基等。The term "aroyl" used herein alone or in combination refers to a group of formula: aryl-CO-, wherein the term "aryl" is as defined above. Examples of suitable aroyl groups include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl, and the like.

本文单独或组合使用的术语“杂环基”是指含至少一个桥环N、O或S原子的3-至10-元非芳族环。所述杂环可任选为芳基稠合环。所述杂环也可任选被至少一个取代基取代，所述取代基独立选自氢、卤素、羟基、氨基、硝基、三氟甲基、三氟甲氧基、烷基、芳烷基、链烯基、链炔基、芳基、氰基、羧基、烷氧羰基、羧基烷基、氧代基、芳基磺酰基和芳烷基氨基羰基等。The term "heterocyclyl" as used herein alone or in combination refers to a 3- to 10-membered non-aromatic ring containing at least one bridging ring N, O or S atom. The heterocycle may optionally be an aryl fused ring. The heterocyclic ring may also be optionally substituted by at least one substituent independently selected from hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl , alkenyl, alkynyl, aryl, cyano, carboxyl, alkoxycarbonyl, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl, etc.

本文使用的术语“烷基杂环基”是指通过杂环基连接到母体分子部分的前面定义的烷基，包括但不限于2-甲基-5-噻唑基、2-甲基-1-吡咯基和5-乙基-2-噻吩基。As used herein, the term "alkylheterocyclyl" means an alkyl group as defined above attached to the parent molecular moiety through a heterocyclyl group, including but not limited to 2-methyl-5-thiazolyl, 2-methyl-1- Pyrrolyl and 5-ethyl-2-thienyl.

本文使用的术语“杂环基烷基”是指通过烷基连接到母体分子部分的前面定义的杂环基，包括但不限于2-噻吩基甲基、2-吡啶基甲基和2-(1-哌啶基)乙基。As used herein, the term "heterocyclylalkyl" refers to a heterocyclyl group as defined above attached to the parent molecular moiety through an alkyl group, including but not limited to 2-thienylmethyl, 2-pyridylmethyl, and 2-( 1-piperidinyl)ethyl.

本文使用的术语“杂环酰基”是指式：杂环基-C(O)-的基团，其中术语“杂环基”同前定义。The term "heterocyclyl" as used herein refers to a group of formula: heterocyclyl-C(O)-, wherein the term "heterocyclyl" is as defined above.

本文使用的术语“缩醛胺”是指结构：RhC(NRiRj)(NRkRl)-的半缩醛，其中Rh、Ri、Rj、Rk和Rl各自独立为氢、烷基或任何其他合适取代基。The term "aminal" as used herein refers to a hemiacetal of the structure: Rh C (NR i R j )(NR k R l )-, where each of R h , R i , R j , R k and R l are independently hydrogen, alkyl or any other suitable substituent.

本文使用的术语“酯”是指-C(O)Rm，其中Rm是氢、烷基或任何其他合适取代基。As used herein, the term "ester" refers to -C(O) Rm , where Rm is hydrogen, alkyl, or any other suitable substituent.

本文使用的术语“氨基甲酸酯”是指基于氨基甲酸NH2C(O)OH的化合物。As used herein, the term "carbamate" refers to a compound based on carbamic acid NH2C (O)OH.

本文使用的术语“旋光异构体”是指仅至少一个原子的立体化学不同的化合物，包括对映体、非对映体和外消旋物。As used herein, the term "optical isomer" refers to compounds that differ in stereochemistry by only at least one atom, including enantiomers, diastereomers and racemates.

应用上述术语意味着包括取代部分和非取代部分。取代可以是一个或多个基团的取代，例如醇类、醚类、酯类、酰胺类、砜类、硫化物类、羟基、硝基、氰基、羧基、胺类、杂原子、低级烷基、低级烷氧基、低级烷氧羰基、烷氧基烷氧基、酰氧基、卤素、三氟甲氧基、三氟甲基、烷基、芳烷基、链烯基、链炔基、芳基、氰基、羧基、烷氧羰基、羧基烷基、环烷基、环烷基烷基、杂环基、烷基杂环基、杂环基烷基、氧代、芳基磺酰基和芳烷基氨基羰基或以上各段的任何取代基或直接连接或通过合适接头连接的取代基中的任何取代基。接头通常为1-3个原子的短链，包括任何组合的-C-、-C(O)-、-NH-、-S-、-S(O)-、-O-、-C(O)O-或-S(O)O-。环可以被取代多次。Use of the above terms is meant to include substituted moieties as well as non-substituted moieties. Substitution can be substitution of one or more groups, such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxyl, amines, heteroatoms, lower alkanes radical, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl , aryl, cyano, carboxyl, alkoxycarbonyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the above paragraphs or any of the substituents attached directly or via a suitable linker. Linkers are usually short chains of 1-3 atoms, including any combination of -C-, -C(O)-, -NH-, -S-, -S(O)-, -O-, -C(O )O- or -S(O)O-. Rings can be substituted multiple times.

术语“吸电子”或“给电子”是指如果氢占据该分子的相同位置时，取代基能够相对于氢吸电子或给电子。这些术语是本领域技术人员熟知的，而且J.March在 Advanced Organic Chemistry，1985，第16-18页中进行论述，该文献通过引用结合到本文中。吸电子基包括卤基、硝基、羧基、低级链烯基、低级链炔基、甲醛基、羧基酰胺基、芳基、季铵基、三氟甲基、磺酰基和芳基低级烷酰基等。给电子基包括诸如以下的基团：羟基、低级烷基、氨基、低级烷基氨基、二(低级烷基)氨基、芳氧基、巯基、低级烷硫基、低级烷基巯基和二硫化物等。本领域技术人员知道，以上所述取代基在不同化学条件下可以具有给电子或吸电子特性。此外，本发明设计了选自上述基团的取代基的任何组合。The term "electron withdrawing" or "electron donating" means that a substituent is capable of withdrawing or donating electrons relative to hydrogen if the hydrogen occupies the same position in the molecule. These terms are well known to those skilled in the art and are discussed by J. March in Advanced Organic Chemistry, 1985, pp. 16-18, which is incorporated herein by reference. Electron-withdrawing groups include halo, nitro, carboxy, lower alkenyl, lower alkynyl, formaldehyde, carboxyamide, aryl, quaternary ammonium, trifluoromethyl, sulfonyl, aryl lower alkanoyl, and the like. Electron donating groups include groups such as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide wait. Those skilled in the art know that the substituents mentioned above may have electron-donating or electron-withdrawing properties under different chemical conditions. In addition, the present invention contemplates any combination of substituents selected from the above groups.

最优选的给电子或吸电子取代基有卤基、硝基、烷酰基、甲醛基、芳基烷酰基、芳氧基、羧基、甲酰胺基、氰基、磺酰基、亚砜、杂环基、胍、季铵基、低级链烯基、低级链炔基、锍盐、羟基、低级烷氧基、低级烷基、氨基、低级烷基氨基、二(低级烷基)氨基、胺低级烷基巯基、巯基烷基、烷硫基、羧基低级烷基、芳基烷氧基、烷酰基氨基、烷酰基(低级烷基)氨基、低级烷基磺酰基氨基、芳基磺酰基氨基、烷基磺酰基(低级烷基)氨基、芳基磺酰基(低级烷基)氨基、低级烷基甲酰胺基、二(低级烷基)甲酰胺基、氨磺酰基、低级烷基氨磺酰基、二(低级烷基)氨磺酰基、低级烷基磺酰基、芳基磺酰基和烷二硫基。The most preferred electron-donating or electron-withdrawing substituents are halo, nitro, alkanoyl, formaldehyde, arylalkanoyl, aryloxy, carboxyl, formamido, cyano, sulfonyl, sulfoxide, heterocyclyl , guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salt, hydroxyl, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkylmercapto, Mercaptoalkyl, alkylthio, carboxy-lower alkyl, arylalkoxy, alkanoylamino, alkanoyl (lower alkyl)amino, lower alkylsulfonylamino, arylsulfonylamino, alkylsulfonyl ( Lower alkyl)amino, arylsulfonyl(lower alkyl)amino, lower alkylformamido, bis(lower alkyl)formamido, sulfamoyl, lower alkylsulfamoyl, di(lower alkyl ) sulfamoyl, lower alkylsulfonyl, arylsulfonyl and alkyldithio.

本文使用的术语“组合物”包括含规定量的规定成分的产品以及规定量的规定成分组合而直接或间接获得的任何产品。As used herein, the term "composition" includes a product comprising the specified ingredients in the specified amounts as well as any product obtained directly or indirectly by combining the specified ingredients in the specified amounts.

本文使用的术语“哺乳动物”包括人和其他动物。As used herein, the term "mammal" includes humans and other animals.

在式I、II和III中Y定义的环可以是单环杂环或芳族环，或可以是二环环。The ring defined by Y in formulas I, II and III may be a monocyclic heterocyclic or aromatic ring, or may be a bicyclic ring.

在式I、II、III、IV和VI中使用的虚线表示，该位置的键可以是单键或双键。例如如果Y和/或W为取代基例如N、C或CH，则原子Y和W之间的键可以是单键或双键。因此，所述式中Y定义的环可以是饱和环或不饱和环，取决于W和/或Y的选择。在式IV和VI中，虚线表示含氮环在指示位置任选含有双键。The dashed lines used in formulas I, II, III, IV and VI indicate that the bond at that position can be a single or double bond. For example if Y and/or W are substituents such as N, C or CH, the bond between atoms Y and W may be a single or double bond. Therefore, the ring defined by Y in said formula can be a saturated ring or an unsaturated ring, depending on the choice of W and/or Y. In formulas IV and VI, dashed lines indicate that the nitrogen-containing ring optionally contains a double bond at the indicated position.

在所述式中，某些R基团可能取代其缔合环多次。R19、R20、R21、R23、R27、R28、R29和R25可各自取代其缔合环一次以上。举例来说R19，当c为0时，缔合环为未取代缔合环，C-2位和C-4位含有氢；而对于R23来说，当g为0时，C-2至C-5位含有氢。In the formulae, certain R groups may substitute multiple times for their associated rings. R 19 , R 20 , R 21 , R 23 , R 27 , R 28 , R 29 and R 25 may each substitute its associated ring one or more times. For example, for R 19 , when c is 0, the associated ring is an unsubstituted associative ring, and the C-2 and C-4 positions contain hydrogen; and for R 23 , when g is 0, C-2 to C-5 containing hydrogen.

上述式中的芳基、烷基、环烷基、杂环基或Y和W定义的环的合适取代基，如果存在的话，包括醇类、胺类、杂原子或直接连接或通过合适接头连接的任何组合的芳基、烷氧基、烷氧基烷氧基、烷基、环烷基或杂环基。接头通常为1-3个原子的短链，包括任何组合的C、C＝O、CO2、O、N、S、S＝O、SO2，例如醚类、酰胺类、胺类、脲类、磺酰胺、氨磺酰类等。Suitable substituents for aryl, alkyl, cycloalkyl, heterocyclyl or rings defined by Y and W in the above formulas, if present, include alcohols, amines, heteroatoms or attached directly or via a suitable linker aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or heterocyclyl in any combination. Linkers are usually short chains of 1-3 atoms, including any combination of C, C=O, CO 2 , O, N, S, S=O, SO 2 , such as ethers, amides, amines, ureas , sulfonamides, sulfonamides, etc.

例如，上述式中的R1、R2、R3、R5、R6、R7和R8可独立为(但不局限于)：氢、烷基、苯基、噻吩基甲基、异丁基、正丁基、2-噻吩基甲基、1，3-噻唑-2-基-甲基、苄基、噻吩基、3-吡啶基甲基、3-甲基-1-苯并噻吩-2-基、烯丙基、3-甲氧基苄基、丙基、2-乙氧基乙基、环丙基甲基、苄基硫烷基(sulfanyl)甲基、苄基磺酰基甲基、苯基硫烷基甲基、苯乙基硫烷基甲基、3-苯基丙基硫烷基甲基、4-((2-甲苯氨基羰基)氨基)苄基、2-吡啶基乙基、2-(1H-吲哚-3-基)乙基、1H-苯并咪唑-2-基、4-哌啶基甲基、3-羟基-4-甲氧基苄基、4-羟基苯乙基、4-氨基苄基、苯基磺酰基甲基、4-(乙酰氨基)苯基、4-甲氧基苯基、4-氨基苯基、4-氯苯基、(4-(苄基磺酰基)氨基)苯基、(4-(甲基磺酰基)氨基)苯基、2-氨基苯基、2-甲基苯基、异丙基、2-氧代-1-吡咯烷基、3-(甲基硫烷基)丙基、(丙基硫烷基)甲基、辛基硫烷基甲基、3-氨基苯基、4-((2-甲苯氨基羰基)氨基)苯基、2-((甲基苄基)氨基)苄基、甲基硫烷基乙基、羟基、氯、氟、溴、脲基、氨基、甲磺酰基氨基、乙酰氨基、乙基硫烷基甲基、2-氯苄基、2-溴苄基、2-氟苄基、2-氯-6-氟苄基、2-氯-4-氟苄基、2，4-二氯苄基、2-氯-6-甲氧基苄基、2-氰基苄基、2，6-二氟苄基、2-氯-5-(三氟甲基)苄基、2-氯-6-甲基苄基、2，6-二甲氧基苄基、2-氯-5-(甲基磺酰基)苄基、2-氯-6-氰基苄基、2-氯-6-乙氧基苄基、2-氯-5-甲氧基苄基、2-氯-5-氟苄基、5-氯-2-氟苄基、乙基、丙基、丁基、戊基、环丙基、叔丁基氨基、丙基氨基、4-甲基-1-哌嗪基、1-氮杂环丁基、4-吗啉代、(4-羧基苯基)氨基、新戊酰氨基、((叔丁基氨基)羰基)氨基、三氟甲基、苄氧基、2-(2-甲氧基乙氧基)乙氧基、2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基和2-(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)乙氧基。For example, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 in the above formula can be independently (but not limited to): hydrogen, alkyl, phenyl, thienylmethyl, iso Butyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridylmethyl, 3-methyl-1-benzothiophene -2-yl, allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfanyl (sulfanyl) methyl, benzylsulfonyl methyl Base, phenylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl, 4-((2-tolylaminocarbonyl)amino)benzyl, 2-pyridyl Ethyl, 2-(1H-indol-3-yl)ethyl, 1H-benzimidazol-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4- Hydroxyphenethyl, 4-aminobenzyl, phenylsulfonylmethyl, 4-(acetylamino)phenyl, 4-methoxyphenyl, 4-aminophenyl, 4-chlorophenyl, (4- (Benzylsulfonyl)amino)phenyl, (4-(methylsulfonyl)amino)phenyl, 2-aminophenyl, 2-methylphenyl, isopropyl, 2-oxo-1-pyrrole Alkyl, 3-(methylsulfanyl)propyl, (propylsulfanyl)methyl, octylsulfanylmethyl, 3-aminophenyl, 4-((2-tolylaminocarbonyl)amino ) phenyl, 2-((methylbenzyl)amino)benzyl, methylsulfanylethyl, hydroxyl, chlorine, fluorine, bromine, ureido, amino, methylsulfonylamino, acetamido, ethylthio Alkylmethyl, 2-chlorobenzyl, 2-bromobenzyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2,4-dichlorobenzyl Base, 2-chloro-6-methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl, 2-chloro-5-(trifluoromethyl)benzyl, 2-chloro-6 -Methylbenzyl, 2,6-dimethoxybenzyl, 2-chloro-5-(methylsulfonyl)benzyl, 2-chloro-6-cyanobenzyl, 2-chloro-6-ethyl Oxybenzyl, 2-chloro-5-methoxybenzyl, 2-chloro-5-fluorobenzyl, 5-chloro-2-fluorobenzyl, ethyl, propyl, butyl, pentyl, cyclo Propyl, tert-butylamino, propylamino, 4-methyl-1-piperazinyl, 1-azetidinyl, 4-morpholino, (4-carboxyphenyl)amino, pivaloylamino , ((tert-butylamino)carbonyl)amino, trifluoromethyl, benzyloxy, 2-(2-methoxyethoxy)ethoxy, 2-(2-(2-methoxyethoxy yl)ethoxy)ethoxy and 2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy.

上述式中的R4取代基可为(但不局限于)1，3-苯并二氧杂环戊-5-基、1-萘基、噻吩基、4-异丁氧基苯基、2，6-二甲基苯基、烯丙氧基苯基、3-溴-4-甲氧基苯基、4-丁氧基苯基、1-苯并呋喃-2-基、2-噻吩基甲基、苯基、甲基硫烷基、苯基硫烷基、苯乙基硫烷基、4-溴-2-噻吩基、3-甲基-2-噻吩基、4-甲基苯基、3，5-二(甲氧基)苯基、4-(甲氧基)苯基、4-氟苯基、3-(甲氧基)苯基、3，4，5-三(甲氧基)苯基、2，3-二氢-1-苯并呋喃-5-基、3-氟苯基、4-(三氟甲基)苯基、4-氟-3-(三氟甲基)苯基、4-(1，1-二甲基乙基)苯基、3，5-二甲基苯基、4-羟基苯基、3，4-二甲基苯基、3-甲基-4-(甲氧基)苯基、4-羟基-3-甲基苯基、3-甲基苯基、2，3-二氢-茚-5-基、2-甲基苯基、2，6-二(甲氧基)苯基、2，6-二羟基苯基、4-氯苯基、3-氯苯基、3，4-二氯苯基、4-((三氟甲基)氧基)苯基、4-乙基苯基、4-(乙氧基)苯、甲基、2-丙基、4，5-二氢-1，3-噁唑-2-基、3-(三氟甲基)苯基、4-(三氟甲氧基)苯基、2，3-二氢-1，4-苯并二氧杂环己-6-基、7-甲氧基-1，3-苯并二氧杂环戊-5-基、3-乙氧基-4-甲氧基苯基、3，4-二甲氧基苯基、3，4-二乙氧基苯基、3-乙氧基苯基、3-甲氧基-4-甲基苯基、3，5-二甲氧基-4-甲基苯基、3-丙氧基苯基、3-丁氧基苯基、3-(2-甲氧基乙氧基)苯基、3，4-二丙氧基苯基、3-(二氟甲氧基)苯基、2-萘基、3-异丙氧基苯基、1-甲基-1H-吲哚-5-基、2，3-二氢-1-苯并呋喃-5-基、1，3-二乙基-2-氧代-2，3-二氢-1H-苯并咪唑-5-基、3-(三氟甲氧基)苯基、1-甲基-1H-吲哚-6-基、3-(环丙氧基)苯基、3-(环丙基甲氧基)苯基、3-(二氟甲氧基)苯基、3-(1，1，2，2-四氟乙氧基)苯基、1-乙基-1H-吲哚-5-基、3-(二乙基氨基)苯基、6-甲氧基-2-萘基、3-[(甲基磺酰基)氨基]苯基、3-[甲基(甲基磺酰基)氨基]苯基、3-[乙基(甲基磺酰基)氨基]苯基、1H-吲哚-5-基、3-氟-4-甲氧基苯基和3-(二氟甲基)苯基。 The R substituent in the above formula can be (but not limited to) 1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2 , 6-dimethylphenyl, allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienyl Methyl, phenyl, methylsulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-thienyl, 3-methyl-2-thienyl, 4-methylphenyl , 3,5-bis(methoxy)phenyl, 4-(methoxy)phenyl, 4-fluorophenyl, 3-(methoxy)phenyl, 3,4,5-tri(methoxy Base) phenyl, 2,3-dihydro-1-benzofuran-5-yl, 3-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3-(trifluoromethyl ) phenyl, 4-(1,1-dimethylethyl)phenyl, 3,5-dimethylphenyl, 4-hydroxyphenyl, 3,4-dimethylphenyl, 3-methyl -4-(methoxy)phenyl, 4-hydroxy-3-methylphenyl, 3-methylphenyl, 2,3-dihydro-inden-5-yl, 2-methylphenyl, 2 , 6-bis(methoxy)phenyl, 2,6-dihydroxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-((trifluoromethyl )oxy)phenyl, 4-ethylphenyl, 4-(ethoxy)benzene, methyl, 2-propyl, 4,5-dihydro-1,3-oxazol-2-yl, 3 -(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 2,3-dihydro-1,4-benzodioxan-6-yl, 7-methoxy -1,3-benzodioxol-5-yl, 3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxy Phenyl, 3-ethoxyphenyl, 3-methoxy-4-methylphenyl, 3,5-dimethoxy-4-methylphenyl, 3-propoxyphenyl, 3- Butoxyphenyl, 3-(2-methoxyethoxy)phenyl, 3,4-dipropoxyphenyl, 3-(difluoromethoxy)phenyl, 2-naphthyl, 3 -Isopropoxyphenyl, 1-methyl-1H-indol-5-yl, 2,3-dihydro-1-benzofuran-5-yl, 1,3-diethyl-2-oxo Substitute-2,3-dihydro-1H-benzimidazol-5-yl, 3-(trifluoromethoxy)phenyl, 1-methyl-1H-indol-6-yl, 3-(cyclopropyl Oxy)phenyl, 3-(cyclopropylmethoxy)phenyl, 3-(difluoromethoxy)phenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl , 1-ethyl-1H-indol-5-yl, 3-(diethylamino)phenyl, 6-methoxy-2-naphthyl, 3-[(methylsulfonyl)amino]phenyl , 3-[methyl(methylsulfonyl)amino]phenyl, 3-[ethyl(methylsulfonyl)amino]phenyl, 1H-indol-5-yl, 3-fluoro-4-methoxy phenyl and 3-(difluoromethyl)phenyl.

两个独立的R1、R2、R3或R5基团一起可连接形成环。Two independent R 1 , R 2 , R 3 or R 5 groups taken together may be joined to form a ring.

R4和R11可连接形成环，例如1-吡咯烷基、1-哌啶子基、4-甲基-1-哌嗪基、4-乙酰基-1-哌嗪基和4-吗啉代等。R 4 and R 11 can be joined to form a ring such as 1-pyrrolidinyl, 1-piperidino, 4-methyl-1-piperazinyl, 4-acetyl-1-piperazinyl and 4-morpholine On behalf of others.

R9和R10可连接形成环，例如环丙基、环丁基、环戊基和环己基等。R 9 and R 10 can be connected to form a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

在随后的反应流程和实施例中使用的缩写有：BOC：叔丁氧基羰基；DMF：二甲基甲酰胺；THF：四氢呋喃；DME：二甲氧基乙烷；DMSO：二甲基亚砜；MM：N-甲基吗啉；DIPEA：二异丙基乙基胺；CDI：1，1’-羰基二咪唑；TBS：TRIS-缓冲盐水；Ms：甲磺酰基；TMEDA：N，N，N’，N’-四甲基乙二胺；DCE：1，2-二氯乙烷；NCS：N-氯代琥珀酰亚胺；NBS：N-溴代琥珀酰亚胺；DPPA：二苯基磷酰基叠氮化物；DEAD：偶氮二羧酸二乙酯；m-CPBA：3-氯过苯甲酸；TFAA：三氟乙酸酐；DCM：二氯甲烷；LHMDS：二(三甲基甲硅烷基)氨基化锂；Cbz：苄氧基羰基。氨基酸缩写如下：C：L-半胱氨酸；D：L-天冬氨酸；E：L-谷氨酸；G：甘氨酸；H：L-组氨酸；I：L-异亮氨酸；L：L-亮氨酸；N：L-天冬酰胺；P：L-脯氨酸；Q：L-谷氨酰胺；S：L-丝氨酸；T：L-苏氨酸；V：L-缬氨酸；W：L-色氨酸。Abbreviations used in subsequent reaction schemes and examples are: BOC: tert-butoxycarbonyl; DMF: dimethylformamide; THF: tetrahydrofuran; DME: dimethoxyethane; DMSO: dimethylsulfoxide ; MM: N-methylmorpholine; DIPEA: diisopropylethylamine; CDI: 1,1'-carbonyldiimidazole; TBS: TRIS-buffered saline; Ms: methylsulfonyl; TMEDA: N,N, N',N'-tetramethylethylenediamine; DCE: 1,2-dichloroethane; NCS: N-chlorosuccinimide; NBS: N-bromosuccinimide; DPPA: diphenyl Phosphoryl azide; DEAD: diethyl azodicarboxylate; m-CPBA: 3-chloroperbenzoic acid; TFAA: trifluoroacetic anhydride; DCM: dichloromethane; silyl) lithium amide; Cbz: benzyloxycarbonyl. Amino acids are abbreviated as follows: C: L-cysteine; D: L-aspartic acid; E: L-glutamic acid; G: glycine; H: L-histidine; I: L-isoleucine ;L: L-leucine; N: L-asparagine; P: L-proline; Q: L-glutamine; S: L-serine; T: L-threonine; V: L - Valine; W: L-tryptophan.

                 具体实施方式 Detailed ways

以下流程显示可用于合成上述结构式的化合物的方法实施例。以下实施例详细描述了本发明代表性化合物。The following schemes show examples of methods that can be used to synthesize compounds of the above formula. Representative compounds of the invention are described in detail in the following examples.

以下流程1说明实施例1介绍的方法。

Figure A0114518200771
Scheme 1 below illustrates the method introduced in Example 1.
Figure A0114518200771

                                    流程1说明实施例2方法的流程2如下所示。

Figure A0114518200781
Process 1 illustrates the process 2 of the method of Example 2 as follows.
Figure A0114518200781

                                         流程2说明实施例3方法的流程3如下所示。 Process 2 The process 3 illustrating the method of Example 3 is as follows.

                                                            流程3说明实施例4方法的流程4如下所示。

Figure A0114518200792
Process 3 Process 4 illustrating the method of Example 4 is as follows.
Figure A0114518200792

                                                            流程4说明实施例5方法的流程5如下所示。 Process 4 The process 5 illustrating the method of Example 5 is as follows.

                        流程5说明实施例6方法的流程6如下所示。

Figure A0114518200802
Process 5 Process 6 illustrating the method of Example 6 is as follows.
Figure A0114518200802

                        流程6说明实施例7方法的流程7如下所示。 Flow 6 Flow 7 illustrating the method of Example 7 is as follows.

                                流程7说明实施例8方法的流程8如下所示。

Figure A0114518200811
Flow 7 Flow 8 illustrating the method of Embodiment 8 is as follows.
Figure A0114518200811

                                          流程8说明实施例9方法的流程9如下所示。

Figure A0114518200812
Process 8 Process 9 illustrating the method of Example 9 is as follows.
Figure A0114518200812

                          流程9说明实施例10方法的流程10如下所示。

Figure A0114518200821
Flow 9 Flow 10 illustrating the method of Example 10 is as follows.
Figure A0114518200821

                                                           流程10说明实施例11方法的流程11如下所示。

Figure A0114518200822
Flow 10 Flow 11 illustrating the method of Example 11 is as follows.
Figure A0114518200822

                           流程11说明实施例12方法的流程12如下所示。

Figure A0114518200831
Flow 11 Flow 12 illustrating the method of Example 12 is as follows.
Figure A0114518200831

                                流程12说明实施例13方法的流程13如下所示。

Figure A0114518200832
Flow 12 Flow 13 illustrating the method of Embodiment 13 is as follows.
Figure A0114518200832

                       流程13说明实施例14方法的流程14如下所示。 Flow 13 Flow 14 illustrating the method of Example 14 is as follows.

                                            流程14说明实施例15方法的流程15如下所示。 Flow 14 Flow 15 illustrating the method of Example 15 is shown below.

                                               流程15说明实施例16方法的流程16如下所示。 Flow 15 Flow 16 illustrating the method of Example 16 is shown below.

                                             流程16说明实施例17方法的流程17如下所示。 Flow 16 Flow 17 illustrating the method of Example 17 is shown below.

                                       流程17说明实施例18方法的流程18如下所示。

Figure A0114518200862
Flow 17 Flow 18 illustrating the method of Example 18 is shown below.
Figure A0114518200862

                                 流程18说明实施例19方法的流程19如下所示。

Figure A0114518200871
Flow 18 Flow 19 illustrating the method of Example 19 is shown below.
Figure A0114518200871

                     流程19说明实施例20方法的流程20如下所示。

Figure A0114518200872
Flow 19 Flow 20 illustrating the method of Example 20 is shown below.
Figure A0114518200872

                     流程20说明实施例21方法的流程21如下所示。 Flow 20 illustrates flow 21 of the method of embodiment 21 as follows.

                                            流程21说明实施例22方法的流程22如下所示。

Figure A0114518200881
Flow 21 Flow 22 illustrating the method of Example 22 is shown below.
Figure A0114518200881

                                              流程22说明实施例23方法的流程23如下所示。

Figure A0114518200882
Flow 22 Flow 23 illustrating the method of Embodiment 23 is as follows.
Figure A0114518200882

                               流程23说明实施例24方法的流程24如下所示。

Figure A0114518200883
Flow 23 Flow 24 illustrating the method of Example 24 is as follows.
Figure A0114518200883

                                               流程24说明实施例25方法的流程25如下所示。 Flow 24 Flow 25 illustrating the method of Example 25 is shown below.

                                                      流程25说明实施例26的流程26如下所示。 Process 25 illustrates the process 26 of Example 26 as follows.

                                         流程26说明实施例27的流程27如下所示。 Process 26 illustrates the process 27 of Example 27 as follows.

                                          流程27说明实施例28的流程28如下所示。 Process 27 illustrates the process 28 of Example 28 as follows.

                                           流程28说明实施例29的流程29如下所示。

Figure A0114518200903
Process 28 illustrates the process 29 of Example 29 as follows.
Figure A0114518200903

                                       流程29说明实施例30的流程30如下所示。

Figure A0114518200911
Process 29 illustrates the process 30 of embodiment 30 as follows.
Figure A0114518200911

                                       流程30说明实施例31的流程31如下所示。 Process 30 illustrates the process 31 of embodiment 31 as follows.

                                 流程31

Figure A0114518200913
Process 31
Figure A0114518200913

                                               流程32

Figure A0114518200921
Process 32
Figure A0114518200921

                              流程33 Process 33

                             流程34

Figure A0114518200932
Process 34
Figure A0114518200932

                             流程35 Process 35

                                               流程36

Figure A0114518200942
Process 36
Figure A0114518200942

                                               流程37 Process 37

                                                      流程38 Process 38

                                                      流程39 Process 39

                            流程40

Figure A0114518200961
Process 40
Figure A0114518200961

                                        流程41

Figure A0114518200962
Process 41
Figure A0114518200962

                                            流程42Process 42

可使用用无机酸或有机酸产生的药学上可接受的盐形式的本发明化合物。术语“药学上可接受的盐”是指这样的盐：在合理的医药判断范围内适用于接触人体组织和低等动物组织而没有过度的毒性、刺激性、变态反应等，而且具有合理利益/风险比。药学上可接受的盐是本领域熟知的。例如S.M.Berge等在 J.Pharmaceutical Sciences，1977，66：1等中详细介绍了药学上可接受的盐。所述盐可在本发明化合物的最后分离和纯化中原位制得或独立使游离碱官能团与合适有机酸反应制得。典型的酸加成盐包括但不限于醋酸盐、己二酸盐、藻酸盐、柠檬酸盐、门冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐，isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酯酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、丁二酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一酸盐。此外，含碱性氮的基团可用以下物质季铵化，例如低级烷基卤如甲基、乙基、丙基和丁基氯、溴和碘；二烷基硫酸盐如二甲基、二乙基、二丁基和二戊基硫酸盐；长链卤化物如癸基、十二烷基、十四烷基和十八烷酰氯、溴和碘；芳烷基卤如苄基溴和苯乙基溴等。因此获得水溶性或油溶性或分散性产物。能够用于形成药学上可接受的酸加成盐的酸的实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸和有机酸如草酸、马来酸、琥珀酸和枸橼酸。The compounds of the present invention may be used in the form of pharmaceutically acceptable salts produced with inorganic or organic acids. The term "pharmaceutically acceptable salt" means a salt which, within the scope of sound medical judgment, is suitable for use in contact with human tissues and lower animal tissues without undue toxicity, irritation, allergic response, etc., and which has a reasonable benefit/ hazard ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 1977, 66: 1, etc. Said salts can be prepared in situ during the final isolation and purification of the compounds of the invention or independently by reacting a free base function with a suitable organic acid. Typical acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate , camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide , 2-hydroxyethanesulfonate (isothiosulfate, isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate , pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate , glutamate, bicarbonate, p-toluenesulfonate and undecanoate. In addition, basic nitrogen-containing groups can be quaternized with, for example, lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodine; dialkyl sulfates such as dimethyl, di Ethyl, dibutyl, and dipentyl sulfate; long-chain halides such as decyl, dodecyl, tetradecyl, and octadecanoyl chloride, bromine, and iodine; aralkyl halides such as benzyl bromide and benzene ethyl bromide etc. Water-soluble or oil-soluble or dispersible products are thus obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric and organic acids such as oxalic, maleic, succinic and citric.

通过使含羧酸的部分与适宜的碱例如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐反应或与氨或有机伯胺、仲胺或叔胺反应，在最后分离和纯化本发明化合物期间，能够原位制备碱加成盐。药学上可接受的盐包括但不局限于碱金属或碱土金属的阳离子，例如锂、钠、钾、钙、镁和铝盐等，以及无毒季铵和胺阳离子，包括铵、四甲基铵、四乙基铵、甲基铵、二甲基铵、三甲基铵、三乙基铵、二乙基铵和乙基铵等。用于形成碱加成盐的其它典型有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。Final separation by reacting the carboxylic acid-containing moiety with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine Base addition salts can be prepared in situ during and during the purification of the compounds of the invention. Pharmaceutically acceptable salts include, but are not limited to, cations of alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc., and non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium , tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium and ethylammonium, etc. Other typical organic amines useful in the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

用于局部给予本发明化合物的剂型包括粉剂、喷雾剂、膏剂和吸入剂。在无菌条件下使所述活性化合物与药学上可接受的载体和任何需要的防腐剂、缓冲剂或可能需要的抛射剂混合。眼科制剂、眼膏剂、粉剂和溶液剂也考虑在本发明范围内。Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

可改变本发明药用组合物中的活性成分实际剂量水平以获得有效剂量的活性化合物，实现具体患者、组合物和给药模式的需要治疗作用。所选择的剂量水平取决于具体化合物的活性、给药途径、所治疗病症的严重程度和所治疗患者的病情和过去病史。然而，本领域常规操作是所述化合物的起始剂量低于实现目的治疗作用的需要剂量，然后逐渐增加剂量直到实现需要的治疗作用。Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an effective dose of the active compound to achieve the desired therapeutic effect for a particular patient, composition and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and past medical history of the patient being treated. However, it is routine practice in the art to start doses of the compounds lower than that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired therapeutic effect is achieved.

当用于以上或其它治疗时，可使用治疗有效量的一种以下形式的本发明化合物：纯净形式或(存在这样的形式的情况下)药学上可接受的盐、酯或前体药物形式。或者所述化合物可以包含目的化合物和一或多种药学上可接受的赋形剂的药用组合物给药。术语本发明化合物的“治疗有效量”意指以适用于任何医学治疗的合适利益/风险比治疗病症的所述化合物的足够量。然而，人们知道，本发明化合物和组合物的总日用剂量由主治医师经合理的医疗判断决定。任何具体患者的具体治疗有效剂量水平取决于各种因素，包括所治疗的病症和病症的严重程度、使用的具体化合物活性、使用的具体组合物、患者的年龄、体重、一般健康状况、性别和饮食、给药时间、给药途径和所使用的具体化合物的排泄率、治疗持续时间、联合应用的药物或与所用具体化合物同时使用的药物以及医学领域熟知的类似因素。例如本领域熟知的所述化合物的起始剂量低于实现目的治疗作用的需要剂量，然后逐渐增加剂量直到实现需要的治疗作用。When used in the above or other treatments, a therapeutically effective amount of a compound of the invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound may be administered in a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients. The term "therapeutically effective amount" of a compound of the invention means a sufficient amount of said compound to treat a condition at an appropriate benefit/risk ratio applicable to any medical treatment. It is understood, however, that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician using sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on various factors, including the condition being treated and the severity of the condition, the activity of the particular compound employed, the particular composition employed, the patient's age, weight, general health, sex, and Diet, time of administration, route of administration and rate of excretion of the particular compound used, duration of treatment, drugs used in combination or concomitantly with the particular compound used and similar factors well known in the medical arts. For example, it is well known in the art that the starting dose of the compound is lower than that required to achieve the desired therapeutic effect and the dosage is gradually increased until the desired therapeutic effect is achieved.

给予人或低等动物的本发明化合物总日剂量可为约0.0001至大约1000 mg/kg/天。对于口服给药，更优选剂量可为约0.001至约5mg/kg/天。如果需要，有效日剂量可分成多个剂量给药；因此单剂量组合物可包含有效日剂量或其构成日剂量的分剂量。The total daily dose of the compounds of this invention administered to humans or lower animals may range from about 0.0001 to about 1000 mg/kg/day. For oral administration, more preferred doses may range from about 0.001 to about 5 mg/kg/day. The effective daily dose may, if desired, be administered in divided doses; thus unit dose compositions may contain the effective daily dose or sub-doses thereof which constitute the daily dose.

本发明还提供包含与一种或多种药学上可接受的无毒载体一起配制的本发明化合物的药用组合物。所述药用组合物可特别配制为固体或液体形式，用于口服给药或胃肠外注射或直肠给药。The present invention also provides pharmaceutical compositions comprising a compound of the present invention formulated together with one or more pharmaceutically acceptable non-toxic carriers. The pharmaceutical compositions may be specially formulated in solid or liquid form for oral administration or parenteral injection or rectal administration.

本发明药用组合物可通过口服、直肠、胃肠外、脑池内、阴道内、腹膜内、局部(如以粉剂、膏剂或滴剂)、口腔颊膜或口腔喷雾或鼻喷雾给予人和其他哺乳动物。本文使用的术语“胃肠外”指的是包括静脉、肌内、腹膜内、胸骨内、皮下和关节腔注射以及输注在内的给药模式。The pharmaceutical compositions of this invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g. as powder, ointment or drops), buccally, or as a buccal or nasal spray to humans and others. mammal. The term "parenteral" as used herein refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

另一方面，本发明提供包含本发明成分和生理学上可耐受的稀释剂的药用组合物。本发明包括一种或多种上述化合物与一种或多种无毒的生理学上可耐受或可接受的稀释剂、载体、佐剂或溶媒(本文总称为稀释剂)一起配制成固体和液体形式的组合物，用于胃肠外注射、鼻内给药，用于口服给药或用于直肠给药或局部给药等。In another aspect, the invention provides a pharmaceutical composition comprising a composition of the invention and a physiologically tolerable diluent. The present invention includes one or more of the above-mentioned compounds and one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles (collectively referred to herein as diluents) formulated into solids and liquids Compositions in the form of parenteral injection, intranasal administration, oral administration or rectal administration or topical administration, etc.

所述组合物也可以借助冠状内管状结构固定模(intracoronary stent)(由细线网组成的管形装置)或借助生物降解聚合物，经导管局部给予到靶部位。所述化合物也可与配基例如抗体结合用于靶向给药。The composition can also be administered locally via a catheter to the target site via an intracoronary stent (a tubular device composed of a mesh of fine wires) or via a biodegradable polymer. The compounds can also be conjugated to ligands such as antibodies for targeted administration.

适用于胃肠外注射的组合物可包括生理学上可接受的无菌水溶液或非水溶液剂、分散剂、混悬剂或乳剂和用于复制为无菌注射溶液或分散液的无菌粉剂。适宜的水性或非水性载体、稀释剂、溶剂或溶媒的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(例如橄榄油)、注射有机酯例如油酸乙酯和它们的适宜混合物。Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate and suitable mixtures thereof.

这些组合物也可包含佐剂，例如防腐剂、润湿剂、乳化剂和分散剂。例如以下各种抗菌剂和抗真菌剂能够确保防止微生物的作用：例如对羟基苯甲酸酯类、氯代丁醇、苯酚、山梨酸等。也可能需要包含等渗剂例如糖、氯化钠等。使用延迟吸收剂例如单硬脂酸铝和明胶可延迟注射药用剂型的吸收。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms is ensured by, for example, various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Delayed absorption of the injectable pharmaceutical forms is delayed by the use of absorption delaying agents, for example, aluminum monostearate and gelatin.

除所述活性化合物以外，混悬剂可包含悬浮剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨醇酯和聚氧乙烯山梨糖醇酐酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄芪胶或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitan esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide , bentonite, agar and tragacanth or a mixture of these substances.

在某些情况下，为了延长药物的作用，需要减缓皮下注射或肌内注射的药物吸收。这可通过使用水溶性差的结晶或无定形物质的液体悬浮液来实现。那么药物的吸收速率取决于其溶出速率，而溶出速率又可能取决于晶体大小和结晶型。或者，把所述药物溶解或悬浮在油溶媒中，延迟胃肠外给予药物剂型的吸收。In some cases, in order to prolong the action of the drug, it is necessary to slow the absorption of the drug given subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of poorly water soluble crystalline or amorphous material. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, the drug is dissolved or suspended in an oil vehicle to delay the absorption of a parenterally administered pharmaceutical form.

通过使所述药物在生物降解聚合物例如聚交酯-聚乙交酯中形成微型包囊骨架，制备注射贮库型剂型。根据药物与聚合物的比例和所使用的具体聚合物的性质，可控制药物释放速率。其它生物降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。还可将药物包埋在与机体组织匹配的脂质体或微乳中，制备贮库型注射制剂。Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Drugs can also be embedded in liposomes or microemulsions compatible with body tissues to prepare depot injection preparations.

例如通过阻留细菌的滤膜过滤或在临用前可用无菌水或其它无菌注射介质溶解或分散的无菌固体组合物中掺入杀菌剂，可使注射制剂无菌。Injectable preparations can be rendered sterile, for example, by filtration through a bacteria-retaining filter or by incorporating bactericidal agents into sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just before use.

用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、粉剂和颗粒剂。在这样的固体剂型中，活性化合物可与至少一种药学上可接受的惰性赋形剂或载体例如枸橼酸钠或磷酸二钙和/或以下任何物质混合：a)填充剂或增充剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸；b)粘合剂，例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶；c)湿润剂，例如甘油；d)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些硅酸盐和碳酸钠；e)液体阻滞剂，例如石蜡；f)吸收促进剂，例如季铵化合物；g)润湿剂，例如单硬脂酸十六烷醇酯和单硬脂酸甘油酯；h)吸收剂，例如高岭土和膨润土粘土，以及i)润滑剂，例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。如果为胶囊剂、片剂和丸剂，所述剂型还可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and/or any of the following: a) fillers or extenders , such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) liquid blockers such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl monostearate and glyceryl monostearate; h) absorbents such as kaolin and bentonite clays, and i) lubricants such as talc, stearin Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

利用诸如乳糖或奶糖以及高分子量聚乙二醇等的赋形剂，相似类型的固体组合物也可用作软填充明胶胶囊和硬填充明胶胶囊的填充剂。Solid compositions of a similar type can also be used as fillers in soft-filled and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

可用包衣和壳体例如肠溶包衣和药物配制领域熟知的其它包衣剂制备片剂、糖锭剂、胶囊剂、丸剂和颗粒剂固体剂型。它们可任选包含遮光剂，而且也可以为这样的组合物：它们任选以延迟方式仅在或优选在某部分肠道释放所述活性成分。可使用的包埋成分的实例包括聚合物物质和蜡。The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

所述活性化合物也可以为微囊化形式，如果合适的话，可含有一种或多种上述赋形剂。The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

用于口服给药的液体剂型包括药学上可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除所述活性化合物以外，液体剂型还可含有本领域常规使用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇和山梨糖醇酐的脂肪酸酯，以及它们的混合物。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Besides the active compound, liquid dosage forms can also contain inert diluents customary in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol , benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran Fatty acid esters of methanol, polyethylene glycol, and sorbitan, and mixtures thereof.

除惰性稀释剂以外，口服组合物还可包含佐剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和香味剂。Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

用于直肠或阴道给药的组合物优选为栓剂，可使本发明化合物与适宜的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合制备所述栓剂，所述赋形剂或载体在室温下为固体，但在体温下为液体，因此在直肠或阴道腔内熔融而释放出所述活性化合物。Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax, which The excipient or carrier is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal canal to release the active compound.

本发明化合物也可以脂质体形式给药。本领域已知，一般用磷脂或其它脂质物质制备脂质体。通过分散在水介质中的单-或多-层水合液晶形成脂质体。可使用能够形成脂质体的任何无毒、生理学上可接受而且可代谢的脂质。除本发明化合物以外，脂质体形式的本发明组合物可包含稳定剂、防腐剂、赋形剂等。优选的脂质为单独使用或一起使用的天然和合成的磷脂和磷脂酰胆碱(卵磷脂)。The compounds of the invention can also be administered in liposome form. As is known in the art, liposomes are generally prepared from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), used alone or together.

制备脂质体的方法是本领域已知的。参见例如Prescott编辑，Method in Cell Biology，第XIV卷，Academic Press，纽约，N.Y.(1976)，第33页以及下列文献等。Methods of preparing liposomes are known in the art. See, eg, Prescott ed., Method in Cell Biology , Vol. XIV, Academic Press, New York, NY (1976), p. 33 and the following references, among others.

本文使用的术语“药学上可接受的前体药物”为本发明化合物的前体药物，它在合理的医疗判断范围内适用于接触人体组织和低等动物组织而没有过度毒性、刺激性、变应反应等，具有相应的合理利益/风险比，以及有效用于其预定用途，以及为(在可能的情况下)本发明化合物的两性离子形式。例如，通过在血液中水解，本发明前体药物可在体内迅速转化为上式的母体化合物。在T.Higuchi和V.Stella， 用 作新型给药体系的前体药物，美国化学协会系列专题研讨会(A.C.S.Symposium Series)的第14卷中和在Edward B.Roche编辑， 药物设计中 的生物可逆性载体(Bioreversible Carrers in Drug Design)，AmericanPharmaceutical Association and Pergamon Press(1987)中有其全面的论述，所述文献通过引用结合到本文中。As used herein, the term "pharmaceutically acceptable prodrug" is a prodrug of a compound of the present invention which, within the scope of sound medical judgment, is suitable for use in contact with human tissues and lower animal tissues without undue toxicity, irritation, mutagenesis, should react, etc., have a corresponding reasonable benefit/risk ratio, and are effective for their intended use, and are (where possible) zwitterionic forms of the compounds of the invention. For example, the prodrugs of the present invention can be rapidly converted in vivo to the parent compound of the above formula by hydrolysis in blood. In T. Higuchi and V. Stella, Prodrugs for Novel Drug Delivery Systems , in Volume 14 of the ACSSymposium Series and edited by Edward B. Roche, Bioreversibility in Drug Design Bioreversible Carrers in Drug Design , American Pharmaceutical Association and Pergamon Press (1987), which is incorporated herein by reference.

给予哺乳动物时通过体内转化不同化合物而形成的本发明化合物包括在本发明范围内。Compounds of the invention formed by in vivo conversion of different compounds when administered to a mammal are included within the scope of the invention.

本发明化合物可作为其中存在不对称或手性中心的立体异构体存在。根据手性碳原子周围的取代基构型，这些立体异构体为“R”或“S”构型。本发明设计了各种立体异构体和它们的混合物。立体异构体包括对映体和非对映体以及对映体或非对映体的混合物。可用从市场上可得到的含有不对称或手性中心的原料合成或通过制备外消旋混合物，然后通过本领域技术人员熟知的拆分外消旋混合物，制备本发明化合物的各种立体异构体。这些拆分方法举例来说有：(1)使对映体混合物结合到手性辅剂上，通过重结晶或层析法分离生成的非对映体混合物，然后从辅剂释放出旋光纯的产物或(2)在手性层析柱上直接分离旋光对映体混合物。The compounds of the invention may exist as stereoisomers in which asymmetric or chiral centers are present. Depending on the configuration of substituents around the chiral carbon atom, these stereoisomers are in the "R" or "S" configuration. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers as well as mixtures of enantiomers or diastereomers. The various stereoisomers of the compounds of the invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution of the racemic mixtures well known to those skilled in the art. body. Examples of such resolution methods are: (1) binding of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and release of the optically pure product from the auxiliary Or (2) direct separation of the mixture of optical enantiomers on a chiral chromatography column.

本发明化合物可以非溶剂化形式以及包括水合物形式如半水合物在内的溶剂化形式存在。一般来说，药学上可接受的溶剂例如水和乙醇等的溶剂化形式对于本发明目的而言是与非溶剂化形式等同的。The compounds of the present invention can exist in unsolvated forms as well as solvated forms including hydrated forms such as hemihydrates. In general, the solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like, are equivalent to the unsolvated forms for the purposes of the present invention.

另一方面，本发明设计了抑制α4β1整联蛋白与VCAM-1结合的方法。本发明方法可在体外或体内使用。按照本发明方法，在有效抑制量的本发明化合物存在下，使表达α4β1整联蛋白的细胞暴露于表达VCAM-1的细胞。In another aspect, the present invention contemplates methods of inhibiting the binding of α4β1 integrin to VCAM-1. The methods of the invention can be used in vitro or in vivo. According to the methods of the invention , cells expressing α4β1 integrin are exposed to cells expressing VCAM-1 in the presence of an effective inhibitory amount of a compound of the invention.

表达α4β1整联蛋白的细胞可以是天然白细胞、肥大细胞或在细胞表面天然表达α4β1的其它细胞类型、或用包含编码α4β1整联蛋白的多核苷酸(例如基因组DNA或cDNA)的表达载体转染的细胞。在一个特别优选的实施方案中，α4β1整联蛋白存在于白细胞例如单核细胞、淋巴细胞或粒细胞(例如嗜酸性粒细胞或嗜碱性粒细胞)的表面。Cells expressing α4β1 integrin can be native leukocytes, mast cells, or other cell types that naturally express α4β1 on the cell surface, or can be expressed with polynucleotides encoding α4β1 integrins (e.g., genomic DNA or cDNA) expression vector transfected cells. In a particularly preferred embodiment, the α4β1 integrin is present on the surface of leukocytes such as monocytes, lymphocytes or granulocytes (eg eosinophils or basophils).

表达VCAM-1的细胞可为天然细胞(例如内皮细胞)或用包含编码VCAM-1的多核苷酸的表达载体转染的细胞。用于产生表达VCAM-1的转染细胞的方法为本领域熟知的方法。Cells expressing VCAM-1 may be natural cells (eg, endothelial cells) or cells transfected with an expression vector comprising a polynucleotide encoding VCAM-1. Methods for generating transfected cells expressing VCAM-1 are well known in the art.

当VCAM-1存在于细胞表面时，优选通过炎性细胞因子例如肿瘤坏死因子-α、白细胞介素-4和白细胞介素-1β诱导表达VCAM-1。When VCAM-1 is present on the cell surface, expression of VCAM-1 is preferably induced by inflammatory cytokines such as tumor necrosis factor-α, interleukin-4 and interleukin-1β.

当表达α4β1整联蛋白和VCAM-1的细胞在生命有机体中时，将有效量的本发明化合物给予所述生命有机体。所述化合物优选为本发明的药用组合物。本发明方法特别适用于治疗与白细胞不受控制地迁移至损伤组织有关的疾病。这样的疾病包括但不局限于哮喘、动脉粥样硬化、类风湿性关节炎、过敏、多发性硬化症、红斑狼疮、炎性肠病、移植排斥反应、接触性超敏反应、I型糖尿病、白血病和脑癌。优选通过血管内、皮下、鼻内、经皮或口服传递实现给药。When cells expressing α4β1 integrin and VCAM-1 are in a living organism, an effective amount of a compound of the invention is administered to the living organism. Said compound is preferably a pharmaceutical composition of the invention. The methods of the invention are particularly useful in the treatment of diseases associated with the uncontrolled migration of leukocytes into damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergies, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, transplant rejection, contact hypersensitivity, type I diabetes, Leukemia and brain cancer. Administration is preferably accomplished by intravascular, subcutaneous, intranasal, transdermal or oral delivery.

本发明还提供选择性抑制α4β1整联蛋白与蛋白质结合的方法，该方法包括在有效抑制量的本发明化合物存在下使整联蛋白暴露于所述蛋白质。在一个优选的实施方案中，α4β1整联蛋白在表达α4β1整联蛋白的天然细胞或转化细胞表面表达。The invention also provides a method of selectively inhibiting the binding of α4β1 integrin to a protein, the method comprising exposing the integrin to said protein in the presence of an effective inhibitory amount of a compound of the invention . In a preferred embodiment, the α4β1 integrin is expressed on the surface of native or transformed cells expressing the α4β1 integrin.

α4β1整联蛋白结合的蛋白质可表达于细胞表面或为细胞外基质组成部分。特别优选的蛋白质为纤连蛋白或透明质酸酶。 α4β1 integrin - binding proteins may be expressed on the cell surface or be part of the extracellular matrix. A particularly preferred protein is fibronectin or hyaluronidase.

在下文实施例中详细描述本发明化合物抑制结合的能力。这些实施例用以描述本发明的优选实施方案和实用性，而不是用其限制本发明，除非在后附的权利要求中另有说明。实施例1 The ability of compounds of the invention to inhibit binding is described in detail in the Examples below. These examples are intended to describe preferred embodiments and practices of the invention and are not intended to limit the invention unless otherwise stated in the appended claims. Example 1

(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-乙基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(10)的合成(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl Synthesis of ]amino}-3-(4-methylphenyl)propionic acid (10)

步骤1：将化合物1(20.8g，135mmol)溶于甲醇(270mL)中，加入披钯碳(以10％钯干重计，Degussa E101NE/W型，～50％水含量，5.75g，2.7mmolPd)。用氢置换大气(在真空和气球氢之间切换5次)，搅拌混合物过夜，然后过滤。真空浓缩滤液，用1∶1己烷∶乙酸乙酯混合物溶解残余物，用水和饱和NaHCO3、饱和NaHCO3和盐水的4∶1混合物洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液得到为白色固体的化合物2(12.43g，74％)。该物质无需纯化即可使用。步骤2：将化合物2(2.64g，21.3mmol)溶于二氯甲烷(50mL)中并冷却至0℃。用三乙胺(3.6mL，25.6mmol)和三甲基乙酰氯(2.90mL，23.4mmol)连续处理冷的溶液。在室温下搅拌溶液6小时，然后回流过夜。混合物分配在二氯甲烷和NaOH水溶液(2N)之间。用盐水洗涤有机层，经MgSO4干燥并过滤，浓缩滤液得到化合物3(3.33g，75％)。步骤3：在干燥氮气氛下，将化合物3(0.50g，2.4mmol)溶于无水THF，(9.6mL)和TMEDA(1.1mL，7.2mmol)中。将生成的溶液冷却至-20℃和-10℃之间，用注射器滴加正丁基锂(1.6M的己烷溶液2.25mL)和叔丁基锂(1.7M的戊烷溶液，2.1mL)连续处理。30分钟后，使浴温回升到-5至0℃并通过注射器用碘乙烷(0.77mL，9.6mmol)处理。在0℃下搅拌溶液2小时，然后在室温下搅拌过夜。用甲醇骤冷混合物并浓缩至干。通过硅胶过滤纯化残余物，用3∶1己烷∶乙酸乙酯洗脱，然后从己烷中重结晶得到化合物4(0.32g，56％。 Step 1: Dissolve compound 1 (20.8g, 135mmol) in methanol (270mL), add palladium on carbon (10% palladium dry weight, Degussa E101NE/W type, ~50% water content, 5.75g, 2.7mmolPd ). The atmosphere was replaced with hydrogen (switching between vacuum and balloon hydrogen 5 times), the mixture was stirred overnight, then filtered. The filtrate was concentrated in vacuo, the residue was taken up with a 1:1 hexane:ethyl acetate mixture and washed with water and a 4:1 mixture of saturated NaHCO3 , saturated NaHCO3 and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2 (12.43 g, 74%) as a white solid. This material was used without purification. Step 2: Compound 2 (2.64 g, 21.3 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0°C. The cold solution was treated successively with triethylamine (3.6 mL, 25.6 mmol) and trimethylacetyl chloride (2.90 mL, 23.4 mmol). The solution was stirred at room temperature for 6 hours, then refluxed overnight. The mixture was partitioned between dichloromethane and aqueous NaOH (2N). The organic layer was washed with brine, dried over MgSO 4 and filtered, the filtrate was concentrated to give compound 3 (3.33 g, 75%). Step 3: Compound 3 (0.50 g, 2.4 mmol) was dissolved in anhydrous THF, (9.6 mL) and TMEDA (1.1 mL, 7.2 mmol) under dry nitrogen atmosphere. The resulting solution was cooled to between -20°C and -10°C, and n-butyllithium (1.6M in hexane, 2.25mL) and tert-butyllithium (1.7M in pentane, 2.1mL) were added dropwise with a syringe Continuous processing. After 30 minutes, the bath temperature was brought back to -5 to 0°C and treated with ethyl iodide (0.77 mL, 9.6 mmol) via syringe. The solution was stirred at 0°C for 2 hours, then at room temperature overnight. The mixture was quenched with methanol and concentrated to dryness. The residue was purified by filtration through silica gel, eluting with 3:1 hexane:ethyl acetate, and then recrystallized from hexane to afford compound 4 (0.32 g, 56%.

步骤4：将化合物4(0.32g，1.3mmol)溶于冰乙酸(4.5mL)中，用碘化钾(0.65g，3.9mmol)处理。在调节在115℃的油浴中加热生成的混合物1.0小时。冷却混合物，用水稀释并使用2N NaOH和2N HCl调节至pH6。用氯仿提取混合物(4次)。用硫代硫酸钠水溶液洗涤合并的提取液，经MgSO4干燥后过滤。减压浓缩滤液得到为白色固体的化合物5(0.25g，86％)。该物质无需进一步纯化即可使用。 Step 4: Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial acetic acid (4.5 mL) and treated with potassium iodide (0.65 g, 3.9 mmol). The resulting mixture was heated in an oil bath adjusted at 115°C for 1.0 hour. The mixture was cooled, diluted with water and adjusted to pH 6 using 2N NaOH and 2N HCl. The mixture was extracted with chloroform (4 times). The combined extracts were washed with aqueous sodium thiosulfate, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give compound 5 (0.25 g, 86%) as a white solid. This material was used without further purification.

步骤5：在0℃下，将化合物5(0.25g，1.1mmol)溶于THF(45mL)中，用双(三甲基甲硅烷基)酰胺钾溶液(0.5M的甲苯溶液，2.7mL)滴加处理。用2-氯代苄基溴(0.16mL，1.2mmol)处理生成的溶液，使溶液温热至室温过夜。混合物分配在2N HCl和乙酸乙酯之间。用盐水洗涤有机层，经MgSO4干燥后过滤。减压浓缩滤液，经层析法(SiO2，梯度洗脱4∶1转换至2∶1己烷∶乙酸乙酯)纯化残余物，得到化合物6(0.16g，41％)。 Step 5: Dissolve compound 5 (0.25g, 1.1mmol) in THF (45mL) at 0°C, dropwise with potassium bis(trimethylsilyl)amide solution (0.5M in toluene, 2.7mL) Plus processing. The resulting solution was treated with 2-chlorobenzyl bromide (0.16 mL, 1.2 mmol), and the solution was allowed to warm to room temperature overnight. The mixture was partitioned between 2N HCl and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography ( SiO2 , gradient elution 4:1 switching to 2:1 hexane:ethyl acetate) to afford compound 6 (0.16 g, 41%).

步骤6：将化合物6(0.16g，0.46mmol)悬浮于1∶1水∶浓HCl(4.6mL)中。使悬浮液回流4小时，回流期间化合物溶解。冷却混合物，用水稀释，用乙醚提取。用过量的饱和碳酸氢钠溶液将水层调节成碱性后，用乙酸乙酯提取混合物。合并提取液，用盐水洗涤，经MgSO4干燥后过滤。减压浓缩滤液得到化合物7(0.081g，67％)。 Step 6: Compound 6 (0.16 g, 0.46 mmol) was suspended in 1:1 water:cone HCl (4.6 mL). The suspension was refluxed for 4 hours during which time the compound dissolved. The mixture was cooled, diluted with water and extracted with ether. After the aqueous layer was made basic with an excess of saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to obtain compound 7 (0.081 g, 67%).

 步骤7：将化合物7(0.080g，0.30mmol)溶于1，2-二氯乙烷(1.2mL)和DIPEA(0.115mL，0.66mmol)中并冷却至0℃。用光气溶液(1.93M的甲苯溶液，0.170mL，0.33mmol)快速处理冷的溶液。30分钟后，通过注射器快速加入化合物8(0.068g，0.33mmol)的1，2-二氯乙烷溶液(0.5mL)。把生成的混合物加热至55℃1小时。混合物分配在二氯甲烷和2 N HCl之间。用饱和NaHCO3水溶液和盐水洗涤有机层，经MgSO4干燥后过滤。浓缩滤液得到化合物9(0.110g，74％)。 Step 7: Compound 7 (0.080 g, 0.30 mmol) was dissolved in 1,2-dichloroethane (1.2 mL) and DIPEA (0.115 mL, 0.66 mmol) and cooled to 0°C. The cold solution was quickly treated with phosgene solution (1.93M in toluene, 0.170 mL, 0.33 mmol). After 30 minutes, a solution of compound 8 (0.068 g, 0.33 mmol) in 1,2-dichloroethane (0.5 mL) was added rapidly via syringe. The resulting mixture was heated to 55°C for 1 hour. The mixture was partitioned between dichloromethane and 2N HCl. The organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over MgSO 4 and filtered. The filtrate was concentrated to obtain compound 9 (0.110 g, 74%).

步骤8：将化合物9(0.11g，0.22mmol)溶于2∶1THF∶H2O(0.88mL)中并用2N NaOH溶液(0.33mL)处理。滴加甲醇，直到得到均匀溶液。搅拌混合物20分钟，用水稀释，然后用乙醚洗涤。用2N HCl酸化水层后，用乙酸乙酯提取。用盐水洗涤乙酸乙酯层，经MgSO4干燥后过滤。浓缩滤液得到(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-乙基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(10，0.095g，92％)。实施例2 Step 8: Compound 9 (0.11 g, 0.22 mmol) was dissolved in 2: 1 THF:H2O (0.88 mL) and treated with 2N NaOH solution (0.33 mL). Methanol was added dropwise until a homogeneous solution was obtained. The mixture was stirred for 20 minutes, diluted with water and washed with ether. After acidifying the aqueous layer with 2N HCl, it was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to give (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl} Amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (10, 0.095 g, 92%). Example 2

(3S)-3-{[({6-甲基-2-氧代-1-(苯甲基)-4-[(苯甲基)氧基]-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(15)的合成步骤1：向化合物11(1.0g，5.9mmol)和K2CO3(2.40g，17.6mmol)丙酮悬浮液(50mL)中加入苄基溴(2.31g，13.5mmol)。回流过夜后，冷却反应物，混合物分配在乙酸乙酯和饱和NaHCO3之间。用稀HCl和盐水洗涤有机层，经MgSO4干燥后过滤，浓缩滤液得到化合物12(1.60g，80％)。(3S)-3-{[({6-Methyl-2-oxo-1-(benzyl)-4-[(benzyl)oxy]-1,2-dihydro-3-pyridine Base}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (15) Synthesis Step 1: Compound 11 (1.0g, 5.9mmol) and K 2 CO 3 (2.40g, 17.6mmol ) acetone suspension (50 mL) was added benzyl bromide (2.31 g, 13.5 mmol). After refluxing overnight, the reaction was cooled and the mixture was partitioned between ethyl acetate and saturated NaHCO3 . The organic layer was washed with dilute HCl and brine, dried over MgSO 4 and filtered, and the filtrate was concentrated to give compound 12 (1.60 g, 80%).

步骤2：将化合物12(0.30g，0.86mmol)、锌粉(0.30g，4.6mmol)和饱和NH4Cl水溶液(0.30mL)混合于MeOH(18mL)中。在室温下使该混合物搅拌1小时，然后加入另外的锌粉(0.30g，4.6mmol)。把生成的不均匀混合物回流过夜。过滤热的混合物并减压浓缩滤液后，把残余物溶于乙酸乙酯中，用饱和NaHCO3水溶液和盐水洗涤。经MgSO4干燥有机层后过滤，减压浓缩滤液得到化合物13(0.18g，66％)。 Step 2: Compound 12 (0.30 g, 0.86 mmol), zinc powder (0.30 g, 4.6 mmol) and saturated aqueous NH 4 Cl (0.30 mL) were mixed in MeOH (18 mL). The mixture was stirred at room temperature for 1 hour, then additional zinc powder (0.30 g, 4.6 mmol) was added. The resulting heterogeneous mixture was refluxed overnight. After filtering the hot mixture and concentrating the filtrate under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13 (0.18 g, 66%).

步骤3：将化合物13(0.30g，0.94mmol.)和DIPEA(0.40mL，2.3mmol.)溶于CH2Cl2中，把混合物冷却至0℃。向溶液中滴加光气1.9M的甲苯溶液，0.55mL，1.0mmol)。在0℃下搅拌反应混合物15分钟，然后加入化合物8(0.19g，0.94mmol)的CH2Cl2溶液(2mL)。在室温下把生成的溶液搅拌过夜，然后倾入到乙酸乙酯中，用饱和NaHCO3水溶液、1N HCl和盐水洗涤。经MgSO4干燥有机层后过滤，减压浓缩滤液。经硅胶快速层析法纯化残余物，用1∶1增加至1∶2的己烷∶乙酸乙酯洗脱，得到化合物14(0.33g，64％)。 Step 3: Compound 13 (0.30 g, 0.94 mmol.) and DIPEA (0.40 mL, 2.3 mmol.) were dissolved in CH2Cl2 , and the mixture was cooled to 0 °C. To the solution was added dropwise phosgene 1.9 M in toluene, 0.55 mL, 1.0 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, then a solution of compound 8 (0.19 g, 0.94 mmol) in CH 2 Cl 2 (2 mL) was added. The resulting solution was stirred overnight at room temperature, then poured into ethyl acetate, washed with saturated aqueous NaHCO 3 , 1N HCl, and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 1:1 increasing to 1:2 hexane:ethyl acetate, to afford compound 14 (0.33 g, 64%).

步骤4：将化合物14(0.33g，0.6mmol)在THF(6mL)中的溶液用2N NaOH(2mL)处理。加入MeOH，直到得到均匀的溶液。在室温下搅拌反应混合物30分钟，将其倾入到H2O(50mL)中。用乙醚洗涤水层(两次)，然后用1N HCl酸化。用乙酸乙酯提取水层(两次)。用盐水洗涤合并的乙酸乙酯提取液(两次)，经MgSO4干燥后过滤。减压浓缩滤液得到为灰白色固体的(3S)-3-{[({6-甲基-2-氧代-1-(苯甲基)-4-[(苯甲基)氧基]-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(15，0.26g，90％)。熔点：124-126℃。实施例3 Step 4: A solution of compound 14 (0.33 g, 0.6 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). MeOH was added until a homogeneous solution was obtained. The reaction mixture was stirred at room temperature for 30 min and poured into H2O (50 mL). The aqueous layer was washed with ether (twice), then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1 as an off-white solid , 2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (15, 0.26 g, 90%). Melting point: 124-126°C. Example 3

(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲基]-6-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(22)的合成(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl Synthesis of }amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (22)

步骤1：在0℃下，向化合物11(10.00g，58.8mmol)的无水DMF溶液(120mL)中加入NaH(60％矿物油分散液，5.40g，135mmol)。在0℃下搅拌混合物15分钟，然后加入2-氯代苄基氯(12.3g，76.4mmol)。在55℃下搅拌过夜后，把混合物倾入到冰水中，用Et2O洗涤两次。酸化水层并过滤生成的沉淀，得到化合物16(14.7g，85％)。 Step 1: To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF (120 mL) was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol) at 0°C. The mixture was stirred at 0°C for 15 minutes, then 2-chlorobenzyl chloride (12.3 g, 76.4 mmol) was added. After stirring overnight at 55°C, the mixture was poured into ice water and washed twice with Et2O . The aqueous layer was acidified and the resulting precipitate was filtered to give compound 16 (14.7 g, 85%).

步骤2：在室温于干燥氮气氛下，将装有化合物16(8.00g，28.6mmol)的烧瓶用橡胶隔膜和气球密封，通过注射器加入POCl3(30.0ml，322mmol)。除去氮气输送管线，在70℃下搅拌反应混合物过夜，然后倾入到冰(300ml)上并搅拌30分钟。用二氯甲烷(300ml)提取生成的混合物，经MgSO4无水有机相后过滤。减压浓缩滤液得到为深棕色固体的化合物17(7.3g，86％)。 Step 2: At room temperature under a dry nitrogen atmosphere, the flask containing compound 16 (8.00 g, 28.6 mmol) was sealed with a rubber septum and a balloon, and POCl 3 (30.0 ml, 322 mmol) was added via syringe. The nitrogen delivery line was removed and the reaction mixture was stirred overnight at 70°C, then poured onto ice (300ml) and stirred for 30 minutes. The resulting mixture was extracted with dichloromethane (300ml), filtered through MgSO4 dry organic phase. The filtrate was concentrated under reduced pressure to afford compound 17 (7.3 g, 86%) as a dark brown solid.

步骤3：在室温下，向配备有冷凝器和装配有气球的橡胶隔板的250ml烧瓶中加入化合物17(2.1g，7.05mmol)、甲醇(55ml)和氢氧化铵水溶液(28-30％，70.0ml，1.14mol)的溶液。把反应混合物加热至65℃反应60小时，仅开放气球。过滤混合物，减压浓缩滤液得到为棕色固体的化合物18(1.5g，76％)。 Step 3: To a 250ml flask equipped with a condenser and a rubber septum fitted with a balloon was added compound 17 (2.1g, 7.05mmol), methanol (55ml) and aqueous ammonium hydroxide (28-30%, 70.0ml, 1.14mol) solution. The reaction mixture was heated to 65°C for 60 hours and only the balloon was opened. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford compound 18 (1.5 g, 76%) as a brown solid.

步骤4：在室温下，向化合物18(0.3g，1.02mmol)的甲醇溶液(50ml)中连续加入饱和氯化铵水溶液(2ml)和锌粉(0.30g，4.6mmol)。在室温下搅拌30分钟后，加入另外的锌粉(0.30g，4.6mmol)并把反应混合物回流过夜。将反应混合物热过滤，减压浓缩滤液。残余物分配在乙酸乙酯和1N NaOH之间。过滤溶液，用乙酸乙酯提取水相。经MgSO4干燥合并的有机相并过滤。减压浓缩滤液得到为棕色固体的化合物19(0.21g，78％)。 Step 4: To a solution of compound 18 (0.3g, 1.02mmol) in methanol (50ml) was continuously added saturated aqueous ammonium chloride (2ml) and zinc powder (0.30g, 4.6mmol) at room temperature. After stirring at room temperature for 30 minutes, additional zinc powder (0.30 g, 4.6 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered hot, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N NaOH. The solution was filtered and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford compound 19 (0.21 g, 78%) as a brown solid.

步骤5：将化合物19(0.10g，0.38mmol)、NMM(0.040mL，0.38mmol)和化合物20(0.14g，0.38mmol)的无水DMF溶液(5mL)加热至50℃过夜。冷却混合物并用乙酸乙酯(60mL)稀释。用0.5N NaOH(3×30mL)和盐水洗涤有机层，经MgSO4干燥后过滤。减压浓缩滤液，经硅胶快速层析法纯化残余物，用9∶1增加至17∶3的CHCl3∶MeOH洗脱，得到为黄色泡沫物的化合物21(0.120g，65％)。 Step 5: A solution (5 mL) of compound 19 (0.10 g, 0.38 mmol), NMM (0.040 mL, 0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF was heated to 50 °C overnight. The mixture was cooled and diluted with ethyl acetate (60 mL). The organic layer was washed with 0.5N NaOH (3 x 30 mL) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with CHCl3 : MeOH 9:1 increasing to 17:3, to afford compound 21 (0.120 g, 65%) as a yellow foam.

步骤6：将化合物21(0.120g，025mmol)的THF溶液(6mL)用2NNaOH(2mL)处理。加入甲醇，直到得到均匀的溶液。在室温下搅拌反应混合物30分钟后，倾入到H2O(50mL)上。用乙醚洗涤水层(两次)，然后用1N HCl酸化。用乙酸乙酯提取水层(两次)。用盐水洗涤合并的乙酸乙酯提取液(两次)，经MgSO4干燥后过滤。减压浓缩滤液得到为灰白色固体的(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲基]-6-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(22，0.100g，89％)。熔点：145-147℃。实施例4 Step 6: A solution of compound 21 (0.120 g, 025 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). Methanol was added until a homogeneous solution was obtained. After stirring the reaction mixture at room temperature for 30 min, it was poured onto H2O (50 mL). The aqueous layer was washed with ether (twice), then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1 as an off-white solid, 2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (22, 0.100 g, 89%). Melting point: 145-147°C. Example 4

(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-(甲氧基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成步骤1：向0℃下的化合物23(10.00g，64.0mmol)的无水DMF溶液(130mL)中加入NaH(60％矿物油分散液，5.90g，147mmol)。在0℃下搅拌混合物15分钟，然后加入2-氯代苄基氯(13.4g，83.3mmol)。在55℃下搅拌过夜后，把混合物倾入到冰水中，用Et2O洗涤(两次)。酸化水层，过滤生成的沉淀得到化合物24(13.5g，75％)。步骤2：将化合物24(1.0g，3.6mmol)、K2CO3(0.85g，6.2mmol)和MeI(1.18g，8.3mmol)的丙酮悬浮液(20mL)回流过夜。用乙酸乙酯稀释反应混合物，用饱和NaHCO3水溶液、1N HCl和盐水洗涤。经MgSO4干燥有机层后过滤，减压浓缩滤液得到化合物25(0.74g，70％)。(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(methoxy)-2-oxo-1,2-dihydro-3-pyridyl] Synthesis of amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid Step 1: To a solution of compound 23 (10.00 g, 64.0 mmol) in anhydrous DMF (130 mL) at 0 °C was added NaH ( 60% dispersion in mineral oil, 5.90 g, 147 mmol). The mixture was stirred at 0°C for 15 minutes, then 2-chlorobenzyl chloride (13.4 g, 83.3 mmol) was added. After stirring overnight at 55°C, the mixture was poured into ice water and washed with Et2O (twice). The aqueous layer was acidified, and the resulting precipitate was filtered to obtain compound 24 (13.5 g, 75%). Step 2: A suspension of compound 24 (1.0 g, 3.6 mmol), K 2 CO 3 (0.85 g, 6.2 mmol) and MeI (1.18 g, 8.3 mmol) in acetone (20 mL) was refluxed overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO 3 , 1N HCl and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 25 (0.74 g, 70%).

按照实施例3描述的方法，用化合物25制备(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-(甲氧基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。MS：计算值：(M+H)+＝469.93；实测值：(M+H)+＝470.01。实施例5 According to the method described in Example 3, compound 25 was used to prepare (3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(methoxy)-2-oxo- 1,2-Dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid. MS: Calculated: (M+H) + = 469.93; Found: (M+H) + = 470.01. Example 5

(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-氟-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] Synthesis of Amino}-3-(4-Methylphenyl)propionic Acid

步骤1：在干燥氮气氛下，将化合物3(0.65g，3.1mmol)溶于无水THF(12.4mL)和TMEDA(0.90mL，6mmol)中。将生成的溶液冷却至-15和-10℃之间并通过注射器滴加正丁基锂(1.6M的己烷溶液，7.75mL，12.4mmol)。1.5小时后，通过注射器向冷的溶液中迅速加入N-氟苯磺酰亚胺(1.07g，3.4mmol)的THF溶液(5mL)。在0℃下搅拌溶液1小时，然后在室温下搅拌3小时。用水骤冷混合物并用氯仿提取(4次)。用盐水洗涤合并的有机提取液，经MgSO4干燥后过滤。减压浓缩滤液，经层析法纯化残余物(SiO2，柱塞凝胶，使用4∶1转换至3∶1己烷∶乙酸乙酯)，得到化合物26(0.177g，25％)。 Step 1: Compound 3 (0.65 g, 3.1 mmol) was dissolved in anhydrous THF (12.4 mL) and TMEDA (0.90 mL, 6 mmol) under dry nitrogen atmosphere. The resulting solution was cooled to between -15 and -10°C and n-butyllithium (1.6M in hexane, 7.75 mL, 12.4 mmol) was added dropwise via syringe. After 1.5 hours, a THF solution (5 mL) of N-fluorobenzenesulfonimide (1.07 g, 3.4 mmol) was added rapidly via syringe to the cold solution. The solution was stirred at 0°C for 1 hour, then at room temperature for 3 hours. The mixture was quenched with water and extracted with chloroform (4 times). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography ( SiO2 , plug gel, using 4:1 switching to 3:1 hexane:ethyl acetate) to afford compound 26 (0.177 g, 25%).

