JP2023000996A - Ketoamide derivatives as protease inhibitors - Google Patents

Abstract

To provide ketoamide derivative compounds having main protease (Mpro) inhibitory activity and useful for the treatment or prevention of the risk of disorders, diseases, and sequelae caused by viral infections; pharmaceutical compositions comprising these compounds; and the use of these compounds and compositions in the prevention or treatment of diseases caused by viruses including coronaviruses.SOLUTION: Compounds represented by the general formula (I) are used.SELECTED DRAWING: None

Description

The present invention relates to ketoamide derivatives with main protease (M ^pro ) inhibitory activity that are useful in the treatment or prevention of disorders, diseases, or sequelae caused by viruses, including coronaviruses. The present invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds by administering an amount of the main protease (M ^pro ) inhibitor effective to inhibit the growth of viruses, including coronaviruses. .

The main protease (M ^pro ), also called 3C-like protease (3CL ^pro ), is a cysteine protease found in positive-sense single-stranded RNA viruses such as coronaviruses. It is the major protease in the coronavirus life cycle and corresponds to nonstructural protein 5 (nsp5). The coronavirus polyprotein is cleaved at 11 conserved sites (Non-Patent Documents 1 and 2). The main protease (M ^pro ) plays an essential role in processing polyproteins translated from viral RNA, and is therefore expected as a drug target for coronavirus infections.

When (SARS-CoV-2) infects host cells, large precursor proteins are translated from viral RNA. This precursor protein is cleaved by various proteases into functional proteins required for viral replication, such as the RNA-dependent RNA polymerase. It plays an important role in the cleavage of precursor proteins and is a protease essential for viral propagation. Therefore, inhibitors of this "main protease" have become antiviral agents and are being developed worldwide. However, no effective compound has yet been found that can be marketed. Therefore, for this purpose, we searched for a novel substance having main protease activity, and finally completed the present invention. INDUSTRIAL APPLICABILITY The present invention inhibits the main protease (M ^pro ) in suppressing the growth of viruses including SARS-CoV-2 (COVID-19) and is useful for treating or preventing disease states or disorders caused by viruses.

Historically, Pfizer has published in WO2005/113580 and WO2006/061714 main protease (M ^pro ) inhibitors or 3C-like proteases targeting SARS-CoV and MERS-CoV. Anti-coronavirus compounds are disclosed as inhibitors. Pfizer recently announced that PF-07321332 is being developed in clinical trials in combination with the PK booster ritonavir. It has been suggested that PF-07321332 alone is insufficient to maintain effective blood levels (Non-Patent Document 3).

Recently, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, in WO2020/030143 (Patent Document 3), a ketoamide compound having a dioxo unit for the prevention or treatment of coronavirus-related diseases and Ebola virus-related diseases disclosed. THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY, in WO2021/226546, discloses ketoamide compounds for the treatment or prevention of diseases associated with coronavirus infection.

However, there is still no effective treatment for the new coronavirus (SARS-CoV-2 (COVID-19)), and there is an urgent need to develop therapeutic drugs for coronavirus infections.

Maier et al. Methods in Molecular Biology, Vol. 1282, DOI 10.1007/978-1-4939-2438-7_1, 2015 Fan et al. THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 279, No. 3, Issue of January 16, pp. 1637-1642, 2004 Owen et al., Science, DOI: 10.1126/science.abl4784, 2021.

WO2005/113580 WO2006/061714 WO2020/030143 WO2021/226546

Technical problems

It is an object of the present invention to provide novel main protease (M ^pro ) inhibitors that are excellent drugs for the treatment or prevention of conditions or disorders caused by viruses, including coronaviruses. They have favorable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion. They are non-toxic and show few side effects. Furthermore, the ideal drug candidate exists in a physical form that is stable, non-hygroscopic, and easy to formulate.