按照实施例1中描述的方法，用化合物26制备(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-氟-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。MS：计算值：(M+H)-＝458.12；实测值：(M+H)+＝458.01。实施例6 According to the method described in Example 1, compound 26 was used to prepare (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-fluoro-2-oxo-1,2 -Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid. MS: Calculated: (M+H) - = 458.12; Found: (M+H) + = 458.01. Example 6

(3S)-4-氯-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-4-chloro-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] Synthesis of Amino}-3-(4-Methylphenyl)propionic Acid

步骤1：将化合物3(0.65g，3.1mmol)溶于THF(21mL)和TMEDA(1.20mL，7.75mmol)中，使其冷却至-15℃。用正丁基锂(1.6M的己烷溶液，4.8mL，7.8mmol)处理溶液。使混合物在-20和-10℃之间维持1小时，然后冷却至-78℃。加入固体N-氯代琥珀酰亚胺(0.45g，3.4mmol)，同时装置处于正氮气流下。使反应物逐渐温热至室温然后搅拌过夜。用水骤冷混合物后，用氯仿提取(4次)。合并有机层，经MgSO4干燥后过滤。减压浓缩滤液，从己烷中重结晶残余物得到化合物27(0.25g，33％)。 Step 1: Compound 3 (0.65 g, 3.1 mmol) was dissolved in THF (21 mL) and TMEDA (1.20 mL, 7.75 mmol) and allowed to cool to -15°C. The solution was treated with n-butyllithium (1.6M in hexane, 4.8 mL, 7.8 mmol). The mixture was maintained between -20 and -10°C for 1 hour, then cooled to -78°C. Solid N-chlorosuccinimide (0.45 g, 3.4 mmol) was added while the apparatus was under a positive nitrogen flow. The reaction was allowed to gradually warm to room temperature and then stirred overnight. After quenching the mixture with water, it was extracted with chloroform (4 times). The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane to obtain compound 27 (0.25 g, 33%).

按照实施例1中描述的方法，用化合物27制备(3S)-4-氯-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。实施例7 According to the method described in Example 1, compound 27 was used to prepare (3S)-4-chloro-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2 -Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid. Example 7

(3S)-4-溴-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-4-bromo-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] Synthesis of Amino}-3-(4-Methylphenyl)propionic Acid

步骤1：在干燥氮气氛下，将化合物3(2.00g，9.6mmol)溶于无水THF(32mL)和TMEDA(2.20mL，14.4mmol)中。把生成的溶液冷却至-20和-10℃之间，通过注射器滴加正丁基锂(1.60M的己烷溶液，18.0mL，28.8mmol)。加完后，把溶液冷却至-78℃，通过注射器滴加溴(0.49mL，10.5mmol)。使溶液缓慢温热至室温过夜，然后用水骤冷并用氯仿提取。有机层经MgSO4干燥后过滤，减压浓缩滤液。从己烷中重结晶残余物得到为褐白色固体的化合物28(1.32g，48％)。 Step 1: Compound 3 (2.00 g, 9.6 mmol) was dissolved in anhydrous THF (32 mL) and TMEDA (2.20 mL, 14.4 mmol) under dry nitrogen atmosphere. The resulting solution was cooled to between -20 and -10°C and n-butyllithium (1.60 M in hexane, 18.0 mL, 28.8 mmol) was added dropwise via syringe. After the addition was complete, the solution was cooled to -78°C and bromine (0.49 mL, 10.5 mmol) was added dropwise via syringe. The solution was allowed to warm slowly to room temperature overnight, then quenched with water and extracted with chloroform. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give compound 28 (1.32 g, 48%) as a beige solid.

按照实施例1中描述的方法，用化合物28制备(3S)-4-溴-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。实施例8 According to the method described in Example 1, compound 28 was used to prepare (3S)-4-bromo-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2 -Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid. Example 8

(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(32)的合成(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] Synthesis of Amino}-3-(4-Methylphenyl)propionic Acid (32)

步骤1：向室温下的化合物24(1.5g，5.3mmol)的甲醇溶液(50ml)中连续加入饱和氯化铵(1.5mL)和锌粉(1.5g，23mmol)。在室温下搅拌30分钟后，加入另外的锌粉(1.5g，23mmol)，将反应混合物回流过夜。趁热过滤反应混合物，减压浓缩滤液。向获得的残余物中加入HCl(1N)直到pH为大约4，过滤收集生成的沉淀，得到为棕色固体的化合物29(0.80g，57％)。 Step 1: To a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 ml) at room temperature were added successively saturated ammonium chloride (1.5 mL) and zinc powder (1.5 g, 23 mmol). After stirring at room temperature for 30 minutes, additional zinc powder (1.5 g, 23 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. HCl (1 N) was added to the obtained residue until the pH was about 4, and the resulting precipitate was collected by filtration to obtain compound 29 (0.80 g, 57%) as a brown solid.

步骤2：将化合物29(0.26g，1.0mmol)和CDI(0.25g，1.6mmol)的DMF溶液(10ml)加热至70℃过夜。冷却至室温后，用乙酸乙酯稀释混合物，用1N HCl(3次)和盐水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液得到为棕色固体的化合物30(0.14g，50％)。 Step 2: A DMF solution (10 ml) of compound 29 (0.26 g, 1.0 mmol) and CDI (0.25 g, 1.6 mmol) was heated to 70° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N HCl (3 times) and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to give compound 30 (0.14 g, 50%) as a brown solid.

步骤3：将化合物30(0.1g，0.36mmol)和化合物8(0.082g，0.40mmol)的无水DMF溶液(5ml)加热至70℃过夜。冷却混合物，用乙酸乙酯稀释，用1N HCl(3次)和盐水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液。经快速层析法(SiO2)纯化残余物，用9∶1CHCl3∶MeOH洗脱得到化合物31(0.17g，97％)。 Step 3: A solution (5 ml) of compound 30 (0.1 g, 0.36 mmol) and compound 8 (0.082 g, 0.40 mmol) in anhydrous DMF was heated to 70° C. overnight. The mixture was cooled, diluted with ethyl acetate, washed with 1N HCl (3 times) and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography ( SiO2 ) eluting with 9: 1 CHCl3:MeOH to afford compound 31 (0.17 g, 97%).

步骤4：用2N NaOH(1ml)处理化合物31(0.170g，0.35mmol)的THF溶液(3ml)。加入甲醇直到得到均匀的溶液。在室温下搅拌反应混合物30分钟，倾入到H2O(50ml)中。用乙醚洗涤水层(两次)，然后用1N HCl酸化。用乙酸乙酯提取水层(两次)。用盐水洗涤合并的乙酸乙酯提取液(两次)，经MgSO4干燥后过滤。减压浓缩滤液得到为灰白色固体的(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(32，0.150g，94％)。熔点：113-115℃。实施例9 Step 4: A THF solution (3 ml) of compound 31 (0.170 g, 0.35 mmol) was treated with 2N NaOH (1 ml). Methanol was added until a homogeneous solution was obtained. The reaction mixture was stirred at room temperature for 30 minutes and poured into H2O (50ml). The aqueous layer was washed with ether (twice), then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro- 3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (32, 0.150 g, 94%). Melting point: 113-115°C. Example 9

(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-苯基-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridyl}amino)carbonyl Synthesis of ]amino}-3-(4-methylphenyl)propionic acid

步骤1：将化合物33(按照在实施例1中描述的方法，用化合物28制得，0.20g，0.50mmol)溶于DMF(1.8ml)和水(0.7ml)中，用K3PO4(0.39g，1.86mmol)和苯基硼酸(0.113g，0.93mmol)处理。将生成的混合物脱氧(在真空和氮之间切换5次)，然后加入四(三苯基膦)钯(0)(8.7mg，0.050mmol)。同前使混合物脱氧并在90℃下加热过夜。冷却混合物，用水稀释，用乙酸乙酯提取(两次)。用盐水洗涤合并的提取液，经MgSO4干燥后通过硅胶过滤，减压浓缩。将残余物悬浮于1∶1水∶浓HCl(2ml)和乙腈(0.5ml)中。使悬浮液回流1小时，然后冷却，分配在乙酸乙酯和饱和NaHCO3水溶液之间。用盐水洗涤乙酸乙酯层，经MgSO4干燥，过滤，减压浓缩。经快速层析法(SiO2，3∶1己烷/乙酸乙酯)纯化残余物，得到化合物34(0.115g，94％)。该物质无需纯化即可使用。 Step 1: Compound 33 (prepared from compound 28 according to the method described in Example 1, 0.20 g, 0.50 mmol) was dissolved in DMF (1.8 ml) and water (0.7 ml), and dissolved in K 3 PO 4 ( 0.39 g, 1.86 mmol) and phenylboronic acid (0.113 g, 0.93 mmol). The resulting mixture was deoxygenated (switching between vacuum and nitrogen 5 times), then tetrakis(triphenylphosphine)palladium(0) (8.7 mg, 0.050 mmol) was added. The mixture was deoxygenated and heated at 90°C overnight as before. The mixture was cooled, diluted with water and extracted with ethyl acetate (twice). The combined extracts were washed with brine, dried over MgSO4 , filtered through silica gel and concentrated under reduced pressure. The residue was suspended in 1:1 water:cone HCl (2ml) and acetonitrile (0.5ml). The suspension was refluxed for 1 h, then cooled and partitioned between ethyl acetate and saturated aqueous NaHCO 3 . The ethyl acetate layer was washed with brine, dried over MgSO4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( SiO2 , 3:1 hexane/ethyl acetate) to afford compound 34 (0.115 g, 94%). This material was used without purification.

按照在实施例1中描述的方法，用化合物34制备(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-苯基-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。1H NMR(400MHz，CD3OD)：δ2.25(s，3H)，2.50(m，2H)，4.89(t，J＝5.9 Hz，1H)，5.34(s，2H)，6.40(d，J＝7.0Hz，1H)，7.0(d，J＝8.0Hz，2H)，7.10(d，J＝8.0Hz，2H)，7.18(m，1H)，7.28(m，2H)，7.35(m，3H)，7.43(m，1H)，7.49(m，3H)。实施例10 According to the method described in Example 1, compound 34 was used to prepare (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1 , 2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid. 1 H NMR (400MHz, CD 3 OD): δ2.25(s, 3H), 2.50(m, 2H), 4.89(t, J=5.9 Hz, 1H), 5.34(s, 2H), 6.40(d, J=7.0Hz, 1H), 7.0(d, J=8.0Hz, 2H), 7.10(d, J=8.0Hz, 2H), 7.18(m, 1H), 7.28(m, 2H), 7.35(m, 3H), 7.43(m, 1H), 7.49(m, 3H). Example 10

(3S)-3-[({[2-甲基-4-(2-甲基丙基)-6-氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(43)的合成(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(benzyl)-1,6-dihydro-5-pyrimidinyl Synthesis of ]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (43)

步骤1：将化合物35(2.00g，18.2mmol)溶于30mL的无水甲醇中。向其中加入苄胺(1.97g，18.2mmol)和三乙胺(2.0g，20.0mmol)。在50℃下搅拌反应混合物3小时，然后减压浓缩。残余物分配在H2O和CH2Cl2之间。有机层经MgSO4干燥后过滤，减压浓缩滤液得到化合物36(2.3g，82％)。 Step 1: Compound 35 (2.00 g, 18.2 mmol) was dissolved in 30 mL of absolute methanol. Benzylamine (1.97 g, 18.2 mmol) and triethylamine (2.0 g, 20.0 mmol) were added thereto. The reaction mixture was stirred at 50 °C for 3 hours, then concentrated under reduced pressure. The residue was partitioned between H2O and CH2Cl2 . The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 36 (2.3 g, 82%).

步骤2：向化合物37(3.50g，26.5mmol)的乙醇(10mL)和吡啶(5ml)溶液中加入异戊醛(2.8mL，27mmol)和哌啶(1mL)。把反应混合物加热至回流3小时后减压浓缩。残余物分配在2N HCl(15mL)和乙酸乙酯(30mL)之间。有机层经MgSO4干燥后过滤，减压浓缩滤液。将残余物经硅胶层析法纯化，用2∶1己烷∶乙酸乙酯洗脱，得到化合物38(3.6g，67％)。 Step 2: To a solution of compound 37 (3.50 g, 26.5 mmol) in ethanol (10 mL) and pyridine (5 ml) was added isovaleraldehyde (2.8 mL, 27 mmol) and piperidine (1 mL). The reaction mixture was heated to reflux for 3 hours and concentrated under reduced pressure. The residue was partitioned between 2N HCl (15 mL) and ethyl acetate (30 mL). The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 2:1 hexanes:ethyl acetate, to afford compound 38 (3.6 g, 67%).

步骤3： 将化合物38(2.5g，12.48mmol)和化合物36(2.52g，13.7mmol)的无水甲醇溶液(25mL)加热至剧烈回流3小时，冷却后减压浓缩。将残余物在硅胶上层析，用2∶1己烷∶乙酸乙酯洗脱，得到化合物39(2.75g，69％)。 Step 3: A solution of compound 38 (2.5g, 12.48mmol) and compound 36 (2.52g, 13.7mmol) in anhydrous methanol (25mL) was heated to vigorous reflux for 3 hours, cooled and then concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 2:1 hexane:ethyl acetate to afford compound 39 (2.75 g, 69%).

步骤4：向化合物39(2.5g，7.9mmol)的CCl4溶液(15mL)中加入NBS(1.4g，8.0mmoL)、K2CO3(11.0g，80.0mmol)和过氧化苯甲酰(50mg，0.20mmol)。把反应混合物加热至回流1小时，冷却至室温，用H2O稀释后用CH2Cl2提取。有机层经MgSO4干燥后过滤，减压浓缩滤液。将残余物在硅胶上层析，用3∶1己烷∶乙酸乙酯洗脱，得到化合物40(0.62g，25％)。步骤5：用2N NaOH(5mL)和THF(3mL)处理化合物40(0.60g，1.9mmol)。在室温下搅拌生成的混合物2小时，用2N HCl酸化后用乙酸乙酯提取。有机层经MgSO4干燥后过滤，减压浓缩滤液得到化合物41(560mg，98％)。 Step 4: To a solution of compound 39 (2.5g, 7.9mmol) in CCl 4 (15mL) was added NBS (1.4g, 8.0mmoL), K 2 CO 3 (11.0g, 80.0mmol) and benzoyl peroxide (50mg , 0.20mmol). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature, diluted with H2O and extracted with CH2Cl2 . The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3:1 hexane:ethyl acetate to afford compound 40 (0.62 g, 25%). Step 5: Compound 40 (0.60 g, 1.9 mmol) was treated with 2N NaOH (5 mL) and THF (3 mL). The resulting mixture was stirred at room temperature for 2 hours, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 41 (560 mg, 98%).

步骤6：向化合物41(0.56g，1.86mmol)的无水苯溶液(10mL)中加入二苯基磷酰叠氮化物(0.56g，2.0mmol)和三乙胺(2.02g，2.0mmol)。把反应混合物加热至90℃1小时，然后加入化合物8(0.39g，1.9mmol)在苯(2mL)中的溶液。在90℃下，把反应物再搅拌1小时，冷却至室温，用10％氯化铵水溶液稀释后用乙酸乙酯提取。有机层经MgSO4干燥后过滤，减压浓缩滤液。将残余物在硅胶上层析，用7∶3乙酸乙酯∶己烷洗脱，得到化合物42(0.38g，40％)。 Step 6: To a solution of compound 41 (0.56 g, 1.86 mmol) in anhydrous benzene (10 mL) was added diphenylphosphoryl azide (0.56 g, 2.0 mmol) and triethylamine (2.02 g, 2.0 mmol). The reaction mixture was heated to 90 °C for 1 hour, then a solution of compound 8 (0.39 g, 1.9 mmol) in benzene (2 mL) was added. The reaction was stirred at 90°C for an additional hour, cooled to room temperature, diluted with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 7:3 ethyl acetate:hexanes to afford compound 42 (0.38 g, 40%).

步骤7：向化合物42(0.35g，0.7mmol)的THF∶MeOH1∶1混合物溶液(8mL)中加入2N NaOH(8mL)。在室温下搅拌反应物3小时，用2NHCl(10mL)酸化后用乙酸乙酯(20mL)提取。有机层经MgSO4干燥后过滤，减压浓缩滤液得到(3S)-3-[({[2-甲基-4-(2-甲基丙基)-6-氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(43，250mg，75％)。MS：计算值：(M+H)+＝477.25m/z；实测值：(M+H)+＝477.17m/z。实施例11 Step 7: To a solution of compound 42 (0.35 g, 0.7 mmol) in a THF:MeOH 1:1 mixture (8 mL) was added 2N NaOH (8 mL). The reaction was stirred at room temperature for 3 hours, acidified with 2N HCl (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO and filtered, and the filtrate was concentrated under reduced pressure to obtain (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(benzyl yl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (43, 250 mg, 75%). MS: Calculated: (M+H) + = 477.25 m/z; Found: (M+H) + = 477.17 m/z. Example 11

(3S)-3-[({[2-甲基-6-氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成(3S)-3-[({[2-Methyl-6-oxo-1-(benzyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-( Synthesis of 4-methylphenyl)propionic acid

步骤1：将化合物36(2.3g，15.5mmol)和化合物44(3.36g，15.5mmol)的无水乙醇溶液(35mL)回流3小时并浓缩。将残余物在硅胶上层析，用1∶1乙酸乙酯∶己烷洗脱，得到化合物45(1.87g，55％收率)。 Step 1: A solution of compound 36 (2.3 g, 15.5 mmol) and compound 44 (3.36 g, 15.5 mmol) in absolute ethanol (35 mL) was refluxed for 3 hours and concentrated. The residue was chromatographed on silica gel eluting with 1:1 ethyl acetate:hexanes to afford compound 45 (1.87 g, 55% yield).

按照在实施例10中描述的方法，用化合物45制备(3S)-3-[({[2-甲基-6-氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。1H NMR(400MHz，CD3OD)：δ2.28(s，3H)，2.35(s，3H)，2.57(m，2H)，5.16(m，1H)，5.30(s，2H)，7.13(m，4H)，7.30(m，5H)，8.50(s，1H)。实施例12 According to the method described in Example 10, compound 45 was used to prepare (3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5 -pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid. 1 H NMR (400MHz, CD 3 OD): δ2.28(s, 3H), 2.35(s, 3H), 2.57(m, 2H), 5.16(m, 1H), 5.30(s, 2H), 7.13( m, 4H), 7.30 (m, 5H), 8.50 (s, 1H). Example 12

(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[({乙基[(乙基氨基)羰基]氨基}羰基)氨基}-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]amino}carbonyl)amino}-2-oxo Synthesis of 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid

步骤1：向0℃下的化合物46(按照在实施例3中描述的方法制得，0.50g，1.8mmol)的THF溶液(10mL)中加入NaH(60％矿物油分散液，0.23g，5.1mmol)。在0℃下搅拌混合物10分钟，然后加入异氰酸乙酯(0.65g，9.15mmol)。在室温下，将混合物搅拌一个周末，用1NHCl骤冷并用乙酸乙酯提取。有机层经MgSO4干燥后过滤，减压浓缩滤液，得到化合物47(0.60g)。该物质无需纯化即可使用。 Step 1: To a THF solution (10 mL) of compound 46 (prepared as described in Example 3, 0.50 g, 1.8 mmol) at 0° C. was added NaH (60% dispersion in mineral oil, 0.23 g, 5.1 mmol). The mixture was stirred at 0°C for 10 minutes, then ethyl isocyanate (0.65 g, 9.15 mmol) was added. The mixture was stirred at room temperature over weekend, quenched with 1N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 47 (0.60 g). This material was used without purification.

按照在实施例3中描述的方法，用化合物47制备(3S)-3-{[({[1-[(2-氯代苯基)甲基]-4-[({乙基[(乙基氨基)羰基]氨基}羰基)氨基}-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。熔点：128-130℃。实施例13 According to the method described in Example 3, compound 47 was used to prepare (3S)-3-{[({[1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethyl (amino)carbonyl]amino}carbonyl)amino}-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid. Melting point: 128-130°C. Example 13

(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-喹啉基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl}amino)carbonyl Synthesis of ]amino}-3-(4-methylphenyl)propionic acid

步骤1：向0℃下的化合物48(2.00g，9.70mmol)的无水DMF溶液(25mL)中加入NaH(60％矿物油分散液，0.89g，22mmol)。在0℃下搅拌混合物15分钟，然后加入2-氯代苄基氯(2.03g，12.6mmol)。在55℃下搅拌过夜后，把混合物倾入到冰水中，用Et2O洗涤(两次)。酸化水层，过滤生成的沉淀得到化合物49(3.45g)。该物质无需纯化即可使用。 Step 1: To a solution of compound 48 (2.00 g, 9.70 mmol) in anhydrous DMF (25 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 0.89 g, 22 mmol). The mixture was stirred at 0°C for 15 minutes, then 2-chlorobenzyl chloride (2.03 g, 12.6 mmol) was added. After stirring overnight at 55°C, the mixture was poured into ice water and washed with Et2O (twice). The aqueous layer was acidified and the resulting precipitate was filtered to give compound 49 (3.45 g). This material was used without purification.

按照在实施例8中描述的方法，用化合物49制备(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-喹啉基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。熔点：134-]36℃。实施例14 Compound 49 was used to prepare (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1 according to the method described in Example 8, 2-Dihydro-3-quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid. Melting point: 134-]36°C. Example 14

(3S)-3-{[({1-[(2-氯代苯基)甲基]-5-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(56)的合成(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl Synthesis of ]amino}-3-(4-methylphenyl)propionic acid (56)

步骤1：在室温于干燥氮气氛下，向化合物51(1.67g，9.81mmol)的DMF悬浮液(33mL)中连续加入2-氯代苄胺(1.30mL，10.8mmol)和EDCI(2.35g，12.3mmol)。在室温下剧烈搅拌生成的混合物5小时，用乙酸乙酯稀释并用2N HCl、H2O(三次)、饱和NaHCO3水溶液和盐水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液得到为浅黄色固体的化合物52(2.55g，100％)。 Step 1: 2-Chlorobenzylamine (1.30 mL, 10.8 mmol) and EDCI (2.35 g, 12.3 mmol). The resulting mixture was stirred vigorously at room temperature for 5 h, diluted with ethyl acetate and washed with 2N HCl, H2O (three times), saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 52 (2.55 g, 100%) as a pale yellow solid.

步骤2：将化合物52(555mg，2.17mmol)和3-二甲基氨基-2-甲基丙烯醛(738mg，6.5mmol)的无水乙醇(4.3mL)和冰乙酸(0.22mL)溶液加热至回流过夜。把生成的混合物冷却至室温，用乙酸乙酯稀释后，用2N HCl(两次)、H2O和盐水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液。将残余物经硅胶层析法纯化，用7∶3增加至1∶1己烷∶乙酸乙酯、最后用19∶19∶2己烷∶乙酸乙酯∶甲醇洗脱，得到为黄色油的化合物53(182mg，27％)。 Step 2: A solution of compound 52 (555mg, 2.17mmol) and 3-dimethylamino-2-methacrolein (738mg, 6.5mmol) in absolute ethanol (4.3mL) and glacial acetic acid (0.22mL) was heated to Reflux overnight. The resulting mixture was cooled to room temperature, diluted with ethyl acetate, washed with 2N HCl (twice), H2O and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 7:3 increasing to 1:1 hexane:ethyl acetate and finally 19:19:2 hexane:ethyl acetate:methanol to afford the compound as a yellow oil 53 (182 mg, 27%).

步骤3：向化合物53(167mg，0.55mmol)的THF溶液(3mL)中加入2N NaOH(1mL)和甲醇(2mL)。搅拌生成的混合物15分钟，用H2O稀释后，用乙醚提取。用2N HCl酸化水层后，用乙酸乙酯提取。用H2O和盐水洗涤乙酸乙酯层，经MgSO4干燥后过滤。减压浓缩滤液得到为白色固体的化合物54(139mg，91％)。 Step 3: To a THF solution (3 mL) of compound 53 (167 mg, 0.55 mmol) was added 2N NaOH (1 mL) and methanol (2 mL). The resulting mixture was stirred for 15 minutes, diluted with H2O , and extracted with ether. After acidifying the aqueous layer with 2N HCl, it was extracted with ethyl acetate. The ethyl acetate layer was washed with H2O and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give compound 54 (139 mg, 91%) as a white solid.

步骤4：在室温于干燥氮气氛下，通过注射器向化合物54(175mg，0.63mmol)的THF(6.7mL)和DIPEA(0.23mL，1.34mmol)悬浮液中加入DPPA(0.29mL，1.34mmol)。在室温下搅拌生成的混合物15分钟，然后加热至回流3.5小时。使混合物冷却至室温，通过套管加入化合物8(278mg，1.34mmol)的THF溶液(6.0mL)和THF(0.7mL)冲洗液。在室温下搅拌生成的混合物过夜，用乙酸乙酯稀释后，用2N HCl(两次)、饱和NaHCO3水溶液和盐水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液。残余物经硅胶层析法纯化，用7∶3、然后用3∶2、最后用1∶1己烷∶乙酸乙酯洗脱，得到为无色油的化合物55(60mg，20％)。 Step 4: To a suspension of compound 54 (175 mg, 0.63 mmol) in THF (6.7 mL) and DIPEA (0.23 mL, 1.34 mmol) was added DPPA (0.29 mL, 1.34 mmol) via syringe at room temperature under dry nitrogen atmosphere. The resulting mixture was stirred at room temperature for 15 minutes, then heated to reflux for 3.5 hours. The mixture was allowed to cool to room temperature and a solution of compound 8 (278 mg, 1.34 mmol) in THF (6.0 mL) and a THF (0.7 mL) rinse were added via cannula. The resulting mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with 2N HCl (twice), saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 7:3, then 3:2, and finally 1:1 hexane:ethyl acetate to afford compound 55 (60 mg, 20%) as a colorless oil.

步骤5：向化合物55(60mg，0.12mmol)的THF溶液(3mL)中加入0.192N NaOH(0.65mL，0.12mmol)和甲醇(2mL)。在室温下搅拌生成的混合物24小时，然后用H2O稀释。减压下除去有机溶剂，用乙醚提取生成的水混合物。将水相冻干得到为灰白色固体的(3S)-3-{[({1-[(2-氯代苯基)甲基]-5-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸钠盐(56，56mg，95％)。MS：(C24H23ClN3O4)-的计算值：452.14m/z；实测值：451.99m/z。实施例15 Step 5: To a THF solution (3 mL) of compound 55 (60 mg, 0.12 mmol) was added 0.192N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL). The resulting mixture was stirred at room temperature for 24 hours, then diluted with H2O . The organic solvent was removed under reduced pressure, and the resulting aqueous mixture was extracted with ether. Lyophilization of the aqueous phase yielded (3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-di Hydrogen-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid sodium salt (56, 56 mg, 95%). MS: Calcd . for ( C24H23ClN3O4 ) - : 452.14 m/ z ; found: 451.99 m/ z . Example 15

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[2-氧代-1-(2-噻吩基甲基)-1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸(62)的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(2-thienylmethyl)-1,2- Synthesis of Dihydro-3-pyridyl]amino}carbonyl)amino]propionic acid (62)

步骤1：在干燥氮气氛下，通过注射器向冷却至0℃的2-噻吩甲醇(1.015g，8.89mmol)的CH2Cl2(17.8ml)溶液中连续加入三乙胺(2.98ml，21.4mmol)和甲磺酰氯(0.69ml，8.9mmol)。在0℃下搅拌生成的混合物15分钟，然后加入2-羟基-3-硝基吡啶(1.496g，10.7mmol)和4-二甲基氨基吡啶(催化量)。使混合物逐渐温热至室温，然后搅拌过夜。用乙酸乙酯稀释混合物，然后用2N HCl、H2O、饱和NaHCO3水溶液和盐水洗涤。有机相经MgSO4干燥后过滤并减压浓缩滤液得到为黄色蜡状固体的58(395mg)。该物质无需纯化即可使用。 Step 1: To a solution of 2-thiophenemethanol (1.015g, 8.89mmol) in CH2Cl2 ( 17.8ml ) cooled to 0°C was continuously added triethylamine (2.98ml, 21.4mmol) via syringe under dry nitrogen atmosphere ) and methanesulfonyl chloride (0.69ml, 8.9mmol). The resulting mixture was stirred at 0°C for 15 minutes, then 2-hydroxy-3-nitropyridine (1.496 g, 10.7 mmol) and 4-dimethylaminopyridine (catalytic amount) were added. The mixture was allowed to warm gradually to room temperature, then stirred overnight. The mixture was diluted with ethyl acetate, then washed with 2N HCl, H2O , saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4 , filtered and the filtrate was concentrated under reduced pressure to give 58 (395 mg) as a yellow waxy solid. This material was used without purification.

步骤2：在室温于干燥氮气氛下，向58(330mg，1.40mmol)的冰乙酸溶液(6.6ml)中加入铁粉(154mg，2.8mmol，-325目)。在油浴中剧烈搅拌下，把生成的溶液加热至60℃20分钟。将混合物冷却至室温，用乙酸乙酯稀释，经C盐过滤。用H2O、饱和NaHCO3和盐水洗涤滤液。有机相经MgSO4干燥后过滤，减压浓缩滤液。残余物通过硅胶过滤，用1∶1己烷∶乙酸乙酯增加至1∶3己烷∶乙酸乙酯洗脱，得到为绿色固体的59(188mg，两步，12％)。 Step 2: To a solution of 58 (330 mg, 1.40 mmol) in glacial acetic acid (6.6 ml) was added iron powder (154 mg, 2.8 mmol, -325 mesh) at room temperature under a dry nitrogen atmosphere. The resulting solution was heated to 60°C for 20 minutes with vigorous stirring in an oil bath. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed with H2O , saturated NaHCO3 and brine. The organic phase was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with 1:1 hexane:ethyl acetate increasing to 1:3 hexane:ethyl acetate to afford 59 (188 mg, 12% over two steps) as a green solid.

步骤3：在干燥氮气氛下，通过注射器向冷却至0℃的59(111mg，0.54mmol)的CH2Cl2(2.7ml)溶液中连续加入N，N-二异丙基乙胺(0.23ml，1.30mmol)和光气(0.31ml，1.9M的甲苯溶液，0.59mmol)。在0℃下搅拌生成的混合物15分钟，然后通过套管加入β-氨基酯60(167mg，0.70mmol)的CH2Cl2溶液(2.7ml)和CH2Cl2冲洗液(1.0ml)。使生成的混合物温热至室温，搅拌2小时，用乙酸乙酯稀释，然后用2N HCl、H2O、饱和NaHCO3和盐水洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液。经硅胶层析法纯化残余物，用1∶1己烷∶乙酸乙酯洗脱，得到为紫色泡沫的61(231mg，91％)。 Step 3: To a solution of 59 (111 mg, 0.54 mmol) in CH 2 Cl 2 (2.7 ml) cooled to 0° C. was continuously added via syringe under a dry nitrogen atmosphere , 1.30mmol) and phosgene (0.31ml, 1.9M in toluene, 0.59mmol). The resulting mixture was stirred at 0°C for 15 minutes, then a solution of β-aminoester 60 (167 mg , 0.70 mmol) in CH2Cl2 (2.7ml) and a CH2Cl2 rinse (1.0ml) were added via cannula. The resulting mixture was allowed to warm to room temperature, stirred for 2 h, diluted with ethyl acetate, then washed with 2N HCl, H2O , saturated NaHCO3 and brine. The organic phase was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 hexanes:ethyl acetate to afford 61 (231 mg, 91%) as a purple foam.

步骤4：在室温下，向酯61(227mg，0.48mmol)的THF溶液(6ml)中加入NaOH(2ml，2N的H2O溶液，4mmol)和甲醇(足以获得澄清溶液，大约2ml)。搅拌生成的混合物15分钟，然后用水稀释并用乙醚提取。用HCl(2N)酸化水相，然后用乙酸乙酯提取。用盐水洗涤有机相，经MgSO4干燥后过滤，减压浓缩滤液得到为白色固体的62(191mg，90％)。1H NMR(400MHz，CD3SOCD3)δ2.63(d，J＝7.3Hz，2H)，4.99(dt，J＝8.4，7.3Hz，1H)，5.30(s，2H)，5.98(m，2H)，6.21(dd，J＝7.5，7.0Hz，1H)，6.78(dd，J＝8.1，1.6Hz，1H)，6.85(d，J＝8.1Hz，1H)，6.88(d，J＝1.6Hz，1H)，6.97(dd，J＝5.1，3.5Hz，1H)，7.17(dd，J＝3.5，1.1Hz，1H)，7.35(dd，J＝7.0，1.8Hz，1H)，7.44(dd，J＝5.1，1.1Hz，1H)，7.67(d，J＝8.4Hz，1H)，7.94(dd，J＝7.5，1.8Hz，1H)，8.40(s，1H)。实施例16 Step 4: To a solution of ester 61 (227mg, 0.48mmol) in THF (6ml) was added NaOH (2ml, 2N in H2O , 4mmol) and methanol (enough to obtain a clear solution, ca. 2ml) at room temperature. The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure to afford 62 (191 mg, 90%) as a white solid. 1 H NMR (400MHz, CD 3 SOCD 3 ) δ2.63(d, J=7.3Hz, 2H), 4.99(dt, J=8.4, 7.3Hz, 1H), 5.30(s, 2H), 5.98(m, 2H), 6.21(dd, J=7.5, 7.0Hz, 1H), 6.78(dd, J=8.1, 1.6Hz, 1H), 6.85(d, J=8.1Hz, 1H), 6.88(d, J=1.6 Hz, 1H), 6.97(dd, J=5.1, 3.5Hz, 1H), 7.17(dd, J=3.5, 1.1Hz, 1H), 7.35(dd, J=7.0, 1.8Hz, 1H), 7.44(dd , J=5.1, 1.1Hz, 1H), 7.67(d, J=8.4Hz, 1H), 7.94(dd, J=7.5, 1.8Hz, 1H), 8.40(s, 1H). Example 16

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[(3S)-2-氧代-1-(2-噻吩基甲基)六氢-3-吡啶基]氨基}羰基)氨基]丙酸(68)的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienylmethyl)hexa Synthesis of Hydrogen-3-pyridyl]amino}carbonyl)amino]propionic acid (68)

步骤1：在室温于干燥氮气氛下，通过注射器向N-α-叔丁氧基羰基-N-δ-苄氧基羰基-L-鸟氨酸63(1.00g，2.73mmol)和碳酸铯(1.33g，4.1mmol)的DMF溶液(10ml)中加入碘甲烷(0.22ml，3.3mmol)。在室温下搅拌生成的混合物18小时，然后用乙酸乙酯稀释，用H2O、10％Na2S2O5、饱和NaHCO3和盐水洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液，得到为浅黄色油的酯64(1.21g)。该物质含有DMF但无需纯化即可使用。 Step 1: N-α-tert-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-ornithine 63 (1.00 g, 2.73 mmol) and cesium carbonate ( 1.33g, 4.1mmol) in DMF (10ml) was added iodomethane (0.22ml, 3.3mmol). The resulting mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate, washed with H2O , 10% Na2S2O5 , saturated NaHCO3 and brine . The organic phase was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure to afford ester 64 (1.21 g) as a light yellow oil. This material contained DMF but was used without purification.

步骤2：在0℃于干燥氮气氛下，向64(0.86g以上方法制得的粗品物质，1.94mmol理论值)的甲醇溶液(10ml)中加入披钯碳(300mg，10％Pd，Degussa E101 NE/W型，湿的，50％(重量)水)。用氢气替代氮气氛(在真空和气球供给的氢气之间交替5次)并在0℃下搅拌混合物30分钟，然后直接过滤到装有2-噻吩甲醛(177mg，1.58mmol)的烧瓶中。浓缩混合物(在室温下的水浴中)，使残余物溶解在二氯乙烷(6ml)中。向该溶液中加入三乙酰氧基硼氢化钠(479mg，2.26mmol)并搅拌混合物2小时，用乙酸乙酯稀释后用饱和NaHCO3(两次)和盐水洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液。通过硅胶过滤残余物，用7∶3己烷∶乙酸乙酯洗脱，得到为无色油的内酰胺65(75mg，两步，12％)。 Step 2: To a methanolic solution (10 ml) of 64 (0.86 g of the crude material prepared above, 1.94 mmol theoretical) was added palladium on carbon (300 mg, 10% Pd, Degussa E101 ) at 0° C. under dry nitrogen atmosphere Type NE/W, wetted, 50% by weight water). The nitrogen atmosphere was replaced with hydrogen (alternating 5 times between vacuum and hydrogen supplied by balloon) and the mixture was stirred at 0°C for 30 min, then filtered directly into a flask containing 2-thiophenecarbaldehyde (177 mg, 1.58 mmol). The mixture was concentrated (in water bath at room temperature) and the residue was dissolved in dichloroethane (6ml). To this solution was added sodium triacetoxyborohydride (479 mg, 2.26 mmol) and the mixture was stirred for 2 hours, diluted with ethyl acetate and washed with saturated NaHCO3 (twice) and brine. The organic phase was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with 7:3 hexanes: ethyl acetate to afford lactam 65 (75 mg, 12% for two steps) as a colorless oil.

步骤3：在室温于干燥氮气氛下，通过注射器向用橡胶隔膜密封的装有65(89mg，0.29mmol)的烧瓶中加入HCl(7.2ml，4.0M的二噁烷溶液，28.8mmol)。除去氮气针并搅拌密封烧瓶中的混合物过夜。用CH2Cl2稀释混合物，然后用饱和NaHCO3洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液，得到为淡黄色油的胺66(60mg，100％)。该物质无需纯化即可使用。 Step 3: To a flask containing 65 (89mg, 0.29mmol) sealed with a rubber septum was added HCl (7.2ml, 4.0M in dioxane, 28.8mmol) via syringe at room temperature under dry nitrogen. The nitrogen needle was removed and the mixture in the sealed flask was stirred overnight. The mixture was diluted with CH2Cl2 , then washed with saturated NaHCO3 . The organic phase was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure to afford amine 66 (60 mg, 100%) as a light yellow oil. This material was used without purification.

步骤4：在室温于干燥氮气氛下，向β-氨基酯60(75mg，0.32mmol)的CH2Cl2溶液(0.6ml)中加入羰基二咪唑(51mg，0.32mmol)。在室温下搅拌生成的混合物5分钟，经套管加入胺66(60mg，0.29mmol)的CH2Cl2溶液(0.6ml)和CH2Cl2(0.2mL)冲洗液。在室温下搅拌生成的混合物3天，然后用乙酸乙酯稀释，用2N HCl(两次)、H2O、饱和NaHCO3和盐水洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液。残余物通过硅胶过滤，用1∶1己烷∶乙酸乙酯增加至2∶3己烷∶乙酸乙酯洗脱，得到脲67(110mg，80％)。 Step 4: To a solution of β-amino ester 60 (75 mg, 0.32 mmol) in CH2Cl2 (0.6 ml ) was added carbonyldiimidazole (51 mg, 0.32 mmol) at room temperature under dry nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of amine 66 (60 mg, 0.29 mmol) in CH2Cl2 (0.6 ml) and a CH2Cl2 (0.2 mL ) rinse were added via cannula. The resulting mixture was stirred at room temperature for 3 days, then diluted with ethyl acetate, washed with 2N HCl (twice), H2O , saturated NaHCO3 and brine. The organic phase was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with 1:1 hexane:ethyl acetate increasing to 2:3 hexane:ethyl acetate to afford urea 67 (110 mg, 80%).

步骤5：在室温下，向脲67(108mg，0.23mmol)的THF溶液(3ml)中加入NaOH(1ml，2N水溶液，2mmol)和甲醇(足以得到澄清溶液，大约2ml)。搅拌生成的混合物15分钟，然后用水稀释，用乙醚提取。用HCl(2N)酸化水相，之后用乙酸乙酯提取。用盐水洗涤乙酸乙酯层，经MgSO4干燥后过滤，减压浓缩滤液，得到为白色泡沫的68(92mg，90％)。1H NMR(400MHz，CD3SOCD3)δ1.45(m，1H)，1.76(m，2H)，2.62(m，2H)，3.25(m重叠H2O，2H)，4.01(m，1H)，4.59(d，J＝15.0Hz，1H)，4.68(d，J＝15.0Hz，1H)，4.96(m，1H)，5.97(s，2H)，6.24(d，J＝6.6Hz，1H)，6.71(d，J＝8.4Hz，1H)，6.75(dd，J＝8.1，1.5Hz，1H)，6.82(d，J＝8.1Hz，1H)，6.85(d，J＝1.5Hz，1H)，6.97(dd，J＝5.1，3.3Hz，1H)，7.03(dd，J＝3.3，1.5Hz，1H)，7.42(dd，J＝5.1，1.5Hz，1H)，12.06(br.s，1H)。实施例17 Step 5: To a solution of urea 67 (108mg, 0.23mmol) in THF (3ml) was added NaOH (1ml, 2N aq, 2mmol) and methanol (enough to give a clear solution, about 2ml) at room temperature. The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO 4 and filtered, the filtrate was concentrated under reduced pressure to give 68 (92 mg, 90%) as a white foam. 1 H NMR (400MHz, CD 3 SOCD 3 ) δ1.45(m, 1H), 1.76(m, 2H), 2.62(m, 2H), 3.25(m overlapping H 2 O, 2H), 4.01(m, 1H ), 4.59(d, J=15.0Hz, 1H), 4.68(d, J=15.0Hz, 1H), 4.96(m, 1H), 5.97(s, 2H), 6.24(d, J=6.6Hz, 1H ), 6.71(d, J=8.4Hz, 1H), 6.75(dd, J=8.1, 1.5Hz, 1H), 6.82(d, J=8.1Hz, 1H), 6.85(d, J=1.5Hz, 1H ), 6.97 (dd, J=5.1, 3.3Hz, 1H), 7.03 (dd, J=3.3, 1.5Hz, 1H), 7.42 (dd, J=5.1, 1.5Hz, 1H), 12.06 (br.s, 1H). Example 17

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[(3S)-2-氧代-1-(2-噻吩基甲基)四氢-1H-吡咯-3-基]氨基}羰基)氨基]丙酸(74)的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienylmethyl) tetra Synthesis of Hydrogen-1H-pyrrol-3-yl]amino}carbonyl)amino]propionic acid (74)

步骤1：在干燥氮气氛下，通过注射器向冷却至-15℃(浴温)的N-叔丁氧基羰基-L-天冬氨酸α-苄基酯(2.10g，6.5mmol)的二甲氧基乙烷溶液(15ml)中连续加入4-甲基吗啉(0.71ml，6.5mmol)和氯甲酸异丁基酯(0.84ml，6.5mmol)。搅拌生成的混合物2分钟，然后过滤，用二甲氧基乙烷(10ml)洗涤固体滤饼。把滤液再次冷却至-15℃(浴温)，加入硼氢化钠(370mg，9.7mmol)的H2O溶液(3ml)，随后立即加入H2O(100ml)。用乙酸乙酯提取混合物(三次)，合并有机层，用冷(0℃)HCl(0.2N)、H2O、饱和NaHCO3和盐水洗涤。经MgSO4干燥生成的有机层，过滤，减压浓缩滤液，得到为无色油的69(2.50g)。该物质含有一些未还原的混合酸酐但是无需纯化即可使用。 Step 1: Add N-tert-butoxycarbonyl-L-aspartic acid α-benzyl ester (2.10 g, 6.5 mmol) via syringe to di 4-Methylmorpholine (0.71ml, 6.5mmol) and isobutyl chloroformate (0.84ml, 6.5mmol) were successively added to the methoxyethane solution (15ml). The resulting mixture was stirred for 2 minutes and then filtered, washing the solid filter cake with dimethoxyethane (10 mL). The filtrate was recooled to -15°C (bath temperature) and sodium borohydride (370mg, 9.7mmol) in H2O (3ml) was added, followed immediately by H2O (100ml). The mixture was extracted with ethyl acetate (three times), and the combined organic layers were washed with cold (0°C) HCl (0.2N), H2O , saturated NaHCO3 and brine. The resulting organic layer was dried over MgSO4 , filtered, and the filtrate was concentrated under reduced pressure to afford 69 (2.50 g) as a colorless oil. This material contained some unreduced mixed anhydride but was used without purification.

步骤2：在干燥氮气氛下，通过注射器向冷却至-65℃的草酰氯(2.4ml，2.0M的CH2Cl2溶液，4.8mmol)的CH2Cl2溶液(30ml)中加入甲基亚砜(0.55ml，7.8mmol)的CH2Cl2溶液(8ml)。在-65℃下搅拌生成的混合物15分钟，然后经套管加入醇69(1.00g，3.2mmol)的CH2Cl2溶液(29ml)和CH2Cl2(3ml)冲洗液。在-65℃下搅拌混合物3小时，然后使之温热至-20℃(浴温)。加入三乙胺(0.96ml，6.9mmol)，随后加入H2O(20ml)。用CH2Cl2提取水层，经MgSO4干燥合并的有机相，过滤。减压浓缩滤液，得到为白色固体的醛70。该物质无需纯化即可立即使用。 Step 2: To a solution of oxalyl chloride (2.4ml, 2.0M in CH2Cl2 , 4.8mmol) in CH2Cl2 (30ml) cooled to -65°C was added methyl sulfide via syringe under dry nitrogen atmosphere. Sulfone (0.55ml, 7.8mmol ) in CH2Cl2 (8ml). The resulting mixture was stirred at -65°C for 15 min, then a solution of alcohol 69 (1.00 g, 3.2 mmol) in CH2Cl2 (29 ml) and a CH2Cl2 (3 ml) rinse were added via cannula. The mixture was stirred at -65°C for 3 hours, then allowed to warm to -20°C (bath temperature). Triethylamine (0.96ml, 6.9mmol) was added followed by H2O (20ml). The aqueous layer was extracted with CH2Cl2 , the combined organic phases were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford aldehyde 70 as a white solid. The material was used immediately without purification.

步骤3：在室温于干燥氮气氛下，向粗品醛70(3.2mmol，理论值)和2-氨基甲基噻吩(402mg，3.35mmol)的二氯乙烷溶液(13ml)中加入三乙酰氧基硼氢化钠(959mg，4.5mmol)。在室温下搅拌生成的混合物过夜，然后用乙酸乙酯稀释，用饱和NaHCO3和盐水洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液。残余物经硅胶层析法纯化，用1∶1己烷∶乙酸乙酯洗脱，得到为白色固体的内酰胺71(220mg，3步，23％)。 Step 3: To a solution of crude aldehyde 70 (3.2 mmol, theoretical) and 2-aminomethylthiophene (402 mg, 3.35 mmol) in dichloroethane (13 mL) was added triacetoxy at room temperature under dry nitrogen atmosphere Sodium borohydride (959 mg, 4.5 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate, washed with saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 hexanes:ethyl acetate to afford lactam 71 (220 mg, 3 steps, 23%) as a white solid.

步骤4：在室温于干燥氮气氛下，通过注射器向用橡胶隔膜密封的71(220mg，0.74mmol)的二噁烷溶液(1.5ml)中加入HCl(1.5ml，4.0M的二噁烷溶液，6.0mmol)。除去氮气针并搅拌密封烧瓶中的混合物5小时。用CH2Cl2稀释混合物，然后用饱和NaHCO3洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液，得到为淡黄色油的胺72(129mg，89％)。该物质无需纯化即可使用。 Step 4: To a solution of 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml) sealed with a rubber septum was added HCl (1.5 ml, 4.0 M in dioxane) via syringe at room temperature under dry nitrogen atmosphere, 6.0 mmol). The nitrogen needle was removed and the mixture in the sealed flask was stirred for 5 hours. The mixture was diluted with CH2Cl2 , then washed with saturated NaHCO3 . The organic phase was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure to afford amine 72 (129 mg, 89%) as a light yellow oil. This material was used without purification.

步骤5：在室温于干燥氮气氛下，向胺72(123mg，0.63mmol)的CH2Cl2溶液(1.5ml)中加入羰基二咪唑(112mg，0.69mmol)。在室温下搅拌生成的混合物5分钟并经套管加入β-氨基酯60(164mg，0.69mmol)的CH2Cl2溶液(0.8ml)和CH2Cl2(0.2ml)冲洗液。在室温下搅拌生成的混合物过夜，然后用乙酸乙酯稀释，用2N HCl(两次)、H2O、饱和NaHCO3和盐水洗涤。有机相经MgSO4干燥后过滤，减压浓缩滤液。通过硅胶过滤残余物，用49∶1氯仿∶甲醇洗脱，得到为无色油的脲73(230mg，80％)，脲73静置时缓慢固化。 Step 5: To a solution of amine 72 (123 mg, 0.63 mmol ) in CH2Cl2 (1.5 ml) was added carbonyldiimidazole (112 mg, 0.69 mmol) at room temperature under dry nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes and a solution of β-amino ester 60 (164 mg, 0.69 mmol) in CH2Cl2 (0.8 ml) and a CH2Cl2 (0.2 ml) rinse were added via cannula. The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate, washed with 2N HCl (twice), H2O , saturated NaHCO3 and brine. The organic phase was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with 49:1 chloroform:methanol to afford urea 73 (230 mg, 80%) as a colorless oil which slowly solidified on standing.

步骤6：在室温下，向脲73(230mg，0.50mmol)的THF溶液(3ml)中加入NaOH(1ml，2N的水溶液，2mmol)和甲醇(1ml)。搅拌生成的混合物1小时，然后用水稀释并用乙醚提取。用HCl(2N)酸化水相，用乙酸乙酯提取。用盐水洗涤乙酸乙酯层，经MgSO4干燥后过滤，减压浓缩滤液，得到为白色泡沫的74(181mg，84％)。1H NMR(400MHz，CD3SOCD3)δ1.64(m，1H)，2.30(m，1H)，2.64(m，2H)，3.20(m，2H)，4.17(dd，J＝8.8，8.4Hz，1H)，4.56(s，2H)，4.96(m，1H)，5.97(s，2H)，6.30(d，J＝7.0Hz，1H)，6.58(d，J＝8.8Hz，1H)，6.77(m，1H)，6.80-6.90(m，2H)，6.96-7.04(m，2H)，7.45(dd，J＝5.1，0.7Hz，1H)，12.10(br.s，1H)。实施例18 Step 6: To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) was added NaOH (1 ml, 2N in water, 2 mmol) and methanol (1 ml) at room temperature. The resulting mixture was stirred for 1 hour, then diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO 4 and filtered, the filtrate was concentrated under reduced pressure to afford 74 (181 mg, 84%) as a white foam. 1 H NMR (400MHz, CD 3 SOCD 3 ) δ1.64(m, 1H), 2.30(m, 1H), 2.64(m, 2H), 3.20(m, 2H), 4.17(dd, J=8.8, 8.4 Hz, 1H), 4.56(s, 2H), 4.96(m, 1H), 5.97(s, 2H), 6.30(d, J=7.0Hz, 1H), 6.58(d, J=8.8Hz, 1H), 6.77 (m, 1H), 6.80-6.90 (m, 2H), 6.96-7.04 (m, 2H), 7.45 (dd, J=5.1, 0.7Hz, 1H), 12.10 (br.s, 1H). Example 18

(3S)-3-[({[5-氯-2-羟基-3-(苯甲基)苯基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成Synthesis of (3S)-3-[({[5-chloro-2-hydroxy-3-(phenylmethyl)phenyl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid

步骤1：向2-苯甲基-3-氯代苯酚(5.00g，22.9mmol)的Et2O(20mL)和6N HCl(50mL)的混合物中连续加入KNO3(2.30g，22.9mmol)和NaNO2(20mg，催化)。搅拌生成的混合物2小时，用水稀释并用乙酸乙酯提取。用水和盐水洗涤有机层，经MgSO4干燥后过滤。减压浓缩滤液，得到99(6.0g，100％)。 Step 1: To a mixture of 2-benzyl-3-chlorophenol (5.00 g, 22.9 mmol) in Et 2 O (20 mL) and 6N HCl (50 mL) were added successively KNO 3 (2.30 g, 22.9 mmol) and NaNO2 (20 mg, catalyzed). The resulting mixture was stirred for 2 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford 99 (6.0 g, 100%).

步骤2：向99(6.0g，22.8mmol)的甲醇溶液(360mL)中加入锌粉(6.0g，92mmol)和饱和NH4Cl水溶液(6mL)。把生成的不均匀混合物回流过夜。过滤热的混合物并减压浓缩滤液后，将残余物溶于乙酸乙酯中并用饱和NaHCO3和盐水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液，得到化合物100(2.93g，55％)。 Step 2: To a solution of 99 (6.0 g, 22.8 mmol) in methanol (360 mL) was added zinc powder (6.0 g, 92 mmol) and saturated aqueous NH 4 Cl (6 mL). The resulting heterogeneous mixture was refluxed overnight. After filtering the hot mixture and concentrating the filtrate under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 100 (2.93 g, 55%).

步骤3：在0℃下，向25(0.20g，0.96mmol)的CH2Cl2溶液中连续加入DIPEA(0.40mL，2.4mmol)和光气(1.93M的甲苯溶液，0.60mL，1.2mmol)。使生成的混合物温热至室温，搅拌20分钟，然后再次冷却至0℃。向该混合物中滴加100(0.25g，1.1mmol)的CH2Cl2溶液。使生成的混合物温热至室温过夜，用水稀释并用CH2Cl2提取。用水和盐水洗涤有机层，经MgSO4干燥后过滤。减压浓缩滤液，经硅胶层析法纯化残余物，用9∶1并增加至5∶1己烷∶乙酸乙酯洗脱，得到101(60mg，12％)。 Step 3: To a solution of 25 (0.20 g, 0.96 mmol) in CH2Cl2 was added successively DIPEA (0.40 mL, 2.4 mmol ) and phosgene (1.93M in toluene, 0.60 mL, 1.2 mmol) at 0°C. The resulting mixture was allowed to warm to room temperature, stirred for 20 minutes, then cooled again to 0 °C. To this mixture was added dropwise a solution of 100 (0.25 g, 1.1 mmol) in CH2Cl2 . The resulting mixture was allowed to warm to room temperature overnight, diluted with water and extracted with CH2Cl2 . The organic layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 9:1 and increasing to 5:1 hexane:ethyl acetate to afford 101 (60 mg, 12%).

按照在实施例1中描述的方法，从101制备(3S)-3-[({[5-氯-2-羟基-3-(苯甲基)苯基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。1H NMR(400MHz，CD3SO2CD3)δ2.26(s，3H)，2.58(dd，J＝15.8，6.6Hz，1H)，2.67(dd，J＝15.8，8.4Hz，1H)，3.49(s，2H)，4.88(m，1H)，7.00-7.70(m，13H)，11.95(br.s，1H)。实施例19 Following the procedure described in Example 1, (3S)-3-[({[5-chloro-2-hydroxy-3-(phenylmethyl)phenyl]amino}carbonyl)amino]-3- (4-Methylphenyl)propanoic acid. 1 H NMR (400MHz, CD 3 SO 2 CD 3 ) δ 2.26 (s, 3H), 2.58 (dd, J=15.8, 6.6Hz, 1H), 2.67 (dd, J=15.8, 8.4Hz, 1H), 3.49 (s, 2H), 4.88 (m, 1H), 7.00-7.70 (m, 13H), 11.95 (br.s, 1H). Example 19

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({丁基[2，5-二氧代-1-(苯甲基)四氢-1H-吡咯-3-基]氨基}羰基)氨基]丙酸的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1-(benzyl)tetrahydro- Synthesis of 1H-pyrrol-3-yl]amino}carbonyl)amino]propionic acid

步骤1：在室温下，将N-苄基马来酰亚胺(2.60g，13.9mmol)和正丁基胺(1.00g，13.7mmol)的THF溶液(15mL)搅拌过夜并减压浓缩。经硅胶层析法纯化残余物，用4∶1增加至2∶1己烷∶乙酸乙酯洗脱，得到102(3.25g，90％)。 Step 1: A THF solution (15 mL) of N-benzylmaleimide (2.60 g, 13.9 mmol) and n-butylamine (1.00 g, 13.7 mmol) was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 4:1 increasing to 2:1 hexanes:ethyl acetate to afford 102 (3.25 g, 90%).

按照在实施例1中描述的方法，用102制备(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({丁基[2，5-二氧代-1-(苯甲基)四氢-1H-吡咯-3-基]氨基}羰基)氨基]丙酸。MP：80-85℃。实施例20 According to the method described in Example 1, (3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5-di Oxo-1-(benzyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propanoic acid. MP: 80-85°C. Example 20

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({1-(环戊基甲基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-[({1-(cyclopentylmethyl)-2-oxo-1,2-dihydro -Synthesis of 3-pyridyl]amino}carbonyl)amino]propionic acid

步骤1：在0℃于氮气氛下，向2-羟基-3-硝基吡啶(200mg，1.4mmol)的CH2Cl2溶液(14mL)中加入环戊烷甲醇(178mg，1.78mmol)，随后加入三苯基膦(551mg，2.1mmol)。在0℃下搅拌溶液15分钟并通过注射器滴加偶氮二羧酸二乙基酯(366mg，2.1mmol)。在0℃下使反应物搅拌1小时，然后在室温下搅拌过夜。用甲醇(20mL)骤冷混合物，用水洗涤(两次)。用二氯甲烷提取水层，经硫酸镁干燥合并的有机层后过滤。浓缩滤液，经硅胶层析法纯化残余物，用1∶1己烷∶乙酸乙酯洗脱，得到为黄色固体的103(299mg，96％收率)。 Step 1: To a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol) in CH2Cl2 (14 mL ) was added cyclopentanemethanol (178 mg, 1.78 mmol) at 0 °C under nitrogen, followed by Add triphenylphosphine (551 mg, 2.1 mmol). The solution was stirred at 0°C for 15 minutes and diethyl azodicarboxylate (366 mg, 2.1 mmol) was added dropwise via syringe. The reaction was stirred at 0°C for 1 hour, then at room temperature overnight. The mixture was quenched with methanol (20 mL), washed with water (twice). The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate, to afford 103 (299 mg, 96% yield) as a yellow solid.

按照在实施例1中描述的方法，用103制备(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({1-(环戊基甲基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸。1H NMR(400MHz，CDCl3)：δ1.2-1.7(m，8H)，2.34(m，1H)，2.81(dd，J＝，1H)，2.95(dd，J＝，1H)，3.92(d，J＝7.7Hz，2H)，5.30(m，1H)，5.92(m，2H)，6.30(t，J＝7.1Hz，1H)，6.68-7.00(m，5H)，8.33(d，J＝7.7Hz，1H)，8.89(s，1H)。实施例21 According to the method described in Example 1, (3S)-3-(1,3-benzodioxol-5-yl)-3-[({1-(cyclopentylmethyl) was prepared from 103 )-2-oxo-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]propionic acid. 1 H NMR (400 MHz, CDCl 3 ): δ1.2-1.7 (m, 8H), 2.34 (m, 1H), 2.81 (dd, J=, 1H), 2.95 (dd, J=, 1H), 3.92 ( d, J=7.7Hz, 2H), 5.30(m, 1H), 5.92(m, 2H), 6.30(t, J=7.1Hz, 1H), 6.68-7.00(m, 5H), 8.33(d, J =7.7Hz, 1H), 8.89(s, 1H). Example 21

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-{[({3-[(2-苯硫基甲基)氨基]苯基}氨基)羰基]氨基}丙酸的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2-phenylthiomethyl)amino]phenyl}amino)carbonyl Synthesis of ]amino}propionic acid

步骤1：向2-噻吩甲醛(0.48g，4.0mmol)的二氯甲烷溶液中加入3-硝基苯胺(0.51g，3.7mmol)。把溶液浓缩至干并加入1，2-二氯乙烷(16mL)。加入分子筛(3，1.1g)，随后加入NaBH(OAc)3(1.01g，4.8mmol)。在室温下搅拌溶液过夜，用氯仿稀释并用水洗涤。有机层经MgSO4干燥后过滤，减压浓缩滤液，得到104(0.72g，84％)。 Step 1: To a solution of 2-thiophenecarbaldehyde (0.48 g, 4.0 mmol) in dichloromethane was added 3-nitroaniline (0.51 g, 3.7 mmol). The solution was concentrated to dryness and 1,2-dichloroethane (16 mL) was added. Molecular sieves (3 Å, 1.1 g) were added followed by NaBH(OAc) 3 (1.01 g, 4.8 mmol). The solution was stirred overnight at room temperature, diluted with chloroform and washed with water. The organic layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to afford 104 (0.72 g, 84%).

步骤2：在0℃下，向104(0.30g，1.3mmol)的CH2Cl2(5.2mL)和三乙胺(0.215mL，1.5mmol)溶液中加入三氟乙酸酐(0.193mL，1.4mmol)。在0℃下搅拌溶液15分钟，除去冰浴并再搅拌混合物15分钟。用CH2Cl2稀释混合物，用2N HCl、水和盐水洗涤。有机层经Na2SO4干燥后过滤，减压浓缩滤液，得到为黄色固体的105(0.38g，100％)。 Step 2: To a solution of 104 (0.30 g, 1.3 mmol) in CH2Cl2 (5.2 mL) and triethylamine (0.215 mL, 1.5 mmol) was added trifluoroacetic anhydride (0.193 mL, 1.4 mmol ) at 0 °C ). The solution was stirred at 0°C for 15 minutes, the ice bath was removed and the mixture was stirred for an additional 15 minutes. The mixture was diluted with CH2Cl2 , washed with 2N HCl, water and brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to afford 105 (0.38 g, 100%) as a yellow solid.

步骤3：在室温下，向105(0.38g，1.4mmol)的乙醇(2.6mL)和乙酸(2.6mL)溶液中加入Fe粉(0.36g，6.5mmol)并在40℃下剧烈搅拌悬浮液直到TLC表明105完全消耗。经C盐过滤混合物，用氯仿洗涤。用饱和碳酸氢钠稀释滤液，经Na2SO4干燥氯仿层后过滤。减压浓缩滤液，经硅胶层析(洗脱梯度6∶1至4∶1己烷∶乙酸乙酯)纯化残余物，得到化合物106(0.102g，25％)。 Step 3: To a solution of 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL) and acetic acid (2.6 mL) was added Fe powder (0.36 g, 6.5 mmol) at room temperature and the suspension was vigorously stirred at 40 °C until TLC indicated complete consumption of 105. The mixture was filtered through celite, washing with chloroform. The filtrate was diluted with saturated sodium bicarbonate, the chloroform layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution gradient 6:1 to 4:1 hexane:ethyl acetate) to afford compound 106 (0.102 g, 25%).

按照在实施例1中描述的方法，用106制备(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-{[({3-[(2-苯硫基甲基)氨基]苯基}氨基)羰基]氨基}丙酸。1H NMR(400MHz，CD3SO2CD3)δ2.50(m，2H重叠DMSO)，4.37(d，J＝5.9Hz，2H)，4.94(m，1H)，5.94(m，2H)，6.06(t，J＝5.8Hz，1H)，6.16(m，1H)，6.59(d，J＝8.8Hz，1H)，6.78(m，3H)，6.85(dd，J＝8.8，7.7Hz，1H)，6.90(s，1H)，6.94(dd，J＝5.2，3.7Hz，1H)，7.00(d，J＝3.3Hz，1H)，7.33(dd，J＝5.1，1.1Hz，1H)，8.5(s，1H)。实施例22 According to the method described in Example 1, (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2-benzene Thiomethyl)amino]phenyl}amino)carbonyl]amino}propionic acid. 1 H NMR (400MHz, CD 3 SO 2 CD 3 ) δ 2.50 (m, 2H overlapping DMSO), 4.37 (d, J=5.9Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06(t, J=5.8Hz, 1H), 6.16(m, 1H), 6.59(d, J=8.8Hz, 1H), 6.78(m, 3H), 6.85(dd, J=8.8, 7.7Hz, 1H ), 6.90(s, 1H), 6.94(dd, J=5.2, 3.7Hz, 1H), 7.00(d, J=3.3Hz, 1H), 7.33(dd, J=5.1, 1.1Hz, 1H), 8.5 (s, 1H). Example 22

3-(1，3-苯并二氧杂环戊-5-基)-2，2-二氟-3-[({[2-氧代-1-(2-苯硫基甲基)1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸的合成3-(1,3-Benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo-1-(2-phenylthiomethyl)1 , 2-dihydro-3-pyridyl] amino} carbonyl) amino] propionic acid synthesis

步骤1：在15分钟内，向冷却至-78℃的(1S，2R，5S)-(+)-甲基(R)-对甲苯亚磺酸酯(3.00g，10.2mmol)的THF溶液(25.5mL)中滴加双(三甲基甲硅烷基)氨基化锂(1.0M的THF溶液，15.3mL)。在室温下搅拌生成的混合物6小时，然后冷却至0℃。迅速加入胡椒醛(3.06g、20.4mmol)和CsF(3.10g，20.4mmol)，在室温下搅拌悬浮液36小时。用饱和NH4Cl骤冷反应物，用乙酸乙酯提取。用盐水洗涤有机层，经Na2SO4干燥后过滤，减压浓缩滤液。从己烷和二氯甲烷中重结晶残余物，得到化合物108(1.36g，46％)。 Step 1: To a THF solution of (1S,2R,5S)-(+)-methyl(R)-p-toluenesulfinate (3.00 g, 10.2 mmol) cooled to -78 °C within 15 minutes ( 25.5 mL) was added dropwise lithium bis(trimethylsilyl)amide (1.0 M in THF, 15.3 mL). The resulting mixture was stirred at room temperature for 6 hours, then cooled to 0 °C. Piperonal (3.06 g, 20.4 mmol) and CsF (3.10 g, 20.4 mmol) were added rapidly and the suspension was stirred at room temperature for 36 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane and dichloromethane to obtain compound 108 (1.36 g, 46%).

步骤2：将溴代二氟乙酸乙酯(0.78mL，6.1mmol)加入到Zn粉(2.00g，30.5mmol)的THF(20.2mL)悬浮液中并回流15分钟。把悬浮液冷却至0℃，加入108(0.87g，3.0mmol)。使悬浮液温热至室温并搅拌过夜。用最小量的饱和NH4Cl骤冷混合物，用乙酸乙酯提取。用饱和NaHCO3水溶液和盐水洗涤有机层，经Na2SO4干燥后过滤。减压浓缩滤液，经硅胶层析(洗脱梯度6∶1至4∶1己烷∶乙酸乙酯)纯化残余物，得到109(0.607g，80％转化时为61％)。 Step 2: Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to a suspension of Zn powder (2.00 g, 30.5 mmol) in THF (20.2 mL) and refluxed for 15 minutes. The suspension was cooled to 0 °C and 108 (0.87 g, 3.0 mmol) was added. The suspension was allowed to warm to room temperature and stirred overnight. The mixture was quenched with a minimal amount of saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution gradient 6:1 to 4:1 hexane:ethyl acetate) to afford 109 (0.607 g, 61% at 80% conversion).

步骤3：在0℃下，向109(0.700g，1.70mmol)的甲醇溶液(4.3mL)中加入三氟乙酸(0.26mL，3.4mmol)。在0℃下搅拌溶液2小时，然后减压浓缩至干，同时使外部温度保持在30℃以下。用乙醚溶解残余物，然后用2N HCl洗涤(两次)。用过量的饱和NaHCO3小心碱化合并的水层，用乙醚提取。经MgSO4干燥醚层后过滤，减压浓缩滤液，得到110(0.326g，80％)。 Step 3: To a solution of 109 (0.700 g, 1.70 mmol) in methanol (4.3 mL) was added trifluoroacetic acid (0.26 mL, 3.4 mmol) at 0°C. The solution was stirred at 0°C for 2 hours, then concentrated to dryness under reduced pressure while keeping the external temperature below 30°C. The residue was taken up with ether and washed with 2N HCl (twice). The combined aqueous layers were carefully basified with excess saturated NaHCO 3 and extracted with ether. The ether layer was dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure to afford 110 (0.326 g, 80%).

按照在实施例1中描述的方法，用110制备3-(1，3-苯并二氧杂环戊-5-基)-2，2-二氟-3-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸。MS：计算值(M-H)-＝476.07；实测值(M-H)-＝476.00。实施例23 According to the method described in Example 1, 3-(1,3-benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo -1-(2-Phenylthiomethyl)-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]propionic acid. MS: Calculated (MH) - = 476.07; Found (MH) - = 476.00. Example 23

(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-({[9-氧代-8-(苯甲基)-2，3，4，5，8，9-六氢-1H-吡啶并[3，4-b]氮杂-1-基]羰基}氨基)丙酸的合成(3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8-(benzyl)-2,3,4,5, Synthesis of 8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propionic acid

步骤1：在-20℃下，通过注射器向3(0.74g，3.6mmol)在THF(14.4mL)和TMEDA(1.60mL，10.8mmol)中的溶液中连续滴加正丁基锂(1.6M的己烷溶液，3.4mL，5.4mmol)和叔丁基锂(1.7M的戊烷溶液，2.5mL，4.3mmol)。将温度温热至-10和0℃之间并维持2小时。向生成的混合物中迅速加入1，4-二溴丁烷(1.75mL，14.7mmol)，使溶液温热至室温并搅拌4天。用水骤冷反应物后用CHCl3提取(三次)。用盐水洗涤合并的提取液，经Na2SO4干燥后过滤。减压浓缩滤液，经硅胶层析纯化残余物，用4∶1己烷∶乙酸乙酯洗脱，得到111(0.41g，44％)。 Step 1: To a solution of 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) and TMEDA (1.60 mL, 10.8 mmol) was continuously added dropwise via syringe at -20 °C n-BuLi (1.6 M in hexane, 3.4 mL, 5.4 mmol) and tert-butyllithium (1.7M in pentane, 2.5 mL, 4.3 mmol). The temperature was warmed to between -10 and 0°C and maintained for 2 hours. To the resulting mixture was added 1,4-dibromobutane (1.75 mL, 14.7 mmol) rapidly, and the solution was allowed to warm to room temperature and stirred for 4 days. The reaction was quenched with water and extracted with CHCl3 (three times). The combined extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 4:1 hexane:ethyl acetate to afford 111 (0.41 g, 44%).

按照在实施例4中描述的方法，用111制备(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-({[9-氧代-8-(苯甲基)-2，3，4，5，8，9-六氢-1H-吡啶并[3，4-b]氮杂-1-基]羰基}氨基)丙酸。MS：计算值(M-H)-＝488.18；实测值(M-H)-＝488.21。实施例24 According to the method described in Example 4, (3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8-( Benzyl)-2,3,4,5,8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propanoic acid. MS: Calculated (MH) - = 488.18; Found (MH) - = 488.21. Example 24

(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-羟基苯基)丙酸的合成(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3 Synthesis of -(4-hydroxyphenyl)propionic acid

步骤1：在0℃下于氮气下，通过注射器向112(按照在实施例15中描述的方法制得，0.19g，0.39mmol)的CH2Cl2溶液中加入BBr3(1.0M的CH2Cl2溶液，1.2mL，1.2mmol)。使混合物逐渐温热至室温，然后搅拌过夜。用水稀释混合物并搅拌30分钟，用饱和NaHCO3水溶液进一步稀释。用水洗涤有机层，合并水层，用2N HCl酸化，然后用乙酸乙酯提取(三次)。经MgSO4干燥合并的乙酸乙酯层后过滤，减压浓缩滤液，得到(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-羟基苯基)丙酸(113，120mg，70％)。1H NMR(400MHz，CD3SO2CD3)δ2.95(d，J＝5.2Hz，2H)，5.28(s，2H)，5.35(ddd，J＝9.2，4.8，4.4Hz，1H)，6.33(t，J＝7.1Hz，1H)，6.60(d，J＝8.8Hz，2H)，7.04(m，5H)，7.22(m，3H)，7.37(dd，J＝7.7，1.5Hz，1H)，8.35(dd，J＝7.6，1.5Hz，1H)，8.80(s，1H)。实施例25 Step 1: To a solution of 112 (prepared as described in Example 15, 0.19 g, 0.39 mmol) in CH 2 Cl 2 was added BBr 3 (1.0 M in CH 2 Cl 2 via syringe at 0° C. under nitrogen. Cl2 solution, 1.2 mL, 1.2 mmol). The mixture was allowed to warm gradually to room temperature, then stirred overnight. The mixture was diluted with water and stirred for 30 min, further diluted with saturated aqueous NaHCO 3 . The organic layer was washed with water, and the combined aqueous layers were acidified with 2N HCl, then extracted with ethyl acetate (three times). The combined ethyl acetate layers were dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure to give (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1 , 2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propanoic acid (113, 120 mg, 70%). 1 H NMR (400MHz, CD 3 SO 2 CD 3 ) δ 2.95 (d, J=5.2Hz, 2H), 5.28(s, 2H), 5.35 (ddd, J=9.2, 4.8, 4.4Hz, 1H), 6.33(t, J=7.1Hz, 1H), 6.60(d, J=8.8Hz, 2H), 7.04(m, 5H), 7.22(m, 3H), 7.37(dd, J=7.7, 1.5Hz, 1H ), 8.35 (dd, J=7.6, 1.5 Hz, 1H), 8.80 (s, 1H). Example 25

(3S)-3-[({[1-[(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸119的合成(3S)-3-[({[1-[(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Synthesis of )amino]-3-(4-methylphenyl)propionic acid 119

步骤1：向干燥氮气氛下的氢化钠(3.6g的60％矿物油分散液，90mmol)的THF悬浮液(300mL)中加入TMEDA(13.2mL，87.5mmol)，使混合物冷却至-20℃。滴加丙酰醋酸甲酯(9.60mL，76.5mmol)，再搅拌溶液15分钟。滴加正丁基锂溶液(90mL，1.6M的己烷溶液，144mmol)，于-20℃搅拌生成的混合物15分钟。然后快速加入甲酸甲酯(6.0mL，97mmol)，搅拌混合物15分钟后，用盐酸(2N，250mL)骤冷混合物。用乙醚(150mL)稀释反应物，用水洗涤有机层2次以上。合并水层，加入氯化钠直到饱和为止。用醋酸乙酯提取该混合物(3次)。用饱和碳酸氢钠溶液和水洗涤原乙醚层。用过量盐酸(2N)酸化合并的水洗涤液，用氯化钠饱和后以醋酸乙酯进行提取(3次)。合并所有醋酸乙酯提取液并经硫酸镁干燥。生成的混合物通过粗硅胶真空过滤，减压浓缩滤液获得为浅黄色油的114(8.27g，68％)。该物质无需纯化即可使用。 Step 1: To a suspension of sodium hydride (3.6 g of a 60% dispersion in mineral oil, 90 mmol) in THF (300 mL) under dry nitrogen was added TMEDA (13.2 mL, 87.5 mmol) and the mixture was cooled to -20 °C. Methyl propionyl acetate (9.60 mL, 76.5 mmol) was added dropwise and the solution was stirred for an additional 15 minutes. A solution of n-butyllithium (90 mL, 1.6 M in hexane, 144 mmol) was added dropwise, and the resulting mixture was stirred at -20°C for 15 minutes. Methyl formate (6.0 mL, 97 mmol) was then added rapidly, and after stirring the mixture for 15 minutes, the mixture was quenched with hydrochloric acid (2N, 250 mL). The reactant was diluted with diethyl ether (150 mL), and the organic layer was washed with water more than 2 times. The aqueous layers were combined and sodium chloride was added until saturation. The mixture was extracted with ethyl acetate (3 times). The original ether layer was washed with saturated sodium bicarbonate solution and water. The combined aqueous washes were acidified with excess hydrochloric acid (2N), saturated with sodium chloride and extracted with ethyl acetate (3 times). All ethyl acetate extracts were combined and dried over magnesium sulfate. The resulting mixture was vacuum filtered through crude silica gel, and the filtrate was concentrated under reduced pressure to afford 114 (8.27 g, 68%) as a pale yellow oil. This material was used without purification.

步骤2：用附加的漏斗向室温下的114(3.95g，25.0mmol)无水甲醇溶液(225mL)中，滴加2-氯苄胺(4.2g，30mmol)的无水甲醇(25mL)溶液。将溶液于45℃加热过夜后回流2小时。使反应混合物冷却至室温并浓缩至干。用二氯甲烷溶解残余物后过滤。收集固体，真空干燥获得为浅黄色固体的115(2.20g，35％)。 Step 2: To a solution of 114 (3.95 g, 25.0 mmol) in dry methanol (225 mL) at room temperature was added dropwise a solution of 2-chlorobenzylamine (4.2 g, 30 mmol) in dry methanol (25 mL) using an additional funnel. The solution was heated at 45°C overnight and then refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in dichloromethane and filtered. The solid was collected and dried in vacuo to afford 115 (2.20 g, 35%) as a pale yellow solid.

步骤3：向室温下的115(840mg，3.4mmol)的冰醋酸(11mL)悬浮液中连续加入亚硝酸钠(46mg，0.67mmol)、水(0.92mL)和硝酸(70％，0.85mL，13.4mmol)。在室温下将生成的浅黄色溶液搅拌过夜后用二氯甲烷和水稀释。用二氯甲烷提取水相，合并有机层，用水(3次)和盐水进行洗涤。有机层经硫酸镁干燥后过滤，减压浓缩滤液获得为亮黄色固体的116(910mg，92％)。该物质无需纯化即可使用。 Step 3: Add sodium nitrite (46 mg, 0.67 mmol), water (0.92 mL) and nitric acid (70%, 0.85 mL, 13.4 mmol). The resulting pale yellow solution was stirred overnight at room temperature and diluted with dichloromethane and water. The aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with water (3 times) and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 116 (910 mg, 92%) as a bright yellow solid. This material was used without purification.

步骤4：在室温于干燥氮气氛下，向116(910mg，3.1mmol)的DMF(10.3mL)溶液中加入锌粉(909mg，13.9mmol)和盐酸三乙胺(2340mg，17.0mmol)。使生成的混合物加热至55℃持续2小时，然后冷却至室温。向生成的混合物中加入CDI(1002mg，6.18mmol)固体。加入后立即有气体放出。然后将混合物加热至80℃1小时，冷却至室温，用二氯甲烷和盐酸(2N)稀释。水相用二氯甲烷提取，合并有机层，用水(4次)和盐水洗涤。有机层经硫酸镁干燥后过滤，减压浓缩滤液获得为黄色固体的117(920mg)。该物质含有少量DMF，但无需纯化即可使用。 Step 4: To a solution of 116 (910 mg, 3.1 mmol) in DMF (10.3 mL) was added zinc powder (909 mg, 13.9 mmol) and triethylamine hydrochloride (2340 mg, 17.0 mmol) at room temperature under dry nitrogen atmosphere. The resulting mixture was heated to 55 °C for 2 hours, then cooled to room temperature. To the resulting mixture was added CDI (1002 mg, 6.18 mmol) as a solid. Gas was released immediately after the addition. The mixture was then heated to 80°C for 1 hour, cooled to room temperature and diluted with dichloromethane and hydrochloric acid (2N). The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with water (4 times) and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 117 (920 mg) as a yellow solid. This material contained a small amount of DMF but was used without purification.

步骤5：在干燥氮气氛下，使117(920mg的粗物质，3.1mmol理论值)和8(800mg，3.86mmol)的21ml THF悬浮液加热至55℃过夜，冷却至室温后用醋酸乙酯稀释。生成的混合物用盐酸(2N)和盐水洗涤2次，有机层经硫酸镁干燥后过滤。减压浓缩滤液，获得的残余物通过硅胶层析法纯化，以7∶3己烷∶醋酸乙酯洗脱获得为浅黄色泡沫的118(1098mg，两步，71％)。 Step 5: Under a dry nitrogen atmosphere, a suspension of 117 (920 mg of crude material, 3.1 mmol theoretical) and 8 (800 mg, 3.86 mmol) in 21 ml of THF was heated to 55 °C overnight, cooled to room temperature and diluted with ethyl acetate . The resulting mixture was washed twice with hydrochloric acid (2N) and brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with 7:3 hexane:ethyl acetate to afford 118 (1098 mg, two steps, 71%) as a pale yellow foam.

步骤6：在室温下，向118(1091mg，2.19mmol)的THF(18mL)溶液中加入氢氧化钠(2N，6mL)和甲醇(112 mL)。搅拌混合物20分钟后，用水稀释，用乙醚提取。用盐酸(2N)酸化水相后，以醋酸乙酯进行提取。用水和盐水洗涤醋酸乙酯层，经硫酸镁干燥后过滤。减压浓缩滤液获得为白色泡沫的119(3S)-3-[({[1-[(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(1045mg，定量)。MS：计算值(M-基)-＝468.13m/z；实测值(M-H)-＝467.99m/z。实施例26 Step 6: To a solution of 118 (1091 mg, 2.19 mmol) in THF (18 mL) was added sodium hydroxide (2N, 6 mL) and methanol (112 mL) at room temperature. After stirring the mixture for 20 minutes, it was diluted with water and extracted with ether. After acidifying the aqueous phase with hydrochloric acid (2N), extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 119(3S)-3-[({[1-[(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-di Hydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (1045 mg, quantitative). MS: calculated (M-base) - = 468.13 m/z; found (MH) - = 467.99 m/z. Example 26

(3S)-3-[({[4-羟基-2-氧代-1-(吡啶-2-基甲基)-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成(3S)-3-[({[4-Hydroxy-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Synthesis of 3-(4-methylphenyl)propionic acid

步骤1：向室温下的23(0.50g，3.2mmol)的DMSO溶液(12.5ml)中加入氢氧化钾粉(0.89g，16mmol)，搅拌混合物1.5小时。向生成的混合物中加入为固体的盐酸2-吡啶甲基氯(0.63g，3.8mmol)，搅拌混合物过夜。此时加入盐酸三乙胺(3.52g，25.6mmol)和DMF(5mL)，然后加入锌粉(1.04g，16.0mmol)。将混合物加热至80℃2小时，然后冷却至室温。向该混合物中加入CDI(1.00g，6.2mmol)，使生成的混合物加热至80℃过夜。用醋酸乙酯和饱和碳酸氢钠水溶液稀释混合物。有机层经硫酸镁干燥后过滤，减压浓缩滤液。残余物通过硅胶垫过滤，用9∶1三氯甲烷∶甲醇洗脱获得120(0.14g，18％)。 Step 1: To a solution of 23 (0.50 g, 3.2 mmol) in DMSO (12.5 ml) at room temperature was added potassium hydroxide powder (0.89 g, 16 mmol), and the mixture was stirred for 1.5 hours. To the resulting mixture was added 2-picolyl chloride hydrochloride (0.63 g, 3.8 mmol) as a solid, and the mixture was stirred overnight. At this point triethylamine hydrochloride (3.52 g, 25.6 mmol) and DMF (5 mL) were added, followed by zinc dust (1.04 g, 16.0 mmol). The mixture was heated to 80 °C for 2 hours and then cooled to room temperature. To this mixture was added CDI (1.00 g, 6.2 mmol) and the resulting mixture was heated to 80 °C overnight. The mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel eluting with 9:1 chloroform:methanol to afford 120 (0.14 g, 18%).

按照实施例25介绍的方法用120制备(3S)-3-[({[4-羟基-2-氧代-1-(吡啶-2-基甲基)-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。MS：计算值(M-H)-＝421.15m/z；实测值(M-H)-＝421.06m/z。实施例27 According to the method described in Example 25, (3S)-3-[({[4-hydroxyl-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridine-3 -yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid. MS: calculated (MH) - = 421.15 m/z; found (MH) - = 421.06 m/z. Example 27

(3S)-3-{[({1-[2-氯-5-(甲基磺酰基)苄基]-4-羟基-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸的合成(3S)-3-{[({1-[2-Chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} Synthesis of amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid

步骤1：在干燥氮气氛下，向冷却至0℃的121(按照实施例4介绍的方法用23制得，220mg，0.67mmol)的无水二氯甲烷溶液(14mL)中加入m-CPBA(610mg，3.6mmol)。使生成的混合物温热至室温并搅拌4小时。用水(50mL)稀释反应物，用二氯甲烷提取水相(2次)。合并有机层经硫酸镁干燥后过滤，减压浓缩滤液。残余物通过硅胶层析法纯化，用9∶1三氯甲烷∶甲醇洗脱获得为黄色固体的122(219mg，91％收率)。 Step 1: Under a dry nitrogen atmosphere, add m-CPBA ( 610 mg, 3.6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was diluted with water (50 mL) and the aqueous phase was extracted with dichloromethane (2x). The combined organic layers were dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 9:1 trichloromethane:methanol to afford 122 (219 mg, 91% yield) as a yellow solid.

按照实施例25介绍的方法用122制备(3S)-3-{[({1-[2-氯-5-(甲基磺酰基)苄基]-4-羟基-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸。MS：计算值(M-H)-＝532.10m/z；实测值(M-H)-＝531.94m/z。实施例28 (3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]-4-hydroxyl-2-oxo-1 was prepared from 122 according to the method described in Example 25, 2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid. MS: calculated (MH) - = 532.10 m/z; found (MH) - = 531.94 m/z. Example 28

(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸的合成(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl )amino]-3-(3-methylphenyl)propionic acid synthesis

步骤1：向在干燥氮气氛下搅拌的123(70mg，0.13mmol)的无水二氯甲烷溶液(3mL)中加入溴化锌(200mg，0.82mmol)。于0℃搅拌溶液1小时。使反应混合物温热至室温并搅拌过夜。此时加入水(50mL)，再搅拌混合物3小时。分离各层，用二氯甲烷提取水层(2次)。经硫酸镁干燥合并有机层后过滤，减压浓缩滤液获得124(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸(60mg，95％收率)。MS：计算值(M-H)-＝484.13m/z；实测值(M-H)-484.00m/z。实施例29 Step 1: To a stirred solution of 123 (70 mg, 0.13 mmol) in dry dichloromethane (3 mL) under dry nitrogen was added zinc bromide (200 mg, 0.82 mmol). The solution was stirred at 0°C for 1 hour. The reaction mixture was allowed to warm to room temperature and stirred overnight. At this point water (50 mL) was added and the mixture was stirred for an additional 3 hours. The layers were separated and the aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 124(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxyl-2-oxo -1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid (60 mg, 95% yield). MS: Calculated (MH) - = 484.13 m/z; Found (MH) - 484.00 m/z. Example 29

(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-5-丙基-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl) Synthesis of amino]-3-(4-methylphenyl)propionic acid

步骤1：在室温下剧烈搅拌干燥气氛下的丙二酰二氯(25.0g，177mmol)和戊腈(25.0g，300.7mmol)的混合物24小时。向生成的不均匀混合物中加入乙醚(50mL)。收集沉淀物，用乙醚洗涤获得为白色固体的125盐酸盐(20.2g，64％)。 Step 1: A dry atmosphere mixture of malonyl chloride (25.0 g, 177 mmol) and valeronitrile (25.0 g, 300.7 mmol) was stirred vigorously at room temperature for 24 hours. Diethyl ether (50 mL) was added to the resulting heterogeneous mixture. The precipitate was collected and washed with ether to give 125 hydrochloride (20.2 g, 64%) as a white solid.

步骤2：向125盐酸盐(6.10g，27.2mmol)的乙醇悬浮液(100mL)中加入三乙胺(5.8g，57.3mmol)和披钯碳(10％钯干重计，Degussa E101NE/W型，水含量约50％，3.5g，1.6mmol Pd)。用氢气代替所述气氛(在真空和气球氢气之间切换5次)，搅拌混合物过夜，然后过滤。减压浓缩滤液获得126·2Et3NHCl(11.0g，94％)。该物质无需进一步纯化即可使用。 Step 2 : Add triethylamine (5.8 g, 57.3 mmol) and palladium on carbon (10% palladium dry weight basis, Degussa E101NE/W to 125 hydrochloride (6.10 g, 27.2 mmol) in ethanol suspension (100 mL) type, water content about 50%, 3.5 g, 1.6 mmol Pd). The atmosphere was replaced with hydrogen (switched 5 times between vacuum and balloon hydrogen) and the mixture was stirred overnight, then filtered. The filtrate was concentrated under reduced pressure to obtain 126·2Et 3 NHCl (11.0 g, 94%). This material was used without further purification.

按照实施例25介绍的方法用126·2Et3NHCl制备(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-5-丙基-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。MS：计算值(M-H)-＝496.16m/z；实测值(M-H)-＝495.94m/z。实施例30 According to the method described in Example 25, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1 was prepared using 126.2Et 3 NHCl, 2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid. MS: Calculated (MH) - = 496.16 m/z; Found (MH) - = 495.94 m/z. Example 30

(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[b] Synthesis of pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid

步骤1：向2-氧代环戊烷羧酸乙酯(3.30g，21.1mmol)的甲苯溶液(45ml)中加入4-氯苄胺(2.56mL，21.1mmol)。使生成的混合物回流过夜，通过Dean-Stark分水器共沸去除水。减压浓缩反应混合物，获得为红色油的127(5.90，99％)。该物质无需纯化即可使用。 Step 1: To a solution of ethyl 2-oxocyclopentanecarboxylate (3.30 g, 21.1 mmol) in toluene (45 ml) was added 4-chlorobenzylamine (2.56 mL, 21.1 mmol). The resulting mixture was refluxed overnight and water was azeotroped through a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure to afford 127 (5.90, 99%) as a red oil. This material was used without purification.

步骤2：向干燥氮气氛下冷却至0℃的127(11.0g，39.3mmol)的无水THF(75mL)溶液加入氢化钠(60％矿物油分散液，1.73g，43.2mmol)。于0℃搅拌反应物10分钟，然后加入乙酰氯(3.9mL，55mmol)。使反应混合物逐渐温热至室温，然后搅拌过夜。减压浓缩生成的混合物，向残余物中加入冰水(200mL)和盐酸(1N，200mL)的混合物。用醋酸乙酯(300mL)提取该混合物，醋酸乙酯层经硫酸镁干燥后过滤。减压浓缩滤液获得为棕色油的128(13.4g)。该物质含有矿物油，但是无需纯化即可使用。 Step 2 : To a solution of 127 (11.0 g, 39.3 mmol) in anhydrous THF (75 mL) cooled to 0 °C under dry nitrogen was added sodium hydride (60% dispersion in mineral oil, 1.73 g, 43.2 mmol). The reaction was stirred at 0 °C for 10 min, then acetyl chloride (3.9 mL, 55 mmol) was added. The reaction mixture was allowed to gradually warm to room temperature, then stirred overnight. The resulting mixture was concentrated under reduced pressure, and a mixture of ice water (200 mL) and hydrochloric acid (1N, 200 mL) was added to the residue. The mixture was extracted with ethyl acetate (300 mL), and the ethyl acetate layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 128 (13.4 g) as a brown oil. This material contains mineral oil but is used without purification.

步骤3：通过注射器向干燥氮气氛下冷却至0℃的粗制品128(13.4g，39.3mmol理论值)的无水THF(50ml)溶液中缓慢加入二(三甲基甲硅烷基)氨基化锂(1.0M的THF溶液，125mL，125mmol)。使反应混合物温热至室温，然后搅拌过夜。减压浓缩混合物，用醋酸乙酯/己烷研磨残余物并过滤。用盐酸(1N，250ml)和水(500ml)洗涤所述固体，获得为棕色固体的129(5.48g，2个步骤，48％)。 Step 3 : To a solution of crude product 128 (13.4 g, 39.3 mmol theoretical) in anhydrous THF (50 ml) cooled to 0 °C under dry nitrogen atmosphere was slowly added lithium bis(trimethylsilyl)amide via syringe (1.0 M in THF, 125 mL, 125 mmol). The reaction mixture was allowed to warm to room temperature, then stirred overnight. The mixture was concentrated under reduced pressure, the residue was triturated with ethyl acetate/hexanes and filtered. The solid was washed with hydrochloric acid (IN, 250ml) and water (500ml) to afford 129 (5.48g, 48% over 2 steps) as a brown solid.

按照实施例25介绍的方法用129制备(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。MS：计算值(M+H)+＝496.16m/z；实测值(M+H)+＝495.99m/z。实施例31 According to the method described in Example 25, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydro- 1H-Cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid. MS: Calcd. (M+H) + = 496.16 m/z; Found (M+H) + = 495.99 m/z. Example 31

(3S)-3-[({[4-{[(叔丁基氨基)羰基]氨基}-1-(2-氯苄基)-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridine-3- Synthesis of [yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid

步骤1：向干燥氮气氛下冷却至0℃的46(500mg，1.79mmol)的无水THF(10mL)溶液中加入氢化钠(60％矿物油分散液，210mg，5.37mmol)，搅拌生成的混合物20分钟。向该混合物中加入异氰酸叔丁酯(0.31mL，2.68mmol)，使反应混合物温热至室温，然后搅拌2天。用水骤冷反应混合物后，用醋酸乙酯提取2次。合并有机层，经硫酸镁干燥后过滤，减压浓缩滤液获得为棕色固体的130(660mg，97％)。 Step 1: To a solution of 46 (500 mg, 1.79 mmol) in dry THF (10 mL) cooled to 0 °C under dry nitrogen was added sodium hydride (60% dispersion in mineral oil, 210 mg, 5.37 mmol) and the resulting mixture was stirred 20 minutes. To this mixture was added tert-butyl isocyanate (0.31 mL, 2.68 mmol), and the reaction mixture was allowed to warm to room temperature, then stirred for 2 days. After quenching the reaction mixture with water, it was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 130 (660 mg, 97%) as a brown solid.

按照实施例3介绍的方法用130制备(3S)-3-[({[4-{[(叔丁基氨基)羰基]氨基}-1-(2-氯苄基)-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。MS：计算值(M-H)-＝552.20m/z；实测值(M-H)-＝551.89m/z。According to the method described in Example 3, (3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid. MS: Calculated (MH) - = 552.20 m/z; Found (MH) - = 551.89 m/z.

可用类似于上述方法的合成方法获得表2、3、4和5的化合物。实施例32 Compounds of Tables 2, 3, 4 and 5 can be obtained by synthetic methods similar to those described above. Example 32

(3S)-3-[({[5-氯-1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸的合成(3S)-3-[({[5-chloro-1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino Synthesis of ]-3-(4-methylphenyl)propionic acid

步骤1：通过注射器向室温、干燥氮气氛下的31(350mg，0.72mmol)的二氯甲烷溶液中加入磺酰氯(1.0M的二氯甲烷溶液，0.65mL，0.65mmol)。于室温下搅拌生成的混合物1小时，则所述化合物分配在二氯甲烷和水之间。有机层用盐水洗涤后经硫酸镁干燥，减压浓缩滤液。残余物通过硅胶层析法纯化，用8∶1、然后用4∶1、而最后用1∶1己烷∶醋酸乙酯进行洗脱，获得131(240mg，64％)。 Step 1: To a solution of 31 (350 mg, 0.72 mmol) in dichloromethane at room temperature under dry nitrogen was added sulfonyl chloride (1.0 M in dichloromethane, 0.65 mL, 0.65 mmol) via syringe. The resulting mixture was stirred at room temperature for 1 hour, then the compound was partitioned between dichloromethane and water. The organic layer was washed with brine and dried over magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 8:1, then 4:1, and finally 1:1 hexane:ethyl acetate to afford 131 (240 mg, 64%).

按照实施例1介绍的方法用131制备(3S)-3-[({[5-氯-1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸。MS：计算值(M-H)-＝488.08；实测值(M-H)-＝487.97。实施例33 Prepare (3S)-3-[({[5-chloro-1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridine according to the method described in Example 1 -3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid. MS: Calculated (MH) - = 488.08; Found (MH) - = 487.97. Example 33

(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2’，6’-二甲氧基-1，1’-联苯基-4-基)丙酸的合成(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl) Synthesis of amino]-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propionic acid

步骤1：在30分钟内，向冷却至-78℃、在火焰干燥烧瓶中、氮气氛下的(R)-(+)-N-苄基-α-甲基苄基胺(5.07g，24mmol)的THF溶液(85mL)中，滴加仲丁基锂(1.3M的环己烷溶液，18.0mL，23.4mmol)。于-78℃再搅拌混合物30分钟，然后滴加4-溴肉桂酸叔丁酯(5.1g、20mmol)的THF溶液(20mL)，使混合物温度回升至室温过夜。加入饱和氯化铵(约50mL)骤冷反应物，用饱和氯化钠洗涤有机层，经硫酸镁干燥后过滤。减压浓缩滤液，残余物通过硅胶层析法纯化，用己烷、升高至3∶1己烷∶醋酸乙酯进行洗脱，获得为浅黄色油的132(4.33g，47％)。 Step 1: To (R)-(+)-N-benzyl-α-methylbenzylamine (5.07 g, 24 mmol ) in THF (85 mL), was added dropwise sec-butyllithium (1.3 M solution in cyclohexane, 18.0 mL, 23.4 mmol). The mixture was stirred at -78°C for another 30 minutes, then a THF solution (20 mL) of tert-butyl 4-bromocinnamate (5.1 g, 20 mmol) was added dropwise, and the temperature of the mixture was allowed to warm to room temperature overnight. The reaction was quenched by adding saturated ammonium chloride (about 50 mL), and the organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with hexanes increasing to 3:1 hexanes: ethyl acetate to afford 132 (4.33 g, 47%) as a pale yellow oil.

步骤2：向室温、干燥氮气氛下的132(7.4g，15mmol)和2，6-二甲氧基苯基硼酸(4.9g，27mmol)的DME(100mL)溶液中，加入磷酸钾细粉(8.0g，37.5mM)和二氯二(三苯基膦)钯(O)(0.5g，0.75mmol)。使混合物脱氧(在真空和氮气之间切换5次)，然后加热至回流8小时。再后冷却混合物，通过Celite521过滤后，减压浓缩滤液。残余物通过硅胶层析法纯化，用己烷、增加至3∶1己烷∶醋酸乙酯进行洗脱获得133(7.8g，95％收率)。 Step 2 : To a solution of 132 (7.4 g, 15 mmol) and 2,6-dimethoxyphenylboronic acid (4.9 g, 27 mmol) in DME (100 mL) at room temperature under a dry nitrogen atmosphere was added finely powdered potassium phosphate ( 8.0 g, 37.5 mM) and dichlorobis(triphenylphosphine)palladium(0) (0.5 g, 0.75 mmol). The mixture was deoxygenated (switching between vacuum and nitrogen 5 times) and then heated to reflux for 8 hours. The mixture was then cooled, filtered through Celite® 521, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes increasing to 3:1 hexanes:ethyl acetate to afford 133 (7.8 g, 95% yield).

步骤3：向250mL烧瓶中的133(3.39g，6.1mmol)的乙醇溶液(80mL)中连续加入醋酸(0.5mL)和披钯碳(10％Pd干重计，含水量约50％，Degussa E101 NE/W型，2.5g，1.2mmol Pd)。在气球氢气氛下搅拌混合物36小时。通过Celite521过滤反应混合物后，减压浓缩滤液。用醋酸乙酯重结晶残余物，获得为白色固体的134·醋酸(1.0g，71％)。 Step 3 : in the ethanol solution (80mL) of 133 (3.39g, 6.1mmol) in the 250mL flask, add acetic acid (0.5mL) and palladium carbon (10%Pd dry weight meter, water content about 50%, Degussa E101 NE/W type, 2.5 g, 1.2 mmol Pd). The mixture was stirred under balloon hydrogen atmosphere for 36 hours. After filtering the reaction mixture through Celite® 521 , the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 134.acetic acid (1.0 g, 71%) as a white solid.

按照实施例25介绍的方法用134·醋酸合成(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2’，6’-二甲氧基-1，1’-联苯基-4-基)丙酸。MS：实测值(M+H)+＝592.04；计算值(M+H)+＝592.19。实施例34 According to the method described in Example 25, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5-methyl-2-oxo-1,2- Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid. MS: found (M+H) + = 592.04; calculated (M+H) + = 592.19. Example 34

(3S)-3-[({[2-(2-氯-6-乙氧基苄基)-5-羟基-6-甲基-3-氧代-2，3-二氢哒嗪-4-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸的合成(3S)-3-[({[2-(2-Chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazine-4 Synthesis of -yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid

步骤1：在10分钟内，向室温、干燥氮气氛下的叔丁醇钠(65g，0.642mol)的THF(1L)溶液中加入乙醇(250mL，5.35mol)。向获得的溶液中分批加入2-氯-6-氟苄腈(100g，0.642mol)。在室温下搅拌反应混合物30分钟，然后在减压下减少至约250mL体积。将生成的混合物倾入氯仿和水中，分离各层。用水(2次)和盐水洗涤有机层，经硫酸镁干燥后过滤。减压浓缩滤液获得浅黄色固体。用己烷重结晶该物质，获得为白色结晶固体的2-氯-6-乙氧基苄腈135(101g，87％收率)。 Step 1: To a solution of sodium tert-butoxide (65 g, 0.642 mol) in THF (1 L) at room temperature under dry nitrogen atmosphere was added ethanol (250 mL, 5.35 mol) over 10 minutes. To the obtained solution was added 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) in portions. The reaction mixture was stirred at room temperature for 30 minutes, then reduced to a volume of about 250 mL under reduced pressure. The resulting mixture was poured into chloroform and water, and the layers were separated. The organic layer was washed with water (2x) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a pale yellow solid. This material was recrystallized from hexanes to afford 2-chloro-6-ethoxybenzonitrile 135 (101 g, 87% yield) as a white crystalline solid.

步骤2：向室温、干燥氮气氛下的2-氯-6-乙氧基苄腈135(93.2g，0.513mol)的THF溶液(350mL)中加入甲硼烷的THF溶液(1.0M，620mL，0.62mol)。将生成的混合物加热至回流3小时，然后冷却至室温。向该溶液中非常缓慢地加入水(250mL)，使其放出氢气。再后在数分钟内加入浓盐酸(50mL)，使溶液加热至50℃2小时。混合物冷却后分配在氯仿和水之间。用氯仿洗涤水层6次。用盐酸(1M)洗涤合并的有机部分，丢弃该有机层。在合并的水层中加入氯仿，然后加入氢氧化钾，直至水相为碱性(pH＞9)时为止。再用氯仿洗涤水层5次。合并有机部分，用水、盐水进行洗涤后，经硫酸镁和硅胶(2g)干燥。过滤该混合物，减压浓缩滤液获得为浅黄色油的2-氯-6-乙氧基苄胺136(60.1g，64％收率)。 Step 2 : Add borane in THF (1.0 M, 620 mL, 0.62mol). The resulting mixture was heated to reflux for 3 hours, then cooled to room temperature. Water (250 mL) was added very slowly to this solution, allowing hydrogen evolution. Concentrated hydrochloric acid (50 mL) was then added over several minutes and the solution was heated to 50°C for 2 hours. After cooling the mixture was partitioned between chloroform and water. The aqueous layer was washed 6 times with chloroform. The combined organic fractions were washed with hydrochloric acid (1M) and the organic layer was discarded. Chloroform was added to the combined aqueous layers, followed by potassium hydroxide until the aqueous phase was basic (pH>9). The aqueous layer was further washed 5 times with chloroform. The combined organic fractions were washed with water, brine and dried over magnesium sulfate and silica gel (2 g). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2-chloro-6-ethoxybenzylamine 136 (60.1 g, 64% yield) as a pale yellow oil.

步骤3：向室温下的2-氯-6-乙氧基苄胺136(7.30g，39.3mmol)的冰醋酸(50mL)和醋酸酐(50mL)溶液中小批量加入亚硝酸钠(6.00g，85.7mmol)。生成的混合物在室温下搅拌过夜后，将其倾入冰水中，用醋酸乙酯提取。用氢氧化钠水溶液(1N，2×100mL)和盐水(2次)洗涤有机层。有机层经硫酸钠干燥后过滤，减压浓缩滤液获得为浅黄色固体的137(9.00g，100％)。 Step 3 : To a solution of 2-chloro-6-ethoxybenzylamine 136 (7.30 g, 39.3 mmol) in glacial acetic acid (50 mL) and acetic anhydride (50 mL) at room temperature was added sodium nitrite (6.00 g, 85.7 mmol). After the resulting mixture was stirred overnight at room temperature, it was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide solution (1 N, 2 x 100 mL) and brine (2 times). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 137 (9.00 g, 100%) as a pale yellow solid.

步骤4：向室温下的137(9.00g，39.3mmol)和四丁基溴化铵(1.0g，3.1mmol)的THF溶液(50ml)中，缓慢加入氢氧化钠水溶液(2N，50mL，100mmol)，使该混合物加热至45℃过夜。使反应混合物冷却至室温，然后用水稀释，以醋酸乙酯进行提取。有机层用盐水洗涤，经硫酸钠干燥后过滤，减压浓缩滤液获得138(7.08g，96％收率)。 Step 4 : To a THF solution (50 ml) of 137 (9.00 g, 39.3 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) at room temperature was slowly added aqueous sodium hydroxide (2N, 50 mL, 100 mmol) , and the mixture was heated to 45 °C overnight. The reaction mixture was cooled to room temperature, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 138 (7.08 g, 96% yield).

步骤5：向室温、干燥氮气氛下的138(7.08g，37.9mmol)的二氯甲烷溶液(55mL)中滴加SOCl2(9.0mL，120mmol)的二氯甲烷溶液(30mL)。生成的混合物在室温下搅拌过夜，然后倾入冰水中。水层用醋酸乙酯提取，合并的有机层用氢氧化钠水溶液(1N，2次)、水(3次)和盐水(2次)洗涤。有机层经硫酸钠干燥后过滤，减压浓缩滤液获得为粘性棕色油的2-氯-6-乙氧基苄基氯139(6.69g，86％收率)。 Step 5 : To a solution of 138 (7.08 g, 37.9 mmol) in dichloromethane (55 mL) at room temperature under dry nitrogen atmosphere was added SOCl2 (9.0 mL, 120 mmol) in dichloromethane (30 mL) dropwise. The resulting mixture was stirred overnight at room temperature, then poured into ice water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with aqueous sodium hydroxide solution (1 N, 2 times), water (3 times) and brine (2 times). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 2-chloro-6-ethoxybenzyl chloride 139 (6.69 g, 86% yield) as a viscous brown oil.

步骤6：在室温下搅拌2-氯-6-乙氧基苄基氯139(6.90g，33.7mmol)和肼(21.60g，673mmol)的甲醇溶液(22mL)3小时。然后混合物分配在二氯甲烷和水之间。有机层经硫酸镁干燥后过滤，减压浓缩滤液获得140(6.18g，92％)。 Step 6 : A solution of 2-chloro-6-ethoxybenzyl chloride 139 (6.90 g, 33.7 mmol) and hydrazine (21.60 g, 673 mmol) in methanol (22 mL) was stirred at room temperature for 3 hours. The mixture was then partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 140 (6.18 g, 92%).

步骤7：向丙酮酸乙酯(3.85mL，33.7mmol)和硫酸镁的三氯甲烷悬浮液(65mL)中缓慢加入140(6.14g，30.6mmol)的三氯甲烷溶液(30mL)。生成的混合物在室温下搅拌过夜。过滤生成的混合物，减压浓缩滤液获得141(8.43g，92％)。该物质无需纯化就可用于下一个步骤。 Step 7 : To a suspension of ethyl pyruvate (3.85 mL, 33.7 mmol) and magnesium sulfate in chloroform (65 mL) was slowly added a solution of 140 (6.14 g, 30.6 mmol) in chloroform (30 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 141 (8.43 g, 92%). This material was used in the next step without purification.

步骤8：向干燥氮气氛下冷却至0℃的141(8.43g，28.2mmol)的无水THF溶液(110mL)中，一次性加入氢化钠(60％矿物油分散液，1.88g，47.1mmol)。生成的混合物于0℃搅拌30分钟，然后缓慢加入甲基丙二酰氯(6.63g，47.10mmol)。使混合物温热至室温，搅拌过夜，用水小心骤冷，然后用醋酸乙酯提取(2次)。合并有机层，用盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液获得142(14.29g)。该物质无须进一步纯化就可用于下一个步骤。 Step 8 : To anhydrous THF solution (110 mL) of 141 (8.43 g, 28.2 mmol) cooled to 0° C. under a dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 1.88 g, 47.1 mmol) was added in one portion . The resulting mixture was stirred at 0°C for 30 minutes, then methylmalonyl chloride (6.63 g, 47.10 mmol) was added slowly. The mixture was allowed to warm to room temperature, stirred overnight, carefully quenched with water, then extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 142 (14.29 g). This material was used in the next step without further purification.

步骤9：向干燥氮气氛下冷却至0℃的粗制品142(14.29g)的无水DMF溶液(60mL)中，一次性加入氢化钠(60％矿物油分散液，2.90g，72.2mmol)。将该溶液加热至60℃过夜，在冰浴中使温度冷却下降，然后与己烷一起振荡。分离各层，将DMF层倾入冰水中。加入盐酸(2N)酸化混合物(pH1)。通过过滤收集沉淀物，然后用醋酸乙酯溶解沉淀物。有机溶液经硫酸镁干燥后过滤，减压浓缩滤液获得143(8.42g，2步，85％收率)。 Step 9 : To a dry DMF solution (60 mL) of crude product 142 (14.29 g) cooled to 0° C. under dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 2.90 g, 72.2 mmol) was added in one portion. The solution was heated to 60°C overnight, allowed to cool down in an ice bath, then shaken with hexane. The layers were separated and the DMF layer was poured into ice water. Hydrochloric acid (2N) was added to acidify the mixture (pH 1). The precipitate was collected by filtration and then dissolved with ethyl acetate. The organic solution was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 143 (8.42 g, 2 steps, 85% yield).

步骤10：使143(8.42g，23.9mmol)在二噁烷(100mL)和盐酸水溶液(60mL，5.2N)中的溶液回流过夜。把该混合物冷却至室温，用水稀释后，以醋酸乙酯提取。有机层用盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液，残余物通过硅胶层析法纯化，用1∶1醋酸乙酯∶己烷、然后用醋酸乙酯、而最后用9∶1醋酸乙酯∶甲醇进行洗脱获得144(2.0g，28％)。 Step 10 : A solution of 143 (8.42 g, 23.9 mmol) in dioxane (100 mL) and aqueous hydrochloric acid (60 mL, 5.2N) was refluxed overnight. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexane, then ethyl acetate, and finally 9:1 ethyl acetate:methanol to afford 144 (2.0 g , 28%).

应用实施例25提供的方法由144制备(3S)-3-[({[2-(2-氯-6-乙氧基苄基)-5-羟基-6-甲基-3-氧代-2，3-二氢哒嗪-4-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸。MS：实测值(M+H)+＝545.05；计算值(M+H)+＝545.18。实施例35 (3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxyl-6-methyl-3-oxo- 2,3-Dihydropyridazin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid. MS: found (M+H) + = 545.05; calculated (M+H) + = 545.18. Example 35

(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(1，3-二乙基-2-氧代-2，3-二氢-1H-苯并咪唑-5-基)丙酸的合成(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[b] Synthesis of pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)propionic acid

步骤1：在干燥氮气氛下使氢化钠(8.00g，60％矿物油分散液，200mmol)和145(8.94g，66.6mmol)在DMF(250mL)中的冰冷混合物逐渐温热至室温。向生成的混合物中加入碘乙烷(16ml，200mmol)，将混合物在室温下搅拌过夜。将反应混合物倾至冰中，用醋酸乙酯提取。有机层用水和盐水洗涤，经硫酸钠干燥后过滤。减压浓缩滤液，用己烷溶解残余物并过滤。减压干燥生成的棕色固体获得146(9.00g，71％收率)。该物质无需纯化即可使用。 Step 1: An ice-cold mixture of sodium hydride (8.00 g, 60% dispersion in mineral oil, 200 mmol) and 145 (8.94 g, 66.6 mmol) in DMF (250 mL) was gradually warmed to room temperature under an atmosphere of dry nitrogen. To the resulting mixture was added iodoethane (16ml, 200mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved with hexane and filtered. The resulting brown solid was dried under reduced pressure to obtain 146 (9.00 g, 71% yield). This material was used without purification.

步骤2：在室温、干燥氮气氛下搅拌DMF(3.6g，49mmol)和POCl3(9.6mL，100mmol)的混合物1小时。然后将装有该混合物的烧瓶置于45℃油浴中，小批量加入146(7.6g，40mmol)。把油浴温度升高至70℃，搅拌混合物过夜，然后冷却至室温。用水稀释混合物，然后用醋酸乙酯提取。有机层用水和盐水洗涤后，经硫酸钠干燥后过滤。减压浓缩滤液获得147∶146的7∶3混合物(6.69g)。该物质无需纯化即可使用。 Step 2 : A mixture of DMF (3.6 g, 49 mmol) and POCl3 (9.6 mL, 100 mmol) was stirred at room temperature under dry nitrogen atmosphere for 1 hour. The flask containing this mixture was then placed in a 45°C oil bath, and 146 (7.6 g, 40 mmol) was added in small portions. The temperature of the oil bath was raised to 70°C and the mixture was stirred overnight and then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a 7:3 mixture of 147:146 (6.69 g). This material was used without purification.

步骤3：向以上获得的147∶146混合物(2.2g)的乙醇溶液(2.2mL)中，连续加入丙二酸(1.16g，11.2mmol)、吡啶(0.44mL)和哌啶(0.99mL)。使产生的混合物加热至回流6小时，然后冷却至室温。混合物用氢氧化钠水溶液(1N)稀释，然后用醋酸乙酯提取(4次)。用盐酸(1N)酸化水相至pH3，过滤获得的悬浮液，用水洗涤固体。收集白色固体，减压干燥获得148(1.69g，两个步骤：49％)。 Step 3 : To an ethanol solution (2.2 mL) of the 147:146 mixture (2.2 g) obtained above, malonic acid (1.16 g, 11.2 mmol), pyridine (0.44 mL) and piperidine (0.99 mL) were successively added. The resulting mixture was heated to reflux for 6 hours, then cooled to room temperature. The mixture was diluted with aqueous sodium hydroxide (1N), then extracted with ethyl acetate (4 times). The aqueous phase was acidified to pH 3 with hydrochloric acid (1N), the resulting suspension was filtered and the solid was washed with water. The white solid was collected and dried under reduced pressure to afford 148 (1.69 g, 49% over two steps).

应用实施例33和25介绍的方法由148制备(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(1，3-二乙基-2-氧代-2，3-二氢-1H-苯并咪唑-5-基)丙酸。MS：实测值(M+H)+＝594.05；计算值(M+H)+＝594.21。实施例36 (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetra Hydrogen-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H- Benzimidazol-5-yl) propionic acid. MS: found (M+H) + = 594.05; calculated (M+H) + = 594.21. Example 36

(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸153的合成(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3- Synthesis of [yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid 153

步骤1：向室温、干燥氮气氛下的114(20.3g，129mmol)的无水甲醇溶液(430mL)中加入2-氯-6-乙氧基苄胺136(31.1g，168mmol)。于45℃加热溶液1小时，然后回流过夜。使反应混合物冷却至室温并浓缩至干。用二氯甲烷溶解残余物后过滤。收集固体，真空干燥获得149(14.7g，39％)。 Step 1: To a solution of 114 (20.3 g, 129 mmol) in dry methanol (430 mL) at room temperature under dry nitrogen was added 2-chloro-6-ethoxybenzylamine 136 (31.1 g, 168 mmol). The solution was heated at 45°C for 1 hour and then refluxed overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in dichloromethane and filtered. The solid was collected and dried in vacuo to afford 149 (14.7 g, 39%).

步骤2：向室温下的149(11.02g，37.8mmol)冰醋酸悬浮液(126mL)中依次加入亚硝酸钠(522mg，7.6mmol)、水(10.5mL)和硝酸(70％，9.6mL，151.2mmol)。将获得的亮黄色溶液在室温下搅拌过夜，然后用二氯甲烷和水稀释。以二氯甲烷提取水相，合并有机层后用水(3次)和盐水洗涤。有机层经硫酸镁干燥后过滤，减压浓缩滤液。用二氯甲烷/醋酸乙酯重结晶残余物，获得为亮黄色固体的150(10.9g，85％)。 Step 2 : Add sodium nitrite (522mg, 7.6mmol), water (10.5mL) and nitric acid (70%, 9.6mL, 151.2 mmol). The resulting bright yellow solution was stirred overnight at room temperature, then diluted with dichloromethane and water. The aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with water (3 times) and brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from dichloromethane/ethyl acetate to afford 150 (10.9 g, 85%) as a bright yellow solid.

步骤3：向室温、干燥氮气氛下的150(10.9g，32.2mmol)的DMF溶液(107mL)中，加入锌粉(9.48g，145mmol)和盐酸三乙胺(24.4g，177mmol)。把获得的混合物加热至55℃1小时，然后冷却至室温。向获得的混合物中加入为固体的CDI(10.4g，64.4mmol)。一旦加入CDI，立即释放出气体。然后使混合物加热至80℃2小时，然后使其冷却至室温并倾入盐酸(2N，1L)中。将产生的悬浮液搅拌20分钟后，用水(1L)稀释并过滤。将固体重悬浮在水(1L)中后过滤。真空干燥固体获得为白色粉末的151(10.78g，100％收率)。 Step 3 : To a solution of 150 (10.9 g, 32.2 mmol) in DMF (107 mL) at room temperature under a dry nitrogen atmosphere was added zinc powder (9.48 g, 145 mmol) and triethylamine hydrochloride (24.4 g, 177 mmol). The obtained mixture was heated to 55°C for 1 hour and then cooled to room temperature. To the obtained mixture was added CDI (10.4 g, 64.4 mmol) as a solid. Upon addition of CDI, gas is released immediately. The mixture was then heated to 80 °C for 2 hours, then allowed to cool to room temperature and poured into hydrochloric acid (2N, 1 L). The resulting suspension was stirred for 20 minutes, diluted with water (1 L) and filtered. The solid was resuspended in water (1 L) and filtered. The solid was dried in vacuo to afford 151 (10.78 g, 100% yield) as a white powder.

步骤4：在干燥氮气氛下使151(10.68g，31.9mmol)和8(8.27g，39.9mmol)在DMF(64mL)中的混合物加热至55℃过夜，冷却至室温后，用醋酸乙酯稀释。用盐酸(2N)、水(4次)和盐水洗涤获得的混合物，使有机层经硫酸镁干燥后过滤。减压浓缩滤液，产生的残余物通过硅胶层析法纯化，用7∶3己烷∶醋酸乙酯洗脱获得为浅黄色泡沫的152(14.2g，82％)。 Step 4 : A mixture of 151 (10.68 g, 31.9 mmol) and 8 (8.27 g, 39.9 mmol) in DMF (64 mL) was heated to 55 °C overnight under dry nitrogen atmosphere, after cooling to room temperature, it was diluted with ethyl acetate . The obtained mixture was washed with hydrochloric acid (2N), water (4 times) and brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with 7:3 hexane:ethyl acetate to afford 152 (14.2 g, 82%) as a pale yellow foam.

步骤5：向室温下的152(11.60g，21.4mmol)的THF溶液(138mL)中，加入氢氧化钠水溶液(2N，46mL)和甲醇(92mL)。搅拌混合物20分钟后，用水稀释，以乙醚进行提取。用盐酸(2N)酸化水相后，用醋酸乙酯提取。醋酸乙酯层用水和盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液获得为浅褐色泡沫的(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸153(10.82，98％收率)。MS：计算值(M-H)-＝512.16；实测值(M-H)-＝512.03。实施例37 Step 5 : To a room temperature solution of 152 (11.60 g, 21.4 mmol) in THF (138 mL) was added aqueous sodium hydroxide (2N, 46 mL) and methanol (92 mL). After stirring the mixture for 20 minutes, it was diluted with water and extracted with ether. After acidifying the aqueous phase with hydrochloric acid (2N), it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid 153 (10.82, 98% yield). MS: Calculated (MH) - = 512.16; Found (MH) - = 512.03. Example 37

(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸156的合成(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3- Synthesis of [yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid 156

步骤1：将干燥氮气氛下的151(8.40g，28.8mmol)和154(8.2g，35mmol)的DMF混合物(100mL)加热至55℃过夜，冷却至室温后，用醋酸乙酯稀释。用盐酸(2N)、水(4次)和盐水洗涤产生的混合物，有机层经硫酸镁干燥后过滤。减压浓缩滤液，残余物通过硅胶层析法纯化，用由8∶2增加至1∶1的己烷∶醋酸乙酯洗脱获得155(11.1g，67％收率)。 Step 1: A DMF mixture (100 mL) of 151 (8.40 g, 28.8 mmol) and 154 (8.2 g, 35 mmol) under dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature, and diluted with ethyl acetate. The resulting mixture was washed with hydrochloric acid (2N), water (4 times) and brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with hexane:ethyl acetate increasing from 8:2 to 1:1 to afford 155 (11.1 g, 67% yield).

步骤2：向室温下的155(9.12g，15.9mmol)的THF溶液(100mL)中加入氢氧化钠水溶液(1N，88mL)和甲醇(63mL)。搅拌混合物20分钟后，用水稀释，以乙醚进行提取。废弃该乙醚层。用盐酸(2N)酸化水相，用乙醚提取(4次)。有机层用水和盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液获得为白色泡沫的(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸156(8.13g，93％)。MS：计算值(M+H)+＝544.19；实测值(M+H)+＝544.04。实施例38 Step 2 : To a room temperature solution of 155 (9.12 g, 15.9 mmol) in THF (100 mL) was added aqueous sodium hydroxide (1 N, 88 mL) and methanol (63 mL). After stirring the mixture for 20 minutes, it was diluted with water and extracted with ether. The ether layer was discarded. The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ether (4 times). The organic layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1 as a white foam , 2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid 156 (8.13 g, 93%). MS: Calcd. (M+H) + = 544.19; found (M+H) + = 544.04. Example 38

(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸159的合成(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3- Synthesis of [yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propionic acid 159

步骤1：在干燥氮气氛下使151(110mg，0.29mmol)、157(130mg，0.34mmol)和NMM(0.50mL，4.5mmol)在DMF(1.0mL)中的混合物加热至55℃过夜，冷却至室温后，用醋酸乙酯稀释。用盐酸(2N)、水(4次)和盐水洗涤生成的混合物，有机层经硫酸镁干燥后过滤。减压浓缩滤液，产生的残余物通过硅胶层析法纯化，用1∶1己烷∶醋酸乙酯洗脱获得158(130mg，73％收率)。 Step 1: A mixture of 151 (110 mg, 0.29 mmol), 157 (130 mg, 0.34 mmol) and NMM (0.50 mL, 4.5 mmol) in DMF (1.0 mL) was heated to 55 °C overnight under dry nitrogen atmosphere, cooled to After room temperature, dilute with ethyl acetate. The resulting mixture was washed with hydrochloric acid (2N), water (4 times) and brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with 1:1 hexane:ethyl acetate to afford 158 (130 mg, 73% yield).

步骤2：向室温下的158(130mg，0.21mmol)的THF溶液(3mL)中加入氢氧化钠水溶液(2N，1mL)和甲醇(2mL)。搅拌混合物20分钟后，用水稀释，以乙醚进行提取。用盐酸(2N)酸化水相，以醋酸乙酯提取。醋酸乙酯层用水和盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液获得(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸159(90mg，74％收率)。MS：实测值(M+H)+＝580.07；计算值(M+H)+＝580.19。实施例39 Step 2 : To a room temperature solution of 158 (130 mg, 0.21 mmol) in THF (3 mL) was added aqueous sodium hydroxide (2N, 1 mL) and methanol (2 mL). After stirring the mixture for 20 minutes, it was diluted with water and extracted with ether. The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-di Hydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid 159 (90 mg, 74% yield). MS: found (M+H) + = 580.07; calculated (M+H) + = 580.19. Example 39

(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸164的合成(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[b] Synthesis of pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid 164

步骤1：在室温下，向129(5.30g，19.2mmol)的冰醋酸悬浮液(64mL)中依次加入亚硝酸钠(266mg，3.9mmol)、水(5.3mL)和硝酸(70％，4.9mL，77mmol)。在室温下搅拌获得的亮黄色溶液过夜，然后倾入水中并过滤，用水洗涤。减压干燥黄色固体获得160(5.35g，87％。 Step 1: To a suspension of 129 (5.30 g, 19.2 mmol) in glacial acetic acid (64 mL) was added sequentially sodium nitrite (266 mg, 3.9 mmol), water (5.3 mL) and nitric acid (70%, 4.9 mL) at room temperature , 77mmol). The resulting bright yellow solution was stirred overnight at room temperature, then poured into water and filtered, washing with water. The yellow solid was dried under reduced pressure to obtain 160 (5.35 g, 87%.

步骤2：向室温、干燥氮气氛下的160(5.35g，16.7mmol)的DMF溶液(56mL)中加入锌粉(4.88g，74.7mmol)和盐酸三乙胺(12.6g，91.5mmol)。使获得的混合物加热至55℃1小时，然后冷却至室温。向产生的混合物中加入为固体的CDI(5.41g，33.4mmol)。加入后立即释放出气体。然后使混合物加热至80℃2小时，然后冷却至室温，倾入盐酸(2N，500mL)中。搅拌获得的悬浮液20分钟后，用水(500mL)稀释并过滤。将固体重悬浮在水(500mL)中后过滤。真空干燥固体获得为白色粉末的161(5.0g，95％收率)。 Step 2 : To a solution of 160 (5.35 g, 16.7 mmol) in DMF (56 mL) at room temperature under dry nitrogen atmosphere was added zinc powder (4.88 g, 74.7 mmol) and triethylamine hydrochloride (12.6 g, 91.5 mmol). The obtained mixture was heated to 55 °C for 1 hour and then cooled to room temperature. To the resulting mixture was added CDI (5.41 g, 33.4 mmol) as a solid. Gas was released immediately after addition. The mixture was then heated to 80°C for 2 hours, then cooled to room temperature and poured into hydrochloric acid (2N, 500 mL). After stirring the resulting suspension for 20 minutes, it was diluted with water (500 mL) and filtered. The solid was resuspended in water (500 mL) and filtered. The solid was dried in vacuo to afford 161 (5.0 g, 95% yield) as a white powder.

步骤3：使161(6.14g，19.4mmol)和162(5.12g，20.3mmol)在DMF(90mL)中的混合物在干燥氮气氛下加热至80℃过夜，冷却至室温后，用醋酸乙酯稀释。用盐酸(2N)、水(4次)和盐水洗涤产生的混合物，有机层经硫酸镁干燥后过滤。减压浓缩滤液，残余物通过硅胶层析法纯化，用7∶3己烷∶醋酸乙酯洗脱获得为浅黄色泡沫的163(8.90g，81％)。 Step 3 : A mixture of 161 (6.14 g, 19.4 mmol) and 162 (5.12 g, 20.3 mmol) in DMF (90 mL) was heated to 80 °C overnight under dry nitrogen atmosphere, after cooling to room temperature, it was diluted with ethyl acetate . The resulting mixture was washed with hydrochloric acid (2N), water (4 times) and brine, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 7:3 hexane:ethyl acetate to afford 163 (8.90 g, 81%) as a pale yellow foam.

步骤4：向室温下的163(8.69g，15.3mmol)的THF溶液(35mL)中加入氢氧化钠水溶液(2N，30mL)和甲醇(30mL)。搅拌混合物过夜，然后用水稀释，以乙醚进行提取。用盐酸(2N)酸化水相，以醋酸乙酯进行提取。醋酸乙酯层用水和盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液获得(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸164(7.50g，91％收率)。MS：实测值(M+H)+＝540.09；计算值(M+H)+＝540.19。实施例40 Step 4 : To a room temperature solution of 163 (8.69 g, 15.3 mmol) in THF (35 mL) was added aqueous sodium hydroxide (2N, 30 mL) and methanol (30 mL). The mixture was stirred overnight, then diluted with water and extracted with ether. The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene Ekeno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid 164 (7.50 g, 91% yield). MS: found (M+H) + = 540.09; calculated (M+H) + = 540.19. Example 40

(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-氯-3-异丙氧基苯基)丙酸的合成(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene [b] Synthesis of pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propionic acid

步骤1：通过注射器向在干燥氮气氛下冷却至0℃的162(200mg，0.80mmol)的冰醋酸混合物(1.65mL)中滴加SO2Cl2(1.2mL，15mmol)的冰醋酸混合物(1.0mL)。在0℃下搅拌生成的混合物30分钟后，使其温热至室温。再搅拌4小时后，重新使混合物冷却至0℃，之后小心加入饱和碳酸氢钠水溶液使其骤冷。用醋酸乙酯提取混合物，有机层用饱和碳酸氢钠水溶液洗涤，经硫酸镁干燥后过滤。减压浓缩滤液，残留物通过硅胶层析法纯化，用2∶1己烷∶醋酸乙酯洗脱获得165(148mg，65％)。 Step 1: To a mixture of 162 (200 mg, 0.80 mmol) in glacial acetic acid (1.65 mL) cooled to 0 °C under a dry nitrogen atmosphere was added dropwise a mixture of SO 2 Cl 2 (1.2 mL, 15 mmol) in glacial acetic acid (1.0 mL). After stirring the resulting mixture at 0°C for 30 minutes, it was allowed to warm to room temperature. After stirring for a further 4 hours, the mixture was re-cooled to 0°C before being quenched by the careful addition of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 2:1 hexane:ethyl acetate to afford 165 (148 mg, 65%).

按照实施例25和30介绍的方法由165制备(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-氯-3-异丙氧基苯基)丙酸。MS：计算值(M-H)-＝586.15；实测值(M-H)-＝585.92。实施例41 According to the method described in Examples 25 and 30, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetra Hydrogen-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propanoic acid. MS: Calculated (MH) - = 586.15; Found (MH) - = 585.92. Example 41

(3S)-3-({[(1-{[2-氯-6-四氢-1(2H)-吡啶基苯基]甲基}-4-羟基-5-甲基-2-氧代-1，2-二氢-3-吡啶基)氨基]羰基}氨基)-3-(4-甲基苯基)丙酸的合成(3S)-3-({[(1-{[2-Chloro-6-tetrahydro-1(2H)-pyridylphenyl]methyl}-4-hydroxy-5-methyl-2-oxo -Synthesis of 1,2-dihydro-3-pyridyl)amino]carbonyl}amino)-3-(4-methylphenyl)propionic acid

步骤1：向冷却至0℃的166(0.35g，1.06mmol，按照实施例34和35介绍的方法制得)在甲醇(7mL)和水(3.5mL)中的悬浮液中，依次加入冰醋酸(189μL，3.2mmol)和亚硝酸钠(178mg，2.65mmol)。使混合物缓慢温热至室温过夜，然后用氯仿和水稀释。检查水相的pH，确保pH为4-5。有机层用盐水洗涤，经硫酸镁干燥后过滤，减压浓缩滤液获得为黄色固体的167(0.35g，92％)。 Step 1: To a suspension of 166 (0.35 g, 1.06 mmol, prepared as described in Examples 34 and 35) in methanol (7 mL) and water (3.5 mL) cooled to 0 °C, glacial acetic acid was added sequentially (189 μL, 3.2 mmol) and sodium nitrite (178 mg, 2.65 mmol). The mixture was allowed to warm slowly to room temperature overnight, then diluted with chloroform and water. Check the pH of the aqueous phase to make sure it is 4-5. The organic layer was washed with brine, dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 167 (0.35 g, 92%) as a yellow solid.

按照实施例25介绍的方法由167制备(3S)-3-({[(1-{[2-氯-6-四氢-1(2H)-吡啶基苯基]甲基}-4-羟基-5-甲基-2-氧代-1，2-二氢-3-吡啶基)氨基]羰基}氨基)-3-(4-甲基苯基)丙酸。MS：计算值(M-H)-＝551.21；实测值(M-H)-＝551.06。实施例42 According to the method described in Example 25, (3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)-pyridylphenyl]methyl}-4-hydroxyl -5-methyl-2-oxo-1,2-dihydro-3-pyridyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid. MS: Calculated (MH) - = 551.21; Found (MH) - = 551.06. Example 42

(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-5-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-(二氟甲基)苯基]丙酸的合成(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridyl} Synthesis of amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propionic acid

步骤1：向干燥氮气氛下的3-溴苯甲醛168(3.00g，16.2mmol)的DMF溶液(69mL)中加入醋酸钯(73mg，0.32mmol)、三邻甲苯膦(197mg，0.65mmol)、丙烯酸乙酯(2.20mL，20.3mmol)和三乙胺(4.50mL，32.4mmol)。使该体系脱氧(在真空和氮气之间切换5次)，将混合物加热至125℃19小时后，使其冷却至室温。将反应物倾入至水中，然后用乙醚提取。有机层用盐酸(4N)和盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液获得169(2.74g，83％)，该物质无需进一步纯化即可使用。 Step 1: To a solution of 3-bromobenzaldehyde 168 (3.00 g, 16.2 mmol) in DMF (69 mL) under a dry nitrogen atmosphere was added palladium acetate (73 mg, 0.32 mmol), tri-o-tolylphosphine (197 mg, 0.65 mmol), Ethyl acrylate (2.20 mL, 20.3 mmol) and triethylamine (4.50 mL, 32.4 mmol). The system was deoxygenated (switching between vacuum and nitrogen 5 times) and the mixture was heated to 125° C. for 19 hours before being allowed to cool to room temperature. The reactant was poured into water, then extracted with ether. The organic layer was washed with hydrochloric acid (4N) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 169 (2.74 g, 83%) which was used without further purification.

步骤2：通过注射器向干燥氮气氛下装有169(1.00g，4.9mmol)的烧瓶中加入(二甲基氨基)三氟化硫(0.96mL，9.8mmol)。将获得的混合物在鼓风屏后加热至90℃25分钟后，使其冷却至室温。用二氯甲烷稀释产生的混合物，以饱和碳酸氢钠水溶液和水进行洗涤。有机层经硫酸镁干燥后过滤，减压浓缩滤液。残余物通过硅胶层析法纯化，用1∶5醋酸乙酯∶己烷洗脱获得170(0.62g，56％)。 Step 2 : To a flask containing 169 (1.00 g, 4.9 mmol) under dry nitrogen was added (dimethylamino)sulfur trifluoride (0.96 mL, 9.8 mmol) via syringe. The obtained mixture was heated to 90° C. behind a fan screen for 25 minutes and allowed to cool to room temperature. The resulting mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 ethyl acetate:hexanes to afford 170 (0.62 g, 56%).

步骤3：在干燥氮气氛下向冷却至-78℃的(R)-(+)-N-苄基-α-甲基苄胺(0.70g，3.3mmol)的THF溶液(6.7mL)中，滴加仲丁基锂(4.22mL，1.3M的环己烷溶液，5.5mmol)。于-78℃下搅拌产生的混合物30分钟后，通过注射器加入170(0.62g，2.74mmol)的THF溶液(3.4mL)。于-78℃搅拌混合物5小时，然后用冰乙醇(2mL)的THF溶液(5mL)骤冷混合物。使反应混合物温热至室温，将其倾入饱和碳酸氢钠水溶液∶醋酸乙酯的1∶1混合物中。有机层用水(2次)和盐水洗涤，经硫酸镁干燥后过滤。减压浓缩滤液，残余物通过硅胶层析法纯化，用1∶5醋酸乙酯∶己烷洗脱获得171(1.2g，100％)。该物质仍然含有少量杂质，但是无需进一步纯化即可使用。 Step 3 : To a solution of (R)-(+)-N-benzyl-α-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 °C under dry nitrogen atmosphere, Sec-butyllithium (4.22 mL, 1.3 M in cyclohexane, 5.5 mmol) was added dropwise. After stirring the resulting mixture at -78 °C for 30 min, a THF solution (3.4 mL) of 170 (0.62 g, 2.74 mmol) was added via syringe. The mixture was stirred at -78°C for 5 hours, then the mixture was quenched with ice ethanol (2 mL) in THF (5 mL). The reaction mixture was allowed to warm to room temperature and poured into a 1:1 mixture of saturated aqueous sodium bicarbonate: ethyl acetate. The organic layer was washed with water (2x) and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:5 ethyl acetate:hexane to afford 171 (1.2 g, 100%). This material still contained minor impurities but was used without further purification.

步骤4：向室温、干燥氮气氛下的171(0.50g，1.14mmol)的乙醇溶液(10mL)中加入Pd/C(10％Pd干重计，50％(重量)的水，DegussaE101 NE/W型，0.25g)和冰乙醇(0.5mL)。用氢气代替干燥氮气氛(在真空和气球氢气之间切换5次)，使混合物加热至35℃6小时。使反应物冷却至室温，然后通过Celite521滤塞过滤，减压浓缩滤液。用三氯甲烷稀释残余物，以饱和碳酸氢钠水溶液洗涤。水层用三氯甲烷提取(2次)，合并的有机层经硫酸镁干燥后过滤。减压浓缩滤液，残余物通过硅胶层析法纯化，用1∶10甲醇∶三氯甲烷洗脱获得172(180mg，67％)。 Step 4 : To a solution of 171 (0.50 g, 1.14 mmol) in ethanol (10 mL) at room temperature under a dry nitrogen atmosphere was added Pd/C (10% Pd dry weight, 50% by weight) of water, DegussaE101 NE/W type, 0.25g) and ice ethanol (0.5mL). The dry nitrogen atmosphere was replaced with hydrogen (switched 5 times between vacuum and balloon hydrogen) and the mixture was heated to 35°C for 6 hours. The reaction was allowed to cool to room temperature then filtered through a plug of Celite (R) 521 and the filtrate concentrated under reduced pressure. The residue was diluted with chloroform and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with CHCl2 (2x), and the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:10 methanol:chloroform to afford 172 (180 mg, 67%).

按照实施例25介绍的方法由172合成(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-5-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-(二氟甲基)苯基]丙酸。MS：计算值(M-H)-＝504.11；实测值(M-H)-＝503.96。实施例43 According to the method described in Example 25, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-5-methyl-2-oxo-1 was synthesized from 172, 2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoic acid. MS: Calculated (MH) - = 504.11; found (MH) - = 503.96. Example 43

通过改变原料应用实施例3、4、8、25、26、27、29、30、34、36、39和41介绍的方法合成若干通式VII和通式VIII的化合物。下表1提供所合成化合物的特征数据。Several compounds of general formula VII and general formula VIII were synthesized by changing the raw materials using the methods introduced in Examples 3, 4, 8, 25, 26, 27, 29, 30, 34, 36, 39 and 41. Table 1 below provides characterization data for the compounds synthesized.

                      表1化合物                        1H NMR(400MHz)5-(2-氯苄基)-3，5-二氢[1，3]  (CD3SO2CD3)δ5.27(s，2H)，6.67(d，J＝7.4噁唑并[4，5-c]吡啶-2，4-二    Hz，1H)，6.88(dd，J＝7.3，1.4Hz，1H)，7.27-酮                            7.37(m，2H)，7.51(dd，J＝7.9，1.5Hz，1H)，Table 1 Compound 1 H NMR (400MHz) 5-(2-chlorobenzyl)-3,5-dihydro[1,3](CD 3 SO 2 CD 3 )δ5.27(s, 2H), 6.67(d , J=7.4 oxazolo[4,5-c]pyridine-2,4-diHz, 1H), 6.88 (dd, J=7.3, 1.4Hz, 1H), 7.27-one 7.37 (m, 2H), 7.51 (dd, J=7.9, 1.5Hz, 1H),

                          7.65(d，J＝7.4Hz，1H)，12.01(br.s，1H).5-(2-氯苄基)-6-甲基-3，5-     (CD3SO2CD3)δ2.27(s，3H)，5.36(s，2H)，二氢[1，3]噁唑并[4，5-c]吡    6.60(d，J＝7.3Hz，1H，6.63(s，1H)，7.27-7.65(d, J=7.4Hz, 1H), 12.01(br.s, 1H).5-(2-chlorobenzyl)-6-methyl-3,5-(CD 3 SO 2 CD 3 )δ2. 27(s, 3H), 5.36(s, 2H), dihydro[1,3]oxazolo[4,5-c]pyridine 6.60(d, J=7.3Hz, 1H, 6.63(s, 1H), 7.27-

                          7.37(m，2H)，7.51(d，J＝7.7Hz，1H)，11.9啶-2，4-二酮                  7.37 (m, 2H), 7.51 (d, J = 7.7 Hz, 1H), 11.9 pyridine-2, 4-dione

                          (br，s，1H).5-(2-氟苄基)-3，5-二氢[1，3]  (CD3SO2CD3)δ5.26(s，2H)，6.65(d，J＝7.3噁唑并[4，5-c]吡啶-2，4-二    Hz，1H)，6.88，7.12-7.26(m，3H)，7.37(m，(br, s, 1H).5-(2-fluorobenzyl)-3,5-dihydro[1,3](CD 3 SO 2 CD 3 )δ5.26(s, 2H), 6.65(d, J=7.3 oxazolo[4,5-c]pyridine-2,4-diHz, 1H), 6.88, 7.12-7.26(m, 3H), 7.37(m,

                          1H)，7.69(d，J＝7.3Hz，1H)，11.93(br.s，酮        1H), 7.69(d, J=7.3Hz, 1H), 11.93(br.s, ketone

                          1H).5-(2-氯-6-氟苄基)-3，5-二     (CD3SO2CD3)δ5.30(s，2H)，6.56(d，J＝7.3氢[1，3]噁唑并[4，5-c]吡啶-   Hz，1H)，7.25(ddd，J＝9.4，8.9，1.1Hz，1H).5-(2-Chloro-6-fluorobenzyl)-3,5-di(CD 3 SO 2 CD 3 )δ5.30(s, 2H), 6.56(d, J=7.3 hydrogen [1, 3] oxazolo[4,5-c]pyridine - Hz, 1H), 7.25 (ddd, J = 9.4, 8.9, 1.1 Hz,

                          1H)，7.37(d，J＝8.0Hz，1H)，7.43(m，2H)，         1H), 7.37(d, J=8.0Hz, 1H), 7.43(m, 2H),

                          2，4-二酮                                                                   

                          11.93(br.s，1H).5-苄基-6-甲基-3，5-二氢       (CD3SO2CD3)δ2.30(s，3H)，5.37(s，2H)，[1，3]噁唑并[4，5-c]吡啶-     6.55(s，1H)，7.10(d，J＝7.0Hz，2H)，7.24-11.93(br.s, 1H).5-benzyl-6-methyl-3,5-dihydro(CD 3 SO 2 CD 3 )δ2.30(s, 3H), 5.37(s, 2H), [ 1,3]oxazolo[4,5-c]pyridine- 6.55(s, 1H), 7.10(d, J=7.0Hz, 2H), 7.24-

                          7.36(m，3H)，11.88(br.s，1H).2，4-二酮5-苄基-3，5-二氢[1，3]噁唑    (CD3SO2CD3)δ5.20(s，2H)，6.60(d，J＝7.3并[4，5-c]吡啶-2，4-二酮      Hz，1H)，7.28-7.36(m，5H)，7.72(d，J＝7.37.36(m, 3H), 11.88(br.s, 1H).2,4-diketone 5-benzyl-3,5-dihydro[1,3]oxazole (CD 3 SO 2 CD 3 )δ5. 20(s, 2H), 6.60(d, J=7.3[4,5-c]pyridine-2,4-dione Hz, 1H), 7.28-7.36(m, 5H), 7.72(d, J= 7.3

                          Hz，1H)，11.97(br.s，1H).5-(2，5-二甲基苄基)-3，5-二   (CDCl3)δ2.27(s，3H)，2.32(s，3H)，5.27(s，氢[1，3]噁唑并[4，5-c]吡啶-   2H)，6.42(d，J＝7.3Hz，1H)6.90(s，1H)，2，4-二酮                     7.09(m，3H)，10.68(br s，1H).5-(2-甲基苄基)-3，5-二氢      (CDCl3)δ2.30(s，3H)，5.28(8，2H)，6.39(d，J[1，3]噁唑并[4，5-c]吡啶-     ＝7.3Hz，1H)，7.06(d，J＝7.3Hz，1H)，7.09Hz, 1H), 11.97(br.s, 1H).5-(2,5-dimethylbenzyl)-3,5-di(CDCl 3 )δ2.27(s, 3H), 2.32(s, 3H), 5.27(s, hydrogen[1,3]oxazolo[4,5-c]pyridine-2H), 6.42(d, J=7.3Hz, 1H), 6.90(s,1H), 2,4- Diketone 7.09 (m, 3H), 10.68 (br s, 1H). 5-(2-methylbenzyl)-3,5-dihydro (CDCl 3 ) δ2.30 (s, 3H), 5.28 (8 , 2H), 6.39 (d, J[1,3]oxazolo[4,5-c]pyridine-=7.3Hz, 1H), 7.06 (d, J=7.3Hz, 1H), 7.09

                          (d，J＝7.7Hz，1H)，7.18-7.28(m，3H)10.912，4-二酮  (d, J=7.7Hz, 1H), 7.18-7.28(m, 3H) 10.912, 4-diketone

                          (br s，1H).5-(2，4-二氯苄基)-3，5-二氢   (CDCl3)δ5.33(s，2H)，6.47(d，J＝7.3Hz，[1，3]噁唑并[4.5-c]吡啶-      1H)，7.29(m，1H)，7.38(d，J＝7.3Hz，1H)，(br s, 1H).5-(2,4-dichlorobenzyl)-3,5-dihydro(CDCl 3 )δ5.33(s, 2H), 6.47(d, J=7.3Hz, [1 , 3] oxazolo[4.5-c]pyridine-1H), 7.29 (m, 1H), 7.38 (d, J=7.3Hz, 1H),

                          7.42-7.48(m，2H)10.77(br s，1H).2，4-二酮5-(2-甲氧基苄基)-3，5-二       (CDCl3)δ3.87(s，1H)，5.24(s，2H)，6.36(d，J氢[1，3]噁唑并[4，5-c]吡啶-    ＝7.5Hz，1H，6.88(d，J＝8.1Hz，1H)，6.972，4-二酮                      (m，1H)，7.30(m，1H)，7.45(d，J＝7.5Hz，7.42-7.48(m, 2H) 10.77(br s, 1H). 2,4-diketone 5-(2-methoxybenzyl)-3,5-di(CDCl 3 )δ3.87(s, 1H ), 5.24(s, 2H), 6.36(d, J Hydro[1,3]oxazolo[4,5-c]pyridine-=7.5Hz, 1H, 6.88(d, J=8.1Hz, 1H), 6.972, 4-diketone (m, 1H), 7.30 (m, 1H), 7.45 (d, J=7.5Hz,

                           1H)，7.55(m，1H)，10.75(br.s，1H).5-(2，5-二氟苄基)-3，5-二      (CDCl3)δ5.26(s，2H)，6.46(d，J＝7.4Hz，氢[1，3]噁唑并[4，5-c]吡啶-    1H)，6.96-7.05(m，2H)，7.30-7.37(m，1H)，2，4-二酮                      7.39(m，1H)，10.68(br.s，1H).5-[2-氯-5-(甲硫基)苄基]-       (CD3SO2CD3)δ2.41(s，3H)，5.24(s，2H)，3，5-二氢[13]噁唑并[4，5-c]    6.65(d，J＝7.2Hz，1H)，6.83(d，J＝2.6Hz，1H), 7.55(m, 1H), 10.75(br.s, 1H).5-(2,5-difluorobenzyl)-3,5-di(CDCl 3 )δ5.26(s, 2H), 6.46 (d, J=7.4Hz, hydrogen [1,3]oxazolo[4,5-c]pyridine-1H), 6.96-7.05 (m, 2H), 7.30-7.37 (m, 1H), 2, 4-diketone 7.39 (m, 1H), 10.68 (br.s, 1H).5-[2-chloro-5-(methylthio)benzyl]-(CD 3 SO 2 CD 3 )δ2.41( s, 3H), 5.24(s, 2H), 3,5-dihydro[13]oxazolo[4,5-c] 6.65(d, J=7.2Hz, 1H), 6.83(d, J=2.6 Hz,

                           1H)，7.25(dd，J＝8.0，2.6Hz，2H)，7.45(d，J＝吡啶-2，4-二酮            1H), 7.25 (dd, J = 8.0, 2.6Hz, 2H), 7.45 (d, J = pyridine-2,4-dione

                           8.0Hz，1H)，7.62(d，J＝7.2Hz，1H)，12.01          8.0Hz, 1H), 7.62(d, J=7.2Hz, 1H), 12.01

                           (br.s，1H).5-(4-氟苄基)-3，5-二氢[1，3]   (CD3SO2CD3)δ5.18(s，2H)，6.61(d，J＝7.4噁唑并[4，5-c]吡啶-2，4-二     Hz，1H)，7.14-7.2(m，2H)，7.35-7.39(m，2H)，酮                             7.74(d，J＝7.3Hz，1H)，11.96(br.s，1H).5-(2-氯-5-甲氧基苄基)-         (CD3SO2CD3)δ3.69(s，3H)，5.22(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]  6.42(d，J＝2.9Hz，1H)，6.65(d，J＝7.3Hz，(br.s, 1H).5-(4-fluorobenzyl)-3,5-dihydro[1,3](CD 3 SO 2 CD 3 )δ5.18(s, 2H), 6.61(d, J=7.4 oxazolo[4,5-c]pyridine-2,4-diHz, 1H), 7.14-7.2(m, 2H), 7.35-7.39(m, 2H), ketone 7.74(d, J= 7.3Hz, 1H), 11.96(br.s, 1H).5-(2-chloro-5-methoxybenzyl)-(CD 3 SO 2 CD 3 )δ3.69(s, 3H), 5.22( s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.42(d, J=2.9Hz, 1H), 6.65(d, J=7.3Hz,

                           1H)，6.94 (dd，J＝8.8，2.9Hz，1H)，7.43(d，J吡啶-2，4-二酮          1H), 6.94 (dd, J=8.8, 2.9Hz, 1H), 7.43 (d, J pyridine-2,4-dione

                           ＝8.8Hz，1H)，7.62(d，J＝7.3Hz，1H)，12.05=8.8Hz, 1H), 7.62 (d, J = 7.3Hz, 1H), 12.05

                           (br.s，1H).5-[3，5-二(三氟甲基)苄基]-     (CD3SO2CD3)δ5.36(s，2H)，6.69(d，J＝7.53，5-二氢[1，3]噁唑并[4，5-c]  Hz，1H)，7.91(d，J＝7.5Hz，1H)，8.08(s，吡啶-2，4-二酮                 3H，12.04(br.S，1H).5-(4-叔丁基苄基)-3，5-二       (CD3SO2CD3)δ1.24(s，9H)，5.15(s，2H)，氢[1，3]噁唑并[4，5-c]吡啶-    6.61(d，J＝7.3Hz，1H)，7.23(d，J＝8.4Hz，(br.s, 1H).5-[3,5-bis(trifluoromethyl)benzyl]-(CD 3 SO 2 CD 3 )δ5.36(s, 2H), 6.69(d, J=7.53 , 5-dihydro[1,3]oxazolo[4,5-c] Hz, 1H), 7.91(d, J=7.5Hz, 1H), 8.08(s, pyridine-2,4-dione 3H , 12.04(br.S, 1H).5-(4-tert-butylbenzyl)-3,5-di(CD 3 SO 2 CD 3 )δ1.24(s, 9H), 5.15(s, 2H) , Hydro[1,3]oxazolo[4,5-c]pyridine - 6.61(d, J=7.3Hz, 1H), 7.23(d, J=8.4Hz,