Relative to other compounds disclosed in the art, the compounds of the present invention exhibit low toxicity, favorable absorption and distribution, favorable solubility, favorable plasma protein binding, less drug-drug interactions, favorable metabolic stability, human It can exhibit low inhibitory activity and/or low QT prolongation activity on delayed rectifier potassium ion channel gene (hERG) channel.

（式中：
R¹およびR²は、(1)水素、(2)ハロゲン、(3)ヒドロキシル、(4)C_1-6アルキル、(5)-O-C_1-6アルキル、(6)C_3-7シクロアルキル、(7)C_3-7シクロアルコキシ、(8)C_2-6アルケニル、(9)-NR^aR^b、(10)(R^a)(R^b)N-C_1-6アルキル、(11)ヘテロシクリル、(12)アリール、(13)ヘテロアリール、(14)アリールC_1-6アルキル、(15)ヘテロアリールC_1-6アルキル、(16)-CN、および(17)C_3-7シクロアルキルC_1-6アルキルからなる群から独立して選択され；ここで、該C_1-6アルキル、該-O-C_1-6アルキル、該C_3-7シクロアルキル、該C_3-7シクロアルコキシ、該C_2-6アルケニル、該ヘテロシクリル、該アリール、該ヘテロアリール、該アリールC_1-6アルキル、該ヘテロアリールC_1-6アルキル、または該C_3-7シクロアルキルC_1-6アルキルは、(1)ヒドロキシル、(2)ハロゲン、および(3)C_1-6アルキルからなる群から独立して選択される1～6個の置換基で任意に置換され；
または、R¹は、R²とN、O、S、二重結合、またはカルボニルを含んでもよい4～7員環を形成してもよく；ここで、該4～7員環は、(1)ヒドロキシル、(2)ハロゲン、および(3)C_1-6アルキルからなる群から独立して選択される1～6個の置換基で任意に置換され；
R^aおよびR^bは、(1)水素、(2)C_1-6アルキル、(3)C_3-7シクロアルキル、(4)ヘテロシクリル、(5)C_3-7シクロアルキルC_1-6アルキル、(6)ヘテロシクリルC_1-6アルキル、(7)アリール、(8)アリールC_1-6アルキル、(9)ヘテロアリール、および(10)ヘテロアリールC_1-6アルキルからなる群から独立して選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該アリールC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6アルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換され；
または、R^aはR^bと、N、O、S、二重結合、またはカルボニルを含んでもよい4～7員環を形成してもよく；ここで、該4～7員環は、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、およびC_1-6アルコキシルからなる群から独立して選択される1つまたは複数の置換基で置換され；
Xは、-CH₂-、-NH-、-N(C_1-6アルキル)-、-O-、または-S-であり；