                           2H)，7.35(d，J＝8.4Hz，2H)，7.74(d，J＝7.32，4-二酮             2H), 7.35(d, J = 8.4Hz, 2H), 7.74(d, J = 7.32, 4-diketone

                           Hz，1H)，12.02(br.s，1H).5-(3-氯苄基)-3，5-二氢[1，3]   (CD3SO2CD3)δ5.20(s，2H)，6.63(d，J＝7.4噁唑并[4，5-c]吡啶-2，4-二     Hz，1H)，7.25(m，1H)，7.35-7.39(m，3H)，酮                             7.76(d，J＝7.4Hz，1H)，11.97(br.s，1H).5-(4-氯苄基)-3，5-二氢[1，3]   (CD3SO2CD3)δ5.19(s，2H)，6.62(d，J＝7.3噁唑并[4，5-c]吡啶-2，4-二     Hz，1H，7.29-7.33(m，2H)，7.37-7.42(m，酮                             2H)，7.73(d，J＝7.3Hz，1H)，11.97(br.s，Hz, 1H), 12.02(br.s, 1H).5-(3-chlorobenzyl)-3,5-dihydro[1,3](CD 3 SO 2 CD 3 )δ5.20(s, 2H ), 6.63 (d, J=7.4 oxazolo[4,5-c]pyridine-2,4-diHz, 1H), 7.25 (m, 1H), 7.35-7.39 (m, 3H), ketone 7.76 ( d, J=7.4Hz, 1H), 11.97(br.s, 1H).5-(4-chlorobenzyl)-3,5-dihydro[1,3](CD 3 SO 2 CD 3 )δ5. 19(s, 2H), 6.62(d, J=7.3oxazolo[4,5-c]pyridine-2,4-diHz, 1H, 7.29-7.33(m, 2H), 7.37-7.42(m, Ketone 2H), 7.73 (d, J=7.3Hz, 1H), 11.97 (br.s,

                           1H).5-[3-(三氟甲基)苄基]-3，5-     n.d.二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮5-(2-溴苄基)-3，5-二氢[1，3]     (CD3SO2CD3)δ5.23(s，2H)，6.68(d，J＝7.4噁唑并[4，5-c]吡啶-2，4-二       Hz，1H)，6.79(m，1H)，7.26(m，1H)，7.34(m，1H).5-[3-(trifluoromethyl)benzyl]-3,5-nd dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione 5- (2-Bromobenzyl)-3,5-dihydro[1,3](CD 3 SO 2 CD 3 )δ5.23(s, 2H), 6.68(d, J=7.4oxazolo[4,5 -c] pyridine-2,4-diHz, 1H), 6.79 (m, 1H), 7.26 (m, 1H), 7.34 (m,

                             1H)，7.64(d，J＝7.4Hz，1H)，7.68(m，1H)，酮           1H), 7.64(d, J=7.4Hz, 1H), 7.68(m, 1H), ketone

                             12.02(br.s，1H).5-(3，4-二氯苄基)-3，5-二氢      (CD3SO2CD3)δ5.19(s，2H)，6.64(d，J＝7.3[1，3]噁唑并[4，5-c]吡啶-        Hz，1H，7.29(m，1H)，7.61(m，2H)，7.77(d，2，4-二酮                        J＝7.3Hz，1H)，11.98(br.s，1H).5-(4-甲基苄基)-3，5-二氢         (CD3SO2CD3)δ2.27(s，3H)，5.14(s，2H).[1，3]噁唑并[4，5-c]吡啶-        6.59(d，J＝7.5Hz，1H)，7.14(d，J＝8.2Hz，12.02(br.s, 1H).5-(3,4-dichlorobenzyl)-3,5-dihydro(CD 3 SO 2 CD 3 )δ5.19(s, 2H), 6.64(d, J =7.3[1,3]oxazolo[4,5-c]pyridine-Hz, 1H, 7.29(m,1H), 7.61(m,2H), 7.77(d,2,4-dione J=7.3 Hz, 1H), 11.98(br.s, 1H).5-(4-methylbenzyl)-3,5-dihydro(CD 3 SO 2 CD 3 )δ2.27(s, 3H), 5.14( s, 2H).[1,3]oxazolo[4,5-c]pyridine-6.59 (d, J=7.5Hz, 1H), 7.14 (d, J=8.2Hz,

                             2H)，7.20(d，J＝8.2Hz，2H)，7.69(d，J＝7.52，4-二酮           2H), 7.20(d, J=8.2Hz, 2H), 7.69(d, J=7.52, 4-diketone

                             Hz，1H)，11.95(br.s，1H).5-(2-氯-6-甲氧基苄基)-           (CD3SO2CD3)δ3.80(s，3H，5.23(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]    6.48(d，J＝7.4Hz，1H)，7.05-7.15(m，3H)，吡啶-2，4-二酮                   7.42(m，1H)，11.95(br.s，1H).5-[4-(三氟甲基)苄基]-3，5-       (CD3SO2CD3)δ5.30(s，2H)，6.65(d，J＝7.3二氢[1，3]噁唑并[4，5-c]吡       Hz，1H)，7.48(d，J＝8.0Hz，2H)，7.71(d，J＝Hz, 1H), 11.95(br.s, 1H).5-(2-chloro-6-methoxybenzyl)-(CD 3 SO 2 CD 3 )δ3.80(s, 3H, 5.23(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.48(d, J=7.4Hz, 1H), 7.05-7.15(m, 3H), pyridine-2,4 -Diketone 7.42 (m, 1H), 11.95 (br.s, 1H).5-[4-(trifluoromethyl)benzyl]-3,5-(CD 3 SO 2 CD 3 )δ 5.30( s, 2H), 6.65 (d, J=7.3 dihydro[1,3]oxazolo[4,5-c]pyridine Hz, 1H), 7.48 (d, J=8.0Hz, 2H), 7.71(d , J＝

                             8.0Hz，2H)，7.76(d，J＝7.3Hz，1H)，11.96啶-2，4-二酮        8.0Hz, 2H), 7.76(d, J=7.3Hz, 1H), 11.96 pyridine-2,4-dione

                             (br.s，1H).5-(3-甲基苄基)-3，5-二氢         (CD3SO2CD3)δ2.27(s，3H)，5.15(s，2H)，[1，3]噁唑并[4，5-c]吡啶-        6.62(d，J＝7.3Hz，1H)，7.10(m，4H)，7.722，4-二酮                        (d，J＝7.3Hz，1H)，12.53(br.s，1H).5-(吡啶-2-基甲基)-3，5-二        (CD3SO2CD3)δ5.29 (s，2H)，6.62(d.J＝7.3氢[1，3]噁唑并[4，5-c]吡啶-      Hz，1H)，7.22-7.33(m，2H)，7.71(d，J＝7.32，4-二酮                        Hz，1H)，7.79(m，1H)，8.50(m，1H)，11.96(br.s, 1H).5-(3-methylbenzyl)-3,5-dihydro(CD 3 SO 2 CD 3 )δ2.27(s, 3H), 5.15(s, 2H), [ 1,3]oxazolo[4,5-c]pyridine-6.62 (d, J=7.3Hz, 1H), 7.10 (m, 4H), 7.722,4-dione (d, J=7.3Hz, 1H ), 12.53 (br.s, 1H).5-(pyridin-2-ylmethyl)-3,5-di(CD 3 SO 2 CD 3 )δ5.29 (s, 2H), 6.62 (dJ=7.3 Hydro[1,3]oxazolo[4,5-c]pyridine-Hz, 1H), 7.22-7.33 (m, 2H), 7.71 (d, J=7.32, 4-diketone Hz, 1H), 7.79 (m, 1H), 8.50 (m, 1H), 11.96

                             (br.s，1H).5-(2-氯苄基)-7-甲基-3，5-        (CD3SO2CD3)δ2.10(s，3H)，5.23(s，2H)，二氢[1，3]噁唑并[4，5-c]吡       6.86(dd，J＝7.7，1.5Hz，1H)，7.31(m，2H)，啶-2，4-二酮                     7.50(m，2H)，12.01(brs，1H).5-(2，4-二氟苄基)-3，5-二氢      (CD3SO2CD3)δ5.21(s，2H)，6.63(d，J＝7.3[1，3]噁唑并[4，5-c]吡啶-        Hz，1H)，7.02-7.07(m，1H)，7.20-7.29(m，2，4-二酮                        2H)，7.65(d，J＝7.3Hz，1H)，11.97(br.s，(br.s, 1H).5-(2-chlorobenzyl)-7-methyl-3,5-(CD 3 SO 2 CD 3 )δ2.10(s, 3H), 5.23(s, 2H) , dihydro[1,3]oxazolo[4,5-c]pyridine 6.86 (dd, J=7.7, 1.5Hz, 1H), 7.31 (m, 2H), pyridine-2,4-dione 7.50 ( m, 2H), 12.01(brs, 1H).5-(2,4-difluorobenzyl)-3,5-dihydro(CD 3 SO 2 CD 3 )δ5.21(s, 2H), 6.63( d, J=7.3[1,3]oxazolo[4,5-c]pyridine-Hz,1H), 7.02-7.07(m,1H), 7.20-7.29(m,2,4-dione 2H) , 7.65 (d, J=7.3Hz, 1H), 11.97 (br.s,

                             1H).5-(2，6-二氟苄基)3，5-二氢       (CD3SO2CD3)δ5.25(s，2H)，6.58(d，J＝7.3[1，3]噁唑并[4，5-c]吡啶-        Hz，1H)，7.02-7.12(m，2H)7.38-7.55(m，1H).5-(2,6-difluorobenzyl)3,5-dihydro(CD 3 SO 2 CD 3 )δ5.25(s, 2H), 6.58(d, J=7.3[1,3] Oxazolo[4,5-c]pyridine - Hz, 1H), 7.02-7.12(m, 2H) 7.38-7.55(m,

                             1H)，7.63(d，J＝7.3Hz，1H)，11.91(br.s，2，4-二酮          1H), 7.63(d, J=7.3Hz, 1H), 11.91(br.s, 2,4-diketone

                             1H).5-[3-(三氟甲氧基)苄基]-         (CD3SO2CD3)δ5.24(s，2H)，6.64(d，J＝7.33，5-二氢[1，3]噁唑并[4，5-c]   Hz，1H)，7.22-7.35(m，3H)，7.46(t，J＝7.71H).5-[3-(trifluoromethoxy)benzyl]-(CD 3 SO 2 CD 3 )δ5.24(s, 2H), 6.64(d, J=7.33, 5-dihydro[1 , 3] oxazolo[4,5-c] Hz, 1H), 7.22-7.35(m, 3H), 7.46(t, J=7.7

                            Hz，1H)，7.78(d，J＝7.3Hz，1H)，11.99(br.s，吡啶-2，4-二酮        Hz, 1H), 7.78(d, J=7.3Hz, 1H), 11.99(br.s, pyridine-2,4-dione

                            1H).5-[4-(三氟甲氧基)苄基]-         (CD3SO2CD3)δ5.23(s，2H)，6.63(d，J＝7.33，5-二氢[1，3]噁唑并[4，5-c]   Hz，1H)，7.29-7.45(m，4H)，7.76(d，J＝7.3吡啶-2，4-二酮                  Hz，1H)，11.98(br.s，1H).5-[2-(三氟甲基)苄基]-3，5-      (CD3SO2CD3)δ5.40(s，2H)，6.73(d，J＝7.3二氢[1，3]噁唑并[4，5-c]吡      Hz，1H)，6.81(d，J＝7.5Hz，1H)，7.51(t，J＝1H).5-[4-(trifluoromethoxy)benzyl]-(CD 3 SO 2 CD 3 )δ5.23(s, 2H), 6.63(d, J=7.33, 5-dihydro[1 , 3] oxazolo[4,5-c] Hz, 1H), 7.29-7.45 (m, 4H), 7.76 (d, J = 7.3 pyridine-2, 4-dione Hz, 1H), 11.98 (br .s, 1H).5-[2-(trifluoromethyl)benzyl]-3,5-(CD 3 SO 2 CD 3 )δ5.40(s, 2H), 6.73(d, J=7.3 di Hydro[1,3]oxazolo[4,5-c]pyridine Hz, 1H), 6.81(d, J=7.5Hz, 1H), 7.51(t, J=

                            7.5Hz，1H)，7.61(t，J＝7.5Hz，1H)，7.70(d，啶2，4-二酮          7.5Hz, 1H), 7.61(t, J=7.5Hz, 1H), 7.70(d, pyridine 2, 4-dione

                            J＝7.3Hz，1H)，7.80(d，J＝7.5Hz，1H)，J＝7.3Hz, 1H), 7.80(d, J＝7.5Hz, 1H),

                            12.04(br.s，1H).5-(3-甲氧基苄基)-3，5-二        n.d.氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮5-(2，3-二氯苄基)-3，5-二氢     n.d.[1，3]噁唑并[4，5-c]吡啶-2，4-二酮5-(3，5-二甲基苄基)-3，5-二     (CD3SO2CD3)δ2.23(s，6H)，5.11(s，2H)，氢[1，3]噁唑并[4，5-c]吡啶-     6.61(d，J＝7.3Hz，1H)，6.91(m，3H)，7.692，4-二酮                       (d，J＝7.3Hz，1H)，12.00(br.s，1H).5-(2-氯苄基)-7-戊基-3，5-       (CD3SO2CD3)δ0.86(t，J＝6.2Hz，3H)，1.27二氢[1，3]噁唑并[4，5-c]吡      (m，6H)，1.65(t，J＝6.7Hz，2H)，5.24(s，2H)，12.04(br.s, 1H).5-(3-Methoxybenzyl)-3,5-dindhydro[1,3]oxazolo[4,5-c]pyridine-2,4-di Ketone 5-(2,3-dichlorobenzyl)-3,5-dihydrond[1,3]oxazolo[4,5-c]pyridine-2,4-dione 5-(3,5 -Dimethylbenzyl)-3,5-bis(CD 3 SO 2 CD 3 )δ 2.23(s, 6H), 5.11(s, 2H), hydrogen [1,3]oxazolo[4,5 -c]pyridine- 6.61(d, J=7.3Hz, 1H), 6.91(m, 3H), 7.692, 4-diketone(d, J=7.3Hz, 1H), 12.00(br.s, 1H). 5-(2-chlorobenzyl)-7-pentyl-3,5-(CD 3 SO 2 CD 3 )δ0.86 (t, J=6.2Hz, 3H), 1.27 dihydro[1,3]oxa Azolo[4,5-c]pyr(m, 6H), 1.65(t, J=6.7Hz, 2H), 5.24(s, 2H),

                            6.83(d，J＝6.6Hz，1H)，7.24-7.34(m，2H)，啶-2，4-二酮                                                                                                                                                                                                                                       

                            7.48(s，1H，7.50(d，J＝7.7Hz，1H)，12.007.48(s, 1H, 7.50(d, J=7.7Hz, 1H), 12.00

                            (br.s，1H).5-(2，4-二氯苄基)-7-甲基-       (CD3SO2CD3)δ2.10(s，3H)，5.19(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]   6.87(d，J＝8.4Hz，1H)，7.38(dd，J＝8.4，2.2(br.s, 1H).5-(2,4-dichlorobenzyl)-7-methyl-(CD 3 SO 2 CD 3 )δ2.10(s, 3H), 5.19(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.87 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.4, 2.2

                            Hz，1H)，7.50(s，1H)，7.69(d，J＝2.2Hz，吡啶-2，4-二酮                                                            period period of 1H), 7.50(s, 1H), 7.69(d, J=2.2Hz, pyridine-2,4-dione

                            1H)，12.02(br.s，1H).5-(2-氯苄基)-7-乙基-3，5-       (CD3SO2CD3)δ1.17(t，J＝7.5Hz，3H)，2.50二氢[1，3]噁唑并[4，5-c]吡      (m，2H overlapping DMSO)，5.25(s，2H)，1H), 12.02(br.s, 1H).5-(2-chlorobenzyl)-7-ethyl-3,5-(CD 3 SO 2 CD 3 )δ1.17(t, J=7.5Hz, 3H), 2.50 dihydro[1,3]oxazolo[4,5-c]pyridine (m, 2H overlapping DMSO), 5.25(s, 2H),

                            6.84(m，1H)，7.30(m，2H)，7.49(m，2H)，啶-2，4-二酮                    6.84(m, 1H), 7.30(m, 2H), 7.49(m, 2H), pyridine-2,4-dione

                            12.02(br.s，1H).7-丁基-5-(2-氯苄基)-3，5-        (CD3SO2CD3)δ0.87(t，J＝7.3Hz，3H)，1.28二氢[1，3]噁唑并[4，5-c]吡       (m，4H，1.54(t，J＝7.1Hz，2H)，5.24(s，2H)，12.02(br.s, 1H).7-Butyl-5-(2-chlorobenzyl)-3,5-(CD 3 SO 2 CD 3 )δ0.87(t, J=7.3Hz, 3H), 1.28 Dihydro[1,3]oxazolo[4,5-c]pyridine (m, 4H, 1.54(t, J=7.1Hz, 2H), 5.24(s, 2H),

                             6.83(d，J＝6.8H，1H)，7.24-7.34(m，2H)，啶-2，4-二酮                    6.83 (d, J = 6.8H, 1H), 7.24-7.34 (m, 2H), pyridine-2, 4-dione

                             7.48-7.56(m，2H)，12.00(br.s，1H).5-[2-氯-5-(三氟甲基)苄           (CD3SO2CD3)δ5.33(s，2H)，6.68(d，J＝7.3基]-3，5-二氢[1，3]噁唑并        Hz，1H)，7.35(s，1H)，7.69-7.79(m，3H)，[4，5-c]吡啶-2，4-二酮           11.96(br.s，1H).5-(2，6-二氯苄基)-3，5-二氢      (CD3SO2CD3)δ5.38(s，2H)，6.53(d，J＝7.4[1，3]噁唑并[4，5-c]吡啶-        Hz，1H)，7.07(d，J＝7.7HZ，1H)，7.45-7.502，4-二酮                        (m，1H)，7.52-7.59(m，2H)，11.99(br.s，1H).5-(2-氯-5-氟苄基)-3，5-二        (CD3SO2CD3)δ5.27(s，2H)，6.67(d.J＝7.3氢[1，3]噁唑并[4，5-c]吡啶-      Hz，1H)，6.72(dd，J＝7.3，3.2Hz，1H)，7.21-7.48-7.56(m, 2H), 12.00(br.s, 1H).5-[2-chloro-5-(trifluoromethyl)benzyl (CD 3 SO 2 CD 3 )δ5.33(s, 2H) , 6.68 (d, J=7.3 base]-3,5-dihydro[1,3]oxazolo Hz, 1H), 7.35 (s, 1H), 7.69-7.79 (m, 3H), [4,5 -c]pyridine-2,4-dione 11.96 (br.s, 1H).5-(2,6-dichlorobenzyl)-3,5-dihydro(CD 3 SO 2 CD 3 )δ5.38 (s, 2H), 6.53 (d, J=7.4[1,3]oxazolo[4,5-c]pyridine-Hz, 1H), 7.07 (d, J=7.7HZ, 1H), 7.45-7.502 , 4-diketone (m, 1H), 7.52-7.59 (m, 2H), 11.99 (br.s, 1H). 5-(2-chloro-5-fluorobenzyl)-3,5-di(CD 3SO 2 CD 3 )δ5.27(s, 2H), 6.67(dJ=7.3hydro[1,3]oxazolo[4,5-c]pyridine-Hz, 1H), 6.72(dd, J=7.3 , 3.2Hz, 1H), 7.21-

                             7.23(m，1H)，7.55-7.59(m，1H)，7.65(d，J＝2，4-二酮                  7.23(m, 1H), 7.55-7.59(m, 1H), 7.65(d, J=2,4-diketone

                             7.3Hz，1H，12.00(br.s，1H).5-(2-氯-6-甲基苄基)-7-甲         (CDCl3)δ2.07(s，3H)，2.29(s，3H)，5.48(s，基-3，5-二氢[1，3]噁唑并         2H)，6.63(s，1H)，7.16(d，J＝7.7Hz，1H)，7.3Hz, 1H, 12.00(br.s, 1H).5-(2-chloro-6-methylbenzyl)-7-methanol (CDCl 3 )δ2.07(s, 3H), 2.29(s, 3H ), 5.48(s, base-3,5-dihydro[1,3]oxazolo 2H), 6.63(s, 1H), 7.16(d, J=7.7Hz, 1H),

                             7.25(t，J＝7.7Hz，1H)，7.34(d，J＝7.7Hz，[4，5-c]吡啶-2，4-二-酮            7.25(t, J=7.7Hz, 1H), 7.34(d, J = 7.7Hz, [4,5-c]pyridine-2,4-di-one

                             1H)，11.33 (br.S，1H).5-(4-氯苄基)-7-甲基-3，5-        (CD3SO2CD3)δ2.08(s，3H)，5.14(s，2H)，二氢[1，3]噁唑并[4，5-c]吡       7.31(d，J＝8.4Hz，2H)，7.41(d，J＝8.4Hz，啶-2，4-二酮                     2H)，7.58(s，1H)，12.03(br.s，1H).5-(2-氯苄基)-5，6，7，8-四氢-    (CD3SO2CD3)δ2.04(m，2H)，2.80(m，4H)，2H-环戊二烯并[b][1，3]噁         5.28(s，2H)，6.68(d，J＝7.3Hz，1H)，7.18-1H), 11.33 (br.S, 1H).5-(4-chlorobenzyl)-7-methyl-3,5-(CD 3 SO 2 CD 3 )δ2.08(s, 3H), 5.14( s, 2H), dihydro[1,3]oxazolo[4,5-c]pyridine 7.31(d, J=8.4Hz, 2H), 7.41(d, J=8.4Hz, pyridine-2,4- Diketone 2H), 7.58(s, 1H), 12.03(br.s, 1H).5-(2-chlorobenzyl)-5,6,7,8-tetrahydro-(CD 3 SO 2 CD 3 ) δ2.04 (m, 2H), 2.80 (m, 4H), 2H-cyclopentadiene[b][1,3]oxa 5.28(s, 2H), 6.68(d, J=7.3Hz, 1H) , 7.18-

                             7.34(m，2H)，7.51(d，J＝7.7Hz，1H)，11.92唑并[5，4-d]吡啶-2，4(3H)-        7.34(m, 2H), 7.51(d, J=7.7Hz, 1H), 11.92 Azolo[5,4-d]pyridine-2,4(3H)-

                             (br.s，1H).二酮7-甲基-5-[4-(甲基磺酰基)         (CD3SO2CD3)δ2.11(s，3H)，2.58(s，3H)，苄基]-3，5-二氢[1，3]噁唑并      5.28(s，2H)，7.58(d，J＝7.3Hz，2H)，7.64(s，(br.s, 1H). Diketone 7-methyl-5-[4-(methylsulfonyl) (CD 3 SO 2 CD 3 )δ2.11(s, 3H), 2.58(s, 3H), Benzyl]-3,5-dihydro[1,3]oxazolo 5.28(s, 2H), 7.58(d, J=7.3Hz, 2H), 7.64(s,

                             1H)，7.91(d，J＝7.3Hz，2H)，12.06(br.s，[4，5-c]吡啶-2，4-二酮                                                                  

                             1H).5-(4-甲氧基苄基)-3，5-二         (CD3SO2CD3)δ3.73(s，3H)，5.10(s，2H)，氢[1，3]噁唑并[4，5-c]吡啶-      6.56(br.d，J＝5.9Hz，1H)，6.89(d，J＝8.81H).5-(4-methoxybenzyl)-3,5-bis(CD 3 SO 2 CD 3 )δ 3.73(s, 3H), 5.10(s, 2H), hydrogen [1,3] Oxazolo[4,5-c]pyridine - 6.56(br.d, J=5.9Hz, 1H), 6.89(d, J=8.8

                             Hz，2H)，7.27(d，J＝8.8Hz，2H)，7.67(br.m，2，4-二酮       Hz, 2H), 7.27(d, J=8.8Hz, 2H), 7.67(br.m, 2,4-diketone

                             1H)，12.06(br.s，1H).5-(2-氯苄基)-7-丙基-3，5-        (CD3SO2CD3)δ0.88(t，J＝7.4Hz，3H)，1.57二氢[1，3]噁唑并[4，5-c]吡       (m，2H)，2.46(m，2H)，5.24(s，2H)，6.84(d，J1H), 12.06(br.s, 1H).5-(2-chlorobenzyl)-7-propyl-3,5-(CD 3 SO 2 CD 3 )δ0.88(t, J=7.4Hz, 3H), 1.57 dihydro[1,3]oxazolo[4,5-c]pyridine (m, 2H), 2.46(m, 2H), 5.24(s, 2H), 6.84(d, J

                             ＝6.2Hz，1H)，7.26-7.38(m，2H)，7.48(s，啶-2，4-二酮=6.2Hz, 1H), 7.26-7.38(m, 2H), 7.48(s, pyridine-2,4-dione

                             1H)，7.50(d，J＝7.7Hz，1H)，12.00(br.s，          1H), 7.50(d, J=7.7Hz, 1H), 12.00(br.s,

                             1H).4-[(2，4-二氧代-2，3-二氢          (CD3SO2CD3)δ2.55(s，6H)，5.31(s，2H)，[1，3]噁唑并[4，5-c]吡啶-          6.67(d，J＝7.3Hz，1H)，7.43-7.51(m，2H)，5(4H)-基)甲基]-N，N-二甲           7.66-7.74(m，2H)，7.77(d，J＝7.3Hz，1H)，1H).4-[(2,4-dioxo-2,3-dihydro(CD 3 SO 2 CD 3 )δ2.55(s, 6H), 5.31(s, 2H), [1,3] Oxazolo[4,5-c]pyridine-6.67 (d, J=7.3Hz, 1H), 7.43-7.51 (m, 2H), 5(4H)-yl)methyl]-N,N-dimethyl 7.66-7.74(m, 2H), 7.77(d, J=7.3Hz, 1H),

                               12.00(br.s，1H).基苯磺酰胺5-(萮基甲基)-3，5-二氢             (CDCl3)δ2.19(s，6H)，2.30(s，3H)，5.25(s，[1，3]噁唑并[4，5-c]吡碇-          2H)，6.31(d，J＝7.3Hz，1H)，6.73(d，J＝7.32，4-二酮                          Hz，1H)，6.94(s，2H)，11.01(br.s，1H).5-(2-氯苄基)-3，5，6，7，8，9-     (CD3SO2CD3)δ1.64(m，4H)，2.50(m，4H)，六氢[1，3]噁唑并[4，5-c]喹         5.34(s，2H)，6.59(d，J＝8.1Hz，1H)，7.25-12.00 (br.s, 1H). phenylsulfonamide 5-(hexylmethyl)-3,5-dihydro (CDCl 3 ) δ2.19 (s, 6H), 2.30 (s, 3H), 5.25 ( s, [1,3]oxazolo[4,5-c]pyridine-2H), 6.31 (d, J=7.3Hz, 1H), 6.73 (d, J=7.32, 4-diketone Hz, 1H ), 6.94(s, 2H), 11.01(br.s, 1H).5-(2-chlorobenzyl)-3,5,6,7,8,9-(CD 3 SO 2 CD 3 )δ1. 64(m, 4H), 2.50(m, 4H), hexahydro[1,3]oxazolo[4,5-c]quine 5.34(s, 2H), 6.59(d, J=8.1Hz, 1H) , 7.25-

                               7.34(m，2H)，7.51(d，J＝7.7Hz，1H)，11.92啉-2，4-二酮...

                               (br.s，1H).5-(2-氯苄基)-7-乙基-6-甲           (CD3SO2CD3)δ1.10(t，J＝7.4Hz，3H)，2.22基-3，5-二氢[1，3]噁唑并           (s，3H)，2.56(m，2H)，5.40(s，2H)，6.58(d，J(br.s, 1H).5-(2-chlorobenzyl)-7-ethyl-6-methyl (CD 3 SO 2 CD 3 )δ1.10 (t, J=7.4Hz, 3H), 2.22 -3,5-dihydro[1,3]oxazolo (s, 3H), 2.56 (m, 2H), 5.40 (s, 2H), 6.58 (d, J

                               ＝7.0Hz，1H)，7.23-7.34(m，2H)，7.52(d，J＝[4，5-c]吡啶-2，4-二酮=7.0Hz, 1H), 7.23-7.34(m, 2H), 7.52(d, J=[4,5-c]pyridine-2,4-dione

                               8.1Hz，1H)，11.92(br.s，1H).5-[2-(甲硫基)苄基]-3，5-二         (CD3SO2CD3)δ2.52(s，3H)，5.19(s，2H)，氢[1，3]噁唑并[4，5-c]吡啶         6.63(d，J＝7.3Hz，1H)，6.76(d，J＝7.7Hz，8.1Hz, 1H), 11.92(br.s, 1H).5-[2-(methylthio)benzyl]-3,5-di(CD 3 SO 2 CD 3 )δ2.52(s, 3H) , 5.19(s, 2H), Hydro[1,3]oxazolo[4,5-c]pyridine 6.63(d, J=7.3Hz, 1H), 6.76(d, J=7.7Hz,

                               1H)，7.09-7.17(m，1H)，7.29-7.37(m，2H)，2，4-二酮...

                               7.55(d，J＝7.3Hz，1H)，11.99(s，1H).2-[(2，4-二氧代-2，3-二氢          (CD3SO2CD3)δ2.81(s，6H)，5.54(s，2H)，[1，3]噁唑并[4，5-c]吡啶-          6.71(d，J＝7.3Hz，1H)，6.81(d，J＝7.3Hz，7.55(d, J=7.3Hz, 1H), 11.99(s, 1H).2-[(2,4-dioxo-2,3-dihydro(CD 3 SO 2 CD 3 )δ2.81(s , 6H), 5.54(s, 2H), [1,3]oxazolo[4,5-c]pyridine-6.71(d, J=7.3Hz, 1H), 6.81(d, J=7.3Hz,

                               1H)，7.49-7.61(m，2H)，7.69(d，J＝7.3Hz，5(4H)-基)甲基]-N，N-二甲                                                                                                                                     

                               1H)，7.85(d，J＝7.3Hz，1H)，12.05(br.s，基苯磺酰胺          1H), 7.85(d, J=7.3Hz, 1H), 12.05(br.s, phenylsulfonamide

                               1H).5-(2，6-二甲氧基苄基)-3，5-        (CD3SO2CD3)δ3.76(s，6H)，5.07(s，2H)，二氢[1，3]噁唑并[4，5-c]吡         6.43(d，J＝7.7Hz，1H)，6.73(d，J＝8.4Hz，1H).5-(2,6-dimethoxybenzyl)-3,5-(CD 3 SO 2 CD 3 )δ3.76(s, 6H), 5.07(s, 2H), dihydro[1 , 3] oxazolo[4,5-c]pyridine 6.43(d, J=7.7Hz, 1H), 6.73(d, J=8.4Hz,

                               2H)，7.00(d，J＝7.7Hz，1H)，7.37(t，J＝8.4啶-2，4-二酮          2H), 7.00(d, J=7.7Hz, 1H), 7.37(t, J=8.4 pyridine-2,4-dione

                               Hz，1H)，11.92(br.s，1H).5-[2-(三氟甲氧基)苄基]-            (CD3SO2CD3)δ5.27(s，2H)，6.65(d，J＝7.33，5-二氢[1，3]噁唑并[4，5-c]      Hz，1H)，7.08(dd，J＝7.3，1.4Hz，1H)，7.30-Hz, 1H), 11.92(br.s, 1H).5-[2-(trifluoromethoxy)benzyl]-(CD 3 SO 2 CD 3 )δ5.27(s, 2H), 6.65(d , J=7.33, 5-dihydro[1,3]oxazolo[4,5-c] Hz, 1H), 7.08 (dd, J=7.3, 1.4Hz, 1H), 7.30-

                               7.49(m，3H)，7.63(d，J＝7.3Hz，1H)，11.99吡啶-2，4-二酮                              7.49 (m, 3H), 7.63 (d, J = 7.3 Hz, 1H), 11.99 pyridine-2, 4-dione

                               (br.s，1H).5-(2-氯苄基)-6，7-二甲基-          (CD3SO2CD3)δ2.12(s，3H)，2.19(s，3H)，3，5-二氢[1，3]噁唑并[4，5-c]      5.40(s，2H)，6.59(d，J＝6.6Hz，1H)，7.25-(br.s, 1H).5-(2-chlorobenzyl)-6,7-dimethyl-(CD 3 SO 2 CD 3 )δ 2.12(s, 3H), 2.19(s, 3H), 3,5-Dihydro[1,3]oxazolo[4,5-c] 5.40(s, 2H), 6.59(d, J=6.6Hz, 1H), 7.25-

                               7.34(m，2H)，7.52(d，J＝7.7Hz，1H)，11.91吡啶-2，4-二酮                          7.34 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H), 11.91 pyridine-2, 4-dione

                               (br.s，1H).5-[2-氯-5-(甲基磺酰基)苄          (CD3SO2CD3)δ3.20(s，3H)，5.35(s，2H)，基]-3，5-二氢[1，3]噁唑并         6.70(d，J＝7.3Hz，1H)，7.55(m，1H)，7.69(br.s, 1H).5-[2-Chloro-5-(methylsulfonyl)benzyl (CD 3 SO 2 CD 3 )δ3.20(s, 3H), 5.35(s, 2H), base] -3,5-Dihydro[1,3]oxazolo 6.70 (d, J=7.3Hz, 1H), 7.55 (m, 1H), 7.69

                              (m，1H)，790(m，2H)，12.04(br.s，1H).[4，5-c]吡啶-2，4-二酮5-(4-氯-2-甲氧基苄基)-            (CD3SO2CD3)δ3.86(s，3H)，5.09(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]     6.60(d，J＝7.3Hz，1H)，6.90-6.98(m，2H)，(m, 1H), 790(m, 2H), 12.04(br.s, 1H).[4,5-c]pyridine-2,4-dione 5-(4-chloro-2-methoxybenzyl base)-(CD 3 SO 2 CD 3 )δ3.86(s, 3H), 5.09(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.60( d, J=7.3Hz, 1H), 6.90-6.98(m, 2H),

                              7.12(d，J＝2.2Hz，1H)，7.59(d，J＝7.3Hz，吡啶-2，4-二酮                                  7.12 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 7.3 Hz, pyridine-2, 4-dione

                              1H)，11.95(br.s，1H).5-(2-氯苄基)-5，6，7，8，9，10-   (CD3SO2CD3)δ1.34(m，2H)，1.56(m，2H)，六氯-2H-环戊二烯并                1.69(m，2H)，2.70(m，4H)，5.45(s，2H)，6.691H), 11.95(br.s, 1H).5-(2-chlorobenzyl)-5,6,7,8,9,10-(CD 3 SO 2 CD 3 )δ1.34(m, 2H) , 1.56 (m, 2H), hexachloro-2H-cyclopentadiene 1.69 (m, 2H), 2.70 (m, 4H), 5.45 (s, 2H), 6.69

                              (d，J＝6.6Hz，1H，7.24-7.35(m，2H)，7.52[b][1，3]噁唑并[5，4-d]吡啶    (d, J=6.6Hz, 1H, 7.24-7.35(m, 2H), 7.52[b][1,3]oxazolo[5,4-d]pyridine

                              (d，J＝7.7Hz，1H)，11.91(br.s，1H).-2，4(3H)-二酮5-[2-(二氟甲氧基)苄基]-           (CD3SO2CD3)δ5.21(s，2H)，6.64(d，J＝7.33，5-二氢[1，3]噁唑并[4，5-c]     Hz，1H)，7.02(d，J＝7.3Hz，1H)，7.20-7.25(d, J=7.7Hz, 1H), 11.91(br.s, 1H).-2,4(3H)-diketone 5-[2-(difluoromethoxy)benzyl]-(CD 3 SO 2 CD 3 )δ5.21(s, 2H), 6.64(d, J=7.33, 5-dihydro[1,3]oxazolo[4,5-c]Hz, 1H), 7.02(d, J =7.3Hz, 1H), 7.20-7.25

                              (m，2H)，7.27(t，J＝74.0Hz，1H)，7.62(d，J＝吡碇-2，4-二酮   (m, 2H), 7.27(t, J=74.0Hz, 1H), 7.62(d, J=pyridine-2,4-dione

                              7.3Hz，1H)，12.00(br.s，1H).7-甲基-5-[(1R)-1-苯乙基]-         (CD3SO2CD3)δ1.72(d，J＝7.3Hz，3H)，2.073，5-二氢[1，3]噁唑并[4，5-c]     (s，3H)，6.27(q，J＝7.3Hz，1H)，7.27-7.40吡啶-2，4-二酮                    (m，6H)，11.95(br.s，1H).5-(4-氯苄基)-7-丙基-3，5-         (CD3SO2CD3)δ0.89(t，J＝7.3Hz，3H)，1.54二氢[1，3]噁唑并[4，5-c]吡        (m，2H)，2.44(t，J＝7.7Hz，2H)，5.15(s，2H)，7.3Hz, 1H), 12.00(br.s, 1H).7-methyl-5-[(1R)-1-phenethyl]-(CD 3 SO 2 CD 3 )δ1.72(d, J= 7.3Hz, 3H), 2.073, 5-dihydro[1,3]oxazolo[4,5-c](s, 3H), 6.27(q, J=7.3Hz, 1H), 7.27-7.40 pyridine- 2,4-Diketone (m, 6H), 11.95(br.s, 1H).5-(4-chlorobenzyl)-7-propyl-3,5-(CD 3 SO 2 CD 3 )δ0. 89(t, J=7.3Hz, 3H), 1.54 dihydro[1,3]oxazolo[4,5-c]pyr(m, 2H), 2.44(t, J=7.7Hz, 2H), 5.15 (s, 2H),

                              7.30(d，J＝8.4Hz，2H)，7.39(d，J＝8.4Hz，啶-2，4-二酮                                      7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, pyridine-2, 4-dione

                              2H)，7.57(s，1H)，11.97(br.s，1H).5-[2-(甲基磺酰基)苄基]-           (CD3SO2CD3)δ3.43(s，3H)，5.60(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]     6.75(d，J＝7.3Hz，1H)，7.49-7.61(m，2H)，2H), 7.57(s, 1H), 11.97(br.s, 1H).5-[2-(methylsulfonyl)benzyl]-(CD 3 SO 2 CD 3 )δ3.43(s, 3H) , 5.60(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.75(d, J=7.3Hz, 1H), 7.49-7.61(m, 2H),

                              7.65-7.70(m，2H)7.89-7.91(m，1H)，12.02吡啶-2，4-二酮                      7.65-7.70 (m, 2H) 7.89-7.91 (m, 1H), 12.02 pyridine-2, 4-dione

                              (br.s，1H).5-(2，6-二甲基苄基)-3，5-二       (CD3SO2CD3)δ2.21(s，6H)，5.16(s，2H)，氢[1，3]噁唑并[4，5-c]吡啶-       6.47(d，J＝7.3Hz，1H)，6.80(d，J＝7.3Hz，(br.s, 1H).5-(2,6-Dimethylbenzyl)-3,5-di(CD 3 SO 2 CD 3 )δ2.21(s, 6H), 5.16(s, 2H) , Hydro[1,3]oxazolo[4,5-c]pyridine - 6.47(d, J=7.3Hz, 1H), 6.80(d, J=7.3Hz,

                              1H)，7.09-7.22(m，3H)，12.00(br.s，1H).2，4-二酮3-氯-2-[(2，4-二氧代-2，3-二      (CD3SO2CD3)δ5.38(s，2H)，6.61(d，7.4Hz，氢[1，3]噁唑并[4，5-c]吡啶-       1H)，7.55(t，J＝8.0Hz，1H)，7.62(d，J＝7.41H), 7.09-7.22(m, 3H), 12.00(br.s, 1H).2,4-diketone 3-chloro-2-[(2,4-dioxo-2,3-two (CD 3SO 2 CD 3 )δ5.38(s, 2H), 6.61(d, 7.4Hz, hydrogen[1,3]oxazolo[4,5-c]pyridine-1H), 7.55(t, J=8.0 Hz, 1H), 7.62 (d, J=7.4

                              Hz，1H)，7.82(d，J＝8.0Hz，1H)，7.87(d，J＝5(4H)-基)甲基]苄腈       Hz, 1H), 7.82(d, J=8.0Hz, 1H), 7.87(d, J=5(4H)-yl)methyl]benzonitrile

                              8.0Hz，1H)，11.96(br.s，1H).5-(2-氯-6-甲基苄基)-6，7-         (CD3SO2CD3)δ2.06(s，3H)，2.09(s，3H)，二甲基-3，5-二氢[1，3]噁唑        2.10(s，3H)，5.58(s，2H)，7.13(d，J＝7.7Hz，8.0Hz, 1H), 11.96(br.s, 1H).5-(2-chloro-6-methylbenzyl)-6,7-(CD 3 SO 2 CD 3 )δ2.06(s, 3H) , 2.09(s, 3H), dimethyl-3,5-dihydro[1,3]oxazole 2.10(s, 3H), 5.58(s, 2H), 7.13(d, J=7.7Hz,

                              1H)，7.20(t，J＝7.7Hz，2H)，7.27(d，J＝7.7并[4，5-c]吡啶-2，4-二酮          1H), 7.20(t, J=7.7Hz, 2H), 7.27(d, J=7.7[4,5-c]pyridine-2,4-dione

                              Hz，1H)，11.84(br.s，1H).2-[(2，4-二氧代-2，3-二氢         (CD3SO2CD3)δ5.40(s，2H)，6.70(d，J＝7.4[1，3]噁唑并[4，5-c]吡啶-         Hz，1H)，7.11(d，J＝7.7Hz，1H)，7.50(t，J＝Hz, 1H), 11.84(br.s, 1H).2-[(2,4-dioxo-2,3-dihydro(CD 3 SO 2 CD 3 )δ5.40(s, 2H), 6.70 (d, J=7.4[1,3]oxazolo[4,5-c]pyridine-Hz, 1H), 7.11(d, J=7.7Hz, 1H), 7.50(t, J=

                              7.7Hz，1H)，7.66(td，J＝7.7，1.1Hz，1H)，5(4H)-基)甲基]苄腈            7.7Hz, 1H), 7.66(td, J=7.7, 1.1Hz, 1H), 5(4H)-yl)methyl]benzonitrile

                              7.74(d，J＝7.4Hz，1H)，7.88(dd，J＝7.7，1.17.74 (d, J=7.4Hz, 1H), 7.88 (dd, J=7.7, 1.1

                              Hz，1H)，12.01(br.s，1H).5-(2-氯-6-甲氧基苄基)-7-          (CD3SO2CD3)δ2.01(s，3H)，3.81(s，3H)，甲基-3，5-二氢[1，3]噁唑并        5.21(s，2H)，6.86(s，1H)，7.11(m，2H)，7.41Hz, 1H), 12.01(br.s, 1H).5-(2-chloro-6-methoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ2.01(s, 3H), 3.81 (s, 3H), methyl-3,5-dihydro[1,3]oxazolo 5.21(s, 2H), 6.86(s, 1H), 7.11(m, 2H), 7.41

                              (t，J＝8.2Hz，1H)，11.96(br.s，1H).[4，5-c]吡啶-2，4-二酮5-[3-(甲硫基)苄基]-3，5-二        (CD3SO2CD3)δ2.45(s，3H)，5.16(s，2H)，氢[1，3]噁唑并[4，5-c]吡啶-       6.61(d，J＝7.3Hz，1H)，7.04(d，J＝7.3Hz，(t, J=8.2Hz, 1H), 11.96 (br.s, 1H).[4,5-c]pyridine-2,4-dione 5-[3-(methylthio)benzyl]-3 , 5-bis(CD 3 SO 2 CD 3 )δ 2.45(s, 3H), 5.16(s, 2H), hydrogen[1,3]oxazolo[4,5-c]pyridine-6.61(d, J=7.3Hz, 1H), 7.04(d, J=7.3Hz,

                              1H)，7.16-7.34(m，3H)，7.73(d，J＝7.3Hz，2，4-二酮          1H), 7.16-7.34(m, 3H), 7.73(d, J=7.3Hz, 2,4-diketone

                              1H)，11.97(br.s，1H).5-(2-氯苄基)-7-环丙基-            (CD3SO2CD3)δ0.70(m，2H)，0.87(m，2H)，3，5-二氢[1，3]噁唑并[4，5-c]     1.79(m，1H)，5.22(s，2H)，6.79(d，J＝7.31H), 11.97(br.s, 1H).5-(2-chlorobenzyl)-7-cyclopropyl-(CD 3 SO 2 CD 3 )δ0.70(m, 2H), 0.87(m, 2H ), 3,5-dihydro[1,3]oxazolo[4,5-c] 1.79(m, 1H), 5.22(s, 2H), 6.79(d, J=7.3

                              Hz，1H)，7.31(m，1H)，7.45(s，1H)，7.50(d，J吡啶-2，4-二酮        Hz, 1H), 7.31(m, 1H), 7.45(s, 1H), 7.50(d, J pyridine-2,4-dione

                              ＝7.7Hz，1H)，12.01(br.s，1H).5-(3-氯苄基)-7-甲基-3，5-         (CD3SO2CD3)δ2.09(d，J＝1.1Hz，3H)，5.15二氢[1，3]噁唑并[4，5-c]吡        (s，2H)，7.26(m，1H)，7.33-7.41(m，3H)，7.59=7.7Hz, 1H), 12.01(br.s, 1H).5-(3-chlorobenzyl)-7-methyl-3,5-(CD 3 SO 2 CD 3 )δ2.09(d, J =1.1Hz, 3H), 5.15 dihydro[1,3]oxazolo[4,5-c]pyr(s,2H), 7.26(m,1H), 7.33-7.41(m,3H), 7.59

                              (q，J＝1.1Hz，1H)，11，97(br.s，1H).啶-2，4-二酮5-(2，6-二氯苄基)-7-甲基-         (CD3SO2CD3)δ2.03(d，J＝1.1Hz，3H)，5.363，5-二氢[1，3]噁唑并[4，5-c]     (s，2H)，6.87(q，J＝1.1Hz，1H)，7.46(dd，J＝(q, J=1.1Hz, 1H), 11,97 (br.s, 1H). Pyridine-2,4-dione 5-(2,6-dichlorobenzyl)-7-methyl-(CD 3 SO 2 CD 3 )δ2.03(d, J=1.1Hz, 3H), 5.363, 5-dihydro[1,3]oxazolo[4,5-c](s, 2H), 6.87(q , J=1.1Hz, 1H), 7.46(dd, J=

                               8.8，7.4Hz，1H)，7.56(d，J＝7.4Hz，1H)，吡啶-2，4-二酮                                                                                                             

                              7.57(J＝8.8Hz，1H)，11.99(br.s，1H).7-甲基-5-(4-甲基苄基)-            (CD3SO2CD3)δ2.07(s，3H)，2.27(s，3H)，3，5-二氢[1，3]噁唑并[4，5-c]     5.10(s，2H)，7.08-7.23(m，4H)，7.52(s，1H)，7.57(J=8.8Hz, 1H), 11.99(br.s, 1H).7-methyl-5-(4-methylbenzyl)-(CD 3 SO 2 CD 3 )δ2.07(s, 3H ), 2.27(s, 3H), 3,5-dihydro[1,3]oxazolo[4,5-c] 5.10(s, 2H), 7.08-7.23(m, 4H), 7.52(s, 1H),

                              11.95(br.s，1H).吡啶-2，4-二酮5-(3，5-二甲氧基苄基)-7-          (CD3SO2CD3)δ2.09(s，3H)，3.71(s，6H)，甲基-3，5-二氢[1，3]噁唑并        5.06(s，2H)，6.42(t，J＝2.2Hz，1H)，6.46(d，11.95(br.s, 1H). Pyridine-2,4-dione 5-(3,5-dimethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ2.09(s, 3H) , 3.71(s, 6H), methyl-3,5-dihydro[1,3]oxazolo 5.06(s, 2H), 6.42(t, J=2.2Hz, 1H), 6.46(d,

                              J＝2.2Hz，2H)，7.51(8，1H)，11.96(br.s，[4，5-c]吡啶-2，4-二酮J=2.2Hz, 2H), 7.51(8,1H), 11.96(br.s, [4,5-c]pyridine-2,4-dione

                              1H).5-(2，6-二氟苄基)-7-甲基-         (CD3SO2CD3)δ2.09(d，J＝1.1Hz，3H)，5.213，5-二氢[1，3]噁唑并[4，5-c]     (s，2H)，7.04-7.13(m，2H)，7.38-7.47(m，2H)，1H).5-(2,6-difluorobenzyl)-7-methyl-(CD 3 SO 2 CD 3 )δ2.09 (d, J=1.1Hz, 3H), 5.213,5-dihydro[ 1,3]oxazolo[4,5-c](s,2H), 7.04-7.13(m,2H), 7.38-7.47(m,2H),

                              11.91(br.s，1H).吡啶-2，4二酮5-[3-(甲基磺酰基)苄基]-           (CD3SO2CD3)δ3.20(s，3H)，5.31(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]     6.66(d，J＝7.3Hz，1H)，7.5-7.7(m，2H)，7.8111.91(br.s, 1H). Pyridine-2,4-dione 5-[3-(methylsulfonyl)benzyl]-(CD 3 SO 2 CD 3 )δ 3.20(s, 3H), 5.31( s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.66(d, J=7.3Hz, 1H), 7.5-7.7(m, 2H), 7.81

                              (d，J＝7.3Hz，1H)，7.83-7.96(m，2H)，11.99吡啶-2，4-二酮   (d, J=7.3Hz, 1H), 7.83-7.96 (m, 2H), 11.99 pyridine-2,4-dione

                              (br.s，1H).5-(2-氯-6-乙氧基苄基)-           (CD3SO2CD3)δ1.25(t，J＝7.0Hz，3H)，4.053，5-二氢[1，3]噁唑并[4，5-c]    (q，J＝7.0Hz，2H)，5.25(s，2H)，6.49(d，J＝(br.s, 1H).5-(2-Chloro-6-ethoxybenzyl)-(CD 3 SO 2 CD 3 )δ1.25 (t, J=7.0Hz, 3H), 4.053, 5- Dihydro[1,3]oxazolo[4,5-c] (q, J=7.0Hz, 2H), 5.25(s, 2H), 6.49(d, J=

                             7.3Hz，1H)，7.06(d，J＝8.4Hz，1H)，7.10(d，吡啶-2，4-二酮                   J＝8.1Hz，1H)，7.12(d，J＝7.3Hz，1H)，7.377.3Hz, 1H), 7.06(d, J=8.4Hz, 1H), 7.10(d, pyridine-2,4-dione J=8.1Hz, 1H), 7.12(d, J=7.3Hz, 1H), 7.37

                             (dd，J＝8.4，8.1Hz，1H)，11.95(br.s，1H).5-(2-氯-6-乙氧基苄基)-7-         (CD3SO2CD3)δ1.25(t，J＝7.0Hz，3H)，2.02甲基-3，5-二氢[1，3]噁唑并       (s，3H)，4.04(q，J＝7.0Hz，2H)，5.23(s，2H)，(dd, J=8.4, 8.1Hz, 1H), 11.95 (br.s, 1H).5-(2-chloro-6-ethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ1. 25(t, J=7.0Hz, 3H), 2.02 methyl-3,5-dihydro[1,3]oxazolo(s, 3H), 4.04(q, J=7.0Hz, 2H), 5.23( s, 2H),

                              6.97(s，1H)，7.04(d，J＝8.4Hz，1H)，7.09(d，[4，5-c]吡啶-2，4-二酮        6.97(s, 1H), 7.04(d, J=8.4Hz, 1H), 7.09(d, [4,5-c]pyridine-2,4-dione

                             J＝8.0Hz，1H)，7.36(dd，J＝8.4，8.0Hz，J＝8.0Hz, 1H), 7.36 (dd, J＝8.4, 8.0Hz,

                             1H)，11.93(br.s，1H).5-(2-氟-6-甲氧基苄基)-7-         (CD3SO2CD3)δ2.05(s，3H)，3.82(s，3H)，甲基-3，5-二氢[1，3]噁唑并       5.12(s，2H)，6.82(dd，J＝9.5，8,4Hz，1H)，1H), 11.93(br.s, 1H).5-(2-fluoro-6-methoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ2.05(s, 3H), 3.82(s , 3H), methyl-3,5-dihydro[1,3]oxazolo 5.12(s, 2H), 6.82(dd, J=9.5, 8,4Hz, 1H),

                             6.91(d，J＝8.4Hz，1H)，7.18(s，1H)，7.37[4，5-c]吡啶-2，4-二酮        6.91(d, J=8.4Hz, 1H), 7.18(s, 1H), 7.37[4,5-c]pyridine-2,4-dione

                             (td，J＝8.4，6.6Hz，1H)，11.89(br.s，1H).5-(2-氯-6-甲氧基苄基)-7-         (CD3SO2CD3)δ0.82(t，J＝7.3Hz，3H)，1.47丙基-3，5-二氢[1，3]噁唑并       (sextet，J＝7.3Hz，2H)，2.38(t，J＝7.3Hz，(td, J=8.4, 6.6Hz, 1H), 11.89 (br.s, 1H).5-(2-chloro-6-methoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ0. 82(t, J=7.3Hz, 3H), 1.47 propyl-3,5-dihydro[1,3]oxazolo (sextet, J=7.3Hz, 2H), 2.38(t, J=7.3Hz,

                             2H)，3.80(s，3H)，5.21(s，2H)，6.89(s，1H)，[4，5-c]吡啶-2，4-二酮                                                                                                                        

                             7.08-7.13(m，2H)，7.40(t，J＝8.3Hz，1H)，                    7.08-7.13(m, 2H), 7.40(t, J=8.3Hz, 1H),

                             11.93(br.s，1H).5-(5-氯-2-氟苄基)-7-甲基-        (CD3SO2CD3)δ2.10(s，3H)，5.18(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]    7.20(dd，J＝6.6，3.0Hz，1H)，7.29(dd，J＝11.93(br.s, 1H).5-(5-chloro-2-fluorobenzyl)-7-methyl-(CD 3 SO 2 CD 3 )δ2.10(s, 3H), 5.18(s, 2H ), 3,5-dihydro[1,3]oxazolo[4,5-c] 7.20 (dd, J=6.6, 3.0Hz, 1H), 7.29 (dd, J=

                             9.6，8.8Hz，1H)，7.42(ddd，J＝8.8，4.4，3.0吡啶-2，4-二酮                                                                           

                             Hz，1H)，7.51(s，1H)，11.96(br.s，1H).5-(2-氯苄基)-7-异丙基-           (CD3SO2CD3)δ1.23(d，J＝7.0Hz，6H)，2.923，5-二氢[1，3]噁唑并[4，5-c]    (m，1H)，5.25(s，2H)，6.83(dd，J＝7.4，2.2Hz, 1H), 7.51(s, 1H), 11.96(br.s, 1H).5-(2-chlorobenzyl)-7-isopropyl-(CD 3 SO 2 CD 3 )δ1.23(d , J=7.0Hz, 6H), 2.923, 5-dihydro[1,3]oxazolo[4,5-c] (m, 1H), 5.25(s, 2H), 6.83(dd, J=7.4 , 2.2

                             Hz，1H)，7.27-7.35(m，2H)，7.49(s，1H)，7.51吡啶-2，4-二酮         Hz, 1H), 7.27-7.35(m, 2H), 7.49(s, 1H), 7.51 pyridine-2,4-dione

                             (dd，J＝7.3，1.8Hz，1H)，12.01(br.s，1H).5-(5-氟-2-甲基苄基)-7-甲         (CD3SO2CD3)δ2.10(d，J＝1.1Hz，3H)，2.30基-3，5-二氢[1，3]噁唑并         (s，3H)，5.13(s，2H)，6.55(dd，J＝9.9，2.6Hz，(dd, J=7.3, 1.8Hz, 1H), 12.01(br.s, 1H).5-(5-fluoro-2-methylbenzyl)-7-methanol (CD 3 SO 2 CD 3 )δ2. 10(d, J=1.1Hz, 3H), 2.30-3,5-dihydro[1,3]oxazolo(s, 3H), 5.13(s, 2H), 6.55(dd, J=9.9, 2.6Hz,

                             1H)，7.01(td，J＝8.4，2.6Hz，1H)，7.25(dd，J[4，5-c]吡啶-2，4-二酮           1H), 7.01(td, J=8.4, 2.6Hz, 1H), 7.25(dd, J[4,5-c]pyridine-2,4-dione

                             ＝8.4，5.9Hz，1.1，7.42(q，1.1Hz，1H)，11.99=8.4, 5.9Hz, 1.1, 7.42(q, 1.1Hz, 1H), 11.99

                             (br.s，1H).7-甲基-5-[(1S)-1-苯基乙          (CD3SO2CD3)δ1.72(d，J＝7.3Hz，3H)，2.07基]-3，5-二氢[1，3]噁唑并        (s，3H)，6.27(q，J＝7.3Hz，1H)，7.27-7.40(br.s, 1H).7-methyl-5-[(1S)-1-phenylethyl (CD 3 SO 2 CD 3 )δ1.72 (d, J=7.3Hz, 3H), 2.07 base] -3,5-Dihydro[1,3]oxazolo (s, 3H), 6.27 (q, J=7.3Hz, 1H), 7.27-7.40

                             (m，6H)，11.95(br.s，1H).[4，5-c]吡啶-2，4-二酮5-(2-氯-5-异丙氧基苄基)-         (CD3SO2CD3)δ1.20(d，J＝6.0Hz，6H)，2.117-甲基-3，5-二氢[1，3]噁唑       (s，3H)，4.50(m，1H)，5.16(s，2H)，6.34(d，J(m, 6H), 11.95(br.s, 1H).[4,5-c]pyridine-2,4-dione 5-(2-chloro-5-isopropoxybenzyl)-(CD 3 SO 2 CD 3 ) δ1.20 (d, J=6.0Hz, 6H), 2.117-methyl-3,5-dihydro[1,3]oxazole (s, 3H), 4.50 (m, 1H), 5.16(s, 2H), 6.34(d, J

                             ＝3.0Hz，1H)，6.91(dd，J＝8.8，3.0Hz，1H)，并[4，5-c]吡啶-2，4-二酮  = 3.0Hz, 1H), 6.91 (dd, J = 8.8, 3.0Hz, 1H), and [4,5-c]pyridine-2,4-dione

                             7.38(d，J＝8.8Hz，1H)，7.47(s，1H)，12.017.38(d, J=8.8Hz, 1H), 7.47(s, 1H), 12.01

                             (br.s，1H).5-(5-乙酰基-2-甲氧基苄         (CD3SO2CD3)δ2.47(s，3H)，3.93(s，3H)，基)-3，5-二氢[1，3]噁唑并      5.16(s，2H)，6.62(d，J＝7.3Hz，1H)，7.16(d，(br.s, 1H).5-(5-acetyl-2-methoxybenzyl (CD 3 SO 2 CD 3 )δ2.47(s, 3H), 3.93(s, 3H), base)-3 , 5-dihydro[1,3]oxazolo 5.16(s, 2H), 6.62(d, J=7.3Hz, 1H), 7.16(d,

                           J＝8.4Hz，1H)，7.59(d，J＝2.2Hz，1H)，7.63[4，5-c]吡啶-2，4-二酮J=8.4Hz, 1H), 7.59(d, J=2.2Hz, 1H), 7.63[4,5-c]pyridine-2,4-dione

                           (d，J＝7.3Hz，1H)，7.97(dd，J＝8.4，2.2Hz，  (d, J=7.3Hz, 1H), 7.97 (dd, J=8.4, 2.2Hz,

                           1H)，11.96(br.s，1H).5-(2-氯苄基)-7-甲基-3，5-      (CD3SO2CD3)δ2.29(s，3H)，5.39(s，2H)，二氢[1，3]噁唑并[4，5-d]哒     7.00(d，J＝7.4Hz，1H)，7.26-7.37(m，2H)，1H), 11.96(br.s, 1H).5-(2-chlorobenzyl)-7-methyl-3,5-(CD 3 SO 2 CD 3 )δ2.29(s, 3H), 5.39( s, 2H), dihydro[1,3]oxazolo[4,5-d]da 7.00(d, J=7.4Hz, 1H), 7.26-7.37(m, 2H),

                           7.51(d，J＝7.7Hz，1H)，12.80(br.s，1H).嗪-2，4-二酮5-[2-氟-6-(三氟甲基)苄         (CD3SO2CD3)δ2.04(s，3H)，5.33(s，2H)，基]-7-甲基-3，5-二氢[1，3]     7.05(s，1H)，7.51-7.72(m，3H)，11.98(br.s，噁唑并[4，5-c]吡啶-2，4-二     1H).酮5-(2-氯-6-甲基苄基)-          (CD3SO2CD3)δ2.02(m，2H)，2.21(s，3H)，5，6，7，8-四氢-2H-环戊二烯    2.64-2.80(m，4H)，5.42(s，2H)，7.05-7.33(m，7.51(d, J=7.7Hz, 1H), 12.80(br.s, 1H).oxazine-2,4-dione 5-[2-fluoro-6-(trifluoromethyl)benzyl (CD 3 SO 2 CD 3 )δ2.04(s, 3H), 5.33(s, 2H), base]-7-methyl-3,5-dihydro[1,3] 7.05(s, 1H), 7.51-7.72(m , 3H), 11.98(br.s, oxazolo[4,5-c]pyridine-2,4-di1H).Kone 5-(2-chloro-6-methylbenzyl)-(CD 3 SO 2 CD 3 )δ2.02(m, 2H), 2.21(s, 3H), 5,6,7,8-tetrahydro-2H-cyclopentadiene 2.64-2.80(m, 4H), 5.42(s, 2H), 7.05-7.33(m,

                           3H)，11.81(br.s，1H).并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮5-(2-氯-6-乙氧基苄基)-7-       (CD3SO2CD3)δ1.08(t，J＝7.7Hz，3H)，1.25乙基-3，5-二氢[1，3]噁唑并     (t，J＝7.0Hz，3H)，2.44(q，J＝7.7Hz，2H)，3H), 11.81(br.s, 1H).[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione 5-(2-chloro-6 -Ethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ1.08 (t, J=7.7Hz, 3H), 1.25 ethyl-3,5-dihydro[1,3]oxazolo (t, J=7.0Hz, 3H), 2.44(q, J=7.7Hz, 2H),

                           4.05(q，J＝7.0Hz，2H)，5.23(s，2H)，6.99(s，[4，5-c]吡啶-2，4-二酮...

                           1H)，7.05(d，J＝8.4Hz，1H)，7.09(d，J＝8.1         1H), 7.05(d, J=8.4Hz, 1H), 7.09(d, J=8.1

                           Hz，1H)，7.36(dd，J＝8.4，8.1Hz，1H)，11.93         Hz, 1H), 7.36(dd, J=8.4, 8.1Hz, 1H), 11.93

                           (br.s，1H).5-(2-氯-6-丙氧基苄基)-7-       (CD3SO2CD3)δ0.88(t，J＝7.3Hz，3H)，1.66甲基-3，5-二氢[1，3]噁唑并     (m，2H)，2.01(d，J＝1.1Hz，3H)，3.95(t，J＝(br.s, 1H).5-(2-Chloro-6-propoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ0.88 (t, J=7.3Hz, 3H), 1.66 Base-3,5-dihydro[1,3]oxazolo (m, 2H), 2.01(d, J=1.1Hz, 3H), 3.95(t, J=

                            6.2Hz，2H)，5.24(s，2H)，6.91(q，J＝1.1Hz，[4，5-c]吡啶-2，4-二酮6.2Hz, 2H), 5.24 (s, 2H), 6.91 (Q, J = 1.1Hz, [4, 5-C] pyridine -2, 4-dione

                           1H)，7.03(d，J＝8.4Hz，1H)，7.10(d，J＝8.1        1H), 7.03(d, J=8.4Hz, 1H), 7.10(d, J=8.1

                           Hz，1H)，7.37(dd，J＝8.4，8.1Hz，1H)，11.95         Hz, 1H), 7.37(dd, J=8.4, 8.1Hz, 1H), 11.95

                           (br.s，1H).5-(2-氯-6-异丁氧基苄基)-       (CD3SO2CD3)δ0.89(d，J＝7.0Hz，6H)，1.957-甲基-3，5-二氢[1，3]噁唑     (m，1H)，2.00(s，3H)，3.79(d，J＝6.2，2H)，(br.s, 1H).5-(2-Chloro-6-isobutoxybenzyl)-(CD 3 SO 2 CD 3 )δ0.89 (d, J=7.0Hz, 6H), 1.957-methanol Base-3,5-dihydro[1,3]oxazole (m, 1H), 2.00 (s, 3H), 3.79 (d, J=6.2, 2H),

                           5.25(s，2H)，6.85(s，1H)，7.06(d，J＝8.4Hz，并[4，5-c]吡啶-2，4-二酮                5.25(s, 2H), 6.85(s, 1H), 7.06(d, J=8.4Hz, and [4,5-c]pyridine-2,4-dione

                           1H)，7.11(d，J＝8.1Hz，1H)，7.38(dd，J＝        1H), 7.11(d, J=8.1Hz, 1H), 7.38(dd, J=

                           8.4，8.1Hz，1H)，11.97(br.s，1H).5-(2-氯-6-乙氧基苄基)-         (CD3SO2CD3)δ1.10(t，J＝7.0Hz，3H)，2.065，6，7，8-四氢-2H-环戊二烯    (m，2H)，2.70-2.92(m，4H)，3.90(q，J＝7.08.4, 8.1Hz, 1H), 11.97(br.s, 1H).5-(2-chloro-6-ethoxybenzyl)-(CD 3 SO 2 CD 3 )δ1.10(t, J=7.0 Hz, 3H), 2.065, 6,7,8-tetrahydro-2H-cyclopentadiene (m, 2H), 2.70-2.92 (m, 4H), 3.90 (q, J=7.0

                           Hz，2H)，5.33(s，2H)，6.93(d，J＝8.4Hz，并[b][1，3]噁唑并[5，4-d]吡       Hz, 2H), 5.33(s, 2H), 6.93(d, J=8.4Hz, and [b][1,3]oxazolo[5,4-d]pyridine

                           1H)，7.03(d，J＝8.1Hz，1H)，7.26(dd，J＝啶-2，4(3H)-二酮          1H), 7.03(d, J=8.1Hz, 1H), 7.26(dd, J=pyridine-2,4(3H)-dione

                           8.4，8.1Hz，1H)，11.75(br.s，1H).5-(2-氯-6-异丙氧基苄基)-       (CD3SO2CD3)δ1.16(d，J＝6.2Hz，6H)，2.027-甲基-3，5-二氢[1，3]噁唑     (s，3H)，4.67(m，1H)，5.21(s，2H)，6.94(s，8.4, 8.1Hz, 1H), 11.75(br.s, 1H).5-(2-chloro-6-isopropoxybenzyl)-(CD 3 SO 2 CD 3 )δ1.16(d, J= 6.2Hz, 6H), 2.027-methyl-3,5-dihydro[1,3]oxazole (s, 3H), 4.67(m, 1H), 5.21(s, 2H), 6.94(s,

                           1H)，7.07(d，J＝8.0Hz，2H)，7.34(t，J＝8.0并[4，5-c]吡啶-2，4-二酮                                                                                           

                           Hz，1H)，11.93(br.s，1H).5-[2-氯-6-(2，2，2-三氟乙氧    (CD3SO2CD3)δ2.01(s，3H)，4.82(q，J＝8.8基)苄基]-7-甲基-3，5-二氢      Hz，2H)，5.24(s，2H)，6.94(s，1H)，7.19(d，JHz, 1H), 11.93(br.s, 1H).5-[2-chloro-6-(2,2,2-trifluoroethoxy (CD 3 SO 2 CD 3 )δ2.01(s, 3H) , 4.82 (q, J=8.8 yl)benzyl]-7-methyl-3,5-dihydro (Hz, 2H), 5.24 (s, 2H), 6.94 (s, 1H), 7.19 (d, J

                           ＝8.4Hz，1H) 7.22(d，J＝8.1Hz，1H)，7.43[1，3]噁唑并[4，5-c]吡啶-=8.4Hz, 1H) 7.22 (d, J = 8.1Hz, 1H), 7.43 [1,3]oxazolo[4,5-c]pyridine-

                           (dd，J＝8.4，8.1Hz，1H)，11.92(br.s，1H).2，4-二酮5-(2-氯-6-乙氧基苄基)-7-       (CD3SO2CD3)δ1.19(t，J＝7.0Hz，3H)，2.19甲基-3，5-二氢[1，3]噁唑并     (s，3H)，3.99(q，J＝7.0Hz，2H)，5.41(s，2H)，(dd, J=8.4, 8.1Hz, 1H), 11.92 (br.s, 1H).2,4-diketone 5-(2-chloro-6-ethoxybenzyl)-7-(CD 3 SO 2 CD 3 ) δ1.19(t, J=7.0Hz, 3H), 2.19 methyl-3,5-dihydro[1,3]oxazolo(s, 3H), 3.99(q, J=7.0Hz , 2H), 5.41(s, 2H),

                            6.98(d，J＝8.4Hz，1H)，7.05(d，J＝8.0Hz，[4，5-d]哒嗪-2，4-二酮          6.98(d, J=8.4Hz, 1H), 7.05(d, J=8.0Hz, [4,5-d]pyridazine-2,4-dione

                           1H)，7.30(dd，J＝8.4，8.0Hz，1H)，12.70(br.          1H), 7.30(dd, J=8.4, 8.0Hz, 1H), 12.70(br.

                           s，1H).5-[2-氯-6-(2-甲氧基乙氧        (CD3SO2CD3)δ2.06(m，2H)，2.74-2.90(m，基)苄基]-5，6，7，8-四氢-2H-   4H)，3.20(s，3H)，3.47(t，J＝4.4Hz，2H)，s, 1H).5-[2-Chloro-6-(2-methoxyethoxy (CD 3 SO 2 CD 3 )δ2.06(m, 2H), 2.74-2.90(m, yl)benzyl] -5,6,7,8-tetrahydro-2H-4H), 3.20(s, 3H), 3.47(t, J=4.4Hz, 2H),

                           4.01(t，J＝4.4Hz，2H)，5.33(s，2H)，6.98(d，环戊二烯并[b][1，3]噁唑并        4.01(t, J=4.4Hz, 2H), 5.33(s, 2H), 6.98(d, cyclopenta[b][1,3]oxazolo

                           J＝8.0Hz，1H)，7.04(d，J＝8.0Hz，1H)，7.27[5，4-d]吡啶-2，4(3H)-二酮J=8.0Hz, 1H), 7.04(d, J=8.0Hz, 1H), 7.27[5,4-d]pyridine-2,4(3H)-dione

                           (t，J＝8.0Hz，1H)，(br.s，1H).5-(2-氯-6-乙氧基苄基)-         (CD3SO2CD3)δ1.03(t，J＝7.0Hz，3H)，2.066，7-二甲基-3，5-二氢[1，3]    (s，3H)，2.22(s，3H)，3.84(q，J＝7.0Hz，2H)，(t, J=8.0Hz, 1H), (br.s, 1H).5-(2-chloro-6-ethoxybenzyl)-(CD 3 SO 2 CD 3 )δ1.03(t, J =7.0Hz, 3H), 2.066, 7-dimethyl-3,5-dihydro[1,3] (s, 3H), 2.22(s, 3H), 3.84 (q, J=7.0Hz, 2H) ,

                           5.48(s，2H)，6.92(d，8.4Hz，1H)，7.03(d，J＝噁唑并[4，5-c]吡啶-2，4-二            5.48(s, 2H), 6.92(d, 8.4Hz, 1H), 7.03(d, J=oxazolo[4,5-c]pyridine-2,4-di

                           8.1Hz，1H)，7.24(dd，J＝8.4，8.1Hz，1H)，酮...

                           11.76(br.s，1H).5-(2-氯-6-乙氧基苄基)-7-       (CD3SO2CD3)δ1.06(m，6H)，2.24(s，3H)，乙基-6-甲基-3，5-二氢[1，3]     2.48-2.56(m overlapping DMSO，2H)，3.8511.76(br.s, 1H).5-(2-Chloro-6-ethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ1.06(m, 6H), 2.24(s, 3H) , Ethyl-6-methyl-3,5-dihydro[1,3] 2.48-2.56 (m overlapping DMSO, 2H), 3.85

                           (q，J＝7.0Hz，2H)，5.48(s，2H)，6.92(d，8.4噁唑并[4，5-c]吡啶-2，4-二    (q, J=7.0Hz, 2H), 5.48(s, 2H), 6.92(d, 8.4 oxazolo[4,5-c]pyridine-2,4-di

                           Hz，1H)，7.03(d，J＝8.1Hz，1H)，7.24(dd，J酮        Hz, 1H), 7.03(d, J=8.1Hz, 1H), 7.24(dd, J

                           ＝8.4，8.1Hz，1H)，11.77(br.s，1H).5-(2-氯苄基)-7-乙基-3，5-      (CD3SO2CD3)δ1.18(t，J＝7.5Hz，3H)，2.70=8.4, 8.1Hz, 1H), 11.77(br.s, 1H).5-(2-chlorobenzyl)-7-ethyl-3,5-(CD 3 SO 2 CD 3 )δ1.18(t , J=7.5Hz, 3H), 2.70

                           (q，J＝7.5Hz，2H)，5.38(s，2H)，7.0-7.6(m，二氢[1，3]噁唑并[4，5-d]哒   (q, J=7.5Hz, 2H), 5.38(s, 2H), 7.0-7.6(m, dihydro[1,3]oxazolo[4,5-d]da

                           4H)，12.77(br.s，1H).嗪-2，4-二酮5-(2-氯-6-乙氧基苄基)-7-       (CD3SO2CD3)δ0.82(t，J＝7.3Hz，3H)，1.24丙基-3，5-二氢[1，3]噁唑并     (t，J＝7.0Hz，3H)，1.48(m，2H)，2.37(t，J＝4H), 12.77 (br.s, 1H). Oxazine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ0.82( t, J=7.3Hz, 3H), 1.24 propyl-3,5-dihydro[1,3]oxazolo (t, J=7.0Hz, 3H), 1.48(m, 2H), 2.37(t, J＝

                           7.3Hz，2H)，4.05(q，J＝7.0Hz，2H)，5.23(s，[4，5-c]吡啶-2，4-二酮            7.3Hz, 2H), 4.05(q, J=7.0Hz, 2H), 5.23(s, [4,5-c]pyridine-2,4-dione

                           2H)，6.93(s，1H)，7.05(d，J＝8.4Hz，1H)，          2H), 6.93(s, 1H), 7.05(d, J=8.4Hz, 1H),

                           7.09(d，J＝8.1Hz，1H)，7.36(dd，J＝8.4，8.1              7.09 (d, J = 8.1 Hz, 1H), 7.36 (dd, J = 8.4, 8.1

                           Hz，1H)，11.94(br.s，1H).5-(2-氯-6-乙氧基苄基)-7-       (CD3SO2CD3)δ0.55(m，2H)，0.81(m，2H)，环丙基-3，5-二氢[1，3]噁唑     1.26(t，J＝7.0Hz，3H)，1.72(m，1H)，4.05(q，Hz, 1H), 11.94(br.s, 1H).5-(2-chloro-6-ethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ0.55(m, 2H), 0.81 (m, 2H), cyclopropyl-3,5-dihydro[1,3]oxazole 1.26(t, J=7.0Hz, 3H), 1.72(m, 1H), 4.05(q,

                           J＝7.0Hz，2H)，5.22(s，2H)，6.95(s，1H)，并[4，5-c]吡啶-2，4-二酮J＝7.0Hz, 2H), 5.22(s, 2H), 6.95(s, 1H), and [4,5-c]pyridine-2,4-dione

                           7.05(d，J＝8.4Hz，1H)，7.09(d，J＝8.1Hz，                7.05(d, J = 8.4Hz, 1H), 7.09(d, J = 8.1Hz,

                           1H)，7.36(dd，J＝8.4，8.1Hz，1H)，11.93(br.          1H), 7.36(dd, J=8.4, 8.1Hz, 1H), 11.93(br.

                           s，1H).5-(2-氯-5-丙氧基苄基)-7-       (CD3SO2CD3)δ0.92(t，J＝7.3Hz，3H)，1.66甲基-3，5-二氢[1，3]噁唑并     (m，2H)，2.10(s，3H)，3.85(m，2H)，5.17(s，s, 1H).5-(2-Chloro-5-propoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ0.92 (t, J=7.3Hz, 3H), 1.66 methyl-3 , 5-dihydro[1,3]oxazolo (m, 2H), 2.10(s, 3H), 3.85(m, 2H), 5.17(s,

                           2H)，6.41(d，J＝3.3Hz，1H)，6.91(dd，J＝[4，5-c]吡啶-2，4-二酮                                                                                               

                           8.8，3.3Hz，1H)，7.39(d，J＝8.8Hz，1H)，8.8, 3.3Hz, 1H), 7.39(d, J=8.8Hz, 1H),

                           7.45(s，1H)，12.00(br.s，1H).5-(2-氯-5-甲氧基苄基)-7-       (CD3SO2CD3)δ2.10(s，3H)，3.9(s，3H)，5.18甲基-3，5-二氢[1，3]噁唑并     (s，2H)，6.42(d，J＝3.0Hz，1H)，6.93 (dd，J＝7.45(s, 1H), 12.00(br.s, 1H).5-(2-chloro-5-methoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ2.10(s, 3H) , 3.9 (s, 3H), 5.18 methyl-3, 5-dihydro [1, 3] oxazolo (s, 2H), 6.42 (d, J = 3.0Hz, 1H), 6.93 (dd, J =

                           8.8，3.0Hz，1H)，7.42(d，J＝8.8Hz，1H)，[4，5-c]吡啶-2，4-二酮              8.8, 3.0Hz, 1H), 7.42(d, J=8.8Hz, 1H), [4,5-c]pyridine-2,4-dione

                           7.44(s，1H)，12.00(br.s，1H).5-(2-氯-6-乙氧基苄基)-6-       (CD3SO2CD3)δ1.07(t，J＝7.0Hz，3H)，2.32甲基-3，5-二氢[1，3]噁唑并     (s，3H)，3.87(q，J＝7.0Hz，2H)，5.42(s，2H)，7.44(s, 1H), 12.00(br.s, 1H).5-(2-chloro-6-ethoxybenzyl)-6-(CD 3 SO 2 CD 3 )δ1.07(t, J= 7.0Hz, 3H), 2.32 methyl-3,5-dihydro[1,3]oxazolo(s, 3H), 3.87(q, J=7.0Hz, 2H), 5.42(s, 2H),

                           6.44(s，1H)，6.92(d，J＝8.4Hz，1H)，7.03(d，[4，5-c]吡啶-2，4-二酮          6.44(s, 1H), 6.92(d, J=8.4Hz, 1H), 7.03(d, [4,5-c]pyridine-2,4-dione

                           J＝8.1Hz，1H)，7.24(dd，J＝8.4，8.1Hz，J＝8.1Hz, 1H), 7.24 (dd, J＝8.4, 8.1Hz,

                           1H)，11.74(br.s，1H).5-(2-氯-5-乙氧基苄基)-7-       (CD3SO2CD3)δ1.26(t，J＝7.0Hz，3H)，2.10甲基-3，5-二氢[1，3]噁唑并     (s，3H)，3.94(q，J＝7.0Hz，2H)，5.17(s，2H)，1H), 11.74(br.s, 1H).5-(2-Chloro-5-ethoxybenzyl)-7-(CD 3 SO 2 CD 3 )δ1.26(t, J=7.0Hz, 3H ), 2.10 methyl-3,5-dihydro[1,3]oxazolo (s, 3H), 3.94 (q, J=7.0Hz, 2H), 5.17 (s, 2H),

                           6.38(d，J＝2.9Hz，1H)，6.91(dd，J＝8.8，2.9[4，5-c]吡啶-2，4-二酮        6.38(d, J=2.9Hz, 1H), 6.91(dd, J=8.8, 2.9[4,5-c]pyridine-2,4-dione

                           Hz，1H)，7.39(d，J＝8.8Hz，1H)，7.44(s，         Hz, 1H), 7.39(d, J=8.8Hz, 1H), 7.44(s,

                           1H)，11.99(br.s，1H).5-[2-氯-5-(哌啶-1-基磺酰       (CD3SO2CD3)δ1.35(m，2H)，1.47(m，4H)，基)苄基]-7-甲基-3，5-二氢       2.10(s，3H)，2.81(m，4H)，5.30(s，2H)，7.181H), 11.99(br.s, 1H).5-[2-chloro-5-(piperidin-1-ylsulfonyl (CD 3 SO 2 CD 3 )δ1.35(m, 2H), 1.47(m , 4H), base) benzyl]-7-methyl-3,5-dihydro 2.10 (s, 3H), 2.81 (m, 4H), 5.30 (s, 2H), 7.18

                           (d，J＝2.2Hz，1H)，7.57(s，1H)，7.67(dd，J＝[1，3]噁唑并[4，5-c]吡啶-   (d, J=2.2Hz, 1H), 7.57(s, 1H), 7.67(dd, J=[1,3]oxazolo[4,5-c]pyridine-

                           8.4，2.2Hz，1H)，7.78(d，J＝8.4Hz，1H)，2，4-二酮                      8.4, 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 2,4-diketone

                           12.07(br.s，1H).5-[2-氯-5-(吡咯烷-1-基磺       (CD3SO2CD3)δ1.62(m，4H)，2.11(s，3H)，酰基)苄基]-7-甲基-3，5-二      3.05(m，4H)，5.30(s，2H)，7.30(s，1H)，7.5712.07(br.s, 1H).5-[2-chloro-5-(pyrrolidin-1-ylsulfonate (CD 3 SO 2 CD 3 )δ1.62(m, 4H), 2.11(s, 3H), Acyl)benzyl]-7-methyl-3,5-di 3.05 (m, 4H), 5.30 (s, 2H), 7.30 (s, 1H), 7.57

                           (s，1H)，7.75-7.82(m，2H)，12.08(br.s，1H).氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮5-[2-氯-6-(环戊基甲氧基)       (CD3SO2CD3)δ1.22(m，2H)，1.51(m，4H)，苄基]-7-甲基-3，5-二氢         1.68(m，2H)，2.00(s，3H)，2.20(m，1H)，3.89(s, 1H), 7.75-7.82 (m, 2H), 12.08 (br.s, 1H). Hydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione 5- [2-Chloro-6-(cyclopentylmethoxy) (CD 3 SO 2 CD 3 ) δ1.22(m, 2H), 1.51(m, 4H), benzyl]-7-methyl-3, 5-dihydro 1.68(m, 2H), 2.00(s, 3H), 2.20(m, 1H), 3.89

                           (d，J＝7.0Hz，2H)，5.24(s，2H)，6.86(s，1H)，[1，3]噁唑并[4，5-c]吡啶-   (d, J=7.0Hz, 2H), 5.24(s, 2H), 6.86(s, 1H), [1,3]oxazolo[4,5-c]pyridine-

                           7.07(d，J＝8.4Hz，1H)，7.11(d，J＝8.1Hz，2，4-二酮...

                           1H)，7.37(dd，J＝8.4，8.1Hz，1H)，11.97(br.          1H), 7.37(dd, J=8.4, 8.1Hz, 1H), 11.97(br.

                           s，1H).5-[2-(苄氧基)-6-氯苄基]-       (CD3SO2CD3)δ1.90(s，3H) 5.15(s，2H)，7-甲基-3，5-二氢[1，3]噁唑     5.25(s，2H)，6.84(s，1H)，7.13(d，J＝8.1Hz，s, 1H).5-[2-(benzyloxy)-6-chlorobenzyl]-(CD 3 SO 2 CD 3 )δ1.90(s, 3H) 5.15(s, 2H), 7-methyl -3,5-dihydro[1,3]oxazole 5.25(s, 2H), 6.84(s, 1H), 7.13(d, J=8.1Hz,

                           1H)，7.19(d，J＝7.7Hz，1H)，7.30-7.37(m并[4，5-c]吡啶-2，4-二酮         1H), 7.19(d, J=7.7Hz, 1H), 7.30-7.37(m[4,5-c]pyridine-2,4-dione

                           5H)，7.39(dd，J＝8.1，7.7Hz，1H)，11.91(br.           5H), 7.39(dd, J=8.1, 7.7Hz, 1H), 11.91(br.

                           s，1H).5-(2，3-二氯-6-乙氧基苄        (CD3SO2CD3)δ1.10(t，J＝7.0Hz，3H)，2.09基)-5，6，7，8-四氢-2H-环戊    (m，2H)2.80(m，2H)，2.89(m，2H)，3.92(q，Js, 1H).5-(2,3-Dichloro-6-ethoxybenzyl (CD 3 SO 2 CD 3 )δ1.10(t, J=7.0Hz, 3H), 2.09yl)-5,6 , 7,8-tetrahydro-2H-cyclopenta(m, 2H) 2.80(m, 2H), 2.89(m, 2H), 3.92(q, J

                           ＝7.0Hz，2H)，5.33(s，2H)，6.98(d，J＝8.8二烯并[b[1，3]噁唑并[5，4-=7.0Hz, 2H), 5.33(s, 2H), 6.98(d, J=8.8 Dieno[b[1,3]oxazolo[5,4-

                           Hz，1H)，7.50(d，J＝8.8Hz，1H)，11.71(br.s，d]吡啶-2，4(3H)-二酮       Hz, 1H), 7.50(d, J=8.8Hz, 1H), 11.71(br.s, d]pyridine-2,4(3H)-dione

                           1H).5-[2-氯-5-(三氟甲基)苄         (CD3SO2CD3)δ2.11(s，3H)，5.29(s，2H)，基]-7-甲基-3，5-二氢[1，3]     7.34(s，1H)，7.54(s，1H)，7.72-7.79(m，2H)，噁唑并[4，5-c]吡啶-2，4-二     12.00(br.s，1H).酮5-(2-氯5-氟苄基)-7-甲基-       (CD3SO2CD3)δ2.11(s，3H)，5.20(s，2H)，3，5-二氢[1，3]噁唑并[4，5-c]  6.71(dd，J＝9.4，2.9Hz，1H)，7.22(td，J＝1H).5-[2-Chloro-5-(trifluoromethyl)benzyl (CD 3 SO 2 CD 3 )δ2.11(s, 3H), 5.29(s, 2H), yl]-7-methyl -3,5-Dihydro[1,3] 7.34(s,1H), 7.54(s,1H), 7.72-7.79(m,2H), oxazolo[4,5-c]pyridine-2,4 -Di 12.00(br.s, 1H). Ketone 5-(2-chloro5-fluorobenzyl)-7-methyl-(CD 3 SO 2 CD 3 )δ 2.11(s, 3H), 5.20(s , 2H), 3,5-dihydro[1,3]oxazolo[4,5-c] 6.71(dd, J=9.4, 2.9Hz, 1H), 7.22(td, J=

                           8.4，2.9Hz，1H)，7.49(s，1H)，7.57(dd，J＝吡啶-2，4-二酮                          8.4, 2.9 Hz, 1H), 7.49 (s, 1H), 7.57 (dd, J = pyridine-2, 4-dione

                           8.4，5.2Hz，1H)，11.99(br.s，1H).实施例42 8.4, 5.2Hz, 1H), 11.99 (br.s, 1H). Example 42

其中使包含具有N-末端Cys的纤连蛋白CS1序列的26-氨基酸肽(CDELPQLVTLPHPNLHGPEILDVPST)和顺丁烯二酰亚胺活化的卵清蛋白偶联的方法用于测定所合成化合物的效力。在4℃下，将牛血清清蛋白(BSA)和结合CS1的卵清蛋白以0.5μg/ml TBS(50mM TRIS，pH7.5；150mM NaCl)包被在96孔聚苯乙烯板上16小时。在室温下用TBS将板洗涤三次后，用包含3％BSA的TBS封闭4小时。试验前，以结合缓冲液(TBS；1mM MgCl2；1mM CaCl2；1mM MnCl2)将封闭板洗涤三次。将用钙黄绿素AM荧光标记的Ramos细胞重悬浮在结合缓冲液(107细胞/ml)中，用含有或不含有化合物的相同缓冲液按1∶2稀释。加入100μM化合物。向各孔中迅速加入细胞(2.5×105细胞/孔)，在37℃下孵育30分钟。用结合缓冲液洗涤三次后，将粘附细胞裂解，使用荧光计定量。结果见表2-7。IC50定义为达到50％抑制所需要的剂量，表2和表4为以μM测量的IC50。IC50值愈低，抑制百分率就愈高，化合物阻止细胞粘附愈有效。A method in which a 26-amino acid peptide comprising the fibronectin CS1 sequence with an N-terminal Cys (CDELPQLVTLPHPNLHGPEILDVPST) was coupled with maleimide-activated ovalbumin was used to determine the potency of the synthesized compounds. Bovine serum albumin (BSA) and CS1-bound ovalbumin were coated on 96-well polystyrene plates in 0.5 μg/ml TBS (50 mM TRIS, pH 7.5; 150 mM NaCl) for 16 hours at 4°C. After washing the plate three times with TBS at room temperature, it was blocked with TBS containing 3% BSA for 4 hours. Blocked plates were washed three times with binding buffer (TBS; 1 mM MgCl 2 ; 1 mM CaCl 2 ; 1 mM MnCl 2 ) before the assay. Ramos cells fluorescently labeled with calcein AM were resuspended in binding buffer ( 107 cells/ml) and diluted 1:2 with the same buffer with or without compound. Add 100 μM compound. Cells (2.5×10 5 cells/well) were quickly added to each well and incubated at 37°C for 30 minutes. After three washes with binding buffer, adherent cells were lysed and quantified using a fluorometer. The results are shown in Table 2-7. IC50 is defined as the dose required to achieve 50% inhibition, Table 2 and Table 4 are IC50 measured in μM. The lower the IC50 value, the higher the percent inhibition and the more effective the compound in preventing cell adhesion.

                             表2 Table 2

                名称                       IC50          质谱数据(m/z)(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[(3S)   -0.2       计算值(M-H)-＝444.12；2-氧代-1-(2-噻吩基甲基)六氢-3-吡啶基]氨基}                实测值(M-H)-＝444.08羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[(3S)-  15         计算值(M-H)-＝430.11；2-氧代-1-(2-噻吩基甲基)四氢-1H-吡咯-3-基]                 实测值(M-H)-＝430.06氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[(3R)-  2          计算值(M-H)-＝444.12；2-氧代-1-(2-噻吩基甲基)六氢-3-吡啶基]氨基}                实测值(M-H)-＝444.05羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[2-氧   0.9        计算值(M-H)-＝440.09；代-1-(2-噻吩基甲基)-1，2-二氢-3-吡啶基]氨                 实测值(M-H)-＝439.98基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-({[((3S)   -0.0003    计算值(M-H)-＝586.23；2-氧代-1-{4-[(2-甲苯氨基羰基)氨基]苄基}六                 实测值(M-H)-＝586.17氢-3-吡啶基)氨基]羰基}氨基)丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[2-氧   0.001      计算值(M-H)-＝582.20；代-1-{4-[(2-甲苯氨基羰基)氨基]苄基}-1，2-二               实测值(M-H)-＝582.20氢-3-吡啶基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-({[((3S)-  nd         nd1-{4-[(2-甲基苄基)氨基]苄基}-2-氧代六氢-吡啶基)氨基]羰基}氨基)丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({丁基    20         计算值(M-H)-＝496.15；[2-氧代-1-(2-噻吩基甲基)-1，2-二氢-3-吡啶基]              实测值(M-H)-＝496.10氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[(3S)-  0.015      计算值(M-H)-＝458.13；2-氧代-1-(2-噻吩基甲基)azepanyl]氨基}羰基)                实测值(M-H)-＝458.09氨基]丙酸Name IC 50 Mass Spectrum Data (m/z) Calculated for (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S) -0.2 (MH) - =444.12; 2-oxo-1-(2-thienylmethyl)hexahydro-3-pyridyl]amino} Found (MH) - =444.08carbonyl)amino]propanoic acid (3S)-3-( 1,3-Benzodioxol-5-yl)-3-[({[(3S)-15 Calcd. (MH) - = 430.11; 2-oxo-1-(2-thienylmethyl Base) Tetrahydro-1H-pyrrol-3-yl] Found (MH) - = 430.06 Amino}carbonyl)amino]propanoic acid (3S)-3-(1,3-benzodioxol-5- yl)-3-[({[(3R)-2 Calcd (MH) - = 444.12; 2-oxo-1-(2-thienylmethyl)hexahydro-3-pyridyl]amino} found (MH) - =444.05carbonyl)amino]propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo0.9 Calcd.(MH ) - = 440.09; Dai-1-(2-thienylmethyl)-1,2-dihydro-3-pyridyl]ammonia found (MH) - = 439.98 yl}carbonyl)amino]propanoic acid (3S) -3-(1,3-benzodioxol-5-yl)-3-({[((3S)-0.0003 Calcd. (MH) - =586.23; 2-oxo-1-{4 -[(2-tolylaminocarbonyl)amino]benzyl}Hex found (MH) - =586.17 hydrogen-3-pyridyl)amino]carbonyl}amino)propanoic acid (3S)-3-(1,3-benzene Dioxol-5-yl)-3-[({[2-oxo 0.001 Calcd. (MH) - =582.20; }-1,2-Two found value (MH) - =582.20 Hydrogen-3-pyridyl]amino}carbonyl)amino]propanoic acid (3S)-3-(1,3-benzodioxol-5 -yl)-3-({[((3S)-nd nd1-{4-[(2-methylbenzyl)amino]benzyl}-2-oxohexahydro-pyridyl)amino]carbonyl}amino )propionic acid (3S)-3-(1,3-benzodioxol-5-yl)-3-[({Butyl 20 Calculated (MH) - =496.15; [2-oxo- 1-(2-Thienylmethyl)-1,2-dihydro-3-pyridyl] found (MH) - = 496.10 amino}carbonyl)amino]propanoic acid (3S)-3-(1,3- Benzodioxol-5-yl)-3-[({[(3S)- 0.015 Calcd. (MH) - =458.13; 2-oxo-1-(2-thienylmethyl)azepanyl] Amino}carbonyl) found (MH) - = 458.09 amino] propionic acid

                                     表3 table 3

         化合物                       IC50(nM)          质谱数据(3S)-3-[({[2-甲基-4-(2-甲基丙基)-6-         10      计算值(M-H)-＝475.23m/z；氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]                 实测值(M-H)-＝475.02m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-        10      计算值(M-H)-＝476.18m/z；[({[2-氧代-1-(苯甲基)-4-丙基-1，2-二                实测值(M-H)-＝475.99m/z氢-3-吡啶基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-        4000    计算值(M-H)-＝488.18mz；({[9-氧代-8-(苯甲基)-2，3，4，5，8，9-六氢          实测值(M-H)-＝488.19m/z-1H-吡啶并[3，4-b]氮杂-1-基]羰基}氨基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-          10      计算值(M-H)-＝466.15m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                  实测值(M-H)-＝465.95m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧        4       计算值(M-H)-＝480.17m/z；代-4-丙基-1，2-二氢-3-吡啶基}氨基)                  实测值(M-H)-＝480.00m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲        5       计算值(M+H)-＝454.15m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                  实测值(M+H)-＝454.09m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({6-甲基-2-氧代-1-(苯甲基)-        5       计算值(M-H)-＝524.22m/z；4-[(苯甲基)氧基]-1，2-二氢-3-吡啶基}                实测值(M-H)-＝524.02m/z氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2，4-       10      计算值(M-H)-＝467.15m/z；二甲基-6-氧代-1，6-二氢-5-嘧啶基}氨                 实测值(M-H)-＝467.00m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2，4-二氯苯基)甲基]-4-       30      计算值(M-H)-＝486.10m/z；甲基-2-氧代-1，2-二氢-3-吡啶基}氨                   实测值(M-H)-＝485.95m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲         10      计算值(M-H)-＝467.15m/z；基]-6-甲基-2-氧代-1，2-二氢-3-吡啶                  实测值(M-H)-＝467.14m/z；基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-(甲       20        计算值(M-H)-＝468.13m/z；氧基)-2-氧代-1，2-二氢-3-吡啶基]氨                    实测值(M-H)-＝467.97m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-氯-1-[(2-氯代苯基)甲           20        计算值(M-H)-＝472.08m/z；基]-2-氧代-1，2-二氢-3-吡啶基}氨基)                   实测值(M-H)-＝471.91m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲        15        计算值(M-H)-＝482.15m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                    实测值(M-H)-＝481.93m/z羰基]氨基}-3-[3-甲基-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲        3         计算值(M+H)+＝470.15m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                    实测值(M+H)+＝470.01m/z羰基]氨基}-3-[4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲        10        计算值(M+H)+＝468.17m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                    实测值(M+H)+＝468.05m/z羰基]氨基}-3-(3，4-二甲基苯基)丙酸(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲         10        计算值(M-H)-＝453.13m/z；基]-2-氧代-1，2-二氢-3-吡啶基}氨基)                   实测值(M-H)-＝453.01m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-氟        15        计算值(M-H)-＝456.12m/z；-2-氧代-1，2-二氢-3-吡啶基}氨基)羰                    实测值(M-H)-＝455.94m/z基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-[(2-氯代苯基)甲基]-2-氧        20        计算值(M-H)-＝529.16 m/z；代-4-(苯基氨基)-1，2-二氢-3-吡啶基]                   实测值(M-H)-＝529.02m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-[(2-氯代苯基)甲基]-2-氧        15        计算值(M-H)-＝530.16m/z；代-4-(2-吡啶基氨基)-1，2-二氢-3-吡啶                  实测值(M-H)-＝529.99m/z基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        10        计算值(M-H)-＝454.11m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝454.05m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧       15     计算值(M-H)-＝544.17m/z；代-4-[(2-吡啶基甲基)氨基]-1，2-二氢-              实测值(M-H)-＝544.03m/z3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧       20     计算值(M-H)-＝544.17m/z；代-4-[(3-吡啶基甲基)氨基]-1，2--二氢-             实测值(M-H)-＝544.02m/z3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-         1      计算值(M-H)-＝523.17m/z；(1，4-噁嗪烷(oxazinan)-4-基)-2-氧代-              实测值(M-H)-＝523.02m/z1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-[(2-氯代苯基)甲基]-2-氧       10     计算值(M-H)-＝495.18m/z；代-4-(丙基氨基)-1，2-二氢-3-吡啶基]               实测值(M-H)-＝495.04m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氟代苯基)甲基]-4-甲       20     计算值(M-H)-＝436.17m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝435.99m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2，6-二氯苯基)甲基]-4-      20     计算值(M-H)-＝486.10m/z；甲基-2-氧代-1，2-二氢-3-吡啶基}氨                 实测值(M-H)-＝485.95m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3R)-3-{[({1-[(2-氯代苯基)甲基]-4-甲       300    计算值(M-H)-＝376.11m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝376.00m/z羰基]氨基}丁酸(3S)-3-{[({1-[(2-溴代苯基)甲基]-4-甲       10     计算值(M-H)-＝496.09m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝495.87m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[4-甲基-2-氧代-1-(苯甲基)-       30     计算值(M-H)-＝418.17m/z；1，2-二氢-3-吡啶基]氨基}羰基)氨基]-               实测值(M-H)-＝417.96m/z3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟     8      计算值(M-H)-＝484.12m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)              实测值(M-H)-＝484.03m/z羰基]氨基}-3-[3-甲基-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧     10     计算值(M-H)-＝514.15m/z；代-4-苯基-1，2-二氢-3-吡啶基}氨基)              实测值(M-H)-＝514.00m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({4-溴-1-[(2-氯代苯基)甲        20     计算值(M-H)-＝516.03m/z；基]-2-氧代-1，2-二氢-3-吡啶基}氨基)             实测值(M-H)-＝515.90m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-     20     计算值(M-H)-＝484.09m/z；{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧            实测值(M-H)-＝484.03m/z代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-       2      计算值(M-H)-＝556.18m/z；[(2-{[2-(甲氧基)乙基]氧基}乙基)氧               实测值(M-H)-＝556.03m/z基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟     15     计算值(M-H)-＝468.13m/z；基-6-甲基-2-氧代-1，2-二氢-3-吡啶基}            实测值(M-H)-＝468.05m/z氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-       3      计算值(M-H)-＝509.20m/z；[(1，1-二甲基乙基)氨基]-2-氧代-1，2-二          实测值(M-H)-＝509.06m/z氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟     10     计算值(M-H)-＝440.10m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)              实测值(M-H)-＝440.04m/z羰基]氨基}-3-苯基丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[4-    3      计算值(M-H)-＝536.20m/z；甲基四氢-1(2H)-吡嗪基]-2-氧代-1，2-             实测值(M-H)-＝636.12m/z二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        5      计算值(M-H)-＝470.11m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                 实测值(M-H)-＝470.05m/z羰基]氨基}-3-[4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        20     计算值(M-H)-＝530.13m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                 实测值(M-H)-＝530.05m/z羰基]氨基}-3-[3，4，5-三(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        15     计算值(M-H)-＝468.13m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                 实测值(M-H)-＝468.08m/z羰基]氨基}-3-(3，5-二甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-          15     计算值(M-H)-＝534.15m/z；[(3-甲基-5-异噁唑基)氨基]-2-氧代-                  实测值(M-H)-＝534.01m/z1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        20     计算值(M-H)-＝454.17m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                 实测值(M-H)-＝454.04m/z羰基]氨基}-3-(3-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        5      计算值(M-H)-＝470.11m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                 实测值(M-H)-＝470.03m/z羰基]氨基}-3-[3-(甲氧基)苯基]丙酸(3S)-3-[3，5-双(甲氧基)苯基]-3-{[({1-       3      计算值(M-H)-＝500.12m/z；[(2-氯代苯基)甲基]-4-羟基-2-氧代-                  实测值(M-H)-＝500.07m/z1，2-二氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        8      计算值(M-H)-＝504.13m/z；基-2-氧代-1，2-二氢-3-喹啉基}氨基)                 实测值(M-H)-＝504.06m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        20     计算值(M-H)-＝508.04m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                 实测值(M-H)-＝508.09m/z羰基]氨基}-3-[3-(三氟甲基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-          2      计算值(M-H)-＝595.21m/z；[({乙基[(乙基氨基)羰基]氨基}羰基)                 实测值(M-H)-＝594.97m/z氨基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({4-(1-azetanyl)-1-[(2-氯代苯      5     计算值(M-H)-＝493.16m/z；基)甲基]-2-氧代-1，2-二-氢-3-吡啶基}              实测值(M-H)-＝493.05m/z氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        30    计算值(M-H)-＝458.09m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝458.03m/z羰基]氨基}-3-(4-氟苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        40    计算值(M-H)-＝458.09m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝458.06m/z羰基]氨基}-3-(3-氟苯基)丙酸(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-          2     计算值(M-H)-＝600.21m/z；({2-[(2-{[2-(甲氧基)乙基]氧基}乙基)               实测值(M-H)-＝600.10m/z氧基]乙基}氧基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟        25    计算值(M-H)-＝508.09m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝508.02m/z羰基]氨基}-3-[4-(三氟甲基)苯基]丙酸(3S)-3-{[({1-[(2-氟代苯基)甲基]-4-羟        30    计算值(M-H)-＝438.15m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝438.07m/z羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-氟苯基)甲基]-4-       10    计算值(M-H)-＝472.11m/z；羟基-2-氧代-1，2-二氢-3-吡啶基}氨                 实测值(M-H)-＝472.06m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟400           计算值(M-H)-＝496.16m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)                实测值(M-H)-＝496.11m/z羰基]氨基}-3-[4-(1，1-二甲基乙基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-5-甲        70    计算值(M-H)-＝452.14m/z；基-2-氧代-1，2-二氢-3-吡啶基}氨基)               实测值(M-H)-＝451.99m/z羰基]氨基}-3-(4-甲基苯基)丙酸3-(4-氯代苯基)-3-{[({1-[(2-氯代苯基)      30     计算值(M-H)-＝474.06m/z；甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶             实测值(M-H)-＝474.07m/z基}氨基)羰基]氨基}丙酸(3S)-3-[({[2-甲基-6-氧代-1-(苯甲基)-      25     计算值(M+H)-＝498.22m/z；4-(2-吡啶基)-1，6-二氢-5-嘧啶基]氨               实测值(M+H)-＝498.10m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸3-(3-氯代苯基)-3-{[({1-[(2-氯代苯基)      30     计算值(M-H)-＝474.06m/z；甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶             实测值(M-H)-＝474.03m/z基}氨基)羰基]氨基}丙酸3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-      40     计算值(M-H)-＝508.02m/z；氧代-1，2-二氢-3-吡啶基}氨基)羰基]               实测值(M-H)-＝507.97m/z氨基}-3-(3，4-二氯苯基)丙酸Compound IC 50 (nM) Mass spectral data Calculated for (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-10 (MH) - = 475.23m/z; oxygen Generation-1-(benzyl)-1,6-dihydro-5-pyrimidinyl] found (MH) - = 475.02 m/z amino}carbonyl)amino]-3-(4-methylphenyl) Propionic acid (3S)-3-(1,3-benzodioxol-5-yl)-3- 10 Calculated (MH) - =476.18m/z; [({[2-oxo- 1-(Benzyl)-4-propyl-1,2-diFound (MH) - =475.99m/z Hydrogen-3-pyridyl]amino}carbonyl)amino]propanoic acid (3S)-3- (1,3-Benzodioxol-5-yl)-3-4000 Calcd. (MH) - =488.18mz; ({[9-oxo-8-(benzyl)-2,3 , 4,5,8,9-Hexahydrofound (MH) - =488.19m/z-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propionic acid (3S) -3-{[({1-[(2-Chlorophenyl)methyl]-4-10 Calculated (MH) - =466.15m/z; base-2-oxo-1,2-dihydro -3-pyridyl}amino) found (MH) - =465.95m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[( 2-Chlorophenyl)methyl]-2-oxo4 Calcd. (MH) - = 480.17 m/z; Substituent-4-propyl-1,2-dihydro-3-pyridyl}amino) found (MH) - =480.00m/zcarbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl] Calcd for -4-methyl5 (M+H) - = 454.15 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}amino) found (M+H) - = 454.09 m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-5 Calculation Value (MH) - = 524.22 m/z; 4-[(phenylmethyl)oxy]-1,2-dihydro-3-pyridyl} Found (MH) - = 524.02 m/z amino)carbonyl] Amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2,4- 10 Calculated (MH) - =467.15m/z; Dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl}ammonia found (MH) - =467.00m/zyl)carbonyl]amino}-3-( 4-Methylphenyl)propanoic acid (3S)-3-{[({1-[(2,4-dichlorophenyl)methyl]-4- 30 Calculated (MH) - = 486.10m/z ;Methyl-2-oxo-1,2-dihydro-3-pyridyl}ammonia Found (MH) - =485.95m/zyl)carbonyl]amino}-3-(4-methylphenyl) Propionic acid (3S)-3-{[({4-Amino-1-[(2-chlorophenyl)methyl 10 Calcd. (MH) - = 467.15m/z; yl]-6-methyl-2 -Oxo-1,2-dihydro-3-pyridine found (MH) - =467.14m/z; base}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S) -3-[({[1-[(2-Chlorophenyl)methyl]-4-(calcd for 20 (MH) - =468.13m/z; oxy)-2-oxo-1, [ ( {4-Chloro-1-[(2-chlorophenyl)methanol calcd. (MH) - =472.08 m/z; yl]-2-oxo-1,2-dihydro-3-pyridyl} Amino) found (MH) - = 471.91m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl )methyl]-4-methan15 Calculated (MH) - =482.15 m/z; Base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - =481.93 m/z carbonyl]amino}-3-[3-methyl-4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl Base]-4-methanol3 Calcd. (M+H) + = 470.15 m/z; Base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (M+H) + =470.01m/zcarbonyl]amino}-3-[4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]- 4-A10 Calcd. (M+H) + = 468.17 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}amino) found (M+H) + = 468.05 m /zcarbonyl]amino}-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl 10 calculation Value (MH) - = 453.13 m/z; base] -2-oxo-1,2-dihydro-3-pyridyl} amino) Found (MH) - = 453.01 m/z carbonyl] amino} -3 -(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-fluoro15 Calculated (MH) - = 456.12m/ z;-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl Found (MH) - =455.94m/zyl]amino}-3-(4-methylphenyl)propane Acid (3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo20 Calcd. (MH) - = 529.16 m/z; Generation-4-(phenylamino )-1,2-dihydro-3-pyridyl] found (MH) - =529.02 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3- [({[1-[(2-Chlorophenyl)methyl]-2-oxo15 Calculated (MH) - =530.16m/z; Generation-4-(2-pyridylamino)-1,2 -Dihydro-3-pyridine found value (MH) - =529.99m/z base]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-{[({1 Calcd for -[(2-chlorophenyl)methyl]-4-hydroxy10 (MH) - =454.11 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}amino ) found (MH) - = 454.05m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl) Methyl]-2-oxo15 Calculated (MH) - =544.17 m/z; Dai-4-[(2-pyridylmethyl)amino]-1,2-dihydro- found (MH) - = 544.03m/z3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl ]-2-Oxo20 Calcd. (MH) - = 544.17 m/z; Dai-4-[(3-pyridylmethyl)amino]-1,2-dihydro- found (MH) - = 544.02 m/z3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-[(2-chlorophenyl)methyl] -4- 1 Calculated (MH) - = 523.17 m/z; (1,4-oxazinan-4-yl)-2-oxo- Found (MH) - = 523.02 m/z1, 2-Dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-[(2-chlorophenyl) Methyl]-2-oxo10 Calculated (MH) - = 495.18 m/z; Dai-4-(propylamino)-1,2-dihydro-3-pyridyl] found (MH) - = 495.04 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-fluorophenyl)methyl]-4-methyl 20 Calculated (MH) - =436.17m/z; base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - =435.99m/zcarbonyl]amino}- 3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2,6-dichlorophenyl)methyl]-4- 20 Calcd. (MH) - = 486.10 m/z; Methyl-2-oxo-1,2-dihydro-3-pyridyl}ammonia Found (MH) - =485.95m/zyl)carbonyl]amino}-3-(4-methyl Phenyl)propanoic acid (3R)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl 300 Calcd. (MH) - =376.11m/z; Base-2- Oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - =376.00m/z carbonyl]amino}butanoic acid (3S)-3-{[({1-[(2- Bromophenyl)methyl]-4-methyl10 Calculated (MH) - = 496.09 m/z; Base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH ) - =495.87m/zcarbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[4-methyl-2-oxo-1-(benzyl ) - 30 Calculated (MH) - = 418.17 m/z; 1,2-dihydro-3-pyridyl] amino} carbonyl) amino] - found (MH) - = 417.96 m/z 3-(4-methyl ylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy8 Calculated (MH) - =484.12m/z; base-2 -oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 484.03 m/z carbonyl]amino}-3-[3-methyl-4-(methoxy)benzene Base]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo10 Calculated (MH) - =514.15m/z; generation-4-benzene Base-1,2-dihydro-3-pyridyl}amino) found (MH) - =514.00m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3- {[({4-bromo-1-[(2-chlorophenyl)methanol 20 Calcd. (MH) - =516.03m/z; base]-2-oxo-1,2-dihydro-3- Pyridyl}amino) found (MH) - =515.90m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-(1,3-benzodioxane Pent-5-yl)-3-20 Calcd. (MH) - = 484.09 m/z; {[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxygen found (MH) - =484.03m/z generation-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}propionic acid (3S)-3-{[({1-[(2-chlorobenzene [(2-{[2-(methoxy)ethyl]oxy}ethyl)Oxygen found (MH ) - =556.03m/z base]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3- {[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy15 Calculated (MH) - =468.13m/z; Base-6-methyl-2-oxo-1,2 -Dihydro-3-pyridyl} Found (MH) - = 468.05m/z amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1 -[(2-Chlorophenyl)methyl]-4- 3 Calculated (MH) - =509.20 m/z; [(1,1-Dimethylethyl)amino]-2-oxo-1 , 2-two measured value (MH) - =509.06m/z Hydrogen-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-{[( Calcd for {1-[(2-chlorophenyl)methyl]-4-hydroxy10 (MH) - =440.10m/z; yl-2-oxo-1,2-dihydro-3-pyridyl }Amino) Found (MH) - =440.04m/zCarbonyl]Amino}-3-Phenylpropanoic acid (3S)-3-{[({1-[(2-Chlorophenyl)methyl]- 4-[4- 3 Calcd. (MH) - = 536.20 m/z; Methyltetrahydro-1(2H)-pyrazinyl]-2-oxo-1,2- Found (MH) - = 636.12 m/z dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl )methyl]-4-hydroxy5 Calculated (MH) - =470.11 m/z; Base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - =470.05 m/zcarbonyl]amino}-3-[4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- Hydroxy 20 Calculated (MH) - = 530.13 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 530.05 m/z carbonyl]amino} -3-[3,4,5-tri(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 15 Calculated (MH) - = 468.13 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 468.08 m/z carbonyl]amino}-3 -(3,5-Dimethylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 15 Calculated (MH) - = 534.15 m/z; [(3-methyl-5-isoxazolyl)amino]-2-oxo- found (MH) - =534.01 m/z 1,2-dihydro-3-pyridyl}amino) Carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy20 Calculated (MH ) - =454.17m/z; Base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - =454.04m/zcarbonyl]amino}-3-(3- Methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy5 Calculated (MH) - = 470.11m/z; base - 2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 470.03 m/z carbonyl]amino}-3-[3-(methoxy)phenyl]propanoic acid (3S)-3-[3,5-bis(methoxy)phenyl]-3-{[({1- 3 Calculated (MH) - =500.12m/z; [(2-chlorophenyl )methyl]-4-hydroxyl-2-oxo- found (MH) - =500.07m/z1,2-dihydro-3-pyridyl}amino)carbonyl]amino}propionic acid (3S)-3- {[({1-[(2-Chlorophenyl)methyl]-4-hydroxy8 Calculated (MH) - =504.13m/z; base-2-oxo-1,2-dihydro-3 -Quinolinyl}amino) found (MH) - =504.06m/z carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-{[({1-[(2 -Chlorophenyl)methyl]-4-hydroxyl 20 Calculated (MH) - =508.04 m/z; base-2-oxo-1,2-dihydro-3-pyridyl}amino) found ( MH) - =508.09m/zcarbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl) [({Ethyl[(ethylamino)carbonyl]amino}carbonyl) found (MH) - =594.97m/zamino] - 2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-{[({4-(1 -azetanyl)-1-[(2-Chlorobenzene 5 Calcd. (MH) - =493.16 m/z; yl)methyl]-2-oxo-1,2-di-hydro-3-pyridyl} Found (MH) - = 493.05m/z amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl )methyl]-4-hydroxy30 Calcd. (MH) - =458.09 m/z; Base-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - =458.03 m/z Carbonyl]amino}-3-(4-fluorophenyl)propionic acid (3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy40 Calculated (MH) - =458.09m/z; base-2-oxo-1,2-dihydro-3-pyridyl}amino) Found (MH) - =458.06m/zcarbonyl]amino}-3-( 3-Fluorophenyl)propanoic acid (3S)-3-[({[1-[(2-chlorophenyl)methyl]-4- 2 Calculated (MH) - =600.21m/z;({ 2-[(2-{[2-(Methoxy)ethyl]oxy}ethyl) found (MH) - = 600.10m/z oxy]ethyl}oxy)-2-oxo- 1,2-Dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorobenzene Base) methyl] -4-hydroxyl 25 Calculated (MH) - = 508.09 m/z; Base -2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 508.02m/zcarbonyl]amino}-3-[4-(trifluoromethyl)phenyl]propanoic acid (3S)-3-{[({1-[(2-fluorophenyl)methyl]- 4-Hydroxy 30 Calcd (MH) - = 438.15 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 438.07 m/z carbonyl] Amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chloro-6-fluorophenyl)methyl]-4- 10 Calculated (MH ) - =472.11m/z; Hydroxy-2-oxo-1,2-dihydro-3-pyridyl}ammonia Found (MH) - =472.06m/zyl)carbonyl]amino}-3-(4 -Methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 400 Calculated (MH) - =496.16m/z; base -2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 496.11 m/z carbonyl]amino}-3-[4-(1,1-dimethylethyl Base)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl 70 Calculated (MH) - =452.14m/z; Base- 2-oxo-1,2-dihydro-3-pyridyl}amino) found (MH) - = 451.99 m/z carbonyl]amino}-3-(4-methylphenyl)propanoic acid 3-( 4-Chlorophenyl)-3-{[({1-[(2-Chlorophenyl)30 Calcd. (MH) - = 474.06m/z; Methyl]-4-hydroxy-2-oxo -1,2-Dihydro-3-pyridine found value (MH) - =474.07m/z base}amino)carbonyl]amino}propanoic acid (3S)-3-[({[2-methyl-6-oxo Gen-1-(benzyl)-25 Calcd. (M+H) - = 498.22 m/z; 4-(2-pyridyl)-1,6-dihydro-5-pyrimidinyl]ammonia found ( M+H) - =498.10m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid 3-(3-chlorophenyl)-3-{[({1-[( 2-Chlorophenyl) 30 Calculated (MH) - = 474.06 m/z; Methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridine Found (MH) - = 474.03 m/z base}amino)carbonyl]amino}propanoic acid 3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2-40 Calculated value (MH) - =508.02 m/z; oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] found (MH) - =507.97 m/z amino}-3-(3,4-dichlorophenyl)propane acid

                                       表4 Table 4

             名称                         IC50           质谱数据(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           0.015        计算值(M-H)-＝452.18m/z；-[({[2-氧代-1-(苯甲基)-3-azepanyl]氨基}羰                  实测值(M-H)-＝452.10m/z基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           0.04         计算值(M-H)-＝477.18m/z；-{[({1-[(3-氰基苯基)甲基]-2-氧代-3-                        实测值(M-H)-＝477.14m/zazepanyl}氨基)羰基]氨基}丙酸(3S)-3-(4-甲基苯基)-3                         0.6          计算值(M-H)-＝410.11m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-                  实测值(M-H)-＝410.00m/z吡啶基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           0.5          计算值(M-H)-＝434.13m/z；-[({[2-氧代-1-(苯甲基)-1，2-二氢-3-吡啶基]                 实测值(M-H)-＝434.05m/z氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           1            计算值(M-H)-＝448.14m/z；-{[({1-[(4-甲基苯基)甲基]-2-氧代-1，2-二                   实测值(M-H)-＝448.02m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           3            计算值(M-H)-＝464.14m/z；-({[(1-{[4-(甲氧基)苯基]甲基}-2-氧代-1，2-                 实测值(M-H)-＝464.03m/z二氢-3-吡啶基)氨基]羰基}氨基)丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           1.5          计算值(M-H)-＝448.15m/z；-{[({1-[(3-甲基苯基)甲基}-2-氧代-1，2-二                   实测值(M-H)-＝448.04m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-[3，5-双(甲氧基)苯基]-3-[({[2-氧代-    0.7          计算值(M-H)-＝456.12m/z；1-(2-苯硫基甲基)-1，2-二氢-3-吡啶基]氨                     实测值(M-H)-＝456.00m/z基}羰基)氨基]丙酸(3S)-3-[4-(甲氧基)苯基]-3-[({[2-氧代-1-(2-    0.8          计算值(M-H)-＝426.11m/z；苯硫基甲基)-1，2-二氢-3-吡啶基]氨基}羰                     实测值(M-H)-＝426.00m/z基)氨基]丙酸(3S)-3-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二    2.5          计算值(M-H)-＝464.09m/z；氢-3-吡啶基]氨基}羰基)氨基]-3-[3-(三氟                     实测值(M-H)-＝463.99m/z甲基)苯基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          50         计算值(M-H)-＝419.12m/z；-[({[3-(苯氧基)苯基]氨基}羰基)氨基]丙酸                 实测值(M-H)-＝418.97m/z(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          5          计算值(M-H)-＝438.11m/z；-{[({3-[(2-苯硫基甲基)氨基]苯基}氨基)羰                 实测值(M-H)-＝438.00m/z基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          0.8        计算值(M-H)-＝468.09m/z；-{[({1-[(3-氯代苯基)甲基]-2-氧代-1，2-二                实测值(M-H)-＝468.01m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          0.8        计算值(M-H)-＝502.12m/z；-({[(2-氧代-1-{[3-(三氟甲基)苯基]甲基}-                 实测值(M-H)-＝502.03m/z1，2-二氢-3-吡啶基)氨基]羰基}氨基)丙酸(3S)-3-(4-氟苯基)-3                          1.6        计算值(M-H)-＝414.09m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-               实测值(M-H)-＝414.01m/z吡啶基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          3          计算值(M-H)-＝468.09m/z；-{[({1-[(4-氯代苯基)甲基]-2-氧代-1，2-二                实测值(M-H)-＝467.99m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          0.5        计算值(M-H)-＝464.14m/z；-({[(1-{[2-(甲氧基)苯基]甲基}-2-氧代-1，2-              实测值(M-H)-＝464.04m/z二氢-3-吡啶基)氨基]羰基}氨基)丙酸(3S)-3-[3-(甲氧基)苯基]-3                    1.4        计算值(M-H)-＝426.11m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-               实测值(M-H)-＝426.02m/z吡啶基]氨基}羰基)氨基]丙酸(3S)-3-                                      1          计算值(M-H)-＝396.10m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-               实测值(M-H)-＝396.01m/z吡啶基]氨基}羰基)氨基]-3-苯基丙酸(3S)-3-                                      0.3        计算值(M-H)-＝486.13m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2--二氢-3-              实测值(M-H)-＝485.98m/z吡啶基]氨基}羰基)氨基]-3-[3，4，5-三(甲氧基)苯基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          0.3        计算值(M-H)-＝468.08m/z；-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二                实测值(M-H)-＝468.03m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3         2        计算值(M-H)-＝452.12m/z；-{[({1-[(4-氟代苯基)甲基]-2-氧代-1，2-二             实测值(M-H)-＝452.00m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸3-(1，3-苯并二氧杂环戊-5-基)-2，2-二氟-3    ＞100    计算值(M-H)-＝476.07m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-            实测值(M-H)-＝476.00m/z吡啶基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3         14       计算值(M-H)-＝478.16m/z；-{[({2-氧代-1-[3-(苯氧基)丙基]-1，2-二氢-            实测值(M-H)-＝478.09m/z3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3         5        计算值(M-H)-＝502.05m/z；-{[({1-[(3，5-二氯苯基)甲基]-2-氧代-1，2-二          实测值(M-H)-＝501.94m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3         6        计算值(M-H)-＝426.16m/z；-[({[1-(环戊基甲基)-2-氧代-1，2-二氢-3-吡            实测值(M-H)-＝426.09m/z啶基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3         15       计算值(M-H)-＝454.09m/z；-{[({2-氧代-1-[2-(2-苯硫基)乙基]-1，2-二氢           实测值(M-H)-＝453.99m/z-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-     0.1      计算值(M+H)+＝440.14m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-             实测值(M+H)+＝440.09m/z甲基苯基)丙酸(3S)-3-(2，3-二氢-1-苯并呋喃-5-基)-3        0.14     计算值(M-H)-＝438.11m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-            实测值(M-H)-＝437.99m/z吡啶基]氨基}羰基)氨基]丙酸(3S)-3-(3-氟苯基)-3                         3        计算值(M-H)-＝414.09m/z；-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二氢-3-            实测值(M-H)-＝413.99m/z吡啶基]氨基}羰基)氨基]丙酸(3S)-3-[({[2-氧代-1-(2-苯硫基甲基)-1，2-二  1.5      计算值(M-H)-＝464.09m/z；氢-3-吡啶基]氨基}羰基)氨基]-3-[4-(三氟               实测值(M-H)-＝463.99m/z甲基)苯基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3         0.5      计算值(M-H)-＝434.13m/z；-[({[6-氧代-1-(苯甲基)-1，6-二氢-3-吡啶基]            实测值(M-H)-＝434.02m/z氨基}羰基)氨基]丙酸(3S)-3-[4-氟-3-(三氟甲基)苯基]-3-[({[2-氧    0.35     计算值(M-H)-＝482.08m/z；代-1-(2-苯硫基甲基)-1，2-二氢-3-吡啶基]               实测值(M-H)-＝481.97m/z氨基}羰基)氨基]丙酸(3S)-3-[4-(1，1-二甲基乙基)苯基]-3-[({[2-    2        计算值(M-H)-＝452.16m/z；氧代-1-(2-苯硫基甲基)-1，2-二氢-3-吡啶                实测值(M-H)-＝452.02m/z基]氨基}羰基)氨基]丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3          70       计算值(M-H)-＝494.19m/z；-[({丁基[2，5-二氧代-1-(苯甲基)四氢-1H-               实测值(M-H)-＝494.12m/z吡咯-3-基]氨基}羰基)氨基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-      0.04     计算值(M+H)+＝516.16m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                 实测值(M+H)+＝516.02m/z[3，4，5-三(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2，6-二氯苯基)甲基]-2-氧代-   0.2      计算值(M+H)+＝474.10m/z；1，2-二-氢-3-吡啶基}氨基)羰基]氨基}-3-(4-             实测值(M+H)+＝474.04m/z甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-      0.2      计算值(M+H)+＝512.10m/z；1，2-二-氢-3-吡啶基}氨基)羰基]氨基}-3-[4-             实测值(M+H)+＝512.04m/z氟-3-(三氟甲基)苯基]丙酸(3S)-3-{[({1-[(2-氟代苯基)甲基]-2-氧代-      0.1      计算值(M-H)-＝422.15m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-              实测值(M-H)-＝422.01m/z甲基苯基)丙酸(3S)-3-(4-甲基苯基)-3-{[({1-[(2-甲基苯基)    0.1      计算值(M-H)-＝418.18m/z；甲基]-2-氧代-1，2-二-氢-3-吡啶基}氨基)羰              实测值(M-H)-＝418.02m/z基]氨基}丙酸(3S)-3-{[({1-[(2-溴代苯基)甲基]-2-氧代-      0.05     计算值(M+H)+＝484.09m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-              实测值(M+H)+＝484.03m/z甲基苯基)丙酸(3S)-3-{[({1-[(2，4-二氯苯基)甲基]-2-氧代-   0.4      计算值(M+H)+＝474.10m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-              实测值(M+H)+＝474.05m/z甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-       0.04        计算值(M-H)-＝466.11m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                     实测值(M-H)-＝466.00m/z(2，3-二氢-1-苯并呋喃-5-基)丙酸(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3           2           计算值(M-H)-＝468.09m/z；-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二                  实测值(M-H)-＝467.97m/z氢-3-吡啶基}氨基)羰基]氨基}丙酸(3S)-3-(4-甲基苯基)-3-({[(2-氧代-1-{[2-       1           计算值(M+H)+＝474.10m/z；(三氟甲基)苯基]甲基}-1，2-二氢-3-吡啶基)                  实测值(M+H)+＝474.09m/z氨基]羰基}氨基)丙酸(3S)-3-{[({1-[(2，5-二氯苯基)甲基]-2-氧代-    0.15        计算值(M+H)+＝474.10m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                  实测值(M+H)+＝474.04m/z甲基苯基)丙酸(2R-2-{[({1-[(2-氯代苯基)甲基]-2-氧代-        50          计算值(M-H)-＝424.10m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-苯                   实测值(M-H)-＝423.99m/z基丙酸(2R)-2-{[({1-[(2-氯代苯基)甲基]-2-氧代-       80          计算值(M-H)-＝410.08m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-2-苯                   实测值(M-H)-＝409.95m/z基乙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-       0.1         计算值(M-H)-＝452.14m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                     实测值(M-H)-＝451.96m/z(3，5--二-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-       0.1         计算值(M-H)-＝424.10m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-苯                   实测值(M-H)-＝424.07m/z基丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-       0.1         计算值(M-H)-＝454.11m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[4-                  实测值(M-H)-＝454.01m/z(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-       0.1         计算值(M-H)-＝440.10m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                  实测值(M-H)-＝440.00m/z羟基苯基)丙酸(3S)-3-({[(1-{[3-(甲氧基)苯基]甲基}-2-氧      0.2         计算值(M-H)-＝434.17m/z；代-1，2-二氢-3-吡啶基)氨基]羰基}氨基)-3-                  实测值(M-H)-＝434.01m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-溴代苯基)甲基]-2-氧代-        0.08        计算值(M-H)-＝558.09m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                      实测值(M-H)-＝557.87m/z[3，4，5-三(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-        0.09        计算值(M+H)+＝454.15m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                      实测值(M+H)+＝454.07m/z(3，4-二甲基苯基)丙酸(3S)-3-[({[5-氯-2-羟基-3-(苯甲基)苯基]氨       8           计算值(M-H)-＝437.12m/z；基}羰基)氨基]-3-(4-甲基苯基)丙酸                           实测值(M-H)-＝437.06m/z(3S)-3-(4-甲基苯基)-3-[({[3-(苯甲基)苯基]      10          计算值(M-H)-＝387.17m/z；氨基}羰基)氨基]丙酸                                        实测值(M-H)-＝387.00m/z(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-        0.04        计算值(M-H)-＝468.13m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-                   实测值(M-H)-＝468.01m/z甲基-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-        0.07        计算值(M-H)-＝454.11m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                   实测值(M-H)-＝454.00m/z羟基-3-甲基苯基)丙酸(3S)-3-{[({1-[(2，3-二氯苯基)甲基]-2-氧代-     0.35        计算值(M-H)-＝472.08m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                   实测值(M-H)-＝471.94m/z甲基苯基)丙酸(3S)-3-[({[1-([1，1’-联苯基]-2-基甲基)-2-氧   2.5         计算值(M-H)-＝480.19m/z；代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-                   实测值(M-H)-＝480.05m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-        0.2         计算值(M-H)-＝438.12m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3-                   实测值(M-H)-＝438.00m/z甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-        3           计算值(M-H)-＝438.12m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(2-                   实测值(M-H)-＝437.99m/z甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-        0.3         计算值(M-H)-＝464.13m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                      实测值(M-H)-＝464.03m/z(2，3-二氢-1H-茚-5-基)丙酸(3S)-3-{[({1-[(2-氰基苯基)甲基]-2-氧代-          0.1            计算值(M+H)+＝431.18m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                        实测值(M+H)+＝431.09m/z甲基苯基)丙酸(3 S)-3-[2，6-双(甲氧基)苯基]-3-{[({1-[(2-       6              计算值(M-H)-＝484.14m/z；氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶                          实测值(M-H)-＝483.96m/z基}氨基)羰基]氨基}丙酸(3S)-3-{[({1-[(3-羟基苯基)甲基]-2-氧代-          0.2            计算值(M+H)+＝420.18m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                        实测值(M+H)+＝422.05m/z甲基苯基)丙酸(3S)-3-[({[2-甲基-6-氧代-1-(苯甲基)-1，6-        0.1            计算值(M-H)-＝419.17m/z；二氢-5-嘧啶基}氨基}羰基)氨基]-3-(4-甲                           实测值(M-H)-＝419.03m/z基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-氧代-          0.1            计算值(M-H)-＝438.12m/z；1，4-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                        实测值(M-H)-＝438.10m/z甲基苯基)丙酸(3S)-3-(4-甲基苯基)-3-{[({1-[(2-硝基苯基)        1              计算值(M+H)+＝451.17m/z；甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰                         实测值(M+H)+＝451.07m/z基]氨基}丙酸(3S)-3-(4-甲基苯基)-3-{[({1-[(4-硝基苯基)        1              计算值(M+H)+＝451.17m/z；甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰                         实测值(M+H)+＝451.09m/z基]氨基}丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-          3              计算值(M-H)-＝456.10m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                           实测值(M-H)-＝456.04m/z(2，6-二羟基苯基)丙酸(3 S)-3-{[({1-[(2，6-二氟苯基)甲基]-2-氧代-      0.3            计算值(M-H)-＝440.14m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                        实测值(M-H)-＝440.00m/z甲基苯基)丙酸(3S)-3-{[({1-[(2，4-二氟苯基)甲基]-2-氧代-       1.3            计算值(M-H)-＝440.14m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                        实测值(M-H)-＝439.96m/z甲基苯基)丙酸(3S)-3-{[({1-[(2，5-二氟苯基)甲基]-2-氧代-       0.8            计算值(M-H)-＝440.14m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                        实测值(M-H)-＝439.96m/z甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-甲基-6-      0.09         计算值(M-H)-＝453.13m/z；氧代-1，6-二氢-5-嘧啶基}氨基)羰基]氨                        实测值(M-H)-＝453.00m/z基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-氟苯基)甲基]-2-氧代      0.1          计算值(M-H)-＝456.11m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                      实测值(M-H)-＝455.94m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-溴-5-氟苯基)甲基]-2-氧代      0.5          计算值(M-H)-＝500.06m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                      实测值(M-H)-＝499.91m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-氟苯基)甲基]-2-氧代      0.35         计算值(M-H)-＝456.11m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                      实测值(M-H)-＝455.93m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-溴代苯基)甲基]-2-氧代-        0.2          计算值(M-H)-＝512.08m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-                    实测值(M-H)-＝511.96m/z甲基-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(3，5-二甲基-4-异噁唑基)甲       3            计算值(M-H)-＝423.17m/z；基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]                    实测值(M-H)-＝423.02m/z氨基}-3-(4-甲基苯基)丙酸(3S)-3-(4-甲基苯基)-3-{[({2-氧代-1-            2.5          计算值(M-H)-＝446.21m/z；[(2，4，6-三甲基苯基)甲基]-1，2-二氢-3-吡啶                 实测值(M-H)-＝446.08m/z基}氨基)羰基]氨基}丙酸(3S)-3-(4-甲基苯基)-3-{[({1-[(2-甲基-1，3-     1            计算值(M-H)-＝425.13m/z；噻唑-4-基)甲基]-2-氧代-1，2-二氢-3-吡啶                     实测值(M-H)-＝424.99m/z基}氨基)羰基]氨基}丙酸(3S)-3-({[(1-{[4-(1，1-二甲基乙基)苯基]甲      6            计算值(M-H)-＝460.22m/z；基}-2-氧代-1，2--二氢-3-吡啶基)氨基]羰基}                   实测值(M-H)-＝460.07m/z氨基)-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(1，3-苯并噁唑-2-基甲基)-2-氧     ＞10         计算值(M-H)-＝445.15m/z；代-1，2-二-氢-3-吡啶基]氨基}羰基)氨基]-3-                   实测值(M-H)-＝445.01m/z(4-甲基苯基)丙酸(3S)-3-({[(1-{2-[(2-羟基苯基)氨基]-2-氧代      ＞10         计算值(M-H)-＝463.16m/z；乙基}-2-氧代-1，2-二氢-3-吡啶基)氨基]羰                   实测值(M-H)-＝463.06m/z基}氨基)-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-硝基苯基)甲基]-2-氧        4        计算值(M-H)-＝483.11m/z；代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                  实测值(M-H)-＝483.01m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(5-氯-2-氟苯基)甲基]-2-氧代        2.5      计算值(M-H)-＝456.11m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                    实测值(M-H)-＝456.00m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氨基-6-氯苯基)甲基]-2-氧        2        计算值(M-H)-＝453.13m/z；代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                  实测值(M-H)-＝453.02m/z(4-甲基苯基)丙酸(3S)-3-({[(1-{[2-氟-4-(三氟甲基)苯基]甲          3        计算值(M-H)-＝490.14m/z；基}-2-氧代-1，2-二氢-3-吡啶基)氨基]羰基}                  实测值(M-H)-＝489.99m/z氨基)-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(5-氯-2-苯硫基)甲基]-2-氧代        1.3      计算值(M-H)-＝444.08m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                    实测值(M-H)-＝443.97m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-溴-5-硝基苯基)甲基]-2-氧        2        计算值(M-H)-＝527.06m/z；代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                  实测值(M-H)-＝526.95m/z(4-甲基苯基)丙酸3-(4-氯苯基)-3-{[({1-[(2-氯代苯基)甲基]-         0.03     计算值(M-H)-＝474.06m/z；4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰                  实测值(M-H)-＝474.07m/z基]氨基}丙酸(3S)-3-[({[2-甲基-6-氧代-1-(苯甲基)-4-(2-        0.025    计算值(M+H)+＝498.22m/z；吡啶基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨                   实测值(M+H)+＝498.10m/z基]-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(5-氨基-2-溴苯基)甲基]-2-氧        0.08     计算值(M-H)-＝497.08m/z；代-1，2-二-氢-3-吡啶基}氨基)羰基]氨基}-3-                 实测值(M-H)-＝497.02m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(2，5-二甲基苯基)甲基]-2-氧        0.15     计算值(M-H)-＝432.19m/z；代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                  实测值(M-H)-＝432.04m/z(4-甲基苯基)丙酸3-(3-氯代苯基)-3-{[({1-[(2-氯代苯基)甲        0.03       计算值(M-H)-＝474.06m/z；基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨                  实测值(M-H)-＝474.03m/z基)羰基]氨基}丙酸3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代      0.04       计算值(M-H)-＝508.02m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                   实测值(M-H)-＝507.97m/z(3，4-二氯苯基)丙酸(3S)-3-({[(1-{[5-(乙酰基氨基)-2-溴代苯        0.2        计算值(M-H)-＝539.09m/z；基]甲基}-2-氧代-1，2-二氢-3-吡啶基)氨基]                 实测值(M-H)-＝539.02m/z羰基}氨基)-3-(4-甲基苯基)丙酸(3S)-3-[({[1-({2-溴-5-[(甲基磺酰基)氨基]      0.25       计算值(M-H)-＝575.06m/z；苯基}甲基)-2-氧代-1，2-二氢-3-吡啶基]氨                  实测值(M-H)-＝575.01m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸3-(4-氯代苯基)-3-{[({1-[(2-氯代苯基)甲        0.4        计算值(M-H)-＝458.07m/z；基]-2-氧代-1，2-＝氢-3-吡啶基}氨基)羰基]                 实测值(M-H)-＝457.96m/z氨基}丙酸3-(3-氯代苯基)-3-{[({1-[(2-氯代苯基)甲        1          计算值(M-H)-＝458.07m/z；基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]                 实测值(M-H)-＝457.93m/z氨基}丙酸3-{[({1-[(2-氯代苯基)甲基]-2-氧代-1，2-二     1          计算值(M-H)-＝492.03m/z；氢-3-吡啶基}氨基)羰基]氨基}-3-(3，4-二氯                 实测值(M-H)-＝491.85m/z苯基)丙酸(3S)-3-{{({1-[(2-溴-4-氯苯基)甲基]-2-氧代     1          计算值(M-H)-＝516.03m/z；-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-                   实测值(M-H)-＝515.91m/z(4-甲基苯基)丙酸(3S)-3-{[({1-[(4-氯代苯基)甲基]-2-氧代-       2          计算值(M-H)-＝438.12m/z；1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-                 实测值(M-H)-＝437.88m/z甲基苯基)丙酸(3S)-3-{{({1-[(2-氯代苯基)甲基]-4-羟基-2-     0.035      计算值(M-H)-＝498.14m/z；氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨                     实测值(M-H)-＝498.05m/z基}-3-[2，3-二甲基-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-     0.015      计算值(M-H)-＝524.08m/z；氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨                     实测值(M-H)-＝524.03m/z基}-3-{4-[(三氟甲基)氧基]苯基}丙酸(3R)-3-[({{1-[(2-氯代苯基)甲基]-4-(1，4-噁        0.1        计算值(M-H)-＝489.19m/z；嗪烷-4-基)-2-氧代-1，2-二氢-3-吡啶基]氨                      实测值(M-H)-＝489.13m/z基}羰基)氨基]-5-甲基己酸(3S)-3-[({[4-羟基-6-甲基-2-氧代-1-(苯甲           0.35       计算值(M-H)-＝434.17m/z；基)-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-                      实测值(M-H)-＝434.08m/z3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-         0.030      计算值(M-H)-＝559.14m/z；[(丙基磺酰基)氨基]-1，2-二氢-3-吡啶基}氨                     实测值(M-H)-＝559.04m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-         0.025      计算值(M-H)-＝468.13m/z；氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨                         实测值(M-H)-＝468.06m/z基}-3-(4-乙基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-         0.02       计算值(M-H)-＝484.13m/z；氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨                         实测值(M-H)-＝484.06m/z基}-3-[4-(乙氧基)苯基]丙酸(3S)-3-[({[4-羟基-2-氧代-1-(苯甲基)-1，2-         0.030      计算值(M-H)-＝420.16m/z；二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲                        实测值(M-H)-＝420.08m/z基苯基)丙酸Name IC 50 Mass Spectrum Data (3S)-3-(1,3-benzodioxol-5-yl)-3 Calcd. (MH)-3 0.015 = 452.18 m/z; -[({[2- Oxo-1-(phenylmethyl)-3-azepanyl]amino}carbonyl Found (MH) - = 452.10m/zyl)amino]propanoic acid (3S)-3-(1,3-benzodiox Heterocyclopent-5-yl)-3 0.04 Calcd. (MH) - = 477.18 m/z; -{[({1-[(3-cyanophenyl)methyl]-2-oxo-3- Found (MH) - =477.14m/zazepanyl}amino)carbonyl]amino}propanoic acid (3S)-3-(4-methylphenyl)-3 0.6 Calculated (MH) - =410.11m/z;- [({[2-oxo-1-(2-phenylthiomethyl)-1,2-dihydro-3-found(MH) - =410.00m/zpyridyl]amino}carbonyl)amino] Propionic acid (3S)-3-(1,3-benzodioxol-5-yl)-3 0.5 Calcd. (MH) - = 434.13 m/z; -[({[2-oxo- 1-(Benzyl)-1,2-dihydro-3-pyridyl] found (MH) - = 434.05 m/z amino}carbonyl)amino]propanoic acid (3S)-3-(1,3- Benzodioxol-5-yl)-3 1 Calcd. (MH) - = 448.14 m/z; -{[({1-[(4-methylphenyl)methyl]-2-oxo Generation-1,2-di found value (MH) - =448.02m/z Hydrogen-3-pyridyl}amino)carbonyl]amino}propanoic acid (3S)-3-(1,3-benzodioxane Pent-5-yl)-3 calcd. (MH) - = 464.14 m/z; -({[(1-{[4-(methoxy)phenyl]methyl}-2-oxo-1 ,2- found (MH) - =464.03m/z dihydro-3-pyridyl)amino]carbonyl}amino)propanoic acid (3S)-3-(1,3-benzodioxol-5 -base)-3 1.5 Calculated (MH) - =448.15m/z; -{[({1-[(3-methylphenyl)methyl}-2-oxo-1,2-di found value (MH) - =448.04m/zhydrogen-3-pyridyl}amino)carbonyl]amino}propionic acid (3S)-3-[3,5-bis(methoxy)phenyl]-3-[({ [2-Oxo- 0.7 Calculated (MH) - = 456.12 m/z; 1-(2-Phenylthiomethyl)-1,2-dihydro-3-pyridyl]ammonia Found (MH) - =456.00m/z base}carbonyl)amino]propanoic acid (3S)-3-[4-(methoxy)phenyl]-3-[({[2-oxo-1-(2- 0.8 calcd value (MH) - =426.11m/z; phenylthiomethyl)-1,2-dihydro-3-pyridyl]amino}carbonyl Found (MH) - =426.00m/zyl)amino]propionic acid ( 3S)-3-[({[2-oxo-1-(2-phenylthiomethyl)-1,2-di2.5 Calcd. (MH) - =464.09m/z; Hydrogen-3-pyridyl ]amino}carbonyl)amino]-3-[3-(trifluorofound (MH) - =463.99m/z methyl)phenyl]propanoic acid (3S)-3-(1,3-benzodiox Heterocyclopent-5-yl)-3 50 Calculated (MH) - = 419.12 m/z; -[({[3-(phenoxy)phenyl]amino}carbonyl)amino]propanoic acid found (MH ) - = 418.97 m/z (3S)-3-(1,3-benzodioxol-5-yl)-3 5 calculated (MH) - = 438.11 m/z; -{[({ 3-[(2-Phenylthiomethyl)amino]phenyl}amino)carbonyl Found (MH) - =438.00m/z base]amino}propanoic acid (3S)-3-(1,3-benzo Dioxol-5-yl)-3 0.8 Calcd. (MH) - = 468.09 m/z; -{[({1-[(3-chlorophenyl)methyl]-2-oxo- 1,2-Measured value (MH) - =468.01m/z Hydrogen-3-pyridyl}amino)carbonyl]amino}propanoic acid (3S)-3-(1,3-benzodioxolane- 5-yl)-3 0.8 Calcd. (MH) - = 502.12 m/z; -({[(2-oxo-1-{[3-(trifluoromethyl)phenyl]methyl}- found (MH) - =502.03m/z1,2-dihydro-3-pyridyl)amino]carbonyl}amino)propanoic acid (3S)-3-(4-fluorophenyl)-3 1.6 Calculated value (MH) - =414.09m/z; -[({[2-oxo-1-(2-phenylthiomethyl)-1,2-dihydro-3-found value (MH) - =414.01m/zpyridyl [ ({1-[(4-Chlorophenyl)methyl]-2-oxo-1,2-diFound (MH) - =467.99m/z Hydrogen-3-pyridyl}amino)carbonyl]amino }propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3 0.5 Calcd. (MH) - =464.14m/z;-({[(1-{[ 2-(Methoxy)phenyl]methyl}-2-oxo-1,2- Found (MH) - =464.04m/z dihydro-3-pyridyl)amino]carbonyl}amino)propanoic acid (3S)-3-[3-(Methoxy)phenyl]-3 1.4 Calculated (MH) - =426.11m/z;-[({[2-oxo-1-(2-phenylthio Methyl)-1,2-dihydro-3- found (MH) - = 426.02 m/z pyridyl] amino} carbonyl) amino] propanoic acid (3S) -3- 1 calculated (MH) - = 396.10 m/z; -[({[2-oxo-1-(2-phenylthiomethyl)-1,2-dihydro-3-found (MH) - =396.01m/zpyridyl]amino }carbonyl)amino]-3-phenylpropanoic acid (3S)-3- 0.3 Calculated (MH) - =486.13m/z;-[({[2-oxo-1-(2-phenylthiomethyl base)-1,2--dihydro-3- found (MH) - =485.98m/z pyridyl]amino}carbonyl)amino]-3-[3,4,5-tri(methoxy)benzene Base]propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3 0.3 Calculated (MH) - =468.08m/z;-{[({1-[ (2-Chlorophenyl)methyl]-2-oxo-1,2-diFound (MH) - =468.03m/z Hydrogen-3-pyridyl}amino)carbonyl]amino}propionic acid (3S )-3-(1,3-benzodioxol-5-yl)-3 2 Calculated (MH) - =452.12m/z;-{[({1-[(4-fluorobenzene Base)methyl]-2-oxo-1,2-diFound (MH) - =452.00m/z Hydrogen-3-pyridyl}amino)carbonyl]amino}propanoic acid 3-(1,3-benzene Dioxol-5-yl)-2,2-difluoro-3 > 100 Calculated (MH) - = 476.07m/z; -[({[2-oxo-1-(2-benzene Thiomethyl)-1,2-dihydro-3- Found(MH) - =476.00m/zpyridyl]amino}carbonyl)amino]propanoic acid (3S)-3-(1,3-benzo Dioxol-5-yl)-3 14 Calcd. (MH) - = 478.16 m/z; -{[({2-oxo-1-[3-(phenoxy)propyl]-1 ,2-Dihydro- found (MH) - =478.09m/z3-pyridyl}amino)carbonyl]amino}propanoic acid (3S)-3-(1,3-benzodioxol-5- Base)-3 5 Calculated value (MH) - =502.05m/z;-{[({1-[(3,5-dichlorophenyl)methyl]-2-oxo-1,2-di found Value (MH) - =501.94m/z Hydrogen-3-pyridyl}amino)carbonyl]amino}propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3 6 Calculated (MH) - = 426.16 m/z; -[({[1-(cyclopentylmethyl)-2-oxo-1,2-dihydro-3-pyridine Found (MH) - = 426.09 m/z pyridyl]amino}carbonyl)amino]propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3 15 Calculated value (MH) - = 454.09m /z; -{[({2-oxo-1-[2-(2-phenylthio)ethyl]-1,2-dihydrofound (MH) - =453.99m/z-3-pyridine Base}amino)carbonyl]amino}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated value (M+H) + = ( 3S)-3-(2,3-Dihydro-1-benzofuran-5-yl)-3 0.14 Calcd. (MH) - = 438.11 m/z; -[({[2-oxo-1- (2-Phenylthiomethyl)-1,2-dihydro-3- Found (MH) - = 437.99m/zpyridyl]amino}carbonyl)amino]propanoic acid (3S)-3-(3- Fluorophenyl)-3 3 Calculated (MH) - = 414.09m/z; -[({[2-oxo-1-(2-phenylthiomethyl)-1,2-dihydro-3- Found (MH) - = 413.99 m/z pyridyl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[2-oxo-1-(2-phenylthiomethyl)-1 , 2-21.5 Calculated (MH) - = 464.09 m/z; Hydrogen-3-pyridyl] amino} carbonyl) amino] -3-[4-(trifluoro Found (MH) - = 463.99 m/z Methyl)phenyl]propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3 0.5 Calculated (MH) - =434.13m/z;-[({ [6-Oxo-1-(phenylmethyl)-1,6-dihydro-3-pyridyl] found (MH) - = 434.02 m/z amino}carbonyl)amino]propanoic acid (3S)-3 -[4-Fluoro-3-(trifluoromethyl)phenyl]-3-[({[2-Oxygen 0.35 Calculated (MH) - =482.08m/z; On behalf of-1-(2-phenylthio Methyl)-1,2-dihydro-3-pyridyl] found (MH) - = 481.97 m/z amino}carbonyl)amino]propanoic acid (3S)-3-[4-(1,1-di Methylethyl)phenyl]-3-[({[2- 2 Calculated (MH) - =452.16m/z; Oxo-1-(2-phenylthiomethyl)-1,2-di Hydrogen-3-pyridine found value (MH) - =452.02m/z base]amino}carbonyl)amino]propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)- 3 70 Calculated (MH) - = 494.19m/z; -[({Butyl[2,5-dioxo-1-(benzyl)tetrahydro-1H- found (MH) - = 494.12m /zpyrrol-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.04 calculated value( M+H) + =516.16m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (M+H) + =516.02m/z [3,4, 5-Tris(methoxy)phenyl]propionic acid (3S)-3-{[({1-[(2,6-dichlorophenyl)methyl]-2-oxo- 0.2 Calculated (M +H) + =474.10 m/z; 1,2-di-hydro-3-pyridyl}amino)carbonyl]amino}-3-(4- found (M+H) + =474.04 m/z methyl Phenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.2 Calcd. (M+H) + =512.10m/z; 1,2-Di-hydro-3-pyridyl}amino)carbonyl]amino}-3-[4- Found (M+H) + =512.04m/z fluoro-3-(trifluoromethyl)phenyl ]propanoic acid (3S)-3-{[({1-[(2-fluorophenyl)methyl]-2-oxo-0.1 Calcd. (MH) - = 422.15m/z; 1,2- Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- Found (MH) - =422.01m/z methylphenyl)propanoic acid (3S)-3-(4-methylbenzene base)-3-{[({1-[(2-methylphenyl) 0.1 Calcd. (MH) - =418.18m/z; methyl]-2-oxo-1,2-di-hydrogen- 3-Pyridyl}amino)carbonyl found value (MH) - =418.02m/z 2-Oxo- 0.05 Calcd. (M+H) + = 484.09 m/z; 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- Found (M+H ) + ＝484.03m/z Methylphenyl)propanoic acid (3S)-3-{[({1-[(2,4-dichlorophenyl)methyl]-2-oxo- 0.4 Calculated value( M+H) + =474.10 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- found (M+H) + =474.05 m/z methyl Phenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-0.04 Calcd. (MH) - = 466.11 m/z; 1, 2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found(MH) - =466.00m/z(2,3-dihydro-1-benzofuran-5-yl)propanoic acid Calcd for (3S)-3-(1,3-benzodioxol-5-yl)-3 2 (MH) - = 468.09 m/z; -{[({1-[(2-chloro Substituted phenyl)methyl]-2-oxo-1,2-di found value (MH) - =467.97m/zhydrogen-3-pyridyl}amino)carbonyl]amino}propanoic acid (3S)-3- (4-methylphenyl)-3-({[(2-oxo-1-{[2- 1 Calcd. (M+H) + = 474.10 m/z; (trifluoromethyl)phenyl] Methyl}-1,2-dihydro-3-pyridyl) found (M+H) + =474.09m/zamino]carbonyl}amino)propanoic acid (3S)-3-{[({1-[ (2,5-Dichlorophenyl)methyl]-2-oxo-0.15 Calcd. (M+H) + = 474.10 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl] Amino}-3-(4- Found (M+H) + =474.04m/z Methylphenyl)propanoic acid (2R-2-{[({1-[(2-chlorophenyl)methyl ]-2-oxo-50 Calcd. (MH) - = 424.10 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-benzene Found (MH) - = 423.99 m/z propionic acid (2R)-2-{[({1-[(2-chlorophenyl)methyl]-2-oxo-80 Calcd. (MH) - =410.08m/z;1 , 2-dihydro-3-pyridyl}amino)carbonyl]amino}-2-benzene found value (MH) - =409.95m/z ethyl acetic acid (3S)-3-{[({1-[(2- Chlorophenyl)methyl]-2-oxo- 0.1 Calcd. (MH) - = 452.14 m/z; 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- found (MH) - = 451.96m/z (3,5--di-methylphenyl) propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2 -Oxo- 0.1 Calculated (MH) - = 424.10 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-benzene Found (MH) - = 424.07 m/z Propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calcd. (MH) - = 454.11m/z; 1,2- Dihydro-3-pyridyl}amino)carbonyl]amino}-3-[4- Found (MH) - =454.01m/z(methoxy)phenyl]propanoic acid (3S)-3-{[( {1-[(2-Chlorophenyl)methyl]-2-oxo-0.1 Calcd. (MH) - = 440.10 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl] Amino}-3-(4- Found (MH) - =440.00m/z Geno-1,2-dihydro-3-pyridyl)amino]carbonyl}amino ) -3- Found (MH) - =434.01 m/z (4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-bromophenyl)methyl]-2-oxo- 0.08 Calculated (MH) - =558.09m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- found (MH) - =557.87m/z[3,4,5-tris(methoxy )phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.09 Calcd. (M+H) + =454.15m/z ; 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (M+H) + =454.07m/z(3,4-Dimethylphenyl)propanoic acid (3S ( 4-Methylphenyl) propionic acid found value (MH) - = 437.06m/z (3S)-3-(4-methylphenyl)-3-[({[3-(phenylmethyl)phenyl ] 10 Calculated (MH) - =387.17m/z; amino}carbonyl)amino]propanoic acid found (MH) - =387.00m/z(3S)-3-{[({1-[(2-chloro substituted phenyl)methyl]-2-oxo-0.04 Calcd. (MH) - =468.13m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3- Found (MH) - = 468.01 m/z Methyl-4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl] -2-Oxo- 0.07 Calculated (MH) - = 454.11 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- Found (MH) - = 454.00m/z Hydroxy-3-methylphenyl)propanoic acid (3S)-3-{[({1-[(2,3-dichlorophenyl)methyl]-2-oxo- 0.35 Calculated value (MH) - =472.08m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- found (MH) - =471.94m/zmethylphenyl) Propionic acid (3S)-3-[({[1-([1,1'-biphenyl]-2-ylmethyl)-2-oxo 2.5 Calculated (MH) - = 480.19m/z; -1,2-Dihydro-3-pyridyl]amino}carbonyl)amino]-3- Found (MH) - =480.05m/z(4-methylphenyl)propionic acid (3S)-3-{ [({1-[(2-Chlorophenyl)methyl]-2-oxo-0.2 Calcd. (MH) - = 438.12 m/z; 1,2-dihydro-3-pyridyl}amino) Carbonyl]amino}-3-(3- Found(MH) - =438.00m/zMethylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl 1,2-dihydro-3-pyridyl}amino)carbonyl]amino} -3- (2- found (MH) - = 437.99 m/z Methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.3 Calculated (MH) - =464.13m/z; 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - =464.03m/z(2,3-Dihydro-1H-indene- 5-yl)propanoic acid (3S)-3-{[({1-[(2-cyanophenyl)methyl]-2-oxo- 0.1 Calcd. (M+H) + =431.18m/z ; 1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- Found (M+H) + = 431.09 m/z methylphenyl) propanoic acid (3 S)- 3-[2,6-bis(methoxy)phenyl]-3-{[({1-[(2- 6 Calcd.(MH) - =484.14m/z; chlorophenyl)methyl] -2-Oxo-1,2-dihydro-3-pyridine Found (MH) - =483.96m/z base}amino)carbonyl]amino}propanoic acid (3S)-3-{[({1-[ (3-Hydroxyphenyl)methyl]-2-oxo- 0.2 Calcd. (M+H) + = 420.18 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}- 3-(4- Found (M+H) + = 422.05m/z Methylphenyl)propanoic acid (3S)-3-[({[2-Methyl-6-oxo-1-(Benzyl Dihydro-5-pyrimidinyl}amino}carbonyl)amino]-3- ( 4-methyl Found (MH) - =419.03m /zylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-oxo- 0.1 Calculated (MH) - = 438.12m/z ; 1,4-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- found (MH) - =438.10m/z methylphenyl)propanoic acid (3S)-3-( 4-Methylphenyl)-3-{[({1-[(2-nitrophenyl)1 Calcd. (M+H) + = 451.17 m/z; Methyl]-2-oxo-1 , 2-dihydro-3-pyridyl}amino)carbonyl found value (M+H) + =451.07m/z base]amino}propanoic acid (3S)-3-(4-methylphenyl)-3- {[({1-[(4-nitrophenyl)1 Calcd. (M+H) + = 451.17m/z; methyl]-2-oxo-1,2-dihydro-3-pyridyl }amino)carbonyl measured value (M+H) + =451.09m/z base]amino}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2- Oxo-3 Calculated (MH) - =456.10m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - =456.04m/z (2 , 6-Dihydroxyphenyl)propanoic acid (3S)-3-{[({1-[(2,6-difluorophenyl)methyl]-2-oxo- 0.3 Calculated (MH) - =440.14m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- found (MH) - =440.00m/zmethylphenyl)propionic acid (3S )-3-{[({1-[(2,4-difluorophenyl)methyl]-2-oxo- 1.3 Calcd. (MH) - = 440.14 m/z; 1,2-dihydro- 3-pyridyl}amino)carbonyl]amino}-3-(4- found (MH) - =439.96m/z methylphenyl)propionic acid (3S)-3-{[({1-[(2 ,5-difluorophenyl)methyl]-2-oxo-0.8 Calcd. (MH) - =440.14m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3 -(4- Found (MH) - = 439.96m/z Methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-methyl oxo-1,6-dihydro-5 - pyrimidinyl}amino)carbonyl]ammonia found (MH) - =453.00m/zyl} -3-(4-Methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chloro-6-fluorophenyl)methyl]-2-oxo0.1 Calculated (MH ) - = 456.11 m/z; -1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- found (MH) - = 455.94m/z (4-methylphenyl)propane Acid (3S)-3-{[({1-[(2-bromo-5-fluorophenyl)methyl]-2-oxo0.5 Calcd. (MH) - = 500.06m/z; -1,2 -Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - =499.91m/z(4-methylphenyl)propionic acid (3S)-3-{[({1 -[(2-Chloro-6-fluorophenyl)methyl]-2-oxo0.35 Calcd. (MH) - =456.11 m/z; -1,2-dihydro-3-pyridyl}amino)carbonyl ]Amino}-3- Found (MH) - = 455.93 m/z (4-methylphenyl) propanoic acid (3S)-3-{[({1-[(2-bromophenyl)methyl ]-2-oxo- 0.2 Calcd. (MH) - = 512.08 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3- found (MH) - =511.96m/z methyl-4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(3,5-dimethyl-4-isoxazolyl)methyl 3 Calculated (MH) - = 423.17 m/z; base]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] found (MH) - = 423.02 m/z amino} -3-(4-methylphenyl)propanoic acid (3S)-3-(4-methylphenyl)-3-{[({2-oxo-1- 2.5 Calculated (MH) - = 446.21 m/z; [(2,4,6-trimethylphenyl)methyl]-1,2-dihydro-3-pyridine found (MH) - =446.08 m/z group}amino)carbonyl]amino }propanoic acid (3S)-3-(4-methylphenyl)-3-{[({1-[(2-methyl-1,3- 1 Calculated value (MH) - =425.13m/z; Thiazol-4-yl)methyl]-2-oxo-1,2-dihydro-3-pyridine Found (MH) - =424.99m/zyl}amino)carbonyl]amino}propionic acid (3S)- 3-({[(1-{[4-(1,1-dimethylethyl)phenyl]methanol calcd. (MH) - =460.22 m/z; base}-2-oxo-1, 2--Dihydro-3-pyridyl)amino]carbonyl} found value (MH) - =460.07m/zamino)-3-(4-methylphenyl)propanoic acid (3S)-3-[({ [1-(1,3-Benzoxazol-2-ylmethyl)-2-oxo > 10 Calculated (MH) - = 445.15m/z; generation-1,2-di-hydro-3-pyridine Base]amino}carbonyl)amino]-3- Found (MH) - =445.01m/z(4-Methylphenyl)propionic acid (3S)-3-({[(1-{2-[(2 -Hydroxyphenyl)amino]-2-oxo>10 Calculated (MH) - =463.16m/z; ethyl}-2-oxo-1,2-dihydro-3-pyridyl)amino]carbonyl Found value (MH) - = 463.06m/z base}amino)-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chloro-6-nitro Phenyl)methyl]-2-oxo4 Calculated (MH) - =483.11 m/z; Substituent-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH ) - =483.01m/z(4-Methylphenyl)propanoic acid (3S)-3-{[({1-[(5-chloro-2-fluorophenyl)methyl]-2-oxo 2.5 Calculated (MH) - = 456.11 m/z; -1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - = 456.00m/z (4-methyl Phenyl)propanoic acid (3S)-3-{[({1-[(2-amino-6-chlorophenyl)methyl]-2-oxo2 Calculated (MH) - =453.13m/z; -1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - =453.02m/z(4-methylphenyl)propionic acid (3S)-3-( {[(1-{[2-Fluoro-4-(trifluoromethyl)phenyl]methanol3 Calcd. (MH) - = 490.14 m/z; base}-2-oxo-1,2-dihydro -3-pyridyl)amino]carbonyl} Found (MH) - =489.99m/zamino)-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[( 5-Chloro-2-phenylthio)methyl]-2-oxo1.3 Calcd. (MH) - = 444.08 m/z; -1,2-dihydro-3-pyridyl}amino)carbonyl]amino} -3- found value (MH) - = 443.97m/z (4-methylphenyl) propanoic acid (3S)-3-{[({1-[(2-bromo-5-nitrophenyl)methyl Calcd (MH) - = 527.06 m/z; Geno-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - = 526.95 m/z (4-methylphenyl)propanoic acid 3-(4-chlorophenyl)-3-{[({1-[(2-chlorophenyl)methyl]- 0.03 Calculated (MH) - =474.06m/z; 4-Hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl Found (MH) - =474.07m/z )-3-[({[2-Methyl-6-oxo-1-(phenylmethyl)-4-(2- 0.025 Calcd. for (M+H) + = 498.22 m/z; pyridyl)- 1,6-Dihydro-5-pyrimidinyl]amino}carbonyl)ammonia found (M+H) + =498.10m/zyl]-3-(4-methylphenyl)propanoic acid (3S)-3 -{[({1-[(5-amino-2-bromophenyl)methyl]-2-oxo0.08 Calcd. (MH) - =497.08m/z; generation-1,2-di-hydrogen-3 -pyridyl}amino)carbonyl]amino}-3- found (MH) - =497.02 m/z (4-methylphenyl)propionic acid (3S)-3-{[({1-[(2, 5-Dimethylphenyl)methyl]-2-oxo0.15 Calcd. (MH) - =432.19m/z; generation-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3 - Found (MH) - = 432.04 m/z (4-methylphenyl) propanoic acid 3-(3-chlorophenyl)-3-{[({1-[(2-chlorophenyl) A0.03 Calculated (MH) - = 474.06m/z; Base] -4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}ammonia Found (MH) - = 474.03m/z Base)carbonyl]amino}propanoic acid 3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2-oxo 0.04 Calculated value (MH) - =508.02m/z; -1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found (MH) - =507.97m/z(3,4-dichlorophenyl)propionic acid (3S)-3 -({[(1-{[5-(acetylamino)-2-bromobenzene 0.2 Calcd. (MH) - =539.09m/z; base]methyl}-2-oxo-1,2- Dihydro-3-pyridyl)amino] found (MH) - =539.02 m/z carbonyl}amino)-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1- ({2-Bromo-5-[(methylsulfonyl)amino] 0.25 Calcd. (MH) - = 575.06 m/z; phenyl}methyl)-2-oxo-1,2-dihydro-3 -pyridyl]ammonia found (MH) - =575.01m/z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid 3-(4-chlorophenyl)-3-{[ ({1-[(2-Chlorophenyl)methanol 0.4 Calcd. (MH) - =458.07 m/z; yl]-2-oxo-1,2-=hydrogen-3-pyridyl}amino)carbonyl ] Measured value (MH) - = 457.96m/z Amino}propionic acid 3-(3-chlorophenyl)-3-{[({1-[(2-chlorophenyl)methanol 1 Calculated value (MH ) - =458.07m/z; base]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl] found (MH) - =457.93m/zamino}propionic acid 3-{ [({1-[(2-Chlorophenyl)methyl]-2-oxo-1,2-di1 Calcd. (MH) - =492.03 m/z; hydrogen-3-pyridyl}amino) Carbonyl]amino}-3-(3,4-dichloro Found (MH) - =491.85m/z phenyl)propanoic acid (3S)-3-{{({1-[(2-bromo-4- Chlorophenyl)methyl]-2-oxo1 Calculated (MH) - =516.03m/z; -1,2-Dihydro-3-pyridyl}amino)carbonyl]amino}-3- Found( MH) - ＝515.91m/z(4-Methylphenyl)propanoic acid (3S)-3-{[({1-[(4-Chlorophenyl)methyl]-2-oxo-2 Calculation Value (MH) - = 438.12 m/z; 1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4- Found (MH) - = 437.88m/z methylphenyl )propanoic acid (3S)-3-{{({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 0.035 Calcd. (MH) - =498.14m/z; oxo- 1,2-Dihydro-3-pyridyl}amino)carbonyl]ammonia found value (MH) - =498.05m/zyl}-3-[2,3-dimethyl-4-(methoxy)benzene base]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2- 0.015 Calcd. (MH) - =524.08m/z; oxo -1,2-Dihydro-3-pyridyl}amino)carbonyl]ammonia found (MH) - =524.03m/zyl}-3-{4-[(trifluoromethyl)oxy]phenyl} Propionic acid (3R)-3-[({{1-[(2-chlorophenyl)methyl]-4-(1,4-oxa0.1 Calcd. (MH) - = 489.19 m/z; oxinane -4-yl)-2-oxo-1,2-dihydro-3-pyridyl]ammonia Found (MH) - =489.13m/zyl}carbonyl)amino]-5-methylhexanoic acid (3S )-3-[({[4-Hydroxy-6-methyl-2-oxo-1-(calculated for Benzene 0.35 (MH) - =434.17m/z; base)-1,2-dihydro- 3-pyridyl]amino}carbonyl)amino]- found (MH) - =434.08m/z3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2- Chlorophenyl)methyl]-2-oxo-4- 0.030 Calcd. (MH) - = 559.14 m/z; [(propylsulfonyl)amino]-1,2-dihydro-3-pyridyl }Ammonia measured value (MH) - =559.04m/zyl)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chloro Phenyl)methyl]-4-hydroxyl-2- 0.025 Calcd. (MH) - = 468.13 m/z; Oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]ammonia found (MH ) - =468.06m/z group}-3-(4-ethylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl -2- 0.02 Calculated (MH) - =484.13m/z; Oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]ammonia Found (MH) - =484.06m/zyl}- 3-[4-(Ethoxy)phenyl]propionic acid (3S)-3-[({[4-Hydroxy-2-oxo-1-(phenylmethyl)-1,2- 0.030 Calculated( MH) - =420.16 m/z; Dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4-methanol Found (MH) - =420.08 m/z (phenylphenyl)propanoic acid