R³は、(1)水素、(2)C_1-6アルキル、(3)C_2-6アルケニル、(4)C_3-7シクロアルキル、(5)ヘテロシクリル、(6)アリール、(7)ヘテロアリール、(8)フェニルC_1-6アルキル、(9)フェニル-Q-ヘテロアリール、(10)フェニル-Q-フェニル、(11)ヘテロアリール-Q-フェニル、(12)ヘテロアリール-Q-ヘテロアリール、(13)-(C=O)C_1-6アルキル、および(14)-(C=O)C_1-6ハロアルキルからなる群から選択され；ここで、該C_1-6アルキル、該C_2-6アルケニル、該C_3-7シクロアルキル、該ヘテロシクリル、該アリール、該ヘテロアリール、該フェニルC_1-6アルキル、該フェニル-Q-ヘテロアリール、該フェニル-Q-フェニル、該ヘテロアリール-Q-フェニル、または該ヘテロアリール-Q-ヘテロアリールは、(1)ヒドロキシル、(2)ハロゲン、(3)C_1-6アルキル、(4)C_1-6ハロアルキル、(5)C_1-6アルコキシ、(6)C_1-6ハロアルコキシ、(7)C_3-7シクロアルキル、(8)ヘテロシクリル、(9)-SF₅、(10)-SR^c、(11)-CN、(12)シアノ置換C_1-6アルキル、(13)-NR^cR^d、(14)-NR^e(C=O)R^c、(15)-(C=O)NR^cR^d、(16)-(C=O)R^c、(17)-CO₂R^c、(18)-NR^e(C=O)NR^cR^d(19)-NR^e(C=O)OR^c、(20)-NR^eSO₂R^c、(21)-SO₂NR^cR^d、(22)-NR^eSO₂NR^cR^d、(23)-S(O)R^c、(24)-SO₂R^c、(25)-O(C=O)R^c、および(26)ニトロからなる群から独立して選択される1～6個の置換基で任意に置換され；好ましくは、R³は、(6)アリール、および(7)ヘテロアリール；より好ましくは、R³は、(6a)2,4-置換アリール、および(7a)2,4-置換ヘテロアリールからなる群から選択され；さらに好ましくは、R³は、(6aa)4-置換フェニル、および(7aa)4-置換ヘテロアリールからなる群から選択され；ここで、置換基は、(1)ヒドロキシル、(2)ハロゲン、(3)C_1-6アルキル、(4)C_1-6ハロアルキル、(5)C_1-6アルコキシ、(6)C_1-6ハロアルコキシ、(7)C_3-7シクロアルキル、(8)ヘテロシクリル、(9)-SF₅、(10)-SR^c、(11)-CN、(12)シアノ置換C_1-6アルキル、(13)-NR^cR^d、 (14)-NR^e(C=O)R^c、(15)-(C=O)NR^cR^d、(16)-(C=O)R^c、(17)-CO₂R^c、(18)-NR^e(C=O)NR^cR^d、(19)-NR^e(C=O)OR^c、(20)-NR^eSO₂R^c、(21)-SO₂NR^cR^d、(22)-NR^eSO₂NR^cR^d、(23)-S(O)R^c、(24)-SO₂R^c、(25)-O(C=O)R^c、および(26)ニトロからなる群から独立して選択され；R^cおよびR^dは、(1)水素、(2)C_1-6アルキル、(3)C_3-7シクロアルキル、(4)ヘテロシクリル、(5)C_3-7シクロアルキルC_1-6アルキル、(6)ヘテロシクリルC_1-6アルキル、(7)アリール、(8)フェニルC_1-6アルキル、(9)ヘテロアリール、および(10)ヘテロアリールC_1-6アルキルからなる群から独立して選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該フェニルC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6アルコキシル、C_1-6ハロアルキル、C_1-6ハロアルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換され；
または、R^cはR^dと、N、O、S、二重結合、またはカルボニルを含んでもよい4～7員環を形成してもよく；ここで、該4～7員環は、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6ハロアルキル、およびC_1-6アルコキシルからなる群から独立して選択される1つまたは複数の置換基で置換され；