                                 表5 table 5

         名称                        IC50(μM)           质谱数据(3S)-3-[({[1-(3-叔丁基-2-甲氧基苄          2.5             计算值(M-H)-＝490.23m/z；基)-2-氧代-1，2-二氢吡啶-3-基]氨                           实测值(M-H)-＝490.11m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({{1-(4-氟苄基)-2-氧代-1，2-       2               计算值(M-H)-＝422.12m/z；二氢吡啶-3-基]氨基}羰基)氨基]-3-                           实测值(M-H)-＝422.00m/z(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.025           计算值(M-H)-＝526.08m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                            实测值(M-H)-＝526.01m/z基)氨基]-3-[4-氟-3-(三氟甲基)苯基]丙酸(3S)-3-[({[1-(2，5-二甲基苄基)-4-羟        0.02            计算值(M-H)-＝448.19m/z；基-2-氧代-1，2-二氢吡啶-3-基]氨                            实测值(M-H)-＝448.00m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-1-(2-甲基苄基)-          0.02            计算值(M-H)-＝434.17m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝434.05m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-羟基苄基)-2-氧代-          0.2             计算值(M-H)-＝420.16m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                            实测值(M-H)-＝420.09m/z基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(3-氯苄基)-2-氧代-1，2-       0.5             计算值(M-H)-＝438.12m/z；二氢吡啶-3-基]氨基}羰基)氨基]-3-                           实测值(M-H)-＝438.01m/z(4-甲基苯基)丙酸(3S)-3-[({{1-(2-氯-6-甲氧基苄基)-          0.1             计算值(M-H)-＝468.13m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝468.08m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.035           计算值(M-H)-＝498.14m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                            实测值(M-H)-＝497.94m/z基)氨基]-3-(4-甲氧基-3，5-二甲基苯基)丙酸4-{[3-[({[(1S)-2-羧基-1-(4-甲基苯          0.004           计算值(M-H)-＝573.15m/z；基)乙基]氨基}羰基)氨基]-1-(2-氯                        实测值(M-H)-＝572.92m/z苄基)-2-氧代-1，2-二氢吡啶-4-基]氨基}苯甲酸(3S)-3-{[({1-(2-氯代苯基)-4-[(2，2-       0.01         计算值(M-H)-＝537.19m/z；二甲基丙酰基)氨基]-2-氧代-1，2-二                      实测值(M-H)-＝536.88m/z氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-甲氧基苄基)-         0.09         计算值(M-H)-＝468.13m/z；2-氧代-1，2-二氢吡啶-3-基}氨基)羰                      实测值(M-H)-＝467.99m/z基]氨基}-3-(4-甲基苯基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-         0.19         计算值(M-H)-＝378.09m/z；氧代-1，2-二氢吡啶-3-基}氨基)羰                        实测值(M-H)-＝378.01m/z基]氨基}丁酸(3S)-3-[({[4-{[(叔丁基氨基)羰基]氨        0.01         计算值(M-H)-＝552.20m/z；基}-1-(2-氯苄基)-2-氧代-1，2-二氢                      实测值(M-H)-＝551.89m/z吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-羟基苄基)-2-         0.25         计算值(M-H)-＝454.12m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝454.03m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氰基苄基)-4-羟基-         0.009        计算值(M-H)-＝445.15m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝445.01m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，4-二氯苄基)-4-羟基-      0.06         计算值(M-H)-＝488.08m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝487.96m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-1-(2-甲氧基苄           0.08         计算值(M-H)-＝450.17m/z；基)-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M-H)-＝450.02m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({{1-(2-氯苄基)-4-羟基-2-0.08                  计算值(M-H)-＝498.14m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝497.95m/z基)氨基]-3-(4-甲氧基-2，5-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-羟基苄基)-2-          0.1          计算值(M-H)-＝454.12m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝454.05m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(3-叔丁基-2-羟基苄            4            计算值(M-H)-＝476.02m/z；基)-2-氧代-1，2-二氢吡啶-3-基]氨                        实测值(M-H)-＝476.00m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.3          计算值(M-H)-＝454.17m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝454.05m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.015        计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝467.95m/z基)氨基]-3-(3-乙基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.01         计算值(M-H)-＝498.10m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝497.85m/z基)氨基]-3-(2，3-二氢-1，4-苯并二氧杂环己-6-基)丙酸(3S)-3-[({[1-(2，5-二氟苄基)-4-羟基-       0.015        计算值(M-H)-＝456.14m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝455.96m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          30           计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝467.87m/z基)氨基]-4-(4-甲基苯基)丁酸(3S)-3-[({[1-[2-氯-5-(甲硫基)苄基]-        0.015        计算值(M-H)-＝500.10m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝499.92m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.005        计算值(M-H)-＝514.10m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝513.86m/z基)氨基]-3-(7-甲氧基-1，3-苯并二氧杂环戊-5-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.002        计算值(M-H)-＝514.13m/z；氧代-1，2-二氢吡啶-3-基}氨基)羰                  实测值(M-H)-＝513.90m/z基]氨基}-3-(3-乙氧基-4-甲氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.015     计算值(M-H)-＝488.10m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝487.92m/z基)氨基]-3-(3-氟-4-甲氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.002     计算值(M-H)-＝500.12m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝500.01m/z基)氨基]-3-(3，4-二甲氧基苯基)丙酸(3S)-3-[({[1-(4-氟苄基)-4-羟基-2-      0.022     计算值(M-H)-＝438.18m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝438.00m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-甲氧基苄基)-2-氧代     0.25      计算值(M-H)-＝434.17m/z；-1，2-二氢吡啶-3-基]氨基}羰基)氨                 实测值(M-H)-＝433.95m/z基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.05      计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝467.94m/z基)氨基]-3-(2，5-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-甲氧基苄基)-      0.012     计算值(M-H)-＝484.13m/z；4-羟基-2-氧代-1，2--二氢吡啶-3-基]               实测值(M-H)-＝484.03m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[3，5-二(三氟甲基)苄     0.3        计算值(M-H)-＝556.13m/z；基]-4-羟基-2-氧代-1，2-二氢吡啶-3-               实测值(M-H)-＝555.95m/z基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(4-叔丁基苄基)-4-羟基   0.03        计算值(M-H)-＝476.22m/z；-2-氧代-1，2-二氢吡啶-3-基]氨基}                 实测值(M-H)-＝476.05m/z羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(3-氯苄基)-4-羟基-2-    0.015       计算值(M-H)-＝454.12m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝453.99m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(4-氯苄基)-4-羟基-2-        0.007        计算值(M-H)-＝454.12m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝454.00m/z基]氨基)-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-2-氧代-1-[3-(三        0.017        计算值(M-H)-＝488.14m/z；氟甲基)苄基]-1，2-二氢吡啶-3-基}                      实测值(M-H)-＝487.99m/z氨基)羰基]氨基}-3-(4-苯甲基)丙酸(3S)-3-[({[1-(2-溴苄基)-4-羟基-2-        0.015        计算值(M-H)-＝498.07m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝497.97m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(3，4-二氯苄基)-4-羟基-     0.045        计算值(M-H)-＝488.08m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                     实测值(M-H)-＝487.96m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-1-(4-甲基苄基)-        0.025        计算值(M-H)-＝434.17m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                     实测值(M-H)-＝434.05m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-        0.003        计算值(M-H)-＝484.13m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                     实测值(M-H)-＝484.02m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-2-氧代-1-[4-(三        0.02         计算值(M-H)-＝488.14m/z；氟甲基)苄基]-1，2-二氢吡啶-3-基}                      实测值(M-H)-＝487.99m/z氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.02         计算值(M-H)-＝524.08m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝523.91m/z基)氨基]-3-[3(三氟甲氧基)苯基]丙酸(3S)-3-[({[4-羟基-1-(3-甲基苄基)-        0.055        计算值(M-H)-＝434.17m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                     实测值(M-H)-＝433.99m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-2-氧代-1-(吡啶-      0.045       计算值(M-H)-＝421.15m/z；2-基甲基)-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝421.06m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-      0.005       计算值(M-H)-＝468.13m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                  实测值(M-H)-＝467.99m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，4-二氟苄基)-4-羟基-   0.03        计算值(M-H)-＝456.14m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝456.01m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，6-二氟苄基)-4-羟基-   0.008       计算值(M-H)-＝456.14m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝456.01m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-2-氧代-1-[3-(三      0.045       计算值(M-H)-＝504.14m/z；氟甲氧基)苄基]-1，2-二氢吡啶-3-                    实测值(M-H)-＝503.98m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-2-氧代-1-[4-(三      0.025       计算值(M-H)-＝504.14m/z；氟甲氧基)苄基]-1，2-二氢吡啶-3-                    实测值(M-H)-＝503.98m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-      0.0015      计算值(M-H)-＝530.13m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                  实测值(M-H)-＝529.91m/z氨基}羰基)氨基]-3-(3，5-二甲氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.05        计算值(M-H)-＝430.08m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                    实测值(M-H)-＝429.94m/z基)氨基]-3-(2-呋喃基)丙酸(3S)-3-{[({4-羟基-2-氧代-1-[2-(三      0.02        计算值(M-H)-＝488.14m/z；氟甲基)苄基]-1，2-二氢吡啶-3-基}                   实测值(M-H)-＝487.96m/z氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.15        计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝467.99m/z基)氨基]-4-(4-甲基苯基)丁酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.0008       计算值(M-H)-＝528.15m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝527.96m/z基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.003        计算值(M-H)-＝484.12m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝483.94m/z基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[4-羟基-1-(3-甲氧基苄          0.04         计算值(M-H)-＝450.17m/z；基)-2-氧代-1，2-二氢吡啶-3-基]氨                      实测值(M-H)-＝450.00m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，3-二氯苄基)-4-羟基-     0.13         计算值(M-H)-＝488.08m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                     实测值(M-H)-＝487.92m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-苄基-2-氧代-5-(三氟甲       1.5          计算值(M-H)-＝472.15m/z；基)-1，2-二氢吡啶-3-基]氨基}羰基)                     实测值(M-H)-＝471.89m/z氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(3，5-二甲基苄基)-4-羟      0.06         计算值(M-H)-＝448.19m/z；基-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M-H)-＝448.02m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-        0.04         计算值(M-H)-＝554.09m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                     实测值(M-H)-＝553.98m/z氨基}羰基)氨基]-3-[4-(三氟甲氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.003        计算值(M-H)-＝484.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝483.95m/z基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸(3S)-3-[({{1-(2-氯苄基)-4-羟基-2-        0.003        计算值(M-H)-＝514.14m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝513.95m/z基)氨基]-3-(3，5-二甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.04           计算值(M-H)-＝524.20m/z；氧代-5-戊基-1，2-二氢吡啶-3-基]氨                       实测值(M-H)-＝523.98m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.005          计算值(M+H)＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M+H)+＝467.99m/z基)氨基]-3-(3，4-二-甲基苯基)丙酸(3S)-3-[({[1-(2，4-二氯苄基)-4-羟基-     0.02           计算值(M-H)-＝502.09m/z；5-甲基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝501.89m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸[2-({[1-(2-氯苄基)-4-羟基-2-氧代-        ＞10           计算值(M-H)-＝455.11m/z；1，2-二氢吡啶-3-基]氨基}羰基)-1-                        实测值(M-H)-＝454.97m/z；(4-甲基苯基)肼基]乙酸(3S)-3-[({[1-(2-氯苄基)-5-乙基-4-        0.01           计算值(M-H)-＝482.15m/z；羟基-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M-H)-＝482.00m/z；基}羰基)氨基]-3-(4-甲基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-        0.05           计算值(M-H)-＝441.09m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                         实测值(M-H)-＝441.00m/z；基]-3-吡啶-3-基丙酸(3S)-3-[({[5-丁基-1-(2-氯苄基)-4-        0.025          计算值(M-H)-＝510.18m/z；羟基-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M-H)-＝509.98m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[2-氯-5-(三氟甲基)苄        0.01           计算值(M-H)-＝522.10m/z；基]-4-羟基-2-氧代-1，2-二氢吡啶-3-                      实测值(M-H)-＝521.97m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({{1-(2-氯-6-甲氧基苄基)-        0.005          计算值(M-H)-＝484.13m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝484.00m/z；氨基}羰基)氨基]-3-(3-甲基苯基)丙酸(3S)-3-[({[1-(2，6-二氯苄基)-4-羟基-     0.013          计算值(M-H)-＝488.08m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                  实测值(M-H)-＝487.91m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-氟苄基)-4-羟      0.014       计算值(M-H)-＝472.11m/z；基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝471.96m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-      0.01        计算值(M-H)-＝482.15m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                  实测值(M-H)-＝481.98m/z3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(4-氯苄基)-4-羟基-5-      0.02        计算值(M-H)-＝468.13m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                  实测值(M-H)-＝467.94m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.003       计算值(M+H)+＝496.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                 实测值(M+H)+＝495.99m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-5-甲基-1-[4-(甲      0.02        计算值(M-H)-＝512.15m/z；基磺酰基)苄基]-2-氧代-1，2-二氢吡                  实测值(M-H)-＝511.96m/z啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-1-(4-甲氧基苄        0.02        计算值(M-H)-＝450.17m/z；基)-2-氧代-1，2-二氢吡啶-3-基]氨                   实测值(M-H)-＝449.99m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.02        计算值(M-H)-＝496.16m/z；氧代-5-丙基-1，2-二氢吡啶-3-基]氨                  实测值(M-H)-＝495.94m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-({[(1-{4-[(二甲基氨基)磺酰      0.035       计算值(M-H)-＝527.16m/z；基]苄基}-4-羟基-2-氧代-1，2-二氢                   实测值(M-H)-＝526.96m/z吡啶-3-基)氨基]羰基}氨基)-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-1-(萮基甲基)-2-      0.06        计算值(M-H)-＝462.20m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                    实测值(M-H)-＝462.02m/z基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       0.02         计算值(M-H)-＝508.16m/z；氧代-1，2，5，6，7，8-六氢喹啉-3-基]氨               实测值(M-H)-＝507.96m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-5-乙基-4-       0.025        计算值(M-H)-＝496.16m/z；羟基-6-甲基-2-氧代-1，2-二氢吡啶-                    实测值(M-H)-＝495.96m/z3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       0.4          计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝467.85m/z基)(甲基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-1-[2-(甲硫基)苄       0.02         计算值(M-H)-＝466.14m/z；基]-2-氧代-1，2-二氢吡啶-3-基}氨                     实测值(M-H)-＝465.97m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-({[(1-{2-[(二甲基氨基)磺酰       0.03         计算值(M-H)-＝527.16m/z；基]苄基}-4-羟基-2-氧代-1，2-二氢                     实测值(M-H)-＝526.97m/z吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，6-二甲氧基苄基)-4-     0.01         计算值(M-H)-＝480.18m/z；羟基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝480.00m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-2-氧代-1-[2-(三      0.025         计算值(M-H)-＝504.14m/z；氟甲氧基)苄基]-1，2-二氢吡啶-3-                      实测值(M-H)-＝503.96m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.35          计算值(M-H)-＝522.10m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝521.95m/z基)氨基]-4-[3-(三氟甲基)苄基]丁酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.003         计算值(M-H)-＝498.14m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝497.97m/z基)氨基]-3-(3-丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-      0.003         计算值(M+H)+＝528.19m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M+H)+＝528.02m/z基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-      0.006        计算值(M-H)-＝482.15m/z；二甲基-2-氧代-1，2-二氢吡啶-3-基]                      实测值(M-H)-＝481.95m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3 S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.005        计算值(M-H)-＝570.20m/z；氧代-5-丙基-1，2-二氢吡啶-3-基]氨                      实测值(M-H)-＝569.98m/z基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-(3-丁氧基苯基)-3-[({[1-(2-         0.005        计算值(M+H)+＝514.17m/z；氯苄基)-4-羟基-2-氧代-1，2-二氢吡                      实测值(M+H)+＝514.00m/z啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-{[({1-[2-氯-5-(甲基磺酰基)         0.003        计算值(M-H)-＝532.10m/z；苄基]-4-羟基-2-氧代-1，2-二氢吡啶-                     实测值(M-H)-＝531.94m/z3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-         0.08         计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝468.03m/z基)氨基]-4-(2-甲基苯基)丁酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         0.003        计算值(M-H)-＝514.14m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝513.95m/z基)氨基]-3-[3-(2-甲氧基乙氧基)苯基]丙酸(3S)-3-[({[1-(4-氯-2-甲氧基苄基)-         0.025        计算值(M-H)-＝484.13m/z；4-羟基-2-氧代-1，2--二氢吡啶-3-基]                     实测值(M-H)-＝483.93m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         0.003        计算值(M-H)-＝556.18m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝555.94m/z基)氨基]-3-(3，4-二丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.12          计算值(M-H)-＝522.18m/z；氧代-2，5，6，7，8，9-六氢-1H-环戊二烯                   实测值(M-H)-＝521.98m/z并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          12            计算值(M-H)-＝530.15m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝529.92m/z基)氨基]-4，4-二苯基丁酸(3S)-3-{[({1-[2-(二氟甲氧基)苯基]-         0.075         计算值(M-H)-＝486.15m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基}                        实测值(M-H)-＝486.00m/z氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-5-甲基-2-氧代-1-         4             计算值(M-H)-＝448.19m/z；[(1R)-1-苯乙基]-1，2-二氢吡啶-3-                         实测值(M-H)-＝447.99m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(4-氯苄基)-4-羟基-2-          0.03          计算值(M-H)-＝496.16m/z；氧代-5-丙基-1，2-二氢吡啶-3-基]氨                        实测值(M-H)-＝495.96m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.05          计算值(M-H)-＝496.16m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝495.98m/z基)氨基]-3-(3，4-二乙基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          0.05          计算值(M-H)-＝476.08m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝475.93m/z基)氨基]-3-(3，5-二氟苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-          0.02          计算值(M-H)-＝490.12m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                          实测值(M-H)-＝489.97m/z基]-3-(2-萘基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-          0.025         计算值(M+H)+＝446.11m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                          实测值(M+H)+＝446.08m/z基]-3-(5-甲基-2-呋喃基)丙酸(3S)-3-[({[1-[2-氯苄基]-4-羟基-2-          0.025         计算值(M-H)-＝584.21m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝583.98m/z基)氨基]-3-(3，4-二丁氧基苯基)丙酸(3S)-3-{[({4-羟基-1-[2-(甲基磺酰         0.035         计算值(M+H)+＝500.15m/z；基)苄基]-2-氧代-1，2-二氢吡啶-3-                       实测值(M+H)+＝500.01m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-        0.2           计算值(M-H)-＝490.12m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                        实测值(M-H)-＝489.91m/z基]-3-(1-萘基)丙酸(3S)-3-[({[1-(4-氯苄基)-4-羟基-2-        0.03          计算值(M-H)-＝526.17m/z；氧代-5-丙基-1，2-二氢吡啶-3-基]氨                      实测值(M-H)-＝525.95m/z基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(4-氯苄基)-4-羟基-2-        0.015         计算值(M-H)-＝570.20m/z；氧代-5-丙基-1，2-二氢吡啶-3-基]氨                      实测值(M-H)-＝569.97m/z基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2，6-二甲基苄基)-4-羟      0.035         计算值(M-H)-＝448.19m/z；基-2-氧代-1，2-二氢吡啶-3-基]氨                        实测值(M-H)-＝448.02m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[3，5-二(三氟甲基)苯基]-3-        0.22          计算值(M-H)-＝576.08m/z；[({[1-(2-氯苄基)-4-羟基-2-氧代-                        实测值(M-H)-＝575.91m/z1，2-二氢吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.006         计算值(M-H)-＝506.09m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝505.93m/z基)氨基]-3-[3-(二氟甲氧基)苯基]丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-        0.225         计算值(M-H)-＝455.11m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                        实测值(M-H)-＝455.09m/z基)氨基]-4-吡啶-2-基丁酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-        0.0006        计算值(M-H)-＝542.17m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                     实测值(M-H)-＝542.06m/z基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-          0.002      计算值(M-H)-＝499.15m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                     实测值(M-H)-＝498.07m/z基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-          0.020      计算值(M+H)+＝500.16甲基-2-氧代-1，2-二氢吡啶-3-基]氨                     m/z；实测值(M+H)+＝500.02基}羰基)氨基]-3-(3-甲氧基-4-甲基                      m/z苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-          0.030      计算值(M-H)-＝504.13m/z；2-氧代-1，2二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝504.04m/z基)氨基]-3-(2-萘基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-          0.015      计算值(M-H)-＝526.17m/z；羟基-5，6-二甲基-2-氧代-1，2-二氢吡                   实测值(M-H)-＝525.95m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-          0.025      计算值(M-H)-＝526.17m/z；羟基-5，6-二甲基-2-氧代-1，2-二氢吡                   实测值(M-H)-＝525.97m/z啶-3-基]氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-          0.004      计算值(M-H)-＝570.20m/z；羟基-5，6-二甲基-2-氧代-1，2-二氢吡                   实测值(M-H)-＝570.00m/z啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[{[1-(2-氯-6-氰基苄基)-4-羟0.007               计算值(M-H)-＝479.11m/z；基-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M-H)-＝478.90m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-         0.03        计算值(M-H)-＝496.16m/z；羟基-5，6-二甲基-2-氧代-1，2-二氢吡                   实测值(M-H)-＝495.97m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-       0.015        计算值(M-H)-＝512.16m/z；二甲基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝511.95m/z氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-       0.003        计算值(M-H)-＝556.18m/z；二甲基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝555.99m/z氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸Name IC 50 (μM) Mass Spec Data (3S)-3-[({[1-(3-tert-butyl-2-methoxybenzyl 2.5 Calcd. (MH) - =490.23m/z; base)-2 -Oxo-1,2-dihydropyridin-3-yl]ammonia found (MH) - =490.11 m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S) -3-[({{1-(4-fluorobenzyl)-2-oxo-1,2- 2 Calcd. (MH) - =422.12m/z; dihydropyridin-3-yl]amino}carbonyl )Amino]-3- Found (MH) - = 422.00 m/z (4-methylphenyl) propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl -2- 0.025 Calculated (MH) - = 526.08 m/z; Oxo-1,2-dihydropyridin-3-yl] amino} carbonyl Found (MH) - = 526.01 m/z base) amino] - 3-[4-Fluoro-3-(trifluoromethyl)phenyl]propionic acid (3S)-3-[({[1-(2,5-dimethylbenzyl)-4-hydroxy 0.02 Calculated (MH) - =448.19m/z; yl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =448.00m/z yl}carbonyl)amino]-3- (4-methylphenyl)propanoic acid (3S)-3-[({[4-hydroxy-1-(2-methylbenzyl)- 0.02 Calcd. (MH) - =434.17m/z; 2- Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =434.05m/zyl)amino]-3-(4-methylphenyl)propionic acid (3S)- 3-[({[1-(2-Hydroxybenzyl)-2-oxo-0.2 Calcd. (MH) - = 420.16 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl) Ammonia found value (MH) - =420.09m/z base]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(3-chlorobenzyl)-2-oxo Dihydropyridin-3-yl] amino} carbonyl) amino ] -3- found (MH) - = 438.01 m/z (4- Methylphenyl)propanoic acid (3S)-3-[({{1-(2-chloro-6-methoxybenzyl)- 0.1 Calcd. (MH) - =468.13m/z; 2-oxo -1,2-Dihydropyridin-3-yl]amino}carbonyl Found (MH) - =468.08m/zyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3- [({[1-(2-Chlorobenzyl)-4-hydroxy-2-0.035 calcd. (MH) - =498.14 m/z; oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl found value (MH) - =497.94m/z base)amino]-3-(4-methoxy-3,5-dimethylphenyl)propanoic acid 4-{[3-[({[(1S )-2-Carboxy-1-(4-methylbenzene 0.004 Calcd. (MH) - = 573.15 m/z; yl)ethyl]amino}carbonyl)amino]-1-(2-chloro Found (MH) - =572.92m/z benzyl)-2-oxo-1,2-dihydropyridin-4-yl]amino}benzoic acid (3S)-3-{[({1-(2-chlorophenyl )-4-[(2,2- 0.01 Calcd. (MH) - = 537.19 m/z; Dimethylpropionyl)amino]-2-oxo-1,2-bis Found (MH) - = 536.88 m/zhydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-5-methoxy 2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl Found (MH) - = 467.99 m/z ]amino}-3-(4-methylphenyl)propanoic acid (3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.19 Calculated (MH) - = 378.09m/z; Oxo-1,2-dihydropyridin-3-yl}amino)carbonyl found value (MH) - =378.01m/zyl]amino}butanoic acid (3S)-3-[({[ 4-{[(tert-butylamino)carbonyl]ammonia 0.01 Calcd. (MH) - = 552.20 m/z; base}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydro Found (MH) - = 551.89m/z -Chloro-5-hydroxybenzyl)-2- 0.25 Calculated (MH) - =454.12 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 454.03 m/z base)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxyl-0.009 Calculated value( MH) - =445.15m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =445.01m/zyl)amino]-3-(4- Methylphenyl)propanoic acid (3S)-3-[({[1-(2,4-dichlorobenzyl)-4-hydroxyl-0.06 Calcd. (MH) - =488.08m/z; 2-oxo Substituent-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =487.96m/zyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3 -[({[4-Hydroxy-1-(2-methoxybenzyl 0.08 Calcd. (MH) - =450.17m/z; yl)-2-oxo-1,2-dihydropyridin-3-yl ]Ammonia found value (MH) - =450.02m/z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({{1-(2-chlorobenzyl )-4-Hydroxy-2-0.08 Calculated (MH) - = 498.14 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 497.95 m/z Base)amino]-3-(4-methoxy-2,5-dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-hydroxybenzyl)- 2- 0.1 Calculated (MH) - =454.12m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =454.05m/zyl)amino]-3 -(4-methylphenyl)propanoic acid (3S)-3-[({[1-(3-tert-butyl-2-hydroxybenzyl 4 Calcd. (MH) - = 476.02 m/z; base)- 2-Oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =476.00m/zyl}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3R )-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 0.3 Calcd. (MH) - =454.17m/z; Oxo-1,2-dihydropyridine-3- Base]amino}carbonyl measured value (MH) - =454.05m/z base)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl Oxo-1,2-dihydropyridin-3-yl] amino }carbonyl Found (MH) - =467.95m/z Z-yl)amino]-3-(3-ethylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.01 Calculated (MH) - =498.10m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =497.85m/zyl)amino]-3-(2,3-dihydro -1,4-benzodioxan-6-yl)propanoic acid (3S)-3-[({[1-(2,5-difluorobenzyl)-4-hydroxyl- 0.015 Calculated ( MH) - =456.14m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =455.96m/zyl)amino]-3-(4- Methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-30 Calcd. (MH) - =468.13m/z; Oxo-1 , 2-dihydropyridin-3-yl]amino}carbonyl found value (MH) - =467.87m/z base)amino]-4-(4-methylphenyl)butanoic acid (3S)-3-[( {[1-[2-Chloro-5-(methylthio)benzyl]- 0.015 Calcd. (MH) - =500.10m/z; 4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl] found (MH) - = 499.92 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-2- 0.005 Calcd. (MH) - = 514.10 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 513.86 m /z base)amino]-3-(7-methoxy-1,3-benzodioxol-5-yl)propanoic acid (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-2- 0.002 Calculated (MH) - = 514.13 m/z; Oxo-1,2-dihydropyridin-3-yl}amino)carbonyl Found (MH) - = 513.90 m /z base]amino}-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl- 2- 0.015 Calculated (MH) - =488.10 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =487.92 m/z yl)amino]-3 -(3-Fluoro-4-methoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.002 Calculated (MH) - = 500.12m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =500.01m/zyl)amino]-3-(3,4-dimethoxy Phenyl)propionic acid (3S)-3-[({[1-(4-fluorobenzyl)-4-hydroxy-2- 0.022 Calcd. (MH) - =438.18m/z; oxo-1,2 -Dihydropyridin-3-yl]amino}carbonyl Found (MH) - =438.00m/zyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[ 1-(2-Methoxybenzyl)-2-oxo0.25 Calcd. (MH) - = 434.17 m/z; -1,2-dihydropyridin-3-yl]amino}carbonyl)Ammonia found ( MH) - =433.95m/zyl]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 0.05 Calculated (MH) - = 468.13 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 467.94 m/z yl)amino]-3-(2 , 5-Dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-5-methoxybenzyl)- 0.012 Calculated (MH) - =484.13m/z; 4-Hydroxy-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - = 484.03 m/z amino}carbonyl)amino]-3-(4-methylphenyl) Propionic acid (3S)-3-{[({1-[3,5-bis(trifluoromethyl)benzyl 0.3 Calcd. (MH) - = 556.13 m/z; yl]-4-hydroxy-2-oxy Substituent-1,2-dihydropyridine-3- found value (MH) - =555.95m/z group]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3- [({[1-(4-tert-butylbenzyl)-4-hydroxy0.03 Calcd. (MH) - = 476.22 m/z; -2-oxo-1,2-dihydropyridin-3-yl] Amino} found (MH) - = 476.05m/z carbonyl) amino] -3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(3-chlorobenzyl)- 4-Hydroxy-2- 0.015 Calculated (MH) - = 454.12 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 453.99 m/z (yl) Amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2- 0.007 Calculated (MH) - = 454.12 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =454.00m/zyl]amino)-3-(4-methylphenyl)propanoic acid (3S)-3-{[({4-Hydroxy-2-oxo-1-[3-(30.017 Calcd. (MH) - =488.14m/z; fluoromethyl)benzyl]-1,2 -Dihydropyridin-3-yl} Found (MH) - =487.99m/zamino)carbonyl]amino}-3-(4-benzyl)propanoic acid (3S)-3-[({[1- (2-Bromobenzyl)-4-hydroxy-2- 0.015 Calcd. (MH) - = 498.07 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =497.97m/zyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(3,4-dichlorobenzyl)-4-hydroxyl- 0.045 Calculated (MH) - = 488.08 m/z; 2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl Found (MH) - = 487.96 m/z base) amino] -3 -(4-methylphenyl)propanoic acid (3S)-3-[({[4-hydroxy-1-(4-methylbenzyl)- 0.025 Calcd. (MH) - =434.17m/z;2 -Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =434.05m/zyl)amino]-3-(4-methylphenyl)propionic acid (3S) -3-[({[1-(2-Chloro-6-methoxybenzyl)- 0.003 Calculated (MH) - =484.13m/z; 4-Hydroxy-2-oxo-1,2-di Hydropyridin-3-yl] found (MH) - = 484.02 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-{[({4-hydroxy -2-Oxo-1-[4-(30.02 Calcd. (MH) - = 488.14 m/z; fluoromethyl)benzyl]-1,2-dihydropyridin-3-yl} found (MH ) - =487.99m/zamino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl- 2- 0.02 Calculated (MH) - =524.08 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =523.91 m/z yl)amino]-3 -[3(trifluoromethoxy)phenyl]propionic acid (3S)-3-[({[4-hydroxy-1-(3-methylbenzyl)- 0.055 Calculated (MH) - =434.17m /z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =433.99m/zyl)amino]-3-(4-methylphenyl)propane Acid (3S)-3-[({[4-Hydroxy-2-oxo-1-(pyridine-0.045 Calcd. (MH) - =421.15m/z; 2-ylmethyl)-1,2-bis Hydropyridin-3-yl]ammonia found (MH) - =421.06m/z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1- Calcd for (2-chlorobenzyl)-4-hydroxy-5- 0.005 (MH) - = 468.13 m/z; found for methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia (MH) - =467.99m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-(2,4-difluorobenzyl) -4-Hydroxy- 0.03 Calculated (MH) - = 456.14 m/z; 2-Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 456.01 m/z )amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2,6-difluorobenzyl)-4-hydroxyl- 0.008 Calculated (MH) - =456.14m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =456.01m/zyl)amino]-3-(4-methylbenzene Base)propanoic acid (3S)-3-{[({4-hydroxy-2-oxo-1-[3-(tri 0.045 Calcd. (MH) - =504.14m/z; fluoromethoxy)benzyl ]-1,2-dihydropyridine-3- found value (MH) - =503.98m/z base}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3- {[({4-Hydroxy-2-oxo-1-[4-(30.025 Calcd. (MH) - =504.14m/z; fluoromethoxy)benzyl]-1,2-dihydropyridine- 3- Found (MH) - = 503.98 m/z base}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro -6-methoxybenzyl)- 0.0015 Calculated (MH) - = 530.13 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - =529.91m/zamino}carbonyl)amino]-3-(3,5-dimethoxyphenyl)propionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4- Hydroxy-2- 0.05 Calculated (MH) - = 430.08 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 429.94 m/z (yl)amino] -3-(2-furyl)propionic acid (3S)-3-{[({4-hydroxyl-2-oxo-1-[2-(three 0.02 calculated value (MH) - = 488.14m/z; Fluoromethyl)benzyl]-1,2-dihydropyridin-3-yl} found (MH) - =487.96m/z amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.15 Calcd. (MH) - =468.13m/z; Oxo-1,2-dihydropyridine- 3-yl]amino}carbonyl found value (MH) - =467.99m/zyl)amino]-4-(4-methylphenyl)butanoic acid (3S)-3-[({[1-(2- Chlorobenzyl)-4-hydroxy-2- 0.0008 Calculated (MH) - = 528.15 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 527.96 m/z base)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.003 Calculated (MH) - =484.12m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =483.94m/zyl)amino]-3-( 3-Ethoxyphenyl)propanoic acid (3S)-3-[({[4-hydroxy-1-(3-methoxybenzyl 0.04 Calcd. (MH) - =450.17m/z; base)-2 -Oxo-1,2-dihydropyridin-3-yl]ammonia found (MH) - =450.00 m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S) -3-[({[1-(2,3-dichlorobenzyl)-4-hydroxyl- 0.13 Calcd. (MH) - =488.08m/z; 2-oxo-1,2-dihydropyridine- 3-yl]amino}carbonyl (MH) - =487.92m/zyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-benzyl- 2-Oxo-5-(calcd for trifluoromethane 1.5 (MH) - = 472.15 m/z; yl)-1,2-dihydropyridin-3-yl]amino}carbonyl) found (MH) - = 471.89m/zamino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(3,5-dimethylbenzyl)-4-hydroxyl 0.06 calculated value( MH) - =448.19m/z; Base-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =448.02m/z base}carbonyl)amino]-3-( 4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)- 0.04 Calcd. (MH) - =554.09m/z; 4- Hydroxy-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - = 553.98 m/z amino}carbonyl)amino]-3-[4-(trifluoromethoxy)benzene Base]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.003 Calcd. (MH) - =484.13m/z; oxo-1,2- Dihydropyridin-3-yl]amino}carbonyl Found (MH) - =483.95m/zyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid (3S)-3 -[({{1-(2-chlorobenzyl)-4-hydroxyl-2-0.003 Calcd. (MH) - =514.14m/z; oxo-1,2-dihydropyridin-3-yl]amino }Carbonyl measured value (MH) - =513.95m/z base)amino]-3-(3,5-dimethoxy-4-methylphenyl)propanoic acid (3S)-3-[({[1 -(2-Chlorobenzyl)-4-hydroxy-2- 0.04 Calcd. (MH) - = 524.20 m/z; found for oxo-5-pentyl-1,2-dihydropyridin-3-yl]ammonia Value(MH) - =523.98m/z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4 -Hydroxy-2- 0.005 Calcd.(M+H)=468.13m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found(M+H) + =467.99m/z base)amino]-3-(3,4-di-methylphenyl)propionic acid (3S)-3-[({[1-(2,4-dichlorobenzyl)-4-hydroxyl- 0.02 Calculation Value (MH) - = 502.09 m/z; 5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Found (MH) - = 501.89 m/z amino}carbonyl)amino] -3-(4-methylphenyl)propanoic acid [2-({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo->10 Calculated value (MH) - =455.11m/ z; 1,2-Dihydropyridin-3-yl]amino}carbonyl)-1- found (MH) - =454.97m/z; (4-methylphenyl)hydrazino]acetic acid (3S)-3 -[({[1-(2-chlorobenzyl)-5-ethyl-4- 0.01 Calcd. (MH) - =482.15m/z; Hydroxy-2-oxo-1,2-dihydropyridine- 3-yl]ammonia found (MH) - =482.00m/z; base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid 3-[({[1-(2-chlorobenzyl )-4-Hydroxy-2-oxo- 0.05 Calculated (MH) - = 441.09 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl) ammonia Found (MH) - = 441.00 m /z;yl]-3-pyridin-3-ylpropanoic acid (3S)-3-[({[5-butyl-1-(2-chlorobenzyl)-4- 0.025 Calculated (MH) - = 510.18m/z; Hydroxy-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (MH) - =509.98m/zyl}carbonyl)amino]-3-(4-methyl Phenyl)propionic acid (3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl 0.01 Calcd. (MH) - = 522.10 m/z; yl]-4-hydroxyl -2-Oxo-1,2-dihydropyridine-3- Found (MH) - = 521.97 m/z base}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S )-3-[({{1-(2-Chloro-6-methoxybenzyl)- 0.005 Calculated (MH) - =484.13m/z; 4-Hydroxy-2-oxo-1,2- Dihydropyridin-3-yl] found (MH) - = 484.00 m/z; amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid (3S)-3-[({[1 -(2,6-Dichlorobenzyl)-4-hydroxy- 0.013 Calcd. (MH) - = 488.08 m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl found Value (MH) - =487.91m/zyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-5-fluorobenzyl) -4-Hydroxy 0.014 Calculated (MH) - = 472.11 m/z; yl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 471.96 m/z yl} Carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 0.01 Calculated (MH) - = 482.15 m/z; Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine - found (MH) - = 481.98 m/z 3-yl]amino}carbonyl)amino]-3- (4-methylphenyl)propanoic acid (3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-5- 0.02 Calcd. (MH) - =468.13m/z; form Base-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =467.94m/z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.003 Calcd. (M+H) + = 496.16m/z; Oxo-2,5,6, 7-Tetrahydro-1H-cyclopentadiene and found (M+H) + =495.99m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl )propanoic acid (3S)-3-{[({4-hydroxy-5-methyl-1-[4-(calcd. (MH) - =512.15m/z; methylsulfonyl)benzyl]- 2-Oxo-1,2-dihydropyridine found (MH) - =511.96m/z pyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S )-3-[({[4-Hydroxy-1-(4-methoxybenzyl 0.02 Calcd. (MH) - =450.17m/z; base)-2-oxo-1,2-dihydropyridine- 3-yl]ammonia found (MH) - =449.99m/zyl}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2- Chlorobenzyl)-4-hydroxy-2- 0.02 Calcd. (MH) - = 496.16 m/z; Oxo-5-propyl-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =495.94m/z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-({[(1-{4-[(dimethylamino)sulfonyl 0.035 Calculated (MH) - = 527.16 m/z; yl]benzyl}-4-hydroxy-2-oxo-1,2-dihydro found (MH) - = 526.96 m/z pyridin-3-yl) Amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid (3S)-3-[({[4-hydroxy-1-(hydrogenylmethyl)-2- 0.06 Calculated (MH) - =462.20m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =462.02m/zyl)amino]-3-(4-methylphenyl )propionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.02 Calcd. (MH) - =508.16m/z; oxo-1,2,5 , 6,7,8-Hexahydroquinolin-3-yl]ammonia Found (MH) - =507.96m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S) -3-[({[1-(2-chlorobenzyl)-5-ethyl-4- 0.025 Calcd. (MH) - =496.16m/z; Hydroxy-6-methyl-2-oxo-1 , 2-Dihydropyridine - found (MH) - = 495.96 m/z 3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[ ( MH) - =467.85m/zyl)(methyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-{[({4-hydroxyl-1-[2-(methyl Thio)benzyl 0.02 Calculated (MH) - = 466.14 m/z; Base] -2-oxo-1,2-dihydropyridin-3-yl} ammonia Found (MH) - = 465.97 m/z )carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-({[(1-{2-[(dimethylamino)sulfonyl 0.03 Calculated value (MH) - = 527.16m/z; base] benzyl}-4-hydroxyl-2-oxo-1,2-dihydrofound (MH) - =526.97m/zpyridin-3-yl]amino}carbonyl)amino]- 3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2,6-dimethoxybenzyl)-4- 0.01 Calculated value (MH) - =480.18m/ z; Hydroxy-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 480.00 m/z (yl}carbonyl)amino]-3-(4-methylphenyl) Propionic acid (3S)-3-{[({4-Hydroxy-2-oxo-1-[2-(tri 0.025 calcd. (MH) - =504.14m/z; fluoromethoxy)benzyl]- 1,2-Dihydropyridine-3- Found (MH) - =503.96m/z base}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3R)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxy-2-0.35 Calcd. (MH) - =522.10 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}Carbonyl found Value (MH) - =521.95m/zyl)amino]-4-[3-(trifluoromethyl)benzyl]butanoic acid (3S)-3-[({[1-(2-chlorobenzyl) -4-Hydroxy-2- 0.003 Calculated (MH) - = 498.14 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 497.97 m/z )amino]-3-(3-propoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.003 Calculated (M+H ) + =528.19m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (M+H) + =528.02m/zyl)amino]-3-(3-ethyl Oxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6- 0.006 Calcd. (MH) - =482.15m/z; Dimethyl Base-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - = 481.95 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid ( 3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-0.005 Calcd. (MH) - =570.20m/z; Oxo-5-propyl-1,2 -Dihydropyridin-3-yl]ammonia found (MH) - =569.98m/zyl}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3- (3-Butoxyphenyl)-3-[({[1-(2- 0.005 Calcd. (M+H) + =514.17m/z; Chlorobenzyl)-4-hydroxy-2-oxo- 1,2-Dihydropyridine found (M+H) + =514.00m/zpyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-{[({1-[2-chloro -5-(Methylsulfonyl) 0.003 Calculated (MH) - = 532.10 m/z; Benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridine - found (MH) - = 531.94m/z3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy- 2- 0.08 Calculated (MH) - =468.13 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =468.03 m/z yl)amino]-4 -(2-Methylphenyl)butanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.003 Calcd. (MH) - =514.14m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =513.95m/zyl)amino]-3-[3-(2-methoxyethoxy)benzene base]propanoic acid (3S)-3-[({[1-(4-chloro-2-methoxybenzyl)- 0.025 Calcd. (MH) - =484.13m/z; 4-hydroxy-2-oxo Substituent-1,2--dihydropyridin-3-yl] found (MH) - = 483.93 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3 -[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.003 Calcd. (MH) - =556.18m/z; oxo-1,2-dihydropyridin-3-yl]amino } Carbonyl measured value (MH) - =555.94m/z base)amino]-3-(3,4-dipropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-2- 0.12 Calcd. (MH) - = 522.18 m/z; Oxo-2,5,6,7,8,9-hexahydro-1H-cyclopentadiene found ( MH) - =521.98m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-( 2-Chlorobenzyl)-4-hydroxy-2-12 Calculated (MH) - = 530.15 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =529.92m/z base)amino]-4,4-diphenylbutanoic acid (3S)-3-{[({1-[2-(difluoromethoxy)phenyl]-0.075 Calculated (MH ) - =486.15m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl} found (MH) - =486.00m/zamino)carbonyl]amino}-3-( 4-Methylphenyl)propanoic acid (3S)-3-{[({4-Hydroxy-5-methyl-2-oxo-1-4 Calculated (MH) - =448.19m/z; [( 1R)-1-phenylethyl]-1,2-dihydropyridine-3- Found (MH) - =447.99m/z base}amino)carbonyl]amino}-3-(4-methylphenyl) Propionic acid (3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2- 0.03 Calcd. (MH) - = 496.16m/z; oxo-5-propyl-1 , 2-dihydropyridin-3-yl]ammonia found value (MH) - =495.96m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxy-2-0.05 Calcd. (MH) - = 496.16 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}Carbonyl found Value (MH) - =495.98m/zyl)amino]-3-(3,4-diethylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)- 4-Hydroxy-2- 0.05 Calculated (MH) - = 476.08 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 475.93 m/z (yl) Amino]-3-(3,5-difluorophenyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.02 Calculated (MH) - = 3 -[( {[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-0.025 calcd. (M+H) + = 446.11 m/z; 1,2-dihydropyridin-3-yl]amino} Carbonyl) ammonia found value (M+H) + = 446.08m/z base] -3-(5-methyl-2-furyl) propanoic acid (3S) -3-[({[1-[2-chloro Benzyl]-4-hydroxy-2- 0.025 Calculated (MH) - = 584.21 m/z; Oxo-1,2-dihydropyridin-3-yl] amino}carbonyl Found (MH) - = 583.98 m /z group)amino]-3-(3,4-dibutoxyphenyl)propanoic acid (3S)-3-{[({4-hydroxyl-1-[2-(methylsulfonyl 0.035 calculated value (M+H) + =500.15 m/z; yl)benzyl]-2-oxo-1,2-dihydropyridine-3- found (M+H) + =500.01 m/z yl}amino) Carbonyl]amino}-3-(4-methylphenyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.2 Calculated (MH) - = 490.12m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)ammonia found value (MH) - =489.91m/zyl]-3-(1-naphthyl)propionic acid (3S)- 3-[({[1-(4-chlorobenzyl)-4-hydroxy-2- 0.03 Calcd. (MH) - = 526.17m/z; Oxo-5-propyl-1,2-dihydropyridine -3-yl]ammonia found value (MH) - =525.95m/z base}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-( 4-Chlorobenzyl)-4-hydroxy-2- 0.015 Calcd. (MH) - = 570.20 m/z; Oxo-5-propyl-1,2-dihydropyridin-3-yl] ammonia found ( MH) - =569.97m/zyl}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2,6-dimethyl benzyl)-4-hydroxy0.035 Calcd. (MH) - = 448.19 m/z; Base-2-oxo-1,2-dihydropyridin-3-yl] ammonia found (MH) - = 448.02 m /z base}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[3,5-bis(trifluoromethyl)phenyl]-3- 0.22 Calculated (MH ) - = 576.08 m/z; [({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo- found (MH) - = 575.91 m/z 1,2-dihydropyridine-3 -yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 0.006 Calcd. (MH) - =506.09m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =505.93m/zyl)amino]-3-[3-(difluoromethoxy)phenyl]propane Acid (3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 0.225 Calcd. (MH) - = 455.11 m/z; Oxo-1,2-dihydropyridine -3-yl]amino}carbonyl found (MH) - =455.09m/zyl)amino]-4-pyridin-2-ylbutanoic acid (3S)-3-[({[1-(2-chlorobenzyl Base)-4-hydroxyl-5- 0.0006 Calculated (MH) - =542.17 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 542.06m/zyl}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy -5- 0.002 Calculated (MH) - = 499.15 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 498.07 m/z base} Carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5- 0.020 Calculated (M+ H) + =500.16 methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia m/z; found (M+H) + =500.02 base}carbonyl)amino]-3-( 3-Methoxy-4-methyl m/z phenyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.030 Calculated (MH) - =504.13m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =504.04m/zyl)amino]-3-(2-naphthyl)propane Acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 0.015 Calcd. (MH) - = 526.17m/z; Hydroxy-5,6-dimethyl -2-Oxo-1,2-dihydropyridine found (MH) - =525.95m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-[({[1-(2-Chloro-6-methylbenzyl)-4- 0.025 Calculated (MH) - =526.17m/z; Hydroxy-5,6-dimethyl- 2-Oxo-1,2-dihydropyridine found (MH) - =525.97m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylbenzene base)propionic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 0.004 Calcd. (MH) - =570.20m/z; Hydroxyl-5,6- Dimethyl-2-oxo-1,2-dihydropyridine found (MH) - =570.00m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxy phenyl)propanoic acid (3S)-3-[{[1-(2-chloro-6-cyanobenzyl)-4-hydroxyl 0.007 Calculated (MH) - =479.11m/z; base-2- Oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =478.90m/zyl}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)- 3-[({[1-(2-Chloro-6-methylbenzyl)-4- 0.03 Calcd. (MH) - = 496.16m/z; Hydroxy-5,6-dimethyl-2-oxo -1,2-Dihydropyridine found (MH) - =495.97m/zpyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3- [({[1-(2-Chlorobenzyl)-4-hydroxyl-5,6-0.015 Calcd. (MH) - =512.16m/z; Dimethyl-2-oxo-1,2-dihydro Pyridin-3-yl] found (MH) - = 511.95 m/z amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxy-5,6- 0.003 Calcd. (MH) - =556.18m/z; Dimethyl-2-oxo-1,2-dihydropyridine- 3-yl] Found (MH) - = 555.99 m/z amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid

                                       表6Table 6

             名称                     IC50             质谱数据(m/z)Name IC 50 mass spectrum data (m/z)

                                      (nM)(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-         2500          计算值(M-H)-＝504.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝503.97m/z基)氨基]-4-(1-萘基)丁酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-      30            计算值(M-H)-＝512.16m/z；二甲基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝511.99m/z氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-      40            计算值(M-H)-＝496.16m/z；二甲基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝496.05m/z氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-         5             计算值(M-H)-＝498.15m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝497.91m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-         2             计算值(M-H)-＝572.18m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝571.96m/z啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-         6             计算值(M-H)-＝528.15m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝527.95m/z啶-3-基]氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-         3             计算值(M-H)-＝528.15m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝527.99m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         15            计算值(M-H)-＝556.09m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝555.97m/z基)氨基]-3-[3-(1，1，2，2-四氟乙氧基)苯基]丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-           700          计算值(M-H)-＝488.08m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                          实测值(M-H)-＝487.96m/z基)氨基]-4-(2-氯苯基)丁酸(3S)-3-{[({4-羟基-1-[3-(甲硫基)苄           20           计算值(M-H)-＝466.14m/z；基]-2-氧代-1，2-二氢吡啶-3-基}氨                         实测值(M-H)-＝466.04m/z基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-           15           计算值(M-H)-＝482.15m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                        实测值(M-H)-＝482.02m/z基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-           3            计算值(M-H)-＝512.16m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                         实测值(M-H)-＝512.03m/z啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-5-环丙基-           20           计算值(M+H)+＝496.16m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                        实测值(M+H)+＝496.05m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(4-氯苯基)-4-羟基-2-           50           计算值(M-H)-＝494.15m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                       实测值(M-H)-＝494.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(3-氯苄基)-4-羟基-5-           20           计算值(M-H)-＝468.13m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                        实测值(M-H)-＝468.02m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，6-二氯苄基)-4-羟基-        20           计算值(M-H)-＝502.09m/z；5-甲基-2-氧代-1，2-二氢吡啶-3-基]                        实测值(M-H)-＝501.92m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[4-羟基-5-甲基-1-(4-甲基          150          计算值(M-H)-＝448.19m/z；苄基)-2-氧代-1，2-二氢吡啶-3-基]氨                     实测值(M-H)-＝448.05m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸3-(1-苯并呋喃-2-基)-3-[({[1-(2-氯         140          计算值(M-H)-＝480.10m/z；苯基)-4-羟基-2-氧代-1，2-二氢吡啶-                     实测值(M-H)-＝479.96m/z3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         3            计算值(M-H)-＝524.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                     实测值(M-H)-＝523.95m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-         15           计算值(M-H)-＝520.13m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                        实测值(M-H)-＝520.00m/z基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-[({[1-(3，5-二甲氧基苄基)-4-       70           计算值(M-H)-＝494.19m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                      实测值(M-H)-＝494.04m/z3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2，6-二氟苄基)-4-羟基-      25           计算值(M-H)-＝470.15m/z；5-甲基-2-氧代-1，2-二氢吡啶-3-基]                      实测值(M-H)-＝470.03m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         3            计算值(M+H)+＝570.20m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                     实测值(M+H)+＝570.00m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-{[({4-羟基-1-[3-(甲基磺酰          25           计算值(M-H)-＝498.13m/z；基)苄基]-2-氧代-1，2-二氢吡啶-3-                       实测值(M-H)-＝498.01m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-         3            计算值(M-H)-＝556.19m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                      实测值(M-H)-＝556.02m/z3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-          4            计算值(M-H)-＝512.16m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                       实测值(M-H)-＝512.02m/z3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丁酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-          45           计算值(M-H)-＝496.16m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                       实测值(M-H)-＝496.01m/z3-基]氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-          25           计算值(M-H)-＝512.16m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                       实测值(M-H)-＝511.97m/z3-基]氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-          115          计算值(M-H)-＝458.11m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                         实测值(M-H)-＝457.99m/z基]-3-(4，5-二甲基-4-呋喃基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-          160          计算值(M-H)-＝520.13m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                         实测值(M-H)-＝519.97m/z基]-3-(4-甲氧基-1-萘基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-          115          计算值(M-H)-＝468.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝467.98m/z基)氨基]-5-苯基戊酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          12           计算值(M-H)-＝534.14m/z；氧代-1，2-二氢喹啉-3-基]氨基}羰                         实测值(M-H)-＝533.94m/z基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          18           计算值(M+H)+＝510.18m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                      实测值(M+H)+＝510.06m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          7            计算值(M+H)+＝500.16m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M+H)+＝500.06m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           3           计算值(M-H)-＝512.16m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝512.03m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-5-环丙基-           14          计算值(M+H)+＝526.17m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M+H)+＝526.01m/z氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-5-环丙基-           6           计算值(M+H)+＝570.20m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M+H)+＝570.04m/z氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           30          计算值(M-H)-＝506.09m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                         实测值(M-H)-＝505.96m/z基)氨基]-3-[4-(二氟甲氧基)苯基]丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-           105         计算值(M-H)-＝491.11m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                         实测值(M-H)-＝490.96m/z基]-3-喹啉-2-基丙酸(3S)-3-[({[1-(2-氟-6-甲氧基苄基)-           10          计算值(M-H)-＝482.17m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝482.02m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-           15          计算值(M+H)+＝528.19m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                        实测值(M+H)+＝528.04m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-           7           计算值(M+H)+＝558.20m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                        实测值(M+H)+＝558.07m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(5-氯-2-氟苄基)-4-羟           15          计算值(M-H)-＝486.12m/z；基-5-甲基-2-氧代-1，2-二氢吡啶-3-                 实测值(M-H)-＝486.00m/z基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       14        计算值(M-H)-＝534-14m/z；氧代-1，2-二氢喹啉-3-基]氨基}羰                   实测值(M-H)-＝533.95m/z基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       4         计算值(M-H)-＝578.17m/z；氧代-1，2-二氢喹啉-3-基]氨基}羰                   实测值(M-H)-＝577.99m/z基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       25        计算值(M-H)-＝518.15m/z；氧代-1，2-二氢喹啉-3-基]氨基}羰                   实测值(M-H)-＝517.96m/z基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       150       计算值(M+H)+＝443.11m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M+H)+＝443.03m/z基)氨基]-3-吡啶-2-基丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       3         计算值(M-H)-＝498.14m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M-H)-＝498.04m/z基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       7         计算值(M-H)-＝528.15m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M-H)-＝528.02m/z基)氨基]-3-(3，5-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-       60        计算值(M+H)+＝498.18m/z；异丙基-2-氧代-1，2-二氢吡啶-3-基]                 实测值(M+H)+＝498.05m/z氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(5-氟-2-甲基苄基)-4-       20        计算值(M+H)+＝468.19m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                 实测值(M+H)+＝468.07m/z3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-{[({4-羟基-5-甲基-2-氧代-1-         1500         计算值(M+H)+＝450.20m/z；[(1S)-1-苯乙基]-1，2-二氢吡啶-3-                        实测值(M+H)+＝450.07m/z基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-          3            计算值(M+H)+＝602.23m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                        实测值(M+H)+＝602.04m/z啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-5-异丙氧基苄            7            计算值(M-H)-＝526.17m/z；基)-4-羟基-5-甲基-2-氧代-1，2-二氢                      实测值(M-H)-＝526.04m/z吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-         15            计算值(M+H)+＝558.20m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                        实测值(M+H)+＝558.05m/z啶-3-基]氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         2             计算值(M+H)+＝544.19m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M+H)+＝544.04m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(5-乙酰基-2-甲氧基苄         33            计算值(M-H)-＝492.18m/z；基)-4-羟基-2-氧代-1，2-二氢吡啶-3-                      实测值(M-H)-＝492.04m/z基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸3-[({[1-(2-氯-6-甲基苄基)-4-羟基-         35            计算值(M-H)-＝548.16m/z；5-甲基-2-氧代-1，2-二氢吡啶-3-基]                       实测值(M-H)-＝548.01m/z氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-         17            计算值(M+H)+＝542.21m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                        实测值(M+H)+＝542.05m/z啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        3           计算值(M-H)-＝493.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝492.95m/z基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸(3S)-3-[({[2-(2-氯苄基)-5-羟基-6-        18          计算值(M+H)+＝471.14m/z；甲基-3-氧代-2，3-二氢哒嗪-4-基]氨                    实测值(M+H)+＝471.00m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-        5           计算值(M-H)-＝534.14m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝533.91m/z基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-[({[2-(2-氯苄基)-5-羟基-6-        5           计算值(M+H)+＝501.15m/z；甲基-3-氧代-2，3-二氢哒嗪-4-基]氨                    实测值(M+H)+＝501.01m/z基}羰基)氨基]-3-(3-乙氧基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-        30          计算值(M+H)+＝448.07m/z；1，2-二氢吡啶-3-基]氨基}羰基)氨                      实测值(M+H)+＝447.97m/z基]-3-噻吩-2-基丙酸(3S)-3-[({[5-氯-1-(2-氯苄基)-4-羟        6           计算值(M-H)-＝488.08m/z；基-2-氧代-1，2-二氢吡啶-3-基]氨                      实测值(M-H)-＝487.97m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-(3-丁氧基苯基)-3-[({[1-(2-        20          计算值(M-H)-＝552.19m/z；氯苄基)-4-羟基-2-氧代-2，5，6，7-四                  实测值(M-H)-＝552.01m/z氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        5           计算值(M-H)-＝524.16m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝524.00m/z基)氨基]-3-[3-(环戊氧基)苯基]丙酸(3S)-3-[({[2-(2-氯苄基)-5-羟基-6-        3           计算值(M+H)+＝545.18m/z；甲基-3-氧代-2，3-二氢哒嗪-4-基]氨                    实测值(M+H)+＝544.98m/z基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         3          计算值(M-H)-＝507.14m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝506.94m/z基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸(3S)-3-[({[2-(2-氯苄基)-5-羟基-6-         10         计算值(M+H)+＝545.18m/z；甲基-3-氧代-2，3-二氢哒嗪-4-基]氨                    实测值(M+H)+＝545.01m/z基}羰基)氨基]-3-(3，5-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         70         计算值(M-H)-＝538.10m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝537.95m/z基}羰基)氨基]-3-[4-(三氟甲氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         10         计算值(M-H)-＝538.10m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝537.95m/z基}羰基)氨基]-3-[3-(三氟甲氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         4          计算值(M+H)+＝486.14m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M+H)+＝486.04m/z基}羰基)氨基]-3-(4-甲氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         15         计算值(M-H)-＝520.13m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                      实测值(M-H)-＝520.03m/z基)氨基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-{[({1-[2-氟-6-(三氟甲基)苄         100        计算值(M-H)-＝520.15m/z；基]-4-羟基-5-甲基-2-氧代-1，2-二氢                   实测值(M-H)-＝519.97m/z吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         10         计算值(M-H)-＝522.10m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝521.96m/z基}羰基)氨基]-3-[3-(三氟甲基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         3          计算值(M-H)-＝484.13m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨               实测值(M-H)-＝484.00m/z基}羰基)氨基]-3-(3-甲氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-       20      计算值(M+H)+＝510.18m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊             实测值(M+H)+＝510.05m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-       4       计算值(M+H)+＝540.19m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊             实测值(M+H)+＝540.10m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-       3       计算值(M+H)+＝540.19m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并              实测值(M+H)+＝540.09m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-       3       计算值(M-H)-＝542.17m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨               实测值(M-H)-＝542.00m/z基}羰基)氨基]-3-(3，5-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-       4       计算值(M-H)-＝556.19m/z；5-乙基-4-羟基-2-氧代-1，2-二氢吡                实测值(M-H)-＝556.01m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-       3       计算值(M+H)+＝530.17m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]               实测值(M+H)+＝530.04m/z氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-       15      计算值(M-H)-＝538.17m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨               实测值(M-H)-＝538.03m/z基}羰基)氨基]-3-[3-(环戊氧基)苯基]丙酸3-(1，1’-联苯-4-基)-3-[({[1-(2-氯苄    130     计算值(M-H)-＝530.15m/z；基)-4-羟基-5-甲基-2-氧代-1，2-二-氢               实测值(M-H)-＝529.96m/z吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        30       计算值(M+H)+＝580.15m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                实测值(M+H)+＝580.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(2，2，2-三氟乙氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-        15       计算值(M+H)+＝554.13m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                 实测值(M+H)+＝554.00m/z基}羰基)氨基]-3-[3-(2，2，2-三氟乙氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-        3        计算值(M+H)+＝514.17m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                 实测值(M+H)+＝514.05m/z基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        4        计算值(M+H)+＝558.20m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                  实测值(M+H)+＝558.05m/z啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(nM)(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 2500 Calcd. (MH) - =504.13m/z; Oxo-1,2-di Hydropyridin-3-yl]amino}carbonyl Found (MH) - =503.97m/zyl)amino]-4-(1-naphthyl)butanoic acid (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxy-5,6-30 Calcd. (MH) - = 512.16 m/z; Dimethyl-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - =511.99m/zamino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4 -Hydroxy-5,6-40 Calculated (MH) - = 496.16 m/z; Dimethyl-2-oxo-1,2-dihydropyridin-3-yl] Found (MH) - = 496.05 m /zamino}carbonyl)amino]-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)- 5 Calculated (MH) - = 498.15 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine Found (MH) - = 497.91 m/z pyridin-3-yl ]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-2 Calcd.( MH) - = 572.18 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH) - = 571.96 m/z pyridin-3-yl]amino}carbonyl )Amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-6 Calculated value( MH) - = 528.15 m/z; 4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH) - = 527.95 m/z pyridin-3-yl]amino}carbonyl )amino]-3-(3-methoxy-4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-3 calculation Value (MH) - = 528.15 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine Found (MH) - = 527.99 m/z pyridin-3-yl]amino }carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 15 Calculated (MH ) - =556.09m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =555.97m/zyl)amino]-3-[3-(1, 1,2,2-Tetrafluoroethoxy)phenyl]propanoic acid (3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 700 Calculated (MH) - =488.08m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =487.96m/zyl)amino]-4-(2-chlorophenyl)butyl Acid (3S)-3-{[({4-Hydroxy-1-[3-(methylthio)benzyl 20 Calcd. (MH) - =466.14m/z; yl]-2-oxo-1,2 -Dihydropyridin-3-yl}ammonia found value (MH) - =466.04m/zyl)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[ Calcd for 1-(2-chlorobenzyl)-4-hydroxy-5-15 (MH) - = 482.15 m/z; methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 482.02m/z base}carbonyl)amino]-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro- 6-Methoxybenzyl)-3 Calculated (MH) - = 512.16 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine Found (MH) - = 512.03m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl )-5-cyclopropyl-20 Calcd. (M+H) + = 496.16 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] found (M+H ) + ＝496.05m/zamino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-(4-chlorophenyl)-4-hydroxyl- 2- 50 Calculated (MH) - = 494.15 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (MH) - = 494.02 m/z [b] Pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(3-chlorobenzyl)-4-hydroxyl-5 - 20 Calculated (MH) - = 468.13 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl] ammonia Found (MH) - = 468.02 m/z (yl}carbonyl) Amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-(2,6-dichlorobenzyl)-4-hydroxyl-20 Calculated (MH) - = 502.09 m/z; 5-methyl-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - = 501.92 m/z amino}carbonyl)amino]-3-(4- Methylphenyl)propanoic acid (3S)-3-[({[4-hydroxy-5-methyl-1-(4-methyl 150 Calcd. (MH) - =448.19m/z; benzyl)- 2-Oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =448.05m/zyl}carbonyl)amino]-3-(4-methylphenyl)propanoic acid 3- (1-Benzofuran-2-yl)-3-[({[1-(2-Chloro140 Calcd. (MH) - =480.10m/z; phenyl)-4-hydroxy-2-oxo- 1,2-Dihydropyridine - found (MH) - = 479.96 m/z 3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)- 4-Hydroxy-2-3 Calculated (MH) - = 524.16 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (MH) - = 523.95 m/z z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy- 2-Oxo-15 Calculated (MH) - = 520.13 m/z; 1,2-dihydropyridin-3-yl] amino} carbonyl) ammonia Found (MH) - = 520.00 m/z base] -3 -(6-Methoxy-2-naphthyl)propanoic acid (3S)-3-[({[1-(3,5-dimethoxybenzyl)-4- 70 Calculated (MH) - = 494.19m/z; Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-found (MH) - =494.04m/z3-yl]amino}carbonyl)amino]-3-(4 -Methylphenyl)propanoic acid (3S)-3-[({[1-(2,6-difluorobenzyl)-4-hydroxyl-25 Calcd. (MH) - =470.15m/z; 5- Methyl-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - = 470.03 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 3 Calcd. (M+H) + =570.20m/z; Oxo-2,5,6, 7-Tetrahydro-1H-cyclopentadiene and found (M+H) + =570.00m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethyl Oxyphenyl)propanoic acid (3S)-3-{[({4-hydroxy-1-[3-(calculated for methylsulfonyl 25 (MH) - =498.13m/z; yl)benzyl]- 2-Oxo-1,2-dihydropyridine-3- Found (MH) - = 498.01 m/z base}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S) -3-[({[1-(2-Chloro-6-methylbenzyl)-4- 3 Calculated (MH) - =556.19m/z; Hydroxy-5-methyl-2-oxo-1 , 2-Dihydropyridine - Found (MH) - = 556.02 m/z 3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3- [({[1-(2-Chloro-6-methylbenzyl)-4- 4 Calculated (MH) - = 512.16m/z; Hydroxy-5-methyl-2-oxo-1,2- Dihydropyridine - found (MH) - = 512.02 m/z 3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)butanoic acid (3S)-3-[({[1- Calcd for (2-chloro-6-methylbenzyl)-4-45 (MH) - = 496.16 m/z; Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine - found (MH) - =496.01m/z3-yl]amino}carbonyl)amino]-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro -6-Methylbenzyl)-4- 25 Calculated (MH) - = 512.16 m/z; Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine- found (MH) - =511.97m/z3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4 -Hydroxy-2-oxo-115 Calculated (MH) - = 458.11 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl) ammonia Found (MH) - = 457.99 m/z ]-3-(4,5-Dimethyl-4-furyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-160 Calculated (MH ) - = 520.13 m/z; 1,2-dihydropyridin-3-yl] amino} carbonyl) ammonia found (MH) - = 519.97 m/z yl] -3-(4-methoxy-1- Naphthyl)propionic acid (3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-115 Calcd. (MH) - =468.13m/z; Oxo-1,2 -Dihydropyridin-3-yl]amino}carbonyl Found (MH) - =467.98m/zyl)amino]-5-phenylpentanoic acid (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxy-2-12 Calculated (MH) - = 534.14 m/z; Oxo-1,2-dihydroquinolin-3-yl]amino}carbonyl Found (MH) - = 533.94 m/z base)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-18 Calculated (M+H) + = 510.18 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + = 510.06 m/z [b]pyridine -3-yl]amino}carbonyl)amino]-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl 4-Hydroxy-2-oxo -1,2-dihydropyridin-3-yl] found (M+H) + = 500.06 m /zamino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-3 calculated value (MH) - =512.16 m/z; 4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH) - =512.03 m/z pyridin-3-yl]amino} Carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-5-cyclopropyl-14 Calcd. (M+H ) + =526.17 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] found (M+H) + =526.01 m/z amino}carbonyl)amino]-3 -(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-5-cyclopropyl-6 Calculated (M+H) + = 570.20m /z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl] found (M+H) + = 570.04 m/z amino}carbonyl)amino]-3-(3,4 -diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-30 Calcd. (MH) - =506.09m/z; oxygen Substituent-1,2-dihydropyridin-3-yl]amino}carbonyl found value (MH) - =505.96m/zyl)amino]-3-[4-(difluoromethoxy)phenyl]propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-105 Calcd. (MH) - = 491.11 m/z; 1,2-dihydropyridin-3-yl] Amino}carbonyl)Ammonia found (MH) - =490.96m/z 4-hydroxy-5-methyl-2-oxo -1,2-dihydropyridine found (MH)- = 482.02m/z Pyridine-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl) - 15 Calculated (M+H) + = 528.19 m/z; 4-Hydroxy-2-oxo-5-propyl-1,2-dihydropyridine Found (M+H) + = 528.04 m/z Pyridine-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl) - 7 Calculated (M+H) + = 558.20 m/z; 4-Hydroxy-2-oxo-5-propyl-1,2-dihydropyridine Found (M+H) + = 558.07 m/z Pyridine-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(5-chloro-2-fluorobenzyl)- 4-Hydroxy15 Calculated (MH) - = 486.12 m/z; Base-5-methyl-2-oxo-1,2-dihydropyridine-3- Found (MH) - = 486.00 m/z base ]Amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-14 Calculated value( MH) - =534-14m/z; Oxo-1,2-dihydroquinolin-3-yl]amino}carbonyl Found (MH) - =533.95m/zyl)amino]-3-(3- Methoxy-4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-4 Calculated value (MH) - =578.17m/ z; Oxo-1,2-dihydroquinolin-3-yl]amino}carbonyl Found (MH) - =577.99m/zyl)amino]-3-(3,4-diethoxyphenyl )propionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 25 Calcd value (MH) - =518.15m/z; oxo-1,2-di Hydroquinolin-3-yl]amino}carbonyl found value (MH) - =517.96m/zyl)amino]-3-(3,4-dimethylphenyl)propanoic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxy-2-150 calcd. (M+H) + = 443.11 m/z; oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl found (M+H) + =443.03m/zyl)amino]-3-pyridin-2-ylpropanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4- Hydroxy-2-3 Calculated (MH) - =498.14 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =498.04 m/zyl)amino] -3-(3-isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-7 Calculated (MH) - = 528.15 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =528.02m/zyl)amino]-3-(3,5-diethoxybenzene Base) propionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5- 60 Calcd. (M+H) + = 498.18m/z; isopropyl-2 -Oxo-1,2-dihydropyridin-3-yl] found (M+H) + = 498.05 m/z amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S )-3-[({[1-(5-fluoro-2-methylbenzyl)-4- 20 Calcd. (M+H) + = 468.19m/z; Hydroxy-5-methyl-2-oxo Dai-1,2-dihydropyridine- Found (M+H) + =468.07m/z3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3 -{[({4-Hydroxy-5-methyl-2-oxo-1-1500 Calcd. (M+H) + = 450.20 m/z; [(1S)-1-phenylethyl]-1, 2-Dihydropyridine-3- Found (M+H) + =450.07m/z base}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[( {[1-(2-Chloro-6-methoxybenzyl)-3 Calcd. (M+H) + = 602.23 m/z; 4-Hydroxy-2-oxo-5-propyl-1,2 - Dihydropyridine found (M+H) + = 602.04 m/z pyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)- 3-[({[1-(2-Chloro-5-isopropoxybenzyl7 Calcd. (MH) - = 526.17m/z; yl)-4-hydroxy-5-methyl-2-oxo- 1,2-Dihydrofound value (MH) - =526.04m/zpyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[( {[1-(2-Chloro-6-methoxybenzyl)-15 Calcd. (M+H) + = 558.20 m/z; 4-Hydroxy-2-oxo-5-propyl-1,2 - Dihydropyridine found (M+H) + = 558.05 m/z pyridin-3-yl] amino} carbonyl) amino] -3-(3-methoxy-4-methylphenyl) propanoic acid (3S )-3-[({[1-(2-Chloro-6-ethoxybenzyl)-2 Calculated (M+H) + =544.19m/z; 4-Hydroxy-5-methyl-2- Oxo-1,2-dihydropyridine found (M+H) + =544.04m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid ( 3S)-3-[({[1-(5-Acetyl-2-methoxybenzyl 33 Calcd. (MH) - = 492.18 m/z; yl)-4-hydroxy-2-oxo-1, 2-Dihydropyridine-3- Found (MH) - = 492.04 m/z base] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid 3-[({[1-(2 -Chloro-6-methylbenzyl)-4-hydroxy-35 Calcd. (MH) - = 548.16 m/z; 5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Found (MH) - = 548.01m/z amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid (3S)-3-[({[1-(2-chloro -6-Methoxybenzyl)-17 Calculated (M+H) + = 542.21 m/z; 4-Hydroxy-2-oxo-5-propyl-1,2-dihydropyridine found (M +H) + =542.05m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dimethylphenyl)propionic acid (3S)-3-[({[1-( 2-Chlorobenzyl)-4-hydroxyl-2-3 Calcd. (MH) - = 493.13 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =492.95m/zyl)amino]-3-(1-methyl-1H-indol-5-yl)propionic acid (3S)-3-[({[2-(2-chlorobenzyl)-5 -Hydroxy-6-18 Calcd. (M+H) + = 471.14 m/z; Methyl-3-oxo-2,3-dihydropyridazin-4-yl]ammonia Found (M+H) + =471.00m/z base}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5- 5 Calculated (MH) - = 534.14 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 533.91 m/z (yl}carbonyl) amino ]-3-(6-methoxy-2-naphthyl)propanoic acid (3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxyl-6-5 Calculated (M+ H) + =501.15 m/z; methyl-3-oxo-2,3-dihydropyridazin-4-yl]ammonia found (M+H) + =501.01 m/z base}carbonyl)amino] -3-(3-ethoxyphenyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-30 Calcd. (M+H) + = 448.07 m/z; 1,2-Dihydropyridin-3-yl]amino}carbonyl)Ammonia found (M+H) + =447.97m/zyl]-3-thiophen-2-ylpropanoic acid (3S)- 3-[({[5-Chloro-1-(2-chlorobenzyl)-4-hydroxy6 Calculated (MH) - =488.08m/z; yl-2-oxo-1,2-dihydropyridine -3-yl]ammonia found (MH) - =487.97m/zyl}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-(3-butoxyphenyl )-3-[({[1-(2- 20 Calcd.(MH) - =552.19m/z; chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrafound Value (MH) - =552.01m/z Hydrogen-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxyl-2-5 Calculated (MH) - =524.16 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - = 524.00m/zyl)amino]-3-[3-(cyclopentyloxy)phenyl]propionic acid (3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxyl-6 - 3 Calculated (M+H) + = 545.18 m/z; Methyl-3-oxo-2,3-dihydropyridazin-4-yl]ammonia Found (M+H) + = 544.98 m/z Z base}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5- 3 Calculated (MH) - = 507.14 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - = 506.94 m/z (yl}carbonyl) amino ]-3-(1-methyl-1H-indol-5-yl)propanoic acid (3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6- 10 Calculated (M+H) + =545.18 m/z; methyl-3-oxo-2,3-dihydropyridazin-4-yl]ammonia found (M+H) + =545.01 m/z yl}carbonyl )Amino]-3-(3,5-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5- 70 Calculated value( MH) - =538.10 m/z; methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (MH) - =537.95 m/z group}carbonyl)amino]-3- Calculated [4-(trifluoromethoxy)phenyl]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-10 (MH) - = 538.10 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =537.95m/zyl}carbonyl)amino]-3-[3-(tri Fluoromethoxy)phenyl]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5- 4 Calcd. (M+H) + =486.14m/z ;Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (M+H) + =486.04m/z base}carbonyl)amino]-3-(4-methoxy Phenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-15 Calcd. (MH) - =520.13m/z; Oxo-1,2 -Dihydropyridin-3-yl]amino}carbonyl Found (MH) - =520.03m/zyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid (3S)-3- {[({1-[2-fluoro-6-(trifluoromethyl)benzyl 100 Calcd. (MH) - =520.15m/z; base]-4-hydroxy-5-methyl-2-oxo- 1,2-Dihydrofound value (MH) - =519.97m/zpyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxyl-5-10 Calcd. (MH) - =522.10m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl ]Ammonia measured value (MH) - =521.96m/z base}carbonyl)amino]-3-[3-(trifluoromethyl)phenyl]propionic acid (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxyl-5-3 Calcd. (MH) - = 484.13 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (MH ) - =484.00m/z base}carbonyl)amino]-3-(3-methoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl )-4- 20 Calculated (M+H) + = 510.18 m/z ; 510.05m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2- Chloro-6-methylbenzyl)-4-4 Calcd. (M+H) + = 540.19 m/z; Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta, found Value (M+H) + = 540.10 m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3- [({[1-(2-Chlorobenzyl)-4-hydroxy-2-3 Calcd. (M+H) + = 540.19 m/z; Oxo-2,5,6,7-tetrahydro-1H -Cyclopentadiene and found (M+H) + =540.09 m/z [b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid ( 3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5-3 Calculated (MH) - =542.17m/z; Methyl-2-oxo-1,2- Dihydropyridin-3-yl]ammonia found (MH) - =542.00m/z base}carbonyl)amino]-3-(3,5-diethoxyphenyl)propanoic acid (3S)-3-[ ({[1-(2-Chloro-6-ethoxybenzyl)- 4 Calculated (MH) - =556.19m/z; 5-Ethyl-4-hydroxy-2-oxo-1,2- Dihydropyridine found value (MH) - =556.01m/z pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-[({[ 1-(2-Chloro-6-ethoxybenzyl)-3 Calculated (M+H) + =530.17m/z; 4-hydroxy-2-oxo-1,2-dihydropyridine-3- Base] Found (M+H) + =530.04m/z amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2- Chlorobenzyl)-4-hydroxy-5-15 Calcd. (MH) - = 538.17 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =538.03m/z base}carbonyl)amino]-3-[3-(cyclopentyloxy)phenyl]propanoic acid 3-(1,1'-biphenyl-4-yl)-3-[({ Calcd for [1-(2-chlorobenzyl 130 (MH) - = 530.15 m/z; yl)-4-hydroxy-5-methyl-2-oxo-1,2-di-hydro Found (MH) - =529.96m/zpyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 30 Calculated value( M+H) + =580.15 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + =580.02 m/z[b]pyridine- 3-yl]amino}carbonyl)amino]-3-[3-(2,2,2-trifluoroethoxy)phenyl]propanoic acid (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxyl-5-15 Calcd. (M+H) + = 554.13 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (M +H) + =554.00m/z base}carbonyl)amino]-3-[3-(2,2,2-trifluoroethoxy)phenyl]propanoic acid (3S)-3-[({[1 Calcd. for -(2-chlorobenzyl)-4-hydroxy-5-3 (M+H) + = 514.17 m/z; methyl-2-oxo-1,2-dihydropyridin-3-yl] Ammonia measured value (M+H) + =514.05m/z base}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2- Chloro-6-ethoxybenzyl)-4 Calculated (M+H) + = 558.20 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found ( M+H) + ＝558.05m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid

                                 表7Table 7

           名称                       IC50               质谱数据(m/z)Name IC 50 mass spectrum data (m/z)

                                      (nM)(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-           9           计算值(M+H)+＝500.16m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M+H)+＝500.01m/z基}羰基)氨基]-3-(4-甲氧基-3-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-           10          计算值(M+H)+＝554.21m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                     实测值(M+H)+＝554.06m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           3           计算值(M+H)+＝580.19m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M+H)+＝580.07m/z啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-           12          计算值(M+H)+＝530.17m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                       实测值(M+H)+＝530.00m/z基}羰基)氨基]-3-(3，5-二甲氧基-4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-           12          计算值(M+H)+＝554.21m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                     实测值(M+H)+＝554.05m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-丙氧基苄基)-           10          计算值(M+H)+＝528.19m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                        实测值(M+H)+＝528.06m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-异丁氧基苄             22          计算值(M+H)+＝542.21m/z；基)-4-羟基-5-甲基-2-氧代-1，2-二氢                      实测值(M+H)+＝542.06m/z吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           15          计算值(M+H)+＝540.19m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                 实测值(M+H)+＝540.07m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         3        计算值(M+H)+＝540.19m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                实测值(M+H)+＝540.04m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4        计算值(M+H)+＝584.22m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                实测值(M+H)+＝584.05m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         40       计算值(M+H)+＝592.19m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                  实测值(M+H)+＝592.04m/z基}羰基)氨基]-3-(2’，6’-二甲氧基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         30       计算值(M+H)+＝509.16m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                  实测值(M+H)+＝509.03m/z基}羰基)氨基]-3-(1-甲基-1H-吲哚-7-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         2        计算值(M+H)+＝570.20m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                实测值(M+H)+＝570.09m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-丙氧基苄基)-         5        计算值(M+H)+＝558.20m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                   实测值(M+H)+＝558.03 m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-异丁氧基苄           14       计算值(M+H)+＝572.22m/z；基)-4-羟基-5-甲基-2-氧代-1，2-二氢                 实测值(M+H)+＝572.05m/z吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-异丙氧基苄           7        计算值(M+H)+＝558.20m/z；基)-4-羟基-5-甲基-2-氧代-1，2-二氢                实测值(M+H)+＝558.03m/z吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-{[({1-[2-氯-6-(2，2，2-三氟乙       4      计算值(M+H)+＝598.16m/z；氧基)苄基]-4-羟基-5-甲基-2-氧代-                  实测值(M+H)+＝597.99m/z1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(3-乙氧基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-          15     计算值(M+H)+＝502.12m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                 实测值(M+H)+＝501.98m/z基)氨基]-3-[4-(甲硫基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          2      计算值(M+H)+＝606.20m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环               实测值(M+H)+＝606.04m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-          6      计算值(M+H)+＝498.14m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                 实测值(M+H)+＝498.02m/z基}羰基)氨基]-3-(2，3-二氢-1-苯并呋喃-5-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          3      计算值(M+H)+＝553.19m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                  实测值(M+H)+＝553.05m/z啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          2      计算值(M+H)+＝542.17m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                  实测值(M+H)+＝542.06m/z啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1-苯并呋喃-5-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          3      计算值(M+H)+＝614.22m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环               实测值(M+H)+＝614.11m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-异丙氧基苄            4      计算值(M+H)+＝558.20m/z；基)-4-羟基-5-甲基-2-氧代-1，2-二氢                实测值(M+H)+＝558.02m/z吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           3          计算值(M+H)+＝558.20m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                       实测值(M+H)+＝558.07m/z啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丁酸(3S)-3-(3-丁氧基苯基)-3-[({[1-(2-           4          计算值(M+H)+＝572.22m/z；氯-6-乙氧基苄基)-4-羟基-5-甲基-2-                      实测值(M+H)+＝572.04m/z氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[5-氯-1-(2-氯-6-乙氧基苄          3          计算值(M+H)+＝564.13m/z；基)-4-羟基-2-氧代-1，2-二氢吡啶-3-                     实测值(M+H)+＝563.99m/z基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           3          计算值(M+H)+＝544.19m/z；4-羟基-2-氧代-1，2-二氢吡啶-3-基]                      实测值(M+H)+＝544.06m/z氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           2          计算值(M+H)+＝524.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                     实测值(M+H)+＝524.03m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1-苯并呋喃-5-基)丙酸(3S)-3-[({[2-(2-氯-6-乙氧基苄基)-           7          计算值(M+H)+＝515.19m/z；5-羟基-6-甲基-3-氧代-2，3-二氢哒                       实测值(M+H)+＝515.05m/z嗪-4-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           3          计算值(M+H)+＝584.21m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                    实测值(M+H)+＝584.10 m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸(3S)-3-[({[2-(2-氯-6-乙氧基苄基)-           3          计算值(M+H)+＝545.18m/z；5-羟基-6-甲基-3-氧代-2，3-二氢哒                       实测值(M+H)+＝545.05m/z嗪-4-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[2-(2-氯-6-乙氧基苄基)-           2           计算值(M+H)+＝559.20m/z；5-羟基-6-甲基-3-氧代-2，3-二氢哒                        实测值(M+H)+＝559.04m/z嗪-4-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           6           计算值(M+H)+＝610.23m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                     实测值(M+H)+＝610.14m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环戊氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           7           计算值(M+H)+＝566.21m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                      实测值(M+H)+＝555.09m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环戊氧基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           2           计算值(M+H)+＝526.17m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                     实测值(M+H)+＝526.07m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-苯基丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           8           计算值(M+H)+＝482.15m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                      实测值(M+H)+＝482.07m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-苯基丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-           5           计算值(M+H)+＝512.16m/z；羟基-5-甲基-2-氧代-1，2-二氢吡啶-                       实测值(M+H)+＝512.03m/z3-基]氨基}羰基)氨基]-3-(2，3-二氢-1-苯并呋喃-5-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           4           计算值(M+H)+＝594.21m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                      实测值(M+H)+＝594.05m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(1，3-二乙基-2-吲哚-2，3-二氢-1H-苯并咪唑-5-基)丙酸(3S)-3-[({[1-(2-氟-6-乙氧基苄基)-           3           计算值(M+H)+＝568.15m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                 实测值(M+H)+＝568.00m/z啶-3-基]氨基}羰基)氨基]-3-[3-(三氟甲基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4      计算值(M+H)+＝584.14m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                 实测值(M+H)+＝584.01m/z啶-3-基]氨基}羰基)氨基]-3-[3-(三氟甲氧基)苯基]丙酸(3S)-3-{[({1-[2-氯-6-(2-甲氧基乙氧        6      计算值(M-H)-＝568.18m/z；基)苄基]-4-羟基-2-氧代-2，5，6，7-四             实测值(M-H)-＝568.03m/z氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[2-氯-6-(2-甲氧基乙氧        4      计算值(M-H)-＝598.19m/z；基)苄基]-4-羟基-2-氧代-2，5，6，7-四             实测值(M-H)-＝598.01m/z氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         4      计算值(M+H)+＝538.17m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并               实测值(M+H)+＝538.09m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙氧基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4      计算值(M-H)-＝556.19m/z；4-羟基-5，6-二甲基-2-氧代-1，2-二氢              实测值(M-H)-＝556.02m/z吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4      计算值(M-H)-＝526.17nm/z；4-羟基-5，6-二甲基-2-氧代-1，2-二氢              实测值(M-H)-＝526.02m/z吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4      计算值(M-H)-＝570.20m/z；5-乙基-4-羟基-6-甲基-2-氧代-1，2-                 实测值(M-H)-＝570.04m/z二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        4       计算值(M-H)-＝540.19m/z；5-乙基-4-羟基-6-甲基-2-氧代-1，2-                实测值(M-H)-＝540.05m/z二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3 S)-3-[({[1-(2-氯苄基)-4-羟基-5-       25      计算值(M+H)+＝562.09m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                实测值(M+H)+＝562.17m/z基}羰基)氨基]-3-(2’-甲氧基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        3       计算值(M-H)-＝570.20m/z；4-羟基-5，6-二甲基-2-氧代-1，2-二氢              实测值(M-H)-＝570.00m/z吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        4       计算值(M-H)-＝512.16m/z；4-羟基-5，6-二甲基-2-氧代-1，2-二氢              实测值(M-H)-＝512.01m/z吡啶-3-基]氨基}羰基)氨基]-3-苯基丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        5       计算值(M-H)-＝584.22m/z；5-乙基-4-羟基-6-甲基-2-氧代-1，2-                实测值(M-H)-＝584.03m/z二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        4       计算值(M-H)-＝526.17m/z；5-乙基-4-羟基-6-甲基-2-氧代-1，2-                实测值(M-H)-＝526.00m/z二氢吡啶-3-基]氨基}羰基)氨基]-3-苯基丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        6       计算值(M-H)-＝592.19m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                 实测值(M-H)-＝592.00m/z啶-3-基]氨基}羰基)氨基]-3-(6-乙氧基-2-萘基)丙酸(3S)-3-[({[2-(2-氯苄基)-6-乙基-5-        22      计算值(M-H)-＝483.14m/z；羟基-3-氧代-2，3-二氢哒嗪-4-基]氨                实测值(M-H)-＝483.03m/z基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        15       计算值(M-H)-＝536.20m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                     实测值(M-H)-＝535.99m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丁基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-            4         计算值(M+H)+＝509.16m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                      实测值(M+H)+＝509.05m/z基}羰基)氨基]-3-(1-甲基-1H-吲哚-6-基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-            4         计算值(M-H)-＝550.17m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                    实测值(M-H)-＝550.01m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-            15        计算值(M-H)-＝574.17m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                     实测值(M-H)-＝574.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(6-乙氧基-2-萘基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-            23        计算值(M-H)-＝526.17m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                       实测值(M-H)-＝526.04m/z啶-3-基]氨基}羰基)氨基]-3-苯基丙酸(3S)-3-[({[2-(2-氯-6-乙氧基苄基)-            22        计算值(M-H)-＝584.22m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                       实测值(M-H)-＝584.09m/z啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-            20        计算值(M-H)-＝540.19m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                       实测值(M-H)-＝540.05m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-            6         计算值(M-H)-＝570.20m/z；4-羟基-2-氧代-5-丙基-1，2-二氢吡                       实测值(M-H)-＝570.04m/z啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-            40        计算值(M-H)-＝530.15m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M-H)-＝530.02m/z基)氨基]-3-(4’-甲基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          4      计算值(M-H)-＝533.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                实测值(M-H)-＝533.00m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          3      计算值(M-H)-＝582.20m/z；5-环丙基-4-羟基-2-氧代-1，2-二氢                  实测值(M-H)-＝582.07m/z吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-          3      计算值(M-H)-＝538.17m/z；5-环丙基-4-羟基-2-氧代-1，2-二氢                  实测值(M-H)-＝538.06m/z吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-丙氧基苄基)-          6      计算值(M-H)-＝526.17m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                  实测值(M-H)-＝526.05m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-甲氧基苄基)-          3      计算值(M-H)-＝498.14m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                  实测值(M-H)-＝498.01m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸3-[({[2-(2-氯-6-乙氧基苄基)-4-羟基         13     计算值(M-H)-＝548.16m/z；-5-甲基-2-氧代-1，2-二氢吡啶-3-基]                实测值(M-H)-＝548.01m/z氨基}羰基)氨基]-3-(2-萘基)丙酸3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基         8      计算值(M-H)-＝576.12m/z；-5-甲基-2-氧代-1，2-二氢吡啶-3-基]                实测值(M-H)-＝576.00m/z氨基}羰基)氨基]-3-[4-(甲基磺酰基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          27     计算值(M-H)-＝560.16m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M-H)-＝560.04m/z基)氨基]-3-(3’-乙氧基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-           20          计算值(M-H)-＝564.19m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                     实测值(M-H)-＝564.00m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丁氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           17          计算值(M-H)-＝550.17m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                      实测值(M-H)-＝550.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丁氧基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-           3           计算值(M-H)-＝556.19m/z；4-羟基-6-甲基-2-氧代-1，2-二氢吡                        实测值(M-H)-＝556.05m/z啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-           10          计算值(M-H)-＝523.17m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝522.99m/z基)氨基]-3-(3-吡咯烷-1-基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-           22          计算值(M-H)-＝537.19m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                       实测值(M-H)-＝537.08m/z基)氨基]-3-(3-哌啶-1-基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-           22          计算值(M-H)-＝580.22m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                     实测值(M-H)-＝580.04m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(1-乙基丙氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-           20          计算值(M-H)-＝566.20m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                      实测值(M-H)-＝566.01m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(1-乙基丙氧基)苯基]丙酸(3S)-3-(4-氯-3-异丙氧基苯基)-3-             23          计算值(M-H)-＝586.15m/z；[({[1-(2-氯-6-甲基苄基)-4-羟基-2-                       实测值(M-H)-＝585.92m/z氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        38         计算值(M-H)-＝572.14m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝572.00m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-氯-3-异丙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        30         计算值(M-H)-＝530.15m/z；氧代-1，2-二氢吡啶-3-基]氨基}羰                     实测值(M-H)-＝530.02m/z基)氨基]-3-(3’-甲基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        3          计算值(M-H)-＝533.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝532.97m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-6-基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        3          计算值(M-H)-＝551.17m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                    实测值(M-H)-＝551.02m/z啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-6-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-        23         计算值(M-H)-＝560.16m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                   实测值(M-H)-＝560.01m/z基}羰基)氨基]-3-(4’-甲氧基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-        55         计算值(M+H)+＝546.18m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                   实测值(M+H)+＝546.11m/z基}羰基)氨基]-3-(2’-甲基-1，1’-联苯-4-基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        3          计算值(M-H)-＝560.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝560.00m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸(3S)-3-(4-氯-3-乙氧基苯基)-3-            25         计算值(M-H)-＝572.14m/z；[({[1-(2-氯-6-甲基苄基)-4-羟基-2-                   实测值(M-H)-＝571.94m/z氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         30         计算值(M-H)-＝558.12m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                   实测值(M-H)-＝557.77m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-氯-3-乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4          计算值(M+H)+＝582.24m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                  实测值(M+H)+＝582.10m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丁基苯基)丙酸(3S)-3-[({[1-(2-氯-5-乙氧基苄基)-         4          计算值(M+H)+＝514.17m/z；4-羟基-5-甲基-2-氧代-1，2-二氢吡                     实测值(M+H)+＝514.08m/z啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-        134         计算值(M+H)+＝534.11m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                    实测值(M+H)+＝534.07m/z基)氨基]-3-[4-(甲基磺酰基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-        225         计算值(M+H)+＝594.09m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                   实测值(M+H)+＝593.98m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(2，4-二氯-3-乙氧基苯基)丙酸(3S)-3-{[({1-[2-氯-5-(哌啶-1-基磺        27          计算值(M-H)-＝615.17m/z；酰基)苄基]-4-羟基-5-甲基-2-氧代-                     实测值(M-H)-＝615.04m/z1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[2-氯-5-(吡咯烷-1-基        15          计算值(M-H)-＝601.15m/z；磺酰基)苄基]-4-羟基-5-甲基-2-氧                      实测值(M-H)-＝601.03m/z代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-        2           计算值(M+H)+＝582.20m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                  实测值(M+H)+＝582.10m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙氧基)苯基]丙酸(3S)-3-{[({1-[2-氯-6-(环戊基甲氧          20        计算值(M-H)-＝566.20m/z；基)苄基]-4-羟基-5-甲基-2-氧代-                      实测值(M-H)-＝566.09m/z1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[2-(苄氧基)-6-氯苄           10        计算值(M-H)-＝574.17m/z；基]-4-羟基-5-甲基-2-氧代-1，2-二氢                  实测值(M-H)-＝574.01m/z吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         3         计算值(M+H)+＝604.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M+H)+＝604.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-氯-4，5-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-         500       计算值(M+H)+＝652.14m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                 实测值(M+H)+＝651.98m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(2，4-二氯-3，5-二乙氧基苯基)丙酸(3R)-3-[({[1-(2-氯苄基)-4-羟基-2-         450       计算值(M+H)+＝638.12m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M+H)+＝637.97m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(2，4-二氯-3，5-二乙氧基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         9         计算值(M+H)+＝552.19m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M+H)+＝552.10m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙基甲氧基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-         4         计算值(M+H)+＝596.21m/z；4-羟基-2-氧代-2，5，6，7-四氢-1H-环                 实测值(M+H)+＝596.11m/z戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙基甲氧基)苯基]丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-         10        计算值(M+H)+＝566.20m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                       实测值(M+H)+＝566.12m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙基甲氧基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-            13           计算值(M-H)-＝544.16m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                         实测值(M-H)-＝544.00m/z基}羰基)氨基]-3-(2，4-二乙氧基嘧啶-5-基)丙酸(3S)-3-[({[1-(2，3-二氯-6-乙氧基苄           5            计算值(M-H)-＝572.13m/z；基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-                     实测值(M-H)-＝571.97m/z环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[3-(环丙基甲氧基)苯基]-3-             7            计算值(M-H)-＝628.16m/z；[({[1-(2，3-二氯-6-乙氧基苄基)-4-羟                       实测值(M-H)-＝627.98m/z基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2，3-二氯-6-乙氧基苄           3            计算值(M-H)-＝602.15m/z；基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-                     实测值(M-H)-＝601.99m/z环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸(3S)-3-[({[1-(2，3-二氯-6-乙氧基苄           5            计算值(M-H)-＝616.16m/z；基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-                     实测值(M-H)-＝616.01m/z环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸(3S)-3-({[[1-(2-氯苄基)-4-甲氧基-            2000         计算值(M-H)-＝482.14m/z；2-氧代-1，2-二氢吡啶-3-基](甲基)氨                        实测值(M-H)-＝482.07m/z基]羰基}氨基)-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-            15           计算值(M-H)-＝560.16m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                         实测值(M-H)-＝559.98m/z基}羰基)氨基]-3-(2’-甲氧基-1，1’-联苯-3-基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-            20           计算值(M-H)-＝458.11m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M-H)-＝457.99m/z基)氨基]-3-(5-甲基-2-呋喃基)丙酸3-[({[1-(2-氯-6-甲基苄基)-4-羟基-          43       计算值(M+H)+＝548.13m/z；5-甲基-2-氧代-1，2-二氢吡啶-3-基]                   实测值(M+H)+-＝548.07m/z氨基}羰基)氨基]-3-[4-(甲基磺酰基)苯基]丙酸3-[({[1-(2-氯苄基)-4-羟基-2-氧代-          5        计算值(M-H)-＝470.11m/z；2，5，6，7-四氢-1H-环戊二烯并[b]吡                  实测值(M-H)-＝469.96m/z啶-3-基]氨基}羰基)氨基]-3-(2-呋喃基)丙酸3-[({[1-(2-氯苄基)-4-羟基-5-甲基-          4        计算值(M-H)-＝444.10m/z；2-氧代-1，2-二氢吡啶-3-基]氨基}羰                   实测值(M-H)-＝443.91m/z基)氨基]-3-(2-呋喃基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          18       计算值(M-H)-＝548.12m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝548.00m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[4-(三氟甲基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          5        计算值(M-H)-＝494.15m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝494.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          10       计算值(M-H)-＝548.12m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝547.99m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(三氟甲基)苯基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-          9        计算值(M-H)-＝508.16m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                  实测值(M-H)-＝508.02m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲基苯基)丙酸(3S)-3-[3，5-二(三氟甲基)苯基]-3-          130      计算值(M-H)-＝615.11m/z；[({[1-(2-氯苄基)-4-羟基-2-氧代-                     实测值(M-H)-＝615.99m/z2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-{[({1-[2-氯-5-(三氟甲基)苄         6          计算值(M-H)-＝536.12m/z；基]-4-羟基-5-甲基-2-氧代-1，2-二氢                   实测值(M-H)-＝535.99m/z吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯-5-氟苄基)-4-羟         5          计算值(M-H)-＝486.12m/z；基-5-甲基-2-氧代-1，2-二氢吡啶-3-                    实测值(M-H)-＝485.97m/z基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-         2          计算值(M-H)-＝525.19m/z；甲基-2-氧代-1，2-二氢吡啶-3-基]氨                    实测值(M-H)-＝525.00m/z基}羰基)氨基]-3-[3-(二乙基氨基)苯基]丙酸3-(1，1’-联苯-4-基)-3-[({[1-(2-氯苄      30         计算值(M-H)-＝556.16m/z；基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-                实测值(M-H)-＝555.99m/z环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]丙酸(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-         8          计算值(M+H)+＝522.17m/z；氧代-2，5，6，7-四氢-1H-环戊二烯并                   实测值(M+H)+＝522.03m/z[b]吡啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1H-茚-5-基)丙酸(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-         10         计算值(M+H)+＝536.19m/z；羟基-2-氧代-2，5，6，7-四氢-1H-环戊                  实测值(M+H)+＝536.08m/z二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1H-茚-5-基)丙酸N-{1-[(2-氯苯基)甲基]-4-羟基-5-甲         6000       计算值(M+H)+＝494.17m/z；基-2-氧代-1，2-二氢-3-吡啶基}-N’-                   实测值(M+H)+＝494.01m/z[(1S)-1-(4-甲基苯基)-2-(1H-1，2，3，4-四唑-5-基)乙基]脲(3S)-3-[1，1’-联苯基]-3-基-3-{[({1-      17         计算值(M-H)-＝556.16m/z；[(2-氯苯基)甲基]-4-羟基-2-氧代-                      实测值(M-H)-＝556.01m/z2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          13          计算值(M-H)-＝564.11m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                     实测值(M-H)-＝564.01m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{4-[(三氟甲基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          13          计算值(M-H)-＝546.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                     实测值(M-H)-＝545.97m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{4-[(二氟甲基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          10          计算值(M-H)-＝564.11m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                     实测值(M-H)-＝563.98m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(三氟甲基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          5           计算值(M-H)-＝546.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                     实测值(M-H)-＝546.01m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(二氟甲基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          4           计算值(M-H)-＝596.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                     实测值(M-H)-＝596.02m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(1，1，2，2-四氟乙基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          11          计算值(M-H)-＝538.17m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                     实测值(M-H)-＝538.04m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3，5-二甲基-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          5           计算值(M+H)+＝549.19m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二             实测值(M+H)+＝549.02m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1-乙基-1H-吲哚-5-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       7      计算值(M-H)-＝516.11m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二             实测值(M-H)-＝516.01m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3，5-二氟苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       3      计算值(M-H)-＝528.13m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二             实测值(M-H)-＝528.00m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3-氟-4-(甲氧基)苯基]丙酸(3S)-3-{[{1-[(2-氯苯基)甲基]-4-羟        17     计算值(M-H)-＝522.18m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二             实测值(M-H)-＝522.04m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-丙基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲        20     计算值(M-H)-＝536.20m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-           实测值(M-H)-＝536.06m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-丙基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       267    计算值(M-H)-＝468.13m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶               实测值(M-H)-＝468.00m/z基}氨基)羰基]氨基}-3-(2-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       25     计算值(M+H)+＝522.1gm/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二             实测值(M+H)+＝522.04m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-环丙基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       22     计算值(M-H)-＝505.13m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶               实测值(M-H)-＝504.98m/z基}氨基)羰基]氨基}-3-(3-喹啉基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       22     计算值(M-H)-＝531.14m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二              实测值(M-H)-＝530.99m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3-喹啉基)丙酸3-({[(1-{[2-氯-6-(乙氧基)苯基]甲         8       计算值(M-H)-＝488.12m/z；基}-4-羟基-5-甲基-2-氧代-1，2-二氢               实测值(M-H)-＝487.98m/z-3-吡啶基)氨基]羰基}氨基)-3-(2-呋喃基)丙酸(3S)-3-[2，4-二(乙氧基)-5-嘧啶基]-       15      计算值(M-H)-＝570.18m/z；3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-               实测值(M-H)-＝570.14m/z氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲        19      计算值(M+H)+＝536.20m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-            实测值(M+H)+＝536.07m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-环丙基苯基)丙酸(3R)-3-{[({1-[(2-氯苯基)甲基]-4-羟       15      计算值(M-H)-＝418.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二              实测值(M-H)-＝418.00m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}丁酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       8       计算值(M-H)-＝508.16m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二              实测值(M-H)-＝508.06m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-乙基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       17      计算值(M-H)-＝522.17m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二              实测值(M-H)-＝522.06m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[4-(1-甲基乙基)苯基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       30      计算值(M-H)-＝482.14m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                实测值(M-H)-＝482.00m/z基}氨基)羰基]氨基}-3-(4-乙基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       175     计算值(M-H)-＝496.16m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                   实测值(M-H)-＝496.01m/z基}氨基)羰基]氨基}-3-[4-(1-甲基乙基)苯基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         6        计算值(M-H)-＝510.14m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                   实测值(M-H)-＝510.00m/z基}氨基)羰基]氨基}-3-[4-(环丙氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         12       计算值(M-H)-＝496.16m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                   实测值(M-H)-＝495.99m/z基}氨基)羰基]氨基}-3-(4-丙基苯基)丙酸3-{[({1-[(2-氯苯基)甲基]-4-羟基-5-         35       计算值(M-H)-＝494.15m/z；甲基-2-氧代-1，2-二氢-3-吡啶基}氨                   实测值(M-H)-＝494.01m/z基)羰基]氨基}-3-(4-环丙基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         18       计算值(M-H)-＝494.15m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                   实测值(M-H)-＝494.02m/z基}氨基)羰基]氨基}-3-(2，3-二氢-1H-茚-5-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         13       计算值(M-H)-＝597.19m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                 实测值(M-H)-＝597.01m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(9-乙基-9H-咔唑-3-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         23       计算值(M-H)-＝571.17m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                   实测值(M-H)-＝570.99m/z基}氨基)羰基]氨基}-3-(9-乙基-9H-咔唑-3-基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲          3        计算值(M-H)-＝547.17m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-               实测值(M-H)-＝547.04m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1-甲基-1H-吲哚-5-基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲             3           计算值(M-H)-＝560.14m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                     实测值(M-H)-＝560.03m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(二氟甲基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            25          计算值(M-H)-＝574.17m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                         实测值(M-H)-＝574.00m/z基}氨基)羰基]氨基}-3-[2-(乙氧基)[1，1’-联苯基]-4-基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            20          计算值(M-H)-＝600.19m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                       实测值(M-H)-＝600.01m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[2-(乙氧基)[1，1’-联苯基]-4-基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            20          计算值(M-H)-＝544.16m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                         实测值(M-H)-＝544.04m/z基}氨基)羰基]氨基}-3-(2’-甲基[1，1’-联苯基]-3-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            18          计算值(M-H)-＝544.16m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                         实测值(M-H)-＝544.00m/z基}氨基)羰基]氨基}-3-(3’-甲基[1，1’-联苯基]-3-基)丙酸(3S)-3-({[(1-{[2-氯-6-四氢-1(2H)-             90          计算值(M-H)-＝551.21m/z；吡啶基苯基]甲基}-4-羟基-5-甲基-                           实测值(M-H)-＝551.06m/z2-氧代-1，2-二氢-3-吡啶基)氨基]羰基}氨基)-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            23          计算值(M-H)-＝544.16m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                         实测值(M-H)-＝543.99m/z基}氨基)羰基]氨基}-3-(4’-甲基[1，1’-联苯基]-3-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟           3            计算值(M-H)-＝551.21m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                       实测值(M-H)-＝551.05m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3-(二乙基氨基)苯基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       20        计算值(M-H)-＝504.11m/z；基-5-甲基-2-氧代-1，3-二氢-3-吡啶                  实测值(M-H)-＝503.96m/z基}氨基)羰基]氨基}-3-[3-(二氟甲基)苯基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       16        计算值(M-H)-＝498.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                实测值(M-H)-＝498.02m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3-氟苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟       9         计算值(M-H)-＝498.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                实测值(M-H)-＝498.01m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-氟苯基)丙酸N-{1-[(2-氯苯基)甲基]-4-羟基-5-甲        ＞10000   计算值(M-H)-＝464.12m/z；基-2-氧代-1，2-二氢-3-吡啶基}-N’-                 实测值(M-H)-＝464.01m/z[(R)-苯基(1H-1，2，3，4-四唑-5-基)甲基]脲(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲        4         计算值(M-H)-＝521.16m/z；基]-4-羟基-5-甲基-2-氧代-1，2-二氢                 实测值(M-H)-＝521.00m/z-3-吡啶基}氨基)羰基]氨基}-3-(1-甲基-1H-吲哚-5-基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲        10        计算值(M-H)-＝565.14m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-              实测值(M-H)-＝565.04m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3-(二乙基氨基)苯基]丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲        4         计算值(M-H)-＝508.16m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-              实测值(M-H)-＝508.03m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲        17        计算值(M-H)-＝494.15m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-              实测值(M-H)-＝494.09m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-苯基丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         8       计算值(M-H)-＝496.13m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                实测值(M-H)-＝495.99m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3-羟基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         9       计算值(M-H)-＝470.11m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                  实测值(M-H)-＝469.98m/z基}氨基)羰基]氨基}-3-(3-羟基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         50      计算值(M-H)-＝558.18m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                  实测值(M-H)-＝558.00m/z基}氨基)羰基]氨基}-3-(3’，5’-二甲基[1，1’-联苯基]-3-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         15      计算值(M-H)-＝455.12m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                  实测值(M-H)-＝454.00m/z基}氨基)羰基]氨基}-3-苯基丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         3       计算值(M-H)-＝573.12m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                实测值(M-H)-＝572.98m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(甲基磺酰基)氨基]苯基}丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲          3       计算值(M-H)-＝587.14m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-              实测值(M-H)-＝586.98m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(甲基磺酰基)氨基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟         4       计算值(M-H)-＝530.13m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                实测值(M-H)-＝530.03m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3-(二氟甲基)苯基]丙酸(2S，3S)-3-{[({1-[(2-氯苯基)甲基]-4-          1500          计算值(M-H)-＝482.15m/z；羟基-5-甲基-2-氧代-1，2-二氢-3-吡                           实测值(M-H)-＝481.99m/z啶基}氨基)羰基]氨基}-2-甲基-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲             15            计算值(M-H)-＝522.18m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                       实测值(M-H)-＝522.04m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(4-乙基苯基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            3             计算值(M-H)-＝550.17m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                         实测值(M-H)-＝550.05m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(2，2-二-甲基-2，3-二氢-1-苯并呋喃-5-基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲             3             计算值(M-H)-＝542.15m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                       实测值(M-H)-＝542.00m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3-氟-4-(甲氧基)苯基]丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲             11            计算值(M-H)-＝578.13m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                       实测值(M-H)-＝578.02m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(三氟甲基)氧基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟            1.6           计算值(M-H)-＝587.14m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                         实测值(M-H)-＝586.99m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[甲基(甲基磺酰基)氨基]苯基}丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲             1.3           计算值(M-H)-＝601.15m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                       实测值(M-H)-＝601.00m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[甲基(甲基磺酰基)氨基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          1         计算值(M-H)-＝601.15m/z；基-2-氧代-2，5，6，7-四氢-1H-环戊二                   实测值(M-H)-＝601.00m/z烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[乙基(甲基磺酰基)氨基]苯基}丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲           1         计算值(M-H)-＝615.17m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                 实测值(M-H)-＝615.04m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[乙基(甲基磺酰基)氨基]苯基}丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          25        计算值(M-H)-＝548.14m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                     实测值(M-H)-＝547.96m/z基}氨基)羰基]氨基}-3-(2’-氟[1，1’-联苯基]-3-基)丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          157       计算值(M-H)-＝598.14m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                     实测值(M-H)-＝597.97m/z基}氨基)羰基]氨基}-3-[2’-(三氟甲基)[1，1’-联苯基]-3-基]丙酸(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟          10        计算值(M-H)-＝472.11m/z；基-5-甲基-2-氧代-1，2-二氢-3-吡啶                     实测值(M-H)-＝471.98m/z基}氨基)羰基]氨基}-3-(2-氟苯基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲           2         计算值(M-H)-＝533.16m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                 实测值(M-H)-＝533.01m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1H-吲哚-5-基)丙酸(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲           11        计算值(M-H)-＝530.13m/z；基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-                 实测值(M-H)-＝530.00m/z环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(3，5-二氟苯基)丙酸(nM) Calcd for (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-9 (M+H) + = 500.16 m/z; methyl-2-oxo Substituent-1,2-dihydropyridin-3-yl]ammonia Found (M+H) + =500.01m/zyl}carbonyl)amino]-3-(4-methoxy-3-methylphenyl )propionic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 10 Calcd. (M+H) + =554.21m/z; Hydroxy-2-Oxygen Dieno-2,5,6,7-tetrahydro-1H-cyclopentyl Found (M+H) + = 554.06m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3 -(3-isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-3 Calcd. (M+H) + = 580.19 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (M+H) + =580.07 m/zpyridin-3-yl]amino}carbonyl)amino] -3-(6-methoxy-2-naphthyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5- 12 Calculated (M+H ) + =530.17m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (M+H) + =530.00m/z group}carbonyl)amino]-3 -(3,5-dimethoxy-4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 12 Calculated (M+H) + = 554.21 m/z; Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene Found (M+H) + = 554.05 m/z dieno [b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propionic acid (3S)-3-[({[1-(2-chloro-6-propoxy 4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (M+H) + = 528.06m/zpyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-isobutyl Oxybenzyl 22 Calculated for (M+H) + = 542.21 m/z; yl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydro Found (M+H) + = 542.06m/zpyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4 Calcd. for -Hydroxy-2-15 (M+H) + = 540.19 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + = 540.07 m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro- 6-Ethoxybenzyl)-3 Calcd. (M+H) + = 540.19 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring found ( M+H) + =540.04m/z pentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[( {[1-(2-Chloro-6-ethoxybenzyl)-4 Calcd. (M+H) + = 584.22 m/z; 4-Hydroxy-2-oxo-2,5,6,7- Tetrahydro-1H-ring Found (M+H) + = 584.05 m/z pentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl ) propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5- 40 Calcd. (M+H) + =592.19m/z; Methyl-2-oxo Substituent-1,2-dihydropyridin-3-yl]ammonia Found (M+H) + =592.04m/zyl}carbonyl)amino]-3-(2',6'-dimethoxy-1 , 1'-biphenyl-4-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-30 Calcd. (M+H) + = 509.16 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (M+H) + =509.03m/zyl}carbonyl)amino]-3-(1- Methyl-1H-indol-7-yl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-2 Calculated (M+H) + = 570.20 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring Found (M+H) + = 570.09 m/z pentadieno[b]pyridine- 3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-propoxybenzyl)- 5 Calculated (M+H) + = 558.20 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine Found (M+H) + = 558.03 m/z pyridine -3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-isobutoxybenzyl 14 Calculated for (M+H) + = 572.22 m/z; yl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydro found (M+H) + = 572.05 m/z Pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-isopropoxybenzyl 7 Calculated (M+H) + = 558.20 m/z; yl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydro Found (M+H) + = 558.03 m/z Z pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-{[({1-[2-chloro-6-(2,2 , calcd for 2-trifluoroethane 4 (M+H) + = 598.16 m/z; oxy)benzyl]-4-hydroxy-5-methyl-2-oxo- found (M+H) + =597.99m/z1,2-Dihydropyridin-3-yl}amino)carbonyl]amino}-3-(3-ethoxyphenyl)propionic acid 3-[({[1-(2-chlorobenzyl )-4-Hydroxy-5-methyl-15 Calculated (M+H) + = 502.12 m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl found (M +H) + =501.98m/zyl)amino]-3-[4-(methylthio)phenyl]propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxy (M+H) + = 606.20 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring Found (M+H) + =606.04m/z pentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propionic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxyl-5-6 Calcd. (M+H) + =498.14m/z; Methyl-2-oxo-1,2-dihydropyridine-3 -Ammonia found value (M+H) + = 498.02m/zyl}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid (3S)- 3-[({[1-(2-Chloro-6-ethoxybenzyl)-3 Calcd. (M+H) + =553.19m/z; 4-Hydroxy-5-methyl-2-oxo -1,2-Dihydropyridine Found (M+H) + =553.05m/zpyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl ) propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-2 Calcd. (M+H) + =542.17m/z; 4-hydroxy-5- Methyl-2-oxo-1,2-dihydropyridine found (M+H) + =542.06 m/z pyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro Calcd for -1-benzofuran-5-yl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-3 (M+H) + = 614.22 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring found (M+H) + = 614.11 m/z pentadieno[b]pyridine-3 -yl]amino}carbonyl)amino]-3-(3,5-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-isopropoxybenzyl 4 Calculated (M+H) + = 558.20 m/z; yl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydro Found (M+H) + = 558.02 m/z zpyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl base)- 3 Calculated (M+H) + = 558.20 m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (M+H) + = 558.07 m /z pyridine-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)butanoic acid (3S)-3-(3-butoxyphenyl)-3-[({[ 1-(2- 4 Calcd. (M+H) + = 572.22 m/z; Chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2- found (M+H) + =572.04m/zoxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[5-chloro-1-(2-chloro-6 Calcd. for -ethoxybenzyl3 (M+H) + = 564.13 m/z; yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3- found (M+H) + =563.99m/z base]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl 4-Hydroxy-2-oxo -1,2-dihydropyridin-3-yl] found (M+H) + = 544.06 m /zamino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-2 Calculated (M+H) + = 524.16 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + = 524.03 m/z [b ]pyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid (3S)-3-[({[2-(2 -Chloro-6-ethoxybenzyl)-7 Calculated (M+H) + = 515.19 m/z; found for 5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridine (M+H) + =515.05m/zazin-4-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid (3S)-3-[({[1-(2 -Chloro-6-ethoxybenzyl)-3 Calculated (M+H) + = 584.21 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring Found (M+H) + = 584.10 m/z pentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid (3S)- 3-[({[2-(2-Chloro-6-ethoxybenzyl)-3 Calcd. (M+H) + = 545.18 m/z; 5-hydroxy-6-methyl-3-oxo -2,3-Dihydropyridine found (M+H) + =545.05m/zazin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S) -3-[({[2-(2-Chloro-6-ethoxybenzyl)-2 Calculated (M+H) + = 559.20 m/z; 5-hydroxy-6-methyl-3-oxo Substituent-2,3-dihydropyridine found value (M+H) + =559.04m/zazin-4-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid ( 3S)-3-[({[1-(2-Chloro-6-ethoxybenzyl)-6 Calcd. (M+H) + = 610.23 m/z; 4-Hydroxy-2-oxo-2 , 5,6,7-Tetrahydro-1H-ring Found (M+H) + = 610.14 m/z pentadiene[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3 -(Cyclopentyloxy)phenyl]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-7 Calcd. (M+H) + = 566.21m /z; oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + =555.09 m/z [b]pyridin-3-yl]amino}carbonyl) Amino]-3-[3-(cyclopentyloxy)phenyl]propanoic acid (3S)-3-[({[1-(2-Chloro-6-ethoxybenzyl)-2 Calculated (M +H) + = 526.17 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring Found (M+H) + = 526.07 m/z pentadiene [b]pyridin-3-yl]amino}carbonyl)amino]-3-phenylpropionic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 8 Calculation Value (M+H) + = 482.15 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + = 482.07 m/z [b] Pyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 5 Calculated ( M+H) + = 512.16 m/z; Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine - found (M+H) + = 512.03 m/z 3-yl]amino}carbonyl )amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl- 2- 4 Calculated (M+H) + = 594.21 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + = 594.05 m/z z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-indole-2,3-dihydro-1H-benzimidazol-5-yl) Propionic acid (3S)-3-[({[1-(2-fluoro-6-ethoxybenzyl)-3 Calcd. (M+H) + = 568.15 m/z; 4-hydroxy-5-methan Base-2-oxo-1,2-dihydropyridine found (M+H) + =568.00m/z pyridin-3-yl]amino}carbonyl)amino]-3-[3-(trifluoromethyl )phenyl]propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4 Calcd. (M+H) + = 584.14 m/z; 4-hydroxyl -5-methyl-2-oxo-1,2-dihydropyridine found (M+H) + =584.01m/z pyridin-3-yl]amino}carbonyl)amino]-3-[3-( Trifluoromethoxy)phenyl]propanoic acid (3S)-3-{[({1-[2-chloro-6-(2-methoxyethoxy 6 Calculated (MH) - =568.18m/z ; Base) benzyl] -4-hydroxy-2-oxo-2,5,6,7-tetra found (MH) - = 568.03 m/z hydrogen -1H- cyclopenta [b] pyridine - 3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[2-chloro-6-(2-methoxyethoxy 4 Calculated (MH) - = 598.19 m/z; yl) benzyl] -4-hydroxy-2-oxo-2,5,6,7-tetra found (MH) - = 598.01 m/z hydrogen - 1H-Cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxy-2-4 Calcd. (M+H) + = 538.17 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + =538.09m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropoxy)phenyl]propanoic acid (3S)-3-[ ({[1-(2-Chloro-6-ethoxybenzyl)-4 Calculated (MH) - =556.19m/z; 4-hydroxy-5,6-dimethyl-2-oxo-1 , 2-dihydrofound value (MH) - =556.02m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid (3S)-3-[( {[1-(2-Chloro-6-ethoxybenzyl)-4 Calculated (MH) - =526.17nm/z; 4-hydroxy-5,6-dimethyl-2-oxo-1, 2-dihydrofound (MH) - = 526.02m/z pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid (3S) -3-[({[ Calcd. for 1-(2-chloro-6-ethoxybenzyl)-4 (MH) - = 570.20 m/z; 5-ethyl-4-hydroxy-6-methyl-2-oxo-1, 2- found (MH) - = 570.04m/z [1-(2-Chloro-6-ethoxybenzyl)-4 Calculated (MH) - =540.19m/z; 5-ethyl-4-hydroxy-6-methyl-2-oxo-1 , 2- Found (MH) - =540.05m/z dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxyl-5-25 Calcd. (M+H) + =562.09m/z; Methyl-2-oxo-1,2-dihydropyridine-3 -yl]ammonia found (M+H) + =562.17m/zyl}carbonyl)amino]-3-(2'-methoxy-1,1'-biphenyl-4-yl)propanoic acid (3S )-3-[({[1-(2-Chloro-6-ethoxybenzyl)-3 Calculated (MH) - =570.20m/z; 4-Hydroxy-5,6-dimethyl-2 -Oxo-1,2-dihydrofound (MH) - =570.00m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid (3S )-3-[({[1-(2-Chloro-6-ethoxybenzyl)-4 Calculated (MH) - =512.16m/z; 4-hydroxy-5,6-dimethyl-2 -Oxo-1,2-dihydrofound value (MH) - =512.01m/zpyridin-3-yl]amino}carbonyl)amino]-3-phenylpropionic acid (3S)-3-[({[ 1-(2-Chloro-6-ethoxybenzyl)-5 Calculated (MH) - = 584.22 m/z; 5-ethyl-4-hydroxy-6-methyl-2-oxo-1, 2- Found (MH) - = 584.03m/z {[1-(2-Chloro-6-ethoxybenzyl)-4 Calculated (MH) - =526.17m/z; 5-Ethyl-4-hydroxy-6-methyl-2-oxo- 1,2- Found (MH) - =526.00m/z dihydropyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoic acid (3S)-3-[({[1-(2 -Chloro-6-ethoxybenzyl)-6 Calculated (MH) - =592.19m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH ) - =592.00m/zpyridin-3-yl]amino}carbonyl)amino]-3-(6-ethoxy-2-naphthyl)propionic acid (3S)-3-[({[2-(2 -Chlorobenzyl)-6-ethyl-5-22 Calculated (MH) - = 483.14 m/z; Hydroxy-3-oxo-2,3-dihydropyridazin-4-yl]ammonia found ( MH) - =483.03m/zyl}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl -2- 15 Calculated (MH) - = 536.20m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (MH) - = 535.99m/z[b ]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isobutylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy -5- 4 Calculated (M+H) + = 509.16 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (M+H) + = 509.05 m /z base}carbonyl)amino]-3-(1-methyl-1H-indol-6-yl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl Base)-4- 4 Calculated (MH) - = 550.17m/z; z Dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropoxy)phenyl]propanoic acid (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxyl-2-15 Calculated (MH) - =574.17m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (MH ) - =574.02m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(6-ethoxy-2-naphthyl)propanoic acid (3S)-3-[({[1 Calculated for -(2-chloro-6-ethoxybenzyl)-23 (MH) - = 526.17 m/z; found for 4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridine Value(MH) - =526.04m/zpyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoic acid (3S)-3-[({[2-(2-chloro-6-ethoxy 4-hydroxy-2-oxo -5-propyl-1,2-dihydropyridine found (MH)- = 584.09m/z Pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl Base)- 20 Calculated (MH) - =540.19m/z; 4-Hydroxy-2-oxo-5-propyl-1,2-dihydropyridine Found (MH) - =540.05m/z 3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-6 Calculated (MH) - = 570.20 m/z; 4-Hydroxy-2-oxo-5-propyl-1,2-dihydropyridine found (MH) - = 570.04 m/z pyridin-3-yl] Amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 40 Calculated ( MH) - =530.15m/z; Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =530.02m/zyl)amino]-3-(4'-methyl Base-1,1'-biphenyl-4-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-4 Calculated value (MH) - = 533.16 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (MH) - =533.00 m/z [b]pyridin-3-yl]amino}carbonyl) Amino]-3-(1-methyl-1H-indol-5-yl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-3 calculation Value (MH) - = 582.20 m/z; 5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydro Found (MH) - = 582.07 m/z pyridin-3-yl]amino }carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-3 calculated value( MH) - = 538.17 m/z; 5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydro found (MH) - = 538.06 m/z pyridin-3-yl]amino}carbonyl )amino]-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-5-propoxybenzyl)-6 Calcd value (MH) - = 526.17m/z; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH) - =526.05m/zpyridin-3-yl]amino}carbonyl)amino]- 3-(4-Methylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-3 Calculated (MH) - = 498.14m/z ; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH) - =498.01m/z pyridin-3-yl]amino}carbonyl)amino]-3-(4 -Methylphenyl)propionic acid 3-[({[2-(2-chloro-6-ethoxybenzyl)-4-hydroxy13 Calcd. (MH) - = 548.16 m/z; -5-Me Base-2-oxo-1,2-dihydropyridin-3-yl] found (MH) - = 548.01m/z amino}carbonyl)amino]-3-(2-naphthyl)propanoic acid 3-[ ({[1-(2-Chloro-6-ethoxybenzyl)-4-hydroxyl8 Calculated (MH) - = 576.12m/z; -5-methyl-2-oxo-1,2- Dihydropyridin-3-yl] Found (MH) - = 576.00 m/z amino}carbonyl)amino]-3-[4-(methylsulfonyl)phenyl]propanoic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxy-2-27 Calcd. (MH) - = 560.16 m/z; Oxo-1,2-dihydropyridin-3-yl]amino}Carbonyl found Value (MH) - =560.04m/zyl)amino]-3-(3'-ethoxy-1,1'-biphenyl-4-yl)propanoic acid (3S)-3-[({[1 -(2-Chloro-6-methylbenzyl)-4- 20 Calculated (MH) - =564.19m/z; Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring Penta Found (MH) - = 564.00 m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclobutoxy)phenyl]propanoic acid (3S) -3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-17 Calcd. (MH) - =550.17m/z; Oxo-2,5,6,7-tetrahydro- 1H-Cyclopentadiene and found (MH) - =550.02m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclobutoxy)phenyl]propanoic acid (3S)-3-[({[1-(2-Chloro-6-ethoxybenzyl)-3 Calculated (MH) - =556.19m/z; 4-Hydroxy-6-methyl-2- Oxo-1,2-dihydropyridine found (MH) - =556.05m/zpyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid 3- [({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-10 Calcd. (MH) - =523.17m/z; 2-oxo-1,2-dihydropyridine-3 -yl]amino}carbonyl found (MH) - =522.99m/zyl)amino]-3-(3-pyrrolidin-1-ylphenyl)propanoic acid 3-[({[1-(2-chloro Benzyl)-4-hydroxyl-5-methyl-22 Calculated (MH) - =537.19m/z; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl found (MH ) - =537.08m/zyl)amino]-3-(3-piperidin-1-ylphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl Base)-4- 22 Calculated (MH) - = 580.22m/z; Dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(1-ethylpropoxy)phenyl]propanoic acid (3S)-3-[({[1 -(2-Chlorobenzyl)-4-hydroxyl-2-20 Calculated (MH) - = 566.20 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found Value(MH) - =566.01m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(1-ethylpropoxy)phenyl]propanoic acid (3S)-3 -(4-Chloro-3-isopropoxyphenyl)-3- 23 Calculated (MH) - =586.15m/z; [({[1-(2-Chloro-6-methylbenzyl)- 4-Hydroxy-2- found (MH) - = 585.92 m/z oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl )Amino]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-38 Calcd. (MH) - =572.14m/z; Oxo-2,5 , 6,7-Tetrahydro-1H-cyclopentadiene and found (MH) - =572.00m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3 -Isopropoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-30 Calcd. (MH) - =530.15m/z; Oxygen Substituent-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =530.02m/zyl)amino]-3-(3'-methyl-1,1'-biphenyl- 4-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-3 Calcd. (MH) - =533.16m/z; Oxo-2, 5,6,7-Tetrahydro-1H-cyclopentadiene and found (MH) - =532.97m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl -1H-indol-6-yl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-3 Calculated (MH) - =551.17m/z ; 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridine found (MH) - =551.02m/z pyridin-3-yl]amino}carbonyl)amino]-3-(1 -Methyl-1H-indol-6-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5-23 Calcd. (MH) - = 560.16 m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =560.01m/zyl}carbonyl)amino]-3-(4'-methyl Oxy-1,1'-biphenyl-4-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-55 Calculated (M+H ) + =546.18m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia found (M+H) + =546.11m/z group}carbonyl)amino]-3 -(2'-methyl-1,1'-biphenyl-4-yl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 3 calculation Value (MH) - =560.16m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and Found (MH) - =560.00m/z[b]pyridine-3- Base]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid (3S)-3-(4-chloro-3-ethoxyphenyl)-3- 25 Calculated (MH) - = 572.14m/z; [({[1-(2-chloro-6-methylbenzyl) -4-hydroxyl-2- found (MH) - = 571.94m/z oxo-2 , 5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[1-(2-chloro Benzyl)-4-hydroxyl-2- 30 Calculated (MH) - = 558.12 m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (MH) - =557.77m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-ethoxyphenyl)propionic acid (3S)-3-[({[1- (2-Chloro-6-ethoxybenzyl)-4 Calcd. (M+H) + = 582.24 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Ring found (M+H) + =582.10 m/z pentadieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isobutylphenyl)propanoic acid (3S )-3-[({[1-(2-Chloro-5-ethoxybenzyl)-4 Calculated (M+H) + =514.17m/z; 4-Hydroxy-5-methyl-2- Oxo-1,2-dihydropyridine found (M+H) + =514.08m/zpyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid 3- [({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-134 Calcd. (M+H) + = 534.11 m/z; 2-oxo-1,2-dihydropyridine -3-yl]amino}carbonyl (M+H) + =534.07m/zyl)amino]-3-[4-(methylsulfonyl)phenyl]propanoic acid (3S)-3-[( {[1-(2-Chlorobenzyl)-4-hydroxyl-2-225 Calcd. (M+H) + =594.09m/z; Oxo-2,5,6,7-tetrahydro-1H-ring Pentadiene and found (M+H) + =593.98 m/z [b]pyridin-3-yl]amino}carbonyl)amino]-3-(2,4-dichloro-3-ethoxyphenyl )propanoic acid (3S)-3-{[({1-[2-Chloro-5-(piperidin-1-ylsulfonyl 27 Calcd. (MH) - =615.17 m/z; acyl)benzyl]-4 -Hydroxy-5-methyl-2-oxo- found (MH) - = 615.04 m/z 1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylbenzene yl)propanoic acid (3S)-3-{[({1-[2-chloro-5-(pyrrolidin-1-yl15 Calcd. (MH) - = 601.15 m/z; sulfonyl)benzyl]- 4-Hydroxy-5-methyl-2-oxo found value (MH) - =601.03m/z generation-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methyl phenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-2 Calcd. (M+H) + = 582.20m/z; 4-hydroxyl -2-Oxo-2,5,6,7-tetrahydro-1H-ring Found (M+H) + = 582.10 m/z pentadieno[b]pyridin-3-yl]amino}carbonyl) Amino]-3-[3-(cyclopropoxy)phenyl]propanoic acid (3S)-3-{[({1-[2-chloro-6-(cyclopentylmethoxy20 Calculated (MH) - = 566.20 m/z; yl)benzyl]-4-hydroxy-5-methyl-2-oxo- found (MH) - = 566.09 m/z 1,2-dihydropyridin-3-yl}amino )carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[2-(benzyloxy)-6-chlorobenzyl 10 Calculated (MH) - =574.17m/z; [yl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydrofound (MH) - =574.01m/zpyridin-3-yl}amino)carbonyl] Amino}-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- 3 Calculated (M+H) + =604.16m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + =604.02m/z[b]pyridin-3-yl]amino }carbonyl)amino]-3-(3-chloro-4,5-diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl) -4- 500 Calcd. (M+H) + = 652.14 m/z; Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta Found (M+H) + = 651.98 m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(2,4-dichloro-3,5-diethoxyphenyl)propanoic acid (3R)-3 -[({[1-(2-chlorobenzyl)-4-hydroxyl-2- 450 Calcd. (M+H) + = 638.12m/z; oxo-2,5,6,7-tetrahydro- 1H-Cyclopentadiene and found (M+H) + =637.97m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(2,4-dichloro-3,5- Diethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-9 Calculated (M+H) + =552.19m/z; Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene and found (M+H) + = 552.10 m/z[b]pyridin-3-yl]amino}carbonyl)amino]- 3-[3-(Cyclopropylmethoxy)phenyl]propanoic acid (3S)-3-[({[1-(2-Chloro-6-ethoxybenzyl)-4 Calculated (M+ H) + = 596.21 m/z; 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-ring Found (M+H) + = 596.11 m/z Pentadiene[ B] pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoic acid (3S)-3-[({[1-(2-chloro- Calcd. for 6-methylbenzyl)-4-10 (M+H) + = 566.20 m/z; found for hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene ( M+H) + =566.12m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propionic acid (3S) -3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5-13 Calcd. (MH) - =544.16m/z; Methyl-2-oxo-1,2-dihydro Pyridin-3-yl]ammonia found value (MH) - =544.00m/zyl}carbonyl)amino]-3-(2,4-diethoxypyrimidin-5-yl)propanoic acid (3S)-3- [({[1-(2,3-dichloro-6-ethoxybenzyl 5 Calcd. (MH) - = 572.13 m/z; yl)-4-hydroxy-2-oxo-2,5,6 , 7-tetrahydro-1H- found (MH) - = 571.97 m/z cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl) Propionic acid (3S)-3-[3-(cyclopropylmethoxy)phenyl]-3- 7 Calculated value (MH) - =628.16m/z; [({[1-(2,3-two Chloro-6-ethoxybenzyl)-4-hydroxyl found (MH) - = 627.98m/z yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene [b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[({[1-(2,3-dichloro-6-ethoxybenzyl3 Calcd. (MH) - = 602.15 m/z; yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 601.99 m/z cyclopenta[b] Pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2,3-dichloro-6-ethoxy Calcd (MH) - = 616.16 m/z; yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 616.01 m/ z cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid (3S)-3-({[[1-(2 -Chlorobenzyl)-4-methoxy-2000 Calculated (MH) - =482.14m/z; 2-oxo-1,2-dihydropyridin-3-yl](methyl)ammonia found ( MH) - =482.07m/zyl]carbonyl}amino)-3-(4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl -5- 15 Calculated (MH) - =560.16m/z; Methyl-2-oxo-1,2-dihydropyridin-3-yl]ammonia Found (MH) - =559.98m/zyl} Carbonyl)amino]-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5 -Methyl-20 Calculated (MH) - =458.11 m/z; 2-Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =457.99 m/zyl) Amino]-3-(5-methyl-2-furyl)propanoic acid 3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-43 Calculated (M+H ) + = 548.13 m/z; 5-methyl-2-oxo-1,2-dihydropyridin-3-yl] Found (M+H) + - = 548.07 m/z amino}carbonyl)amino] Calculated value for -3-[4-(methylsulfonyl)phenyl]propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5 (MH) - = 470.11 m/z; 2,5,6,7-Tetrahydro-1H-cyclopenta[b]pyridine found (MH) - =469.96 m/z [pyridin-3-yl]amino}carbonyl)amino] -3-(2-furyl)propanoic acid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-4 Calcd. (MH) - =444.10m/z;2 -Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl Found (MH) - =443.91m/zyl)amino]-3-(2-furyl)propionic acid (3S)-3 -[({[1-(2-chlorobenzyl)-4-hydroxyl-2-18 Calcd. (MH) - =548.12m/z; Oxo-2,5,6,7-tetrahydro-1H- Cyclopentadiene and found (MH) - =548.00m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid (3S )-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-5 Calcd. (MH) - =494.15m/z; Oxo-2,5,6,7-tetrahydro -1H-cyclopentadiene and found (MH) - =494.02m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propionic acid (3S) -3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-10 Calcd. (MH) - =548.12m/z; Oxo-2,5,6,7-tetrahydro- 1H-Cyclopentadiene and found (MH) - =547.99m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-9 Calcd. (MH) - =508.16m/z; Oxo-2,5,6,7- Tetrahydro-1H-cyclopentadiene and found (MH) - =508.02m/z[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethylphenyl) Propionic acid (3S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-130 Calculated (MH) - =615.11m/z; [({[1-(2-chlorobenzyl base)-4-hydroxy-2-oxo- found (MH) - =615.99 m/z 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino }carbonyl)amino]propanoic acid (3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl 6 Calculated (MH) - =536.12m/z; base]-4 -Hydroxy-5-methyl-2-oxo-1,2-dihydrofound value (MH) - =535.99m/zpyridin-3-yl}amino)carbonyl]amino}-3-(4-methyl Phenyl)propanoic acid (3S)-3-[({[1-(2-chloro-5-fluorobenzyl)-4-hydroxy5 Calcd. (MH) - = 486.12 m/z; Base-2-oxo-1,2-dihydropyridine-3- Found (MH) - =485.97m/z base]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid ( 3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5-2 Calcd. (MH) - =525.19m/z; Methyl-2-oxo-1,2- Dihydropyridin-3-yl]ammonia found (MH) - =525.00m/zyl}carbonyl)amino]-3-[3-(diethylamino)phenyl]propanoic acid 3-(1,1' -biphenyl-4-yl)-3-[({[1-(2-chlorobenzyl 30 Calcd. (MH) - =556.16m/z; yl)-4-hydroxy-2-oxo-2,5 , 6,7-Tetrahydro-1H- Found (MH) - = 555.99m/z Cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid (3S)-3-[ ({[1-(2-Chlorobenzyl)-4-hydroxyl-2-8 Calcd. (M+H) + =522.17m/z; Oxo-2,5,6,7-tetrahydro-1H- Cyclopentadiene and found (M+H) + =522.03 m/z [b]pyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1H-indene-5- Base) propanoic acid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4- 10 Calcd. (M+H) + =536.19m/z; Hydroxy-2- Oxo-2,5,6,7-Tetrahydro-1H-Cyclopenta Found (M+H) + = 536.08 m/z dieno[b]pyridin-3-yl]amino}carbonyl)amino]- 3-(2,3-Dihydro-1H-inden-5-yl)propanoic acid N-{1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methanol 6000 Calculated (M+ H) + =494.17m/z; base-2-oxo-1,2-dihydro-3-pyridyl}-N'- Found (M+H) + =494.01m/z[(1S)- 1-(4-methylphenyl)-2-(1H-1,2,3,4-tetrazol-5-yl)ethyl]urea (3S)-3-[1,1'-biphenyl ]-3-yl-3-{[({1- 17 Calcd. (MH) - = 556.16 m/z; [(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- found (MH) - =556.01m/z2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}propionic acid (3S)-3-{ Calcd for [({1-[(2-chlorophenyl)methyl]-4-hydroxy13 (MH) - = 564.11 m/z; yl-2-oxo-2,5,6,7-tetrahydro -1H-cyclopentadiol found (MH) - =564.01m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{4-[(trifluoromethyl)oxy] Phenyl}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy13 Calcd. (MH) - = 546.12 m/z; yl-2-oxo Found-2,5,6,7-tetrahydro-1H-cyclopentadiol(MH) - =545.97m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{ 4-[(Difluoromethyl)oxy]phenyl}propanoic acid (3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-hydroxy10 Calculated (MH) - = 564.11 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (MH) - = 563.98 m/z alkeno[b]pyridine-3- Base}amino)carbonyl]amino}-3-{3-[(trifluoromethyl)oxy]phenyl}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl Calcd (MH) - = 546.12 m/z for base]-4-hydroxy5; Found (MH) - = 546.01 for base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoic acid (3S)-3-{[( Calcd for {1-[(2-chlorophenyl)methyl]-4-hydroxy4 (MH) - =596.12m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H - Found cyclopentadi (MH) - = 596.02 m/z alkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(1,1,2,2-tetrafluoro Ethyl)oxy]phenyl}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy11 Calculated (MH) - =538.17m/z ; Base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi found (MH) - = 538.04 m/z alkeno[b]pyridin-3-yl}amino)carbonyl] Amino}-3-[3,5-dimethyl-4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]- 4-Hydroxy5 Calcd. (M+H) + = 549.19 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi Found (M+H) + = 549.02m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1-ethyl-1H-indol-5-yl)propanoic acid (3S)-3-{[( Calcd for {1-[(2-chlorophenyl)methyl]-4-hydroxy7 (MH) - =516.11 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H -Measured value of cyclopentadi(MH) - =516.01m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3,5-difluorophenyl)propionic acid (3S) -3-{[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy3 Calculated (MH) - =528.13m/z; Base-2-oxo-2,5,6, 7-Tetrahydro-1H-cyclopentadiol found (MH) - =528.00m/z alkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-fluoro-4-(methyl Oxy)phenyl]propanoic acid (3S)-3-{[{1-[(2-chlorophenyl)methyl]-4-hydroxy17 Calculated (MH) - =522.18m/z; base-2 -Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (MH) - =522.04 m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3 -(4-Propylphenyl)propanoic acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methane 20 Calculated value (MH) - = 536.20m/z; base]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - =536.06 m/z cyclopenta[b]pyridin-3-yl} Amino)carbonyl]amino}-3-(4-propylphenyl)propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 267 Calculated ( MH) - = 468.13 m/z; base-5-methyl-2-oxo-1,2-dihydro-3-pyridine found (MH) - = 468.00 m/z base}amino)carbonyl]amino} -3-(2-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy25 Calcd. (M+H) + = 522.1 gm/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (M+H) + = 522.04 m/z alkeno[b]pyridine-3- Base}amino)carbonyl]amino}-3-(4-cyclopropylphenyl)propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 22 Calculated (MH) - = 505.13 m/z; yl-5-methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - = 504.98 m/z yl}amino)carbonyl ]Amino}-3-(3-quinolyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 22 Calculated (MH) - = 531.14 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (MH) - =530.99 m/zalkeno[b]pyridin-3-yl} Amino)carbonyl]amino}-3-(3-quinolyl)propanoic acid 3-({[(1-{[2-chloro-6-(ethoxy)phenyl]methanol8 Calcd. (MH) - =488.12m/z; base}-4-hydroxy-5-methyl-2-oxo-1,2-dihydrofound (MH) - =487.98m/z-3-pyridyl)amino]carbonyl} Amino)-3-(2-furyl)propanoic acid (3S)-3-[2,4-bis(ethoxy)-5-pyrimidinyl]-15 Calculated (MH) - =570.18m/z; 3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2- found (MH) - = 570.14m/z oxo-2,5,6,7-tetrahydro -1H-Cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}propanoic acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl) A19 Calculated (M+H) + =536.20 m/z; yl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (M+H) + = 536.07m/z Cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-cyclopropylphenyl)propanoic acid (3R)-3-{[({1- Calcd. for [(2-chlorophenyl)methyl]-4-hydroxy15 (MH) - = 418.12 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta Two found value (MH) - =418.00m/z alkeno[b]pyridin-3-yl}amino)carbonyl]amino}butanoic acid (3S)-3-{[({1-[(2-chlorophenyl )Methyl]-4-hydroxy8 Calculated (MH) - = 508.16 m/z; Base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi Found (MH) - =508.06m/z alkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-ethylphenyl)propionic acid (3S)-3-{[({1-[(2 -Chlorophenyl)methyl]-4-hydroxy17 Calcd. (MH) - = 522.17 m/z; Found for yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene (MH) - =522.06m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-[4-(1-methylethyl)phenyl]propanoic acid (3S)-3 -{[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy 30 Calculated (MH) - =482.14m/z; Base-5-methyl-2-oxo-1,2 -Dihydro-3-pyridine found value (MH) - =482.00m/z base}amino)carbonyl]amino}-3-(4-ethylphenyl)propionic acid (3S)-3-{[({1 -[(2-Chlorophenyl)methyl]-4-Hydroxy 175 Calculated (MH) - =496.16m/z; Base-5-methyl-2-oxo-1,2-dihydro-3- Pyridine measured value (MH) - =496.01m/z base}amino)carbonyl]amino}-3-[4-(1-methylethyl)phenyl]propanoic acid (3S)-3-{[({1 Calcd for -[(2-chlorophenyl)methyl]-4-hydroxy6 (MH) - =510.14 m/z; base-5-methyl-2-oxo-1,2-dihydro-3- Pyridine found value (MH) - =510.00m/z base}amino)carbonyl]amino}-3-[4-(cyclopropyloxy)phenyl]propanoic acid (3S)-3-{[({1-[ (2-Chlorophenyl)methyl]-4-hydroxy12 Calcd. (MH) - = 496.16 m/z; Found for base-5-methyl-2-oxo-1,2-dihydro-3-pyridine Value (MH) - =495.99m/z base}amino)carbonyl]amino}-3-(4-propylphenyl)propanoic acid 3-{[({1-[(2-chlorophenyl)methyl] -4-Hydroxy-5-35 Calculated (MH) - = 494.15 m/z; Methyl-2-oxo-1,2-dihydro-3-pyridyl}ammonia Found (MH) - = 494.01 m /z base)carbonyl]amino}-3-(4-cyclopropylphenyl)propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 18 Calculated (MH) - = 494.15 m/z; yl-5-methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - = 494.02 m/z yl}amino)carbonyl ]amino}-3-(2,3-dihydro-1H-inden-5-yl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- Hydroxyl 13 Calculated (MH) - = 597.19 m/z; Ethyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol Found (MH) - = 597.01 m/z [b]pyridin-3-yl}amino)carbonyl]amino}-3-(9-ethyl-9H-carbazol-3-yl)propionic acid (3S)-3-{[({1-[(2 -Chlorophenyl)methyl]-4-hydroxyl 23 Calculated (MH) - =571.17 m/z; Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine found ( MH) - =570.99m/z base}amino)carbonyl]amino}-3-(9-ethyl-9H-carbazol-3-yl)propionic acid (3S)-3-{[({1-[( 2-Chloro-6-methylphenyl)methanol 3 Calculated (MH) - =547.17m/z; yl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (MH) - = 547.04 m/z Cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propane Acid (3S)-3-{[({1-[(2-Chloro-6-methylphenyl)methane3 Calcd. (MH) - = 560.14m/z; yl]-4-hydroxy-2-oxo Generation-2,5,6,7-tetrahydro-1H- Found (MH) - =560.03m/z cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{ 3-[(Difluoromethyl)oxy]phenyl}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy25 Calculated (MH) - = 574.17 m/z; yl-5-methyl-2-oxo-1,2-dihydro-3-pyridine found (MH) - = 574.00 m/z yl}amino)carbonyl]amino}-3 -[2-(ethoxy)[1,1'-biphenyl]-4-yl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]- 4-Hydroxy20 Calcd (MH) - = 600.19 m/z; Ethyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol Found (MH) - = 600.01 m/z Ekeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-[2-(ethoxy)[1,1'-biphenyl]-4-yl]propanoic acid (3S)-3 -{[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy20 Calculated (MH) - =544.16m/z; Base-5-methyl-2-oxo-1,2 - Dihydro-3-pyridine found value (MH) - =544.04m/z base}amino)carbonyl]amino}-3-(2'-methyl[1,1'-biphenyl]-3-yl) Propionic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy18 Calcd. (MH) - =544.16m/z; yl-5-methyl-2 -Oxo-1,2-dihydro-3-pyridine Found (MH) - =544.00m/zyl}amino)carbonyl]amino}-3-(3'-methyl[1,1'-biphenyl Base]-3-yl)propanoic acid (3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)-90 Calculated (MH) - =551.21m/z; Pyridylphenyl]methyl}-4-hydroxy-5-methyl- found (MH) - =551.06m/z2-oxo-1,2-dihydro-3-pyridyl)amino]carbonyl}amino )-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 23 Calcd. (MH) - = 544.16 m/z; Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - =543.99 m/z base}amino)carbonyl]amino}-3-(4 Calculation of '-methyl[1,1'-biphenyl]-3-yl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy3 Value (MH) - = 551.21 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi Found (MH) - = 551.05 m/z alkeno[b] Pyridin-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl Calcd (MH) - =504.11 m/z for base]-4-hydroxy20; Found (MH) - =503.96 m for base-5-methyl-2-oxo-1,3-dihydro-3-pyridine /z base}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl] -4-Hydroxy16 Calculated (MH) - = 498.12 m/z; Base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi Found (MH) - = 498.02 m/z Zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3-fluorophenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl) Methyl]-4-hydroxy9 Calculated (MH) - = 498.12 m/z; Base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi Found (MH) - = 498.01m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-fluorophenyl)propanoic acid N-{1-[(2-chlorophenyl)methyl]- 4-Hydroxy-5-methyl>10000 Calculated (MH) - = 464.12 m/z; yl-2-oxo-1,2-dihydro-3-pyridyl}-N'- Found (MH) - =464.01m/z[(R)-phenyl(1H-1,2,3,4-tetrazol-5-yl)methyl]urea(3S)-3-{[({1-[(2- Chloro-6-methylphenyl)methanol 4 Calculated (MH) - = 521.16 m/z; yl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydro found (MH ) - =521.00m/z-3-pyridyl}amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propionic acid (3S)-3-{[({1 Calcd for -[(2-chloro-6-methylphenyl)methanol 10 (MH) - = 565.14 m/z; yl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro -1H- Found (MH) - =565.04m/z cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propane Acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methanol4 Calcd. (MH) - =508.16m/z; yl]-4-hydroxy-2-oxo Generation-2,5,6,7-tetrahydro-1H- Found (MH) - =508.03m/z cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-( 3-Methylphenyl)propanoic acid (3S)-3-{[({1-[(2-Chloro-6-methylphenyl)methyl 17 Calcd. (MH) - = 494.15 m/z; base] -4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 494.09 m/z cyclopenta[b]pyridin-3-yl}amino) Carbonyl]amino}-3-phenylpropanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy8 Calculated (MH) - =496.13m/z ; Base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadi found (MH) - =495.99m/zalkeno[b]pyridin-3-yl}amino)carbonyl] Amino}-3-(3-hydroxyphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy9 Calculated (MH) - = 470.11 m/z; base-5-methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - =469.98 m/z base}amino)carbonyl]amino}-3-(3 -Hydroxyphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy50 Calcd. (MH) - =558.18m/z; base-5 -Methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - =558.00m/zyl}amino)carbonyl]amino}-3-(3',5'-dimethyl Base[1,1'-biphenyl]-3-yl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 15 Calculated (MH ) - = 455.12 m/z; base-5-methyl-2-oxo-1,2-dihydro-3-pyridine found (MH) - = 454.00 m/z base}amino)carbonyl]amino}- 3-Phenylpropanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy3 Calcd. (MH) - =573.12m/z; Base-2- Oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (MH) - =572.98m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3- Calculated for {3-[(methylsulfonyl)amino]phenyl}propanoic acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methanol3 (MH) - = 587.14 m/z; yl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 586.98 m/z cyclopenta[b] Pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoic acid (3S)-3-{[({1-[(2-chlorobenzene yl)methyl]-4-hydroxy4 Calculated (MH) - = 530.13 m/z; yl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (MH) - =530.03m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoic acid (2S, 3S)-3-{[ ({1-[(2-Chlorophenyl)methyl]-4- 1500 Calculated (MH) - =482.15m/z; Hydroxy-5-methyl-2-oxo-1,2-dihydro- 3-pyridine found value (MH) - =481.99m/z pyridyl}amino)carbonyl]amino}-2-methyl-3-(4-methylphenyl)propionic acid (3S)-3-{[( {1-[(2-Chloro-6-methylphenyl)methanol calcd. (MH) - =522.18 m/z; yl]-4-hydroxy-2-oxo-2,5,6,7- Tetrahydro-1H- Found (MH) - = 522.04 m/z Cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-ethylphenyl)propanoic acid ( 3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-Hydroxy3 Calculated (MH) - =550.17m/z; Base-2-oxo-2,5, 6,7-Tetrahydro-1H-cyclopentadiol found (MH) - =550.05m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(2,2-di- Methyl-2,3-dihydro-1-benzofuran-5-yl)propionic acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methanol3 calculation Value (MH) - = 542.15 m/z; yl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 542.00 m/z cyclopentadiene Ekeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-fluoro-4-(methoxy)phenyl]propanoic acid (3S)-3-{[({1-[ Calcd for (2-chloro-6-methylphenyl)methanol 11 (MH) - = 578.13 m/z; yl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H - Found (MH) - = 578.02 m/z Cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(trifluoromethyl)oxy]phenyl }propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 1.6 Calculated (MH) - =587.14m/z; base-2-oxo- 2,5,6,7-Tetrahydro-1H-cyclopentadiol found (MH) - =586.99m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3- [Methyl(methylsulfonyl)amino]phenyl}propanoic acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methanol 1.3 Calculated (MH) - = 601.15 m/z; yl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 601.00 m/z cyclopenta[b]pyridine -3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid (3S)-3-{[({1-[(2-chloro Phenyl)methyl]-4-hydroxy1 Calculated (MH) - = 601.15 m/z; Base-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiol found (MH ) - =601.00m/zalkeno[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propionic acid (3S)- 3-{[({1-[(2-Chloro-6-methylphenyl)methanol Calcd. (MH) - =615.17m/z; yl]-4-hydroxy-2-oxo-2,5 , 6,7-Tetrahydro-1H- Found (MH) - = 615.04 m/z Cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl (Methylsulfonyl)amino]phenyl}propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 25 Calculated (MH) - ＝548.14m /z; Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - =547.96m/z base}amino)carbonyl]amino}-3-(2'-Fluoro[1,1'-biphenyl]-3-yl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl 157 Calculated ( MH) - =598.14 m/z; base-5-methyl-2-oxo-1,2-dihydro-3-pyridine found (MH) - =597.97 m/z group}amino)carbonyl]amino} -3-[2'-(trifluoromethyl)[1,1'-biphenyl]-3-yl]propanoic acid (3S)-3-{[({1-[(2-chlorophenyl) Methyl]-4-hydroxy10 Calculated (MH) - = 472.11 m/z; Base-5-methyl-2-oxo-1,2-dihydro-3-pyridine Found (MH) - = 471.98 m/z base}amino)carbonyl]amino}-3-(2-fluorophenyl)propanoic acid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl 2 Calculated (MH) - = 533.16 m/z; yl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found (MH) - = 533.01 m/z cyclopenta Dieno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1H-indol-5-yl)propanoic acid (3S)-3-{[({1-[(2-chloro Calcd for -6-methylphenyl)methan11 (MH) - = 530.13 m/z; yl] -4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- found ( MH) - =530.00m/z cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3,5-difluorophenyl)propionic acid