R^eは、(1)水素、(2)C_1-6アルキル、および(3)C_1-6ハロアルキルからなる群から独立に選択され；
Qは、(1)結合、(2)-(CH₂)_n-、(3)-O-、(4)-O-(CH₂)_n-、(5)-(CH₂)_n-O-、(6)-NH-、および(7)-N(C_1-6アルキル)-からなる群から選択され；
nは、1、2、3、または4であり；
A環は、N-含有ヘテロシクリル、N-含有ヘテロアリール、N-含有部分飽和ヘテロアリール、N-含有単環式または二環式ヘテロシクリル、N-含有スピロヘテロシクリル、フェニルで置換されているN-含有ヘテロシクリル、N-含有二環式飽和または部分飽和ヘテロアリールからなる群から選択され；好ましくは、N-含有Ｃ_3-12単環式または二環式ヘテロシクリルまたはN-含有Ｃ_3-12スピロ-ヘテロシクリルであり；ここで、該Aは、R⁴から独立して選択される1～4個の置換基で任意に置換され；
R⁴は、(1)ハロゲン、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル、(5)C_1-6アルコキシル、(6)C_1-6ハロアルキル、(7)C_1-6ハロアルコキシル、および(8)-CNからなる群から独立して選択され；
Yは、-CN、-(C=O)H、-(C=O)CH₂OH、または-(C=O)(C=O)NHR⁵；好ましくは、Yは、-(C=O)(C=O)NHR⁵であり；
R⁵は、(1)水素、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル、(5)ヘテロシクリル、(6)C_3-7シクロアルキルC_1-6アルキル、(7)ヘテロシクリルC_1-6アルキル、(8)アリール、(9)フェニルC_1-6アルキル、(10)ヘテロアリール、および(11)ヘテロアリールC_1-6アルキルからなる群から選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該フェニルC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6ハロアルキル、C_1-6アルコキシル、C_1-6ハロアルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換され；
好ましくは、アリールはフェニルまたはナフチルであり；
好ましくは、ヘテロアリールは、O、N、S、およびカルボニルから独立して選択される1～4個のヘテロ原子を有する5～15員環であり；より好ましくは、該ヘテロアリールは、O、N、およびSから独立して選択される1～4個のヘテロ原子を有する不飽和5～6員環、またはO、N、Sおよびカルボニルから独立して選択される1～4個のヘテロ原子を有する不飽和または部分的に飽和した9～10員環であり；さらに好ましくは、該ヘテロアリールは、チオフェニル、チアゾリル、イソキサゾリル、ピラゾリル、ピラジル、テトラゾリル、フラニル、ピロリル、イミダゾリル、オキサゾリル、イソチアゾリル、トリアゾリル、チアジアゾリル、ピリジル、ピリミジル、ピリダジニル、ピラジニル、ピラニル、トリアジニル、3,6-ジヒドロ-2H-ピラン、1,2,3,6-テトラヒドロピリジル、ベンゾフラニル、ベンゾチオフェン、ベンゾトリアゾリル、ベンゾオキサゾリル、インドリル、インダゾリル、ベンゾイミダゾリル、またはピロロピリジルである）；
またはラセミ体、またはエナンチオマー、またはジアステレオマー、
またはその薬学的に許容される塩、またはそのプロドラッグである。 The present invention provides:
[1] A compound of formula (I):