所有引用的参考文献通过引用结合到本文中。All cited references are hereby incorporated by reference.

借助以上说明和实施例阐明了本发明。以上说明为非限制性阐明，因为其许多改变方案对本领域技术人员是显而易见的。因此，本发明包括在后附权利要求书的范围和精神内的所有这样的改变方案。The invention has been elucidated by means of the above description and examples. The above description is non-limiting, as many variations thereof will be apparent to those skilled in the art. Accordingly, this invention embraces all such modifications that come within the scope and spirit of the appended claims.

在不偏离以下权利要求书定义的本发明构思和范围条件下，可对本文介绍的本发明方法的构成、操作和安排进行改变。Changes may be made in the composition, operation and arrangement of the methods of the invention described herein without departing from the concept and scope of the invention as defined by the following claims.

                            序列表<110>得克萨斯生物技术公司(Texas Biotechnology Corporation)<120>抑制整联蛋白与其受体结合的羧酸衍生物<140>01145182.3<141>2001-12-29<160>1<170>PatentIn Release #1.0，Version #1.30<210>1<211>26<212>蛋白质<400>1Sequence Listing <110> Texas Biotechnology Corporation (Texas Biotechnology Corporation) <120> Carboxylic acid derivatives that inhibit the binding of integrin to its receptor <140>01145182.3<141>2001-12-29<160>1<170>PatentIn Release #1.0, Version #1.30<210>1<211>26<212>Protein<400>1

Cys Asp Glu Leu Pro Gln Leu Val Thr Leu Pro His Pro Asn Leu HisCys Asp Glu Leu Pro Gln Leu Val Thr Leu Pro His Pro Asn Leu His

1               5                   10                  151 5 10 15

Gly Pro Glu Ile Leu Asp Val Pro Ser ThrGly Pro Glu Ile Leu Asp Val Pro Ser Thr

            20                  2520 25

Claims (31)

1.一种以下结构式的化合物或其药学上可接受的盐，其中Y在每次出现时独立选自C(O)、N、CR1、C(R2)(R3)、NR5、1. A compound of the following structural formula or a pharmaceutically acceptable salt thereof, wherein Y is at each occurrence independently selected from C(O), N, CR 1 , C(R 2 )(R 3 ), NR 5 , CH、O和S；q是3-10的整数；A选自O、S、C(R16)(R17)和NR6；E选自CH2、O、S和NR7；J选自O、S和NR8；T选自C(O)和(CH2)b，其中b是0-3的整数；M选自C(R9)(R10)和(CH2)u，其中u是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；X选自CO2B、PO3H2、SO3H、SO2NH2、SO2NHCOR12、OPO3H2、C(O)NHC(O)R13、C(O)NHSO2R14、羟基、四唑基和氢；W选自C、CR15和N；以及B、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16和R17在每次出现时独立选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、-SH、-CN、-NO2、-NH2、-OH、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-CH, O and S; q is an integer of 3-10; A is selected from O, S, C(R 16 )(R 17 ) and NR 6 ; E is selected from CH 2 , O, S and NR 7 ; J is selected from O, S and NR 8 ; T is selected from C(O) and (CH 2 ) b , wherein b is an integer from 0 to 3; M is selected from C(R 9 )(R 10 ) and (CH 2 ) u , wherein u is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; X is selected from CO 2 B, PO 3 H 2 , SO 3 H, SO 2 NH 2. SO 2 NHCOR 12 , OPO 3 H 2 , C(O)NHC(O)R 13 , C(O)NHSO 2 R 14 , hydroxyl, tetrazolyl and hydrogen; W is selected from C, CR 15 and N; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R are independently selected at each occurrence from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, Aliphatic acyl, -CF 3 , -CO 2 H, -SH, -CN, -NO 2 , -NH 2 , -OH, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl) , -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenes Amino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, - C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH, -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl 胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl 基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group, 杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle 基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene 磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) 团；group;     其中B、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、Where B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ,         R12、R13、R14、R15、R16、R16和R17为未取代的基R 12 , R 13 , R 14 , R 15 , R 16 , R 16 and R 17 are unsubstituted groups         团或被至少一个给电子或吸电子基团取代的基A group or a group substituted by at least one electron-donating or electron-withdrawing group         团；group;     其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;     其中当M为C(R9)(R10)时，R9和R10一起可形成一个环；Wherein when M is C(R 9 )(R 10 ), R 9 and R 10 together can form a ring;     以及其中当A为NR6和至少一个Y为CR1时，R1和R6 and where when A is NR 6 and at least one Y is CR 1 , R 1 and R 6     一起可形成一个环；前提是当A是C(R16)(R17)时，E不是NR7。Together can form a ring; provided that when A is C(R 16 )(R 17 ), E is not NR 7 . 2.权利要求1的化合物，其中：A为NR6；E为NR7；J为O；M为C(R9)(R10)；q是4或5；T为(CH2)b，其中b是0；L为(CH2)n，其中n是0；X为CO2B；W为C或CR15；R4选自芳基、烷基芳基、芳烷基、杂环基、烷基杂环基和杂环基2. The compound of claim 1, wherein: A is NR 6 ; E is NR 7 ; J is O; M is C(R 9 )(R 10 ); q is 4 or 5; T is (CH 2 ) b , wherein b is 0; L is (CH 2 ) n , wherein n is 0; X is CO 2 B; W is C or CR 15 ; R 4 is selected from aryl, alkylaryl, aralkyl, heterocyclyl , alkylheterocyclyl and heterocyclyl 烷基；以及alkyl; and R6、R7、R9、R10和R15独立选自氢和低级烷基。R 6 , R 7 , R 9 , R 10 and R 15 are independently selected from hydrogen and lower alkyl. 3.权利要求1的化合物，它为其选自酯、氨基甲酸酯、缩醛胺、酰胺、旋光异构体和药物前体的衍生物。3. The compound of claim 1 which is a derivative selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 4.一种以下结构式的化合物或其药学上可接受的盐，其中Y在每次出现时独立选自C(O)、N、CR1、C(R2)(R3)、NR5、4. A compound of the following structural formula or a pharmaceutically acceptable salt thereof, wherein Y is at each occurrence independently selected from C(O), N, CR 1 , C(R 2 )(R 3 ), NR 5 , CH、O和S；q是3-7的整数；T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；W选自C、CR15和N；以及B、R1、R2、R3、R4、R5、R6、R7、R9、R10、R11和R15独立选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、-SH、-CN、-NO2、-NH2、-OH、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰CH, O and S; q is an integer of 3-7; T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; W is selected from C, CR 15 and N; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R and R are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy , alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl , -CF 3 , -CO 2 H, -SH, -CN, -NO 2 , -NH 2 , -OH, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 Alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC (O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, Di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N (C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formamido, cycloalkyl, cyclo alkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl 基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group, 杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle 基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene 磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) 团；group; 其中B、R1、R2、R3、R4、R5、R6、R7、R9、R10、R11和R15 where B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 and R 15     为未取代基团或被至少一个给电子或吸电子基团取代的 is an unsubstituted group or is substituted by at least one electron-donating or electron-withdrawing group     基团；group; 其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring; 以及其中R9和R10一起可形成一个环；And wherein R 9 and R 10 together can form a ring; 而且其中当至少一个Y为CR1时，R1和R6一起可形成一个And wherein when at least one Y is CR 1 , R 1 and R 6 together can form a     环。Ring. 5.权利要求4的化合物，其中：5. The compound of claim 4, wherein: q为4或5；q is 4 or 5; W为C或CR15；W is C or CR 15 ; T为(CH2)b，其中b是0；T is (CH 2 ) b , where b is 0; L为(CH2)n，其中n是0；L is (CH 2 ) n , where n is 0; R4选自芳基、烷基芳基、芳烷基、杂环基、烷基杂环基和杂环基 R is selected from aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl and heterocyclyl    烷基；以及Alkyl; and R6、R7、R9、R10和R15独立选自氢和低级烷基。R 6 , R 7 , R 9 , R 10 and R 15 are independently selected from hydrogen and lower alkyl. 6.权利要求4的化合物，它为其选自酯、氨基甲酸酯、缩醛胺、酰胺、旋光异构体和药物前体的衍生物。6. The compound of claim 4 which is a derivative selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 7.一种以下结构式的化合物或其药学上可接受的盐，
Figure A0114518200061
其中Y在每次出现时独立选自C(O)、N、CR1、C(R2)(R3)、NR5、7. A compound of the following structural formula or a pharmaceutically acceptable salt thereof,
Figure A0114518200061
wherein Y is at each occurrence independently selected from C(O), N, CR 1 , C(R 2 )(R 3 ), NR 5 , CH、O和S；q是2-5的整数；T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；R5、R6、R7、R11和R18独立选自烷基、链烯基、链炔基、羟烷基、CH, O and S; q is an integer of 2-5; T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; R 5 , R 6 , R 7 , R 11 and R 18 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, 脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、Aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH, 卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环Haloalkyl, Alkoxyalkoxy, Formaldehyde, Formamide, Cycloalkyl, Cyclo 烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基Alkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, aryl 氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、Amino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, 芳链烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate 基、芳氧基烷基、氢和-C(O)NH(苄基)基团；以及B、R1、R2、R3、R4、R9和R10独立选自氢、卤素、烷基、链烯radical, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) group; and B, R 1 , R 2 , R 3 , R 4 , R 9 and R 10 are independently selected from hydrogen, halogen, Alkyl, Alkene 基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、group, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, 羟烷基、脂族酰基、-CF3、-CO2H、-SH、-CN、硝基、氨基、Hydroxyalkyl, Aliphatic Acyl, -CF 3 , -CO 2 H, -SH, -CN, Nitro, Amino, 羟基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3 Hydroxy, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-Alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 - C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), - NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 ) 氨基、-C(O)O-(C1-C3)烷基、-C(O)NH-(C1-C3)烷基、-Amino, -C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C 1 -C 3 )alkyl, - C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkane 基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、group, alkoxyalkoxy group, formaldehyde group, formamide group, cycloalkyl group, cycloalkenyl group, 环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、Cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, 联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain 烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3 Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧Alkyl), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxy 基烷基和-C(O)NH(苄基)基团；Alkyl and -C(O)NH(benzyl) groups; 其中B、R1、R2、R3、R4、R5、R6、R7、R9、R10、R11和R18 where B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 and R 18     为未取代基团或被至少一个给电子或吸电子基团取代的 is an unsubstituted group or is substituted by at least one electron-donating or electron-withdrawing group     基团；group; 其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring; 以及其中R9和R10一起可形成一个环；And wherein R 9 and R 10 together can form a ring; 而且其中当至少一个Y为CR1时，R1和R6一起可形成一个And wherein when at least one Y is CR 1 , R 1 and R 6 together can form a     环。Ring. 8.权利要求7的化合物，其中：8. The compound of claim 7, wherein: R18选自氢、烷基、芳基、芳烷基、环烷基、烷基杂环基、杂环基 R is selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, alkyl heterocyclyl, heterocyclyl    烷基和杂环基；Alkyl and heterocyclyl; T为(CH2)b，其中b是0；T is (CH 2 ) b , where b is 0; L为(CH2)n，其中n是0；L is (CH 2 ) n , where n is 0; Y选自CR1和C(R2)(R3)；以及Y is selected from CR 1 and C(R 2 )(R 3 ); and q为2或3。q is 2 or 3. 9.权利要求7的化合物，它为其选自酯、氨基甲酸酯、缩醛胺、酰胺、旋光异构体和药物前体的衍生物。9. The compound of claim 7, which is a derivative selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 10.权利要求7的化合物，其中
Figure A0114518200071
选自和
Figure A0114518200082
其中R19、R20、R21和R28在每次出现时独立选自卤素、烷基、链10. The compound of claim 7, wherein
Figure A0114518200071
selected from and
Figure A0114518200082
wherein R 19 , R 20 , R 21 and R 28 are at each occurrence independently selected from halogen, alkyl, chain 烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、Alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, 羟烷基、脂族酰基、-CF3、羟基、-CO2H、巯基、氰基、硝基、Hydroxyalkyl, aliphatic acyl, -CF 3 , hydroxyl, -CO 2 H, mercapto, cyano, nitro, 氨基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3 Amino, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-Alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 - C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), - NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 ) 氨基、-C(O)O-(C1-C3)烷基、-C(O)NH-(C1-C3)烷基、-Amino, -C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C 1 -C 3 )alkyl, - C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkane 基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、group, alkoxyalkoxy group, formaldehyde group, formamide group, cycloalkyl group, cycloalkenyl group, 环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、Cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, 联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain 烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3 Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧Alkyl), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxy 基烷基和-C(O)NH(苄基)基团；R18选自烷基、链烯基、链炔基、羟烷基、脂族酰基、链炔基氨基、R is selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, 烷氧羰基、杂环酰基、-CH＝NOH、卤代烷基、烷氧基烷氧基、Alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkyl, alkoxyalkoxy, 甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、Formaldehyde, formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, 芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二Aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, di 芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂Arylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylhetero 环基、杂环基烷基、氨基甲酸酯基、芳氧基烷基、氢和Cyclic, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(苄基)基团；R22选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、-C(O)NH(benzyl) group; R22 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, 链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、Alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, -SH、-CN、硝基、氨基、羟基、链炔基氨基、烷氧羰基、杂-SH, -CN, nitro, amino, hydroxyl, alkynylamino, alkoxycarbonyl, hetero 环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-Cycloacyl, carboxyl, -N(C 1 -C 3 alkyl) -C(O)(C 1 -C 3 alkyl), - NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 - C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, 烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3烷基)、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 alkyl), -C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH, -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl 胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl 基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group, 杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle 基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene 磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) 团；c为0-2的整数；d为0-3的整数；e为0-4的整数；及i为0-2的整数。c is an integer of 0-2; d is an integer of 0-3; e is an integer of 0-4; and i is an integer of 0-2. 11.权利要求7的化合物，其中：R18为芳烷基；R4为芳基；T为(CH2)b，其中b是0；L为(CH2)n，其中n为0；B、R6、R7、R9和R10各自独立为氢。11. The compound of claim 7, wherein: R 18 is aralkyl; R 4 is aryl; T is (CH 2 ) b , wherein b is 0; L is (CH 2 ) n , wherein n is 0; B , R 6 , R 7 , R 9 and R 10 are each independently hydrogen. 12.一种以下结构式的化合物或其药学上可接受的盐，
Figure A0114518200101
其中T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；g为0-7的整数；以及B、R4、R9、R10和R23在每次出现时独立选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基团；R6、R7、R11和R18各自独立选自烷基、链烯基、链炔基、羟烷基、脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基12. A compound of the following structural formula or a pharmaceutically acceptable salt thereof,
Figure A0114518200101
wherein T is selected from C(O) and (CH 2 ) b , wherein b is an integer from 0 to 3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; g is 0 - an integer of 7; and B, R 4 , R 9 , R 10 and R 23 at each occurrence are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy , alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxycarbonyl, Heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O )NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkyl Oxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy group, formaldehyde group, formamide group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, cycloalkylalkyl group, aryl group, aroyl group, aryloxy group, arylamino group, biaryl group, thioaryl group, Diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl , -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; R 6 , R 7 , R 11 and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkyl, Alkoxyalkoxy, formaldehyde, formamido, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, aryl     氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、  Amino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,     芳链烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯 Aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate     基、芳氧基烷基、氢和-C(O)NH(苄基)基团；radical, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; 其中B、R4、R6、R7、R9、R10、R11、R18和R23为未取代基团或Wherein B, R 4 , R 6 , R 7 , R 9 , R 10 , R 11 , R 18 and R 23 are unsubstituted groups or     被至少一个给电子或吸电子基团取代的基团；A group substituted with at least one electron-donating or electron-withdrawing group;         其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;         以及R9和R10一起可形成一个环。And R 9 and R 10 together may form a ring. 13.权利要求12的化合物，它为其选自酯、氨基甲酸酯、缩醛胺、酰胺、旋光异构体和药物前体的衍生物。13. The compound of claim 12 which is a derivative selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 14.一种以下结构式的化合物或其药学上可接受的盐，其中h为0-5的整数；B、R9、R10、R24和R25各自独立选自氢、卤素、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHCC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、   联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基团；R27在每次出现时独立选自卤素、羟基、烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、氰基、硝基、氨基、链炔基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、-N(C1-C3烷基)SO2(C1-C3烷基)、-N(C1-C3烷基)SO2(芳基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-C(O)NH--(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基团；R6、R7和R18各自独立选自烷基、链烯基、链炔基、羟烷基、脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯基、芳氧基烷基、氢和-C(O)NH(苄基)基团；以及R26选自氢、烷基、链烯基、链炔基、羟烷基、脂族酰基、-CF3、14. A compound of the following structural formula or a pharmaceutically acceptable salt thereof, Wherein h is an integer of 0-5; B, R 9 , R 10 , R 24 and R 25 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, Alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxycarbonyl, hetero Cycloacyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O) NH(C 1 -C 3 alkyl), -NHCC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxy Alkylalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy , formaldehyde, formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, di Arylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl) , -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; R 27 in each Occurrences are independently selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3. -CO 2 H, mercapto, cyano, nitro, amino, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), -N(C 1 -C 3 alkyl)SO 2 (C 1 -C 3 alkyl), -N (C 1 -C 3 alkyl)SO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, -C(O)NH--(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkyl) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formamido, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl , aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclyl Alkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl), -SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl and -C(O)NH(benzyl) group; R 6 , R 7 and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, Alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkyl, alkoxyalkoxy, formaldehyde, formamido, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl , aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, Heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; and R is selected from hydrogen, alkyl, alkenyl, alkynyl , hydroxyalkyl, aliphatic acyl, -CF 3 ,     烷氧羰基、杂环酰基、羧基、-C(O)O-(C1-C3)烷基、-Alkoxycarbonyl, heterocyclic acyl, carboxyl, -C(O)O-(C 1 -C 3 )alkyl, -     C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-PO3H2、卤代烷C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -PO 3 H 2 , haloalkane     基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、芳Base, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl     基、芳酰基、联芳基、杂环基、烷基芳基、芳链烯基、芳烷yl, aroyl, biaryl, heterocyclyl, alkylaryl, arylalkenyl, aryl     基、烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、group, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl),     亚磺酰氨基、芳氧基烷基和-C(O)NH(苄基)基团；  Sulfonamido, aryloxyalkyl and -C(O)NH(benzyl) groups; 其中B、R6、R7、R9、R10、R18、R24、R25、R26和R27为未取代基Wherein B, R 6 , R 7 , R 9 , R 10 , R 18 , R 24 , R 25 , R 26 and R 27 are unsubstituted groups     团或被至少一个给电子或吸电子基团取代的基团；group or a group substituted by at least one electron-donating or electron-withdrawing group;     其中R18和R24一起可形成一个环；Wherein R 18 and R 24 together can form a ring;     R24和R25一起可形成一个环；R 24 and R 25 together may form a ring;     R25和R26一起可形成一个环；R 25 and R 26 together may form a ring;     以及其中R9和R10一起可形成一个环。And wherein R 9 and R 10 together may form a ring. 15.权利要求14的化合物，其中B、R6、R7、R9、R10、R24、R25和R26各自独立为氢，而R18为取代芳烷基或未取代芳烷基。15. The compound of claim 14, wherein B, R 6 , R 7 , R 9 , R 10 , R 24 , R 25 and R 26 are each independently hydrogen, and R 18 is substituted aralkyl or unsubstituted aralkyl . 16.权利要求14的化合物，它为其选自酯、氨基甲酸酯、缩醛胺、酰胺、旋光异构体和药物前体的衍生物。16. The compound of claim 14 which is a derivative selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 17.一种以下结构式的化合物或其药学上可接受的盐，其中Z在每次出现时独立选自C(O)、N、CR30、C(R31)(R32)、NR33、17. A compound of the following structural formula or a pharmaceutically acceptable salt thereof, wherein Z at each occurrence is independently selected from C(O), N, CR 30 , C(R 31 )(R 32 ), NR 33 , CH、O和S；z是3-6的整数；k为0-5的整数；T选自C(O)和(CH2)b，其中b是0-3的整数；L选自O、NR11、S和(CH2)n，其中n是0或1；R6、R7、R11、R18和R23各自独立选自烷基、链烯基、链炔基、CH, O and S; z is an integer of 3-6; k is an integer of 0-5; T is selected from C(O) and (CH 2 ) b , wherein b is an integer of 0-3; L is selected from O, NR 11 , S and (CH 2 ) n , wherein n is 0 or 1; R 6 , R 7 , R 11 , R 18 and R 23 are each independently selected from alkyl, alkenyl, alkynyl, 羟烷基、脂族酰基、链炔基氨基、烷氧羰基、杂环酰基、Hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH＝NOH、卤代烷基、烷氧基烷氧基、甲醛基、甲酰胺基、-CH=NOH, haloalkyl, alkoxyalkoxy, formaldehyde, formamide, 环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰基、芳Cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryl 氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、杂环基、Oxygen, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, 烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环基烷基、Alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, 氨基甲酸酯基、芳氧基烷基、氢和-C(O)NH(苄基)基团；B、R4、R9、R10、R30、R31和R32在每次出现时选自氢、卤素、Carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; B, R 4 , R 9 , R 10 , R 30 , R 31 and R 32 in each occurrence When selected from hydrogen, halogen, 烷基、链烯基、链炔基、烷氧基、链烯氧基、链炔氧基、硫Alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, sulfur 代烷氧基、羟烷基、脂族酰基、-CF3、-CO2H、巯基、羟基、Substituted alkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO 2 H, mercapto, hydroxyl, 氰基、硝基、氨基、链炔基氨基、烷氧羰基、杂环酰基、羧Cyano, nitro, amino, alkynylamino, alkoxycarbonyl, heterocyclic acyl, carboxy 基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-NHC(O)N(C1-C3烷group, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C 1 -C 3 alkane 基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-C6烷基)、-Base) C (O) NH (C 1 -C 3 alkyl), -NHC (O) NH (C 1 -C 6 alkyl), - NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、烷基氨基、NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, 链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、-Alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, - C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH, -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl 胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl 基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group, 杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle 基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene 磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) 团；以及R29在每次出现时独立选自卤素、烷基、链烯基、链炔基、烷氧基、group; and R 29 at each occurrence is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, 链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族酰基、-CF3、Alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 , -CO2H、巯基、氰基、硝基、氨基、羟基、链炔基氨基、烷氧-CO 2 H, mercapto, cyano, nitro, amino, hydroxyl, alkynylamino, alkoxy     羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、-Carbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl) -C(O)(C 1 -C 3 alkyl), -     NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1-NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 -     C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl,     烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl,     -C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH,     -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl     胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰  Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl     基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、Base, aryloxy, arylamino, biaryl, thioaryl, diarylamino,     杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle     基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene     磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl)     团；group; 其中B、R4、R5、R6、R7、R9、R10、R11、R18、R29、R30、R31、Wherein B, R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 18 , R 29 , R 30 , R 31 ,     R32和R33为未取代基团或被至少一个给电子或吸电子基团取R 32 and R 33 are unsubstituted groups or replaced by at least one electron-donating or electron-withdrawing group     代的基团；generation of groups;     其中当L为NR11时，R4和R11一起可形成一个环；Wherein when L is NR 11 , R 4 and R 11 together can form a ring;     以及其中R9和R10一起可形成一个环。And wherein R 9 and R 10 together may form a ring. 18.权利要求17的化合物，它为其选自酯、氨基甲酸酯、缩醛胺、酰胺、旋光异构体和药物前体的衍生物。18. The compound of claim 17 which is a derivative selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 19.权利要求17的化合物，其中z为3或4。19. The compound of claim 17, wherein z is 3 or 4. 20.一种以下结构式的化合物， 20. A compound of the formula, 其中R24和R25各自独立选自氢、卤素、烷基、链烯基、链炔基、Wherein R 24 and R 25 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,     烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族Alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic     酰基、-CF3、巯基、羟基、-CO2H、氰基、硝基、氨基、链炔Acyl, -CF 3 , Mercapto, Hydroxyl, -CO 2 H, Cyano, Nitro, Amino, Alkyne     基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3 Amino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3     烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-Alkyl), -NHC(O)N(C 1 -C 3 Alkyl)C(O)NH(C 1 -C 3 Alkyl), -     NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳NHC (O) NH (C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl     基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、group), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino,     -C(O)O-(C1-C3)烷基、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷-C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkane     基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧radical) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy     基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基yl, formaldehyde, formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl     烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳Alkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl     基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、Base, diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl,     烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-Alkyl heterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl), -     SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl     和-C(O)NH(苄基)基团；以及and -C(O)NH(benzyl) groups; and R18和R34各自独立选自烷基、链烯基、链炔基、羟烷基、脂族酰R and R are each independently selected from alkyl, alkenyl, alkynyl , hydroxyalkyl, aliphatic acyl     基、链炔基氨基、烷氧羰基、杂环酰基、-CH＝NOH、卤代烷Alkyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkane     基、烷氧基烷氧基、甲醛基、甲酰胺基、环烷基、环烯基、 , alkoxyalkoxy, formaldehyde, formamide, cycloalkyl, cycloalkenyl,     环炔基、环烷基烷基、芳基、芳酰基、芳氧基、芳基氨基、  Cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,     联芳基、硫代芳基、二芳基氨基、杂环基、烷基芳基、芳链  Biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aromatic chain     烯基、芳烷基、烷基杂环基、杂环基烷基、氨基甲酸酯基、Alkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate,     芳氧基烷基、氢和-C(O)NH(苄基)基团；Aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups;         其中R18、R24、R25和R34为未取代基团或被至少一个给Wherein R 18 , R 24 , R 25 and R 34 are unsubstituted groups or are given by at least one             电子或吸电子基团取代的基团；A group substituted with an electron or electron-withdrawing group;         以及其中R24和R25一起可形成一个环；and wherein R 24 and R 25 together may form a ring; 前提是当R24和R25一起形成一个环时，所形成的环不是苯。Provided that when R24 and R25 together form a ring, the ring formed is not benzene. 21.权利要求20的化合物，其中R34为氢；R18为芳烷基；而R24和R25各自独立为氢、低级烷基和其中R24和R25一起可形成一个环的低级烷基。21. The compound of claim 20, wherein R 34 is hydrogen; R 18 is aralkyl; and R 24 and R 25 are each independently hydrogen, lower alkyl, and lower alkane wherein R 24 and R 25 together can form a ring base. 22.一种以下结构式的权利要求20的化合物，
Figure A0114518200171
其中R24和R25各自独立选自氢、卤素、烷基、链烯基、链炔基、22. A compound of claim 20 of the formula,
Figure A0114518200171
Wherein R 24 and R 25 are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, 烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族Alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic 酰基、-CF3、巯基、羟基、-CO2H、氰基、硝基、氨基、链炔Acyl, -CF 3 , Mercapto, Hydroxyl, -CO 2 H, Cyano, Nitro, Amino, Alkyne 基氨基、烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3 Amino, alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 烷基)、-NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-Alkyl), -NHC(O)N(C 1 -C 3 Alkyl)C(O)NH(C 1 -C 3 Alkyl), - NHC(O)NH(C1-C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳NHC (O) NH (C 1 -C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl 基)、烷氧基烷基、烷基氨基、链烯基氨基、二(C1-C3)氨基、group), alkoxyalkyl, alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C1-C3)烷基、-C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷-C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3 alkane 基)2、-CH＝NOH、-PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧radical) 2 , -CH=NOH, -PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy 基、甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基group, formaldehyde group, formamide group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, cycloalkyl group 烷基、芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳Alkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl 基、二芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、base, diarylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, 烷基杂环基、杂环基烷基、磺酰基、-SO2-(C1-C3烷基)、-Alkyl heterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(C 1 -C 3 alkyl), - SO3-(C1-C3烷基)、亚磺酰氨基、氨基甲酸酯基、芳氧基烷基SO 3 -(C 1 -C 3 alkyl), sulfonylamino, carbamate, aryloxyalkyl 和-C(O)NH(苄基)基团；R34选自烷基、链烯基、链炔基、羟烷基、脂族酰基、链炔基氨基、and -C(O)NH(benzyl) groups; R is selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, 烷氧羰基、杂环酰基、-CH＝NOH、卤代烷基、烷氧基烷氧基、Alkoxycarbonyl, heterocyclic acyl, -CH=NOH, haloalkyl, alkoxyalkoxy, 甲醛基、甲酰胺基、环烷基、环烯基、环炔基、环烷基烷基、Formaldehyde, formamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, 芳基、芳酰基、芳氧基、芳基氨基、联芳基、硫代芳基、二Aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, di 芳基氨基、杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂Arylamino, heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylhetero 环基、杂环基烷基、氨基甲酸酯基、芳氧基烷基、氢和-Cyclic, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and - C(O)NH(苄基)基团；以及R35在每次出现时独立选自卤素、羟基、烷基、链烯基、链炔基、C(O)NH(benzyl) group; and R at each occurrence is independently selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, 烷氧基、链烯氧基、链炔氧基、硫代烷氧基、羟烷基、脂族Alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, hydroxyalkyl, aliphatic 酰基、-CF3、-CO2H、巯基、氰基、硝基、氨基、链炔基氨基、Acyl, -CF 3 , -CO 2 H, mercapto, cyano, nitro, amino, alkynylamino, 烷氧羰基、杂环酰基、羧基、-N(C1-C3烷基)-C(O)(C1-C3烷基)、Alkoxycarbonyl, heterocyclic acyl, carboxyl, -N(C 1 -C 3 alkyl)-C(O)(C 1 -C 3 alkyl), -NHC(O)N(C1-C3烷基)C(O)NH(C1-C3烷基)、-NHC(O)NH(C1--NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C 1 -C 3 alkyl), -NHC(O)NH(C 1 - C6烷基)、-NHSO2(C1-C3烷基)、-NHSO2(芳基)、烷氧基烷基、C 6 alkyl), -NHSO 2 (C 1 -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, 烷基氨基、链烯基氨基、二(C1-C3)氨基、-C(O)O-(C1-C3)烷基、Alkylamino, alkenylamino, di(C 1 -C 3 )amino, -C(O)O-(C 1 -C 3 )alkyl, -C(O)NH-(C1-C3)烷基、-C(O)N(C1-C3烷基)2、-CH＝NOH、-C(O)NH-(C 1 -C 3 )alkyl, -C(O)N(C 1 -C 3alkyl ) 2 , -CH=NOH, -PO3H2、-OPO3H2、卤代烷基、烷氧基烷氧基、甲醛基、甲酰-PO 3 H 2 , -OPO 3 H 2 , haloalkyl, alkoxyalkoxy, formaldehyde, formyl 胺基、环烷基、环烯基、环炔基、环烷基烷基、芳基、芳酰Amino, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl 基、芳氧基、芳基氨基、联芳基、硫代芳基、二芳基氨基、group, aryloxy group, arylamino group, biaryl group, thioaryl group, diarylamino group, 杂环基、烷基芳基、芳链烯基、芳烷基、烷基杂环基、杂环Heterocyclyl, alkylaryl, arylalkenyl, aralkyl, alkylheterocyclyl, heterocycle 基烷基、磺酰基、-SO2-(C1-C3烷基)、-SO3-(C1-C3烷基)、亚Alkyl, Sulfonyl, -SO 2 -(C 1 -C 3 Alkyl), -SO 3 -(C 1 -C 3 Alkyl), Alkylene 磺酰氨基、氨基甲酸酯基、芳氧基烷基和-C(O)NH(苄基)基Sulfonylamino, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) 团；group;     其中R24、R25、R34和R35为未取代基团或被至少一个给Wherein R 24 , R 25 , R 34 and R 35 are unsubstituted groups or are given by at least one         电子或吸电子基团取代的基团；以及groups substituted with electron or electron-withdrawing groups; and m为0-5的整数。m is an integer of 0-5. 23.权利要求22的化合物，其中R34为氢；m为0-3的整数，而R35在每次出现时选自烷基、卤素、烷氧基、卤代烷基、磺酰基、羟基和氰基。23. The compound of claim 22, wherein R 34 is hydrogen; m is an integer from 0 to 3, and R 35 is selected from the group consisting of alkyl, halogen, alkoxy, haloalkyl, sulfonyl, hydroxyl and cyano in each occurrence base. 24.权利要求20的化合物，它选自：5-(2-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-苄基-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-苄基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，5-二甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，4-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，5-二氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(甲硫基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3，5-二(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-叔丁基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-溴苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3，4-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[4-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(吡啶-2-基甲基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，4-二氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(三氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[4-(三氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，3-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3，5-二甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-戊基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，4-二氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-乙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-丁基-5-(2-氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(三氟甲基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氯苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-氟苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，7-甲基-5-[4-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，4-(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]-N，N-二甲基苯磺酰胺，5-(萮基甲基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-3，5，6，7，8，9-六氢[1，3]噁唑并[4，5-c]喹啉-2，4-二酮，5-(2-氯苄基)-7-乙基-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(甲硫基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，2-[(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]-N，N-二甲基苯磺酰胺，5-(2，6-二甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(三氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-6，7-二甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯-2-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-5，6，7，8，9，10-六氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-[2-(二氟甲氧基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-甲基-5-[(1R)-1-苯乙基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(4-氯苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，3-氯-2-[(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]苄腈，5-(2-氯-6-甲基苄基)-6，7-二甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，2-[(2，4-二氧代-2，3-二氢[1，3]噁唑并[4，5-c]吡啶-5(4H)-基)甲基]苄腈，5-(2-氯-6-甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(甲硫基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-环丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-甲基-5-(4-甲基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(3，5-二甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，6-二氟苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[3-(甲基磺酰基)苄基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氟-6-甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲氧基苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(5-氯-2-氟苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-异丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(5-氟-2-甲基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，7-甲基-5-[(1S)-1-苯基乙基基]-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-异丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(5-乙酰基-2-甲氧基苄基)-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-d]哒嗪-2，4-二酮，5-[2-氟-6-(三氟甲基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-甲基苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-(2-氯-6-乙氧基苄基)-7-乙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-异丁氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-(2-氯-6-异丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-6-(2，2，2-三氟乙氧基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-d]哒嗪-2，4-二酮，5-[2-氯-6-(2-甲氧基乙氧基)苄基]-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-(2-氯-6-乙氧基苄基)-6，7-二甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-乙基-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯苄基)-7-乙基-3，5-二氢[1，3]噁唑并[4，5-d]哒嗪-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-7-环丙基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-丙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-甲氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-6-乙氧基苄基)-6-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2-氯-5-乙氧基苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(哌啶-1-基磺酰基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-5-(吡咯烷-1-基磺酰基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-氯-6-(环戊基甲氧基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-[2-(苄氧基)-6-氯苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮，5-(2，3-二氯-6-乙氧基苄基)-5，6，7，8-四氢-2H-环戊二烯并[b][1，3]噁唑并[5，4-d]吡啶-2，4(3H)-二酮，5-[2-氯-5-(三氟甲基)苄基]-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮和5-(2-氯-5-氟苄基)-7-甲基-3，5-二氢[1，3]噁唑并[4，5-c]吡啶-2，4-二酮。24. The compound of claim 20, which is selected from the group consisting of: 5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-di Ketone, 5-(2-chlorobenzyl)-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-( 2-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-fluorobenzyl) -3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-benzyl-6-methyl-3,5-dihydro[1, 3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-benzyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-(2,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4-dichloro Benzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-methoxybenzyl)-3,5- Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,5-difluorobenzyl)-3,5-dihydro[1,3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(methylthio)benzyl]-3,5-dihydro[1,3]oxazole And[4,5-c]pyridine-2,4-dione, 5-(4-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine- 2,4-diketone, 5-(2-chloro-5-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4- Diketone, 5-[3,5-bis(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione , 5-(4-tert-butylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl Base)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxa Azolo[4,5-c]pyridine-2,4-dione, 5-(2-bromobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-dione, 5-(3,4-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione , 5-(4-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6 -methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(trifluoromethyl)benzyl Base]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methylbenzyl)-3,5-dihydro [1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(pyridin-2-ylmethyl)-3,5-dihydro[1,3]oxazolo [4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5- c] pyridine-2,4-dione, 5-(2,4-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4 -diketone, 5-(2,6-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[ 3-(trifluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(tri Fluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(trifluoromethyl) Benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methoxybenzyl)-3,5- Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,3-dichlorobenzyl)-3,5-dihydro[1,3] Oxazolo[4,5-c]pyridine-2,4-dione, 5-(3,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4, 5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-pentyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-(2,4-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-(2-chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione , 7-butyl-5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2 -Chloro-5-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2, 6-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-fluorobenzyl )-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methylbenzyl)-7-methyl Base-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-7-methyl-3,5 -Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-5,6,7,8-tetrahydro-2H- Cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 7-methyl-5-[4-(methylsulfonyl ) benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-methoxybenzyl)-3,5 -Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-propyl-3,5-dihydro[1 ,3]oxazolo[4,5-c]pyridine-2,4-dione, 4-(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4, 5-c]pyridin-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide, 5-(helicylmethyl)-3,5-dihydro[1,3]oxazole And[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-3,5,6,7,8,9-hexahydro[1,3]oxazolo[ 4,5-c]quinoline-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazolo [4,5-c]pyridine-2,4-dione, 5-[2-(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c ]pyridine-2,4-dione, 2-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridine-5(4H)- Base) methyl]-N,N-dimethylbenzenesulfonamide, 5-(2,6-dimethoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-[2-(trifluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-(2-chlorobenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-[2-chloro-5-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2, 4-diketone, 5-(4-chloro-2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione , 5-(2-chlorobenzyl)-5,6,7,8,9,10-hexahydro-2H-cyclopentadiene[b][1,3]oxazolo[5,4-d ]pyridine-2,4(3H)-dione, 5-[2-(difluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c] Pyridine-2,4-dione, 7-methyl-5-[(1R)-1-phenylethyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-(4-chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4- Diketone, 5-[2-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5- (2,6-Dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 3-chloro-2-[( 2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2-chloro -6-methylbenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 2-[ (2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2- Chloro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3 -(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)- 7-cyclopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl)-7-methyl -3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dichlorobenzyl)-7-methyl-3 , 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-5-(4-methylbenzyl)-3,5-di Hydrogen[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3,5-dimethoxybenzyl)-7-methyl-3,5-di Hydrogen[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-difluorobenzyl)-7-methyl-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxa Azolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-3,5-dihydro[1,3]oxazolo[4 , 5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[ 4,5-c]pyridine-2,4-dione, 5-(2-fluoro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo [4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazole And[4,5-c]pyridine-2,4-dione, 5-(5-chloro-2-fluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo [4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-isopropyl-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-(5-fluoro-2-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 7-methyl-5-[(1S)-1-phenylethyl]-3,5-dihydro[1,3]oxazolo[4, 5-c]pyridine-2,4-dione, 5-(2-chloro-5-isopropoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[ 4,5-c]pyridine-2,4-dione, 5-(5-acetyl-2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine -2,4-diketone, 5-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5 -c]pyridine-2,4-dione, 5-(2-chloro-6-methylbenzyl)-5,6,7,8-tetrahydro-2H-cyclopentadiene[b][1 , 3] Oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-6-ethoxybenzyl)-7-ethyl-3,5- Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-propoxybenzyl)-7-methyl-3,5 -Dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-isobutoxybenzyl)-7-methyl-3 , 5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-5,6,7 , 8-tetrahydro-2H-cyclopentadieno[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro- 6-isopropoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2- Chloro-6-(2,2,2-trifluoroethoxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2 , 4-diketone, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine -2,4-diketone, 5-[2-chloro-6-(2-methoxyethoxy)benzyl]-5,6,7,8-tetrahydro-2H-cyclopentadieno[ b] [1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-6-ethoxybenzyl)-6,7-dione Methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7 -Ethyl-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7 -Ethyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl) -7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl )-7-cyclopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-propoxy Benzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-methoxy benzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethane Oxybenzyl)-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5- Ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5 -(piperidin-1-ylsulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-Chloro-5-(pyrrolidin-1-ylsulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine -2,4-diketone, 5-[2-chloro-6-(cyclopentylmethoxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4 ,5-c]pyridine-2,4-dione, 5-[2-(benzyloxy)-6-chlorobenzyl]-7-methyl-3,5-dihydro[1,3]oxazole And[4,5-c]pyridine-2,4-dione, 5-(2,3-dichloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-ring Pentadieno[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-[2-chloro-5-(trifluoromethyl)benzyl Base]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione and 5-(2-chloro-5-fluorobenzyl )-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione. 25.一种化合物，它选自：(3S)-3-[({[2-甲基-4-(2-甲基丙基)-6-氧代-1-(苯甲基)-1，6-二氢-5-嘧啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-[({[2-氧代-1-(苯甲基)-4-丙基-1，2-二氢-3-吡啶基]氨基}羰基)氨基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-乙基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-丙基-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({6-甲基-2-氧代-1-(苯甲基)-4-[(苯甲基)氧基]-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-2，4-二甲基-6-氧代-1，6-二氢-5-嘧啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲基]-6-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[4-(甲氧基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3，4-二甲基苯基)丙酸，(3S)-3-{[({4-氨基-1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-(1，4-噁嗪烷-4-基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-[(2-氯代苯基)甲基]-2-氧代-4-(丙基氨基)-1，2-二氢-3-吡啶基]氨基}羰基)氨基基]-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-溴代苯基)甲基]-4-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-甲基-4-(甲氧基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-2-氧代-4-苯基-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[(2-{[2-(甲氧基)乙基]氧基}乙基)氧基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-6-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[(1，1-二甲基乙基)氨基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{{({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-苯基丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-[4-甲基四氢-1(2H)-哌嗪基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[4-(甲氧基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3，5-二甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(3-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-(甲氧基)苯基]丙酸，(3S)-3-[3，5-二(甲氧基)苯基]-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-喹啉基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-[3-(三氟甲基)苯基]丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-4-({乙基[(乙基氨基)羰基]氨基}羰基)氨基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({4-(1-azetanyl)-1-[(2-氯代苯基)甲基]-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-[(2-氯代苯基)甲基]-4-({2-[(2-{[2-(甲氧基)乙基]氧基}乙基)氧基]乙基}氧基)-2-氧代-1，2-二氢-3-吡啶基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氟代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯-6-氟代苯基)甲基]-4-羟基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯代苯基)甲基]-5-甲基-2-氧代-1，2-二氢-3-吡啶基}氨基)羰基)氨基}-3-(4-甲基苯基)丙酸，(3S)-3-(1，3-苯并二氧杂环戊-5-基)-3-((((2-氧代-1-((4-(三氟甲基)苯基)甲基)-1，2-二氢-3-吡啶基)氨基)羰基)氨基)丙酸，(3S)-3-((((1-((2-氯代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-氟代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-溴代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2，4-二氯苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-氯-6-氟代苯基)甲基)-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-((((1-((2-氯代苯基)甲基)-4-羟基-2-氧代-1，2-二氢-3-吡啶基)氨基)羰基)氨基)-3-(4-三氟甲基)氧基)苯基)丙酸(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，4-{[3-[({[(1S)-2-羧基-1-(4-甲基苯基)乙基]氨基}羰基)氨基]-1-(2-氯苄基)-2-氧代-1，2-二氢吡啶-4-]氨基}苯甲酸(3S)-3-{[({1-[(2-氯代苄基)-4-[(2，2-二甲基丙酰基)氨基]-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[4-{[(叔丁基氨基)羰基]氨基}-1-(2-氯苄基)-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氰基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2，3-二氢-1，4-苯并二氧杂环己-6-基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(7-甲氧基-1，3-苯并二氧杂环戊-5-基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基-4-甲氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲氧基苯基)丙酸，(3S)-3-[({[1-(4-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2，6-二氟苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-甲氧基-4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲氧基-4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-5-乙基-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-{[({1-[2-氯-5-(三氟甲基)苄基]-4-羟基-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2，6-二甲氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-5-丙基-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-5-丙基-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-(3-丁氧基苯基)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]丙酸，(3S)-3-{[({1-[2-氯-5-(甲基磺酰基)苄基]-4-羟基-2-氧代-1，2-二氢吡啶-3-基}氨基)羰基]氨基}-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(2-甲氧基乙氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(二氟甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-氰基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(2-萘基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基)氨基}羰基)氨基)]-3-(3，4-二乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-甲基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基)氨基}羰基)氨基)-3-(2，3-二氢-1-苯并呋喃-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二乙氧基苯基)丙酸，(3S)-3-[({[5-氯-1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-苯基丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(1，3-二乙基-2-氧代-2，3-二氢-1H-苯并咪唑-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基)氨基}羰基)氨基]-3-[3-(三氟甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5，6-二甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-5-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-5-环丙基-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-5-环丙基-4-羟基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-5-甲氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基)氨基}羰基)氨基)-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-6-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(1-甲基-1H-吲哚-6-基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙基甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-[3-(环丙基甲氧基)苯基]丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3，5-二甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(二氟甲基)氧基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(1，1，2，2-四氟乙基)氧基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1-乙基-1H-吲哚-5-基)丙酸和(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-[3-(二乙基氨基)苯基]丙酸，以及它们的药学上可接受的盐。25. A compound selected from the group consisting of: (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(benzyl)-1 , 6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-(1,3-benzodioxol- 5-yl)-3-[({[2-oxo-1-(phenylmethyl)-4-propyl-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl ]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-propane Base-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2- Chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid , (3S)-3-{[({6-methyl-2-oxo-1-(benzyl)-4-[(benzyl)oxy]-1,2-dihydro-3- Pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2, 4-Dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{ [({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1 , 2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[4-(methoxy)phenyl]propanoic acid, (3S)-3-{[({1-[(2- Chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(3,4-dimethylphenyl )propionic acid, (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl} Amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2 -Oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-[({[1-[( 2-Chlorophenyl)methyl]-4-(1,4-oxazinan-4-yl)-2-oxo-1,2-dihydro-3-pyridyl]amino}carbonyl)amino] -3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4-(propylamino )-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2 -Bromophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propane acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino) Carbonyl]amino}-3-[3-methyl-4-(methoxy)phenyl]propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl] -2-oxo-4-phenyl-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{ [({1-[(2-chlorophenyl)methyl]-4-[(2-{[2-(methoxy)ethyl]oxy}ethyl)oxy]-2-oxo -1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chloro Substituted phenyl)methyl]-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl ) propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(1,1-dimethylethyl)amino]-2-oxo -1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{{({1-[(2-chloro Substituted phenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-phenylpropionic acid, (3S)-3-{ [({1-[(2-Chlorophenyl)methyl]-4-[4-methyltetrahydro-1(2H)-piperazinyl]-2-oxo-1,2-dihydro- 3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]- 4-Hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[4-(methoxy)phenyl]propanoic acid, (3S)-3- {[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-( 3,5-Dimethylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2 -Dihydro-3-pyridyl}amino)carbonyl]amino}-3-(3-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chlorophenyl) Methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3-(methoxy)phenyl]propanoic acid, (3S )-3-[3,5-bis(methoxy)phenyl]-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2-oxo-1 , 2-dihydro-3-pyridyl}amino)carbonyl]amino}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxyl-2 -Oxo-1,2-dihydro-3-quinolyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (3S)-3-{[({1-[( 2-Chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl) Phenyl]propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-({ethyl[(ethylamino)carbonyl]amino}carbonyl)amino ]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({4 -(1-azetanyl)-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4 -Methylphenyl)propanoic acid, (3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-({2-[(2-{[2-(methyl Oxy)ethyl]oxy}ethyl)oxy]ethyl}oxy)-2-oxo-1,2-dihydro-3-pyridyl]amino}carbonyl)amino]-3-(4 -Methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro- 3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-{[({1-[(2-chloro-6-fluorophenyl) Methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3 -{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl)amino}-3 -(4-methylphenyl)propionic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-((((2-oxo-1-( (4-(trifluoromethyl)phenyl)methyl)-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)propanoic acid, (3S)-3-((((1-( (2-chlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl)propionic acid, ( 3S)-3-((((1-((2-fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3- (4-methylphenyl)propanoic acid, (3S)-3-((((1-((2-bromophenyl)methyl)-2-oxo-1,2-dihydro-3- Pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl)propionic acid, (3S)-3-((((1-((2,4-dichlorophenyl)methyl)- 2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl)propionic acid, (3S)-3-((((1-( (2-Chloro-6-fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridyl)amino)carbonyl)amino)-3-(4-methylphenyl) Propionic acid, (3S)-3-((((1-((2-chlorophenyl)methyl)-4-hydroxy-2-oxo-1,2-dihydro-3-pyridyl)amino )carbonyl)amino)-3-(4-trifluoromethyl)oxy)phenyl)propanoic acid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)- 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, 4-{[3-[({[(1S) -2-carboxy-1-(4-methylphenyl)ethyl]amino}carbonyl)amino]-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridine-4- ]amino}benzoic acid (3S)-3-{[({1-[(2-chlorobenzyl)-4-[(2,2-dimethylpropionyl)amino]-2-oxo-1 , 2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3-[({[4-{[(tert-butylamino )carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl) Propionic acid, (3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino ]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydro Pyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1,4-benzodioxan-6-yl)propanoic acid, (3S)-3-[( {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(7-methoxy-1 , 3-benzodioxol-5-yl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-1,2 -Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid, (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dimethoxyphenyl)propionic acid , (3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino)-3 -(4-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2 -Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4 -Hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3 -[({[1-(2,6-difluorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4 -methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxyl-2-oxo-1,2-dihydro Pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)- 4-Hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3 -[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxy (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxy-4-methylphenyl)propanoic acid, (3S)-3- [({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-di Methylphenyl) propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl Base]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid, (3S)-3- [({[1-(2-Chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- (3-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl )-4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4- Methylphenyl) propanoic acid, (3S)-3-[({[1-(2,6-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propionic acid, (3S)-3-[({[1-(2 -Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl) Propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3- Base]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo -5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propionic acid, (3S)-3-(3 -Butoxyphenyl)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino ]propanoic acid, (3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2- Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(2-methoxyethoxy)phenyl]propanoic acid, (3S)-3-[ ({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dipropane Oxyphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3-[3-(difluoromethoxy)phenyl]propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-5- Methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3- [({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-( 3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5,6-dimethyl-2- Oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propionic acid, (3S)-3-[({[1 -(2-Chloro-6-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylbenzene base) propionic acid, 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3 -(2-naphthyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2 -Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro- 6-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino}carbonyl)amino)]-3-(3,4- Diethoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl ]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl Base-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methoxyphenyl)propionic acid, (3S)-3-[({[ 1-(2-Chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl ]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4- Hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid, (3S)-3-[({[ 1-(2-Chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3 -(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2 , 5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propionic acid, (3S) -3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl )-4-hydroxyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino}carbonyl)amino)-3-(2,3-dihydro-1-benzofuran -5-yl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7 -Tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-diethoxyphenyl)propionic acid, (3S)-3- [({[5-chloro-1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino ]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-2-oxo -1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, (3S)-3-[({[1-(2- Chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl )amino]-3-(3-propoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-2- Oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoic acid, (3S)-3- [({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl] Amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)propanoic acid, (3S)-3-[ ({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino}carbonyl)amino ]-3-[3-(trifluoromethoxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl- 5,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S) -3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadieno[b]pyridine-3 -yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propionic acid, (3S)-3-[({[1-(2-chloro-6-ethyl Oxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxybenzene base) propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2- Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-5-methoxy benzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino}carbonyl)amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-Chloro-6-ethoxybenzyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3- Base]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)- 4-Hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6-yl) Propionic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropoxy)phenyl]propanoic acid, (3S)-3-[({[1 -(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino ]-3-[3-(cyclopropylmethoxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy -2-Oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethyl Oxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -Cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethylphenyl)propionic acid, (3S)-3-{[({1- [(2-Chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino) Carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]- 4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[( 1,1,2,2-tetrafluoroethyl)oxy]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy- 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadieno[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1-ethyl-1H-ind Indol-5-yl)propionic acid and (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7- Tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propionic acid, and their pharmaceutically acceptable of salt. 26.(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸及其药学上可接受的盐。26. (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl)amino]-3-(4-methylphenyl)propionic acid and pharmaceutically acceptable salts thereof. 27.(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸及其药学上可接受的盐。27. (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene[ b] pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid and pharmaceutically acceptable salts thereof. 28.(3S)-3-[({[1-(2-氯苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-[3-(二乙基氨基)苯基]丙酸及其药学上可接受的盐。28. (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino} Carbonyl)amino]-3-[3-(diethylamino)phenyl]propionic acid and pharmaceutically acceptable salts thereof. 29.一种化合物，它选自：(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(4-甲基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(3-乙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-异丙氧基苯基)丙酸，(3S)-3-[({[1-(2-氯-6-乙氧基苄基)-4-羟基-5-甲基-2-氧代-1，2-二氢吡啶-3-基]氨基}羰基)氨基]-3-(6-甲氧基-2-萘基)丙酸，(3S)-3-[({[1-(2-氯苄基)-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基]氨基}羰基)氨基]-3-(3-甲基苯基)丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1-甲基-1H-吲哚-5-基)丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[甲基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[甲基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[乙基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-{3-[乙基(甲基磺酰基)氨基]苯基}丙酸，(3S)-3-{[({1-[(2-氯-6-甲基苯基)甲基]-4-羟基-2-氧代-2，5，6，7-四氢-1H-环戊二烯并[b]吡啶-3-基}氨基)羰基]氨基}-3-(1H-吲哚-5-基)丙酸，以及它们的药学上可接受的盐。29. A compound selected from the group consisting of: (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxyl-5-methyl-2-oxo- 1,2-Dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propionic acid, (3S)-3-[({[1-(2-chloro-6 -ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxybenzene base) propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene Ekeno[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro- 6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy -2-naphthyl)propionic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H -cyclopentadien[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2 -Chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl} Amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl] -4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ (Methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo Generation-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino] Phenyl}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H-Cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3 -{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadiene And[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1 -[(2-Chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino )carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro-6-methyl Phenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}- 3-{3-[Ethyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl] -4-Hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1H-ind Indol-5-yl) propionic acid, and their pharmaceutically acceptable salts. 30.一种药用组合物，该组合物包含：30. A pharmaceutical composition comprising: 权利要求1的化合物和药学上可接受的载体。The compound of claim 1 and a pharmaceutically acceptable carrier. 31.一种选择性抑制哺乳动物α4β1整联蛋白结合的方法，该方法包括给予所述哺乳动物治疗量的权利要求1化合物。31. A method of selectively inhibiting [alpha] 4 [beta ]l integrin binding in a mammal, the method comprising administering to said mammal a therapeutic amount of a compound of claim 1.
CNB011451823A 2001-10-09 2001-12-29 Carboxylic acid derivatives inhibiting the binding of integrins to their receptors Expired - Fee Related CN100491353C (en)

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US09/973,142 US6972296B2 (en) 1999-05-07 2001-10-09 Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US09/973142 2001-10-09

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CN110914242A (en) * 2017-04-26 2020-03-24 阿维亚拉药品有限公司 Propionic acid derivatives and methods of use thereof
WO2024051819A1 (en) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Propionic acid derivative and use thereof in medicine
WO2025124544A1 (en) * 2023-12-14 2025-06-19 华润医药研究院（深圳）有限公司 3,4-dihydro-2h-benzo[b][1,4]dioxepane compound, and preparation method therefor and pharmaceutical use thereof

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Publication number Priority date Publication date Assignee Title
CN102459179A (en) * 2009-04-27 2012-05-16 艾伦药物公司 Pyridinone antagonists of alpha-4 integrins
CN110914242A (en) * 2017-04-26 2020-03-24 阿维亚拉药品有限公司 Propionic acid derivatives and methods of use thereof
CN110914242B (en) * 2017-04-26 2023-07-25 阿维亚拉药品有限公司 Propionic acid derivatives and methods of use thereof
WO2024051819A1 (en) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Propionic acid derivative and use thereof in medicine
WO2025124544A1 (en) * 2023-12-14 2025-06-19 华润医药研究院（深圳）有限公司 3,4-dihydro-2h-benzo[b][1,4]dioxepane compound, and preparation method therefor and pharmaceutical use thereof

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CA2366800C (en) 2010-08-10

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