(in the formula:
R ¹ and R ² are (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C _1-6 alkyl, (5) -OC _1-6 alkyl, (6) C _3-7 cycloalkyl , (7) _C3-7 cycloalkoxy, (8) C2-6 alkenyl, (9) -NR ^a R ^b , (10) (R ^a )(R ^b )NC _{1-6 alkyl} , (11) heterocyclyl , (12) aryl, (13) heteroaryl, (14) arylC _1-6 alkyl, (15) heteroarylC _1-6 alkyl, (16) -CN, and (17) C _3-7 cycloalkylC independently selected from the group consisting of _1-6 alkyl; wherein said C _1-6 alkyl, said -OC _1-6 alkyl, said C _3-7 cycloalkyl, said C _3-7 cycloalkoxy, said C _2-6 alkenyl, said heterocyclyl, said aryl, said heteroaryl, said arylC _1-6 alkyl, said heteroarylC _1-6 alkyl, or said C _3-7 cycloalkylC _1-6 alkyl is (1) optionally substituted with 1 to 6 substituents independently selected from the group consisting of hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
Alternatively, R ¹ and R ² may form a 4- to 7-membered ring that may contain N, O, S, double bonds, or carbonyl; wherein the 4- to 7-membered ring is (1 optionally substituted with 1 to 6 substituents independently selected from the group consisting of: ) hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
R ^a and R ^b are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) arylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said aryl C _1-6 alkyl, said heteroaryl, or said heteroaryl C _1-6 alkyl is unsubstituted or the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl and -CN substituted with one or more substituents independently selected from;
Alternatively, R ^a and R ^b may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, and C _1-6 alkoxyl;
X is _-CH2- , -NH-, -N( _C1-6alkyl )-, -O-, or -S-;
R ³ is (1) hydrogen, (2) C _1-6 alkyl, (3) C _2-6 alkenyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) aryl, (7) heteroaryl, (8) phenylC _1-6 alkyl, (9) phenyl-Q-heteroaryl, (10) phenyl-Q-phenyl, (11) heteroaryl-Q-phenyl, (12) heteroaryl-Q- selected from the group consisting of heteroaryl, (13)-(C=O)C _1-6 alkyl, and (14)-(C=O)C _1-6 haloalkyl; wherein said C _1-6 alkyl, said C _2-6 alkenyl, said C _3-7 cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, said phenyl C _1-6 alkyl, said phenyl-Q-heteroaryl, said phenyl-Q-phenyl, said hetero Aryl-Q-phenyl or said heteroaryl-Q-heteroaryl is (1) hydroxyl, (2) halogen, (3) C _1-6 alkyl, (4) C _1-6 haloalkyl, (5) C _{1 -6} alkoxy, (6) C _1-6 haloalkoxy, (7) C _3-7 cycloalkyl, (8) heterocyclyl, (9) -SF ₅ , (10) -SR ^c , (11) -CN, ( 12) cyano-substituted C _1-6 alkyl, (13) ^-NRcRd , (14) ^-NRe (C=O) ^Rc , (15)-( ^C =O ^{) NRcRd} , (16) -(C=O)Rc, (17) ^-CO2Rc , (18) _-NRe ( ^C =O) ^NRcRd (19) ^{-NRe ( C} =O) ^ORc , (20) ^-NReSO2Rc , ₍ 21) _-SO2NRcRd , ₍ 22 ^{) -NReSO2NRcRd} , ⁽ 23)-S ₍ O ^{) Rc} , ⁽ 24) ^-SO2R optionally substituted with 1 to 6 substituents independently selected from the group consisting of ^c , (25)-O(C=O)R ^c , and (26) nitro; preferably R ³ is (6) aryl, and ( ⁷ ) heteroaryl; more preferably R3 is selected from the group consisting of (6a) 2,4-substituted aryl and (7a) 2,4-substituted heteroaryl; is selected from the group consisting of ( ^6aa ) 4-substituted phenyl, and (7aa) 4-substituted heteroaryl; wherein the substituents are (1) hydroxyl, (2) halogen, (3) _{C1- 6} alkyl, (4) C _1-6 haloalkyl, (5) C _1-6 alkoxy, (6) C _1-6 haloalkoxy, (7) C _3-7 cycloalkyl, (8) heterocyclyl, (9)- _SF5 , (10) ^-SRc , (11)-CN, (12) cyano-substituted _C1-6alkyl , (13) ^-NRcRd , (14) ^-NRe ( ^C =O) ^Rc , (15)-(C=O) ^NRcRd , (16)-( ^C =O) ^Rc , (17) ^-CO2Rc , (18) _-NRe ( ^C =O ^{) NRcRd} , (19) ^-NRe ( ^C =O) ^ORc , ( ₂₀ ^{) -NReSO2Rc} , ₍ 21 ^{) -SO2NRcRd} , ⁽ 22 ⁾ _-NReSO2NRcRd , (23)-S(O)Rc, (24) ^-SO2Rc , ₍ 25)-O( ^C =O) ^Rc , and (26) nitro; ^Rc and R ^d are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl, ( 6) independently selected from the group consisting of heterocyclylC _1-6 alkyl, (7) aryl, (8) phenylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl; wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclyl C _1-6 alkyl, said aryl, said phenyl C _{1 -6} alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl, C _1-6 haloalkyl, C ₁ substituted with one or more substituents independently selected from the group consisting of _-6 haloalkoxyl, and -CN;
Alternatively, R ^c and R ^d may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxyl;
R ^e is independently selected from the group consisting of (1) hydrogen, (2) C _1-6 alkyl, and (3) C _1-6 haloalkyl;
Q is (1) a bond, (2)-( _CH2 ) _n- , (3)-O-, (4)-O-( _CH2 ) _n- , (5)-( _CH2 ) _n -O -, (6)-NH-, and (7)-N(C _1-6 alkyl)-;
n is 1, 2, 3, or 4;
Ring A is N-containing heterocyclyl, N-containing heteroaryl, N-containing partially saturated heteroaryl, N-containing monocyclic or bicyclic heterocyclyl, N-containing spiroheterocyclyl, N-containing substituted with phenyl selected from the group consisting of heterocyclyl, N-containing bicyclic saturated or partially saturated heteroaryl; preferably N-containing C _3-12 monocyclic or bicyclic heterocyclyl or N-containing C _3-12 spiro-heterocyclyl wherein A is optionally substituted with 1 to 4 substituents independently selected from R ⁴ ;
R ⁴ is (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) C _1-6 alkoxyl, (6) C _1-6 haloalkyl , (7) C _1-6 haloalkoxyl, and (8) -CN;
Y is -CN, -(C=O)H, -(C=O) _CH2OH , or -(C=O)(C=O) ^NHR5 ; preferably Y is -(C=O )(C=O)NHR ⁵ ;
R ⁵ is (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) C _3-7 cycloalkylC _1- selected from the group consisting of ₆ alkyl, (7) heterocyclylC _1-6 alkyl, (8) aryl, (9) phenylC _1-6 alkyl, (10) heteroaryl, and (11) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclyl C _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C substituted with one or more substituents independently selected from the group consisting of _1-6 haloalkoxyl, and -CN;
preferably aryl is phenyl or naphthyl;
Preferably, heteroaryl is a 5-15 membered ring having 1-4 heteroatoms independently selected from O, N, S, and carbonyl; unsaturated 5- to 6-membered ring having 1-4 heteroatoms independently selected from N and S, or 1-4 heteroatoms independently selected from O, N, S and carbonyl more preferably said heteroaryl is thiophenyl, thiazolyl, isoxazolyl, pyrazolyl, pyrazyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl , thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyranyl, triazinyl, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridyl, benzofuranyl, benzothiophene, benzotriazolyl, benzoxazolyl , indolyl, indazolyl, benzimidazolyl, or pyrrolopyridyl);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

（式中、
R¹およびR²は、(1)水素、(2)ハロゲン、(3)ヒドロキシル、(4)C_1-6アルキル、(5)-O-C_1-6アルキル、(6)C_3-7シクロアルキル、(7)C_3-7シクロアルコキシ、(8)C_2-6アルケニル、(9)-NR^aR^b、(10)(R^a)(R^b)N-C_1-6アルキル、(11)ヘテロシクリル、(12)アリール、(13)ヘテロアリール、(14)アリールC_1-6アルキル、(15)ヘテロアリールC_1-6アルキル、(16)-CN、および(17)C_3-7シクロアルキルC_1-6アルキルからなる群から独立して選択され；ここで、該C_1-6アルキル、該-O-C_1-6アルキル、該C_3-7シクロアルキル、該C_3-7シクロアルコキシ、該C_2-6アルケニル、該ヘテロシクリル、該アリール、該ヘテロアリール、該アリールC_1-6アルキル、該ヘテロアリールC_1-6アルキル、または該C_3-7シクロアルキルC_1-6アルキルは、(1)ヒドロキシル、(2)ハロゲン、および(3)C_1-6アルキルからなる群から独立して選択される1～6個の置換基で任意に置換され；
または、R¹はR²と、N、O、S、二重結合、またはカルボニルを含んでもよい4～7員環を形成してもよく；ここで、該4～7員環は、(1)ヒドロキシル、(2)ハロゲン、および(3)C_1-6アルキルからなる群から独立して選択される1～6個の置換基で任意に置換され；
R^aおよびR^bは、(1)水素、(2)C_1-6アルキル、(3)C_3-7シクロアルキル、(4)ヘテロシクリル、(5)C_3-7シクロアルキルC_1-6アルキル、(6)ヘテロシクリルC_1-6アルキル、(7)アリール、(8)アリールC_1-6アルキル、(9)ヘテロアリール、および(10)ヘテロアリールC_1-6アルキルからなる群から独立して選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該アリールC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6アルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換され；
または、R^aはR^bと、N、O、S、二重結合、またはカルボニルを含んでもよい4～7員環を形成してもよく；ここで、該4～7員環は、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、およびC_1-6アルコキシルからなる群から独立して選択される1つまたは複数の置換基で置換され；
Xは- CH₂-、-NH-、-N(C_1-6アルキル)-、-O-、または-S-であり；
R³は、(1)水素、(2)C_1-6アルキル、(3)C_2-6アルケニル、(4)C_3-7シクロアルキル、(5)ヘテロシクリル、(6)アリール、(7)ヘテロアリール、(8)フェニルC_1-6アルキル、(9)フェニル-Q-ヘテロアリール、(10)フェニル-Q-フェニル、(11)ヘテロアリール-Q-フェニル、(12)ヘテロアリール-Q-ヘテロアリール、(13)-(C=O)C_1-6アルキル、および(14)-(C=O)C_1-6ハロアルキルからなる群から選択され；ここで、該C_1-6アルキル、該C_2-6アルケニル、該C_3-7シクロアルキル、該ヘテロシクリル、該アリール、該ヘテロアリール、該フェニルC1-6アルキル、該フェニル-Q-ヘテロアリール、該フェニル-Q-フェニル、該ヘテロアリール 該-Q-フェニル、または該ヘテロアリール-Q-ヘテロアリールは、(1)ヒドロキシル、(2)ハロゲン、(3)C_1-6アルキル、(4)C_1-6ハロアルキル、(5)C_1-6アルコキシ、(6)C_1-6ハロアルコキシ、(7)C_3-7シクロアルキル、(8)ヘテロシクリル、(9)-SF₅、(10)-SR^c、(11)-CN、(12)シアノ置換C_1-6アルキル、(13)-NR^cR^d、(14)-NR^e(C=O)R^c、(15)-(C=O)NR^cR^d、(16)-(C=O)R^c、(17)-CO₂R^c、(18)-NR^e(C=O)NR^cR^d、(19)-NR^e(C=O)OR^c、(20)-NR^eSO₂R^c、(21)-SO₂NR^cR^d、(22)-NR^eSO₂NR^cR^d、(23)-S(O)R^c、(24)-SO₂R^c、(25)-O(C=O)R^c、および(26)ニトロからなる群から独立して選択される1～6個の置換基で任意に置換され；
R^cおよびR^dは、(1)水素、(2)C_1-6アルキル、(3)C_3-7シクロアルキル、(4)ヘテロシクリル、(5)C_3-7シクロアルキルC_1-6アルキル、(6)ヘテロシクリルC_1-6アルキル、(7)アリール、(8)フェニルC_1-6アルキル、(9)ヘテロアリール、および(10)ヘテロアリールC_1-6アルキルからなる群から独立して選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該フェニルC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6アルコキシル、C_1-6ハロアルキル、C_1-6ハロアルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換され；
または、R^cはR^dと、N、O、S、二重結合、またはカルボニルを含んでもよい4～7員環を形成してもよく；ここで、該4～7員環は、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6ハロアルキル、およびC_1-6アルコキシルからなる群から独立して選択される1つまたは複数の置換基で置換され；
R^eは、(1)水素、(2)C_1-6アルキル、および(3)C_1-6ハロアルキルからなる群から独立して選択され；
Qは、(1)結合、(2)-(CH₂)_n-、(3)-O-、(4)-O-(CH₂)_n-、(5)-(CH₂)_n-O-、(6)-NH-、および(7)-N(C_1-6アルキル)-からなる群から選択され；
nは、1、2、3、または4であり；

R⁴は、(1)ハロゲン、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル(5)C_1-6アルコキシル、(6)C_1-6ハロアルキル(7)C_1-6ハロアルコキシル、および(8)-CNからなる群から独立して選択され；
mは0、1、2、3、または4であり；
R⁵は、(1)水素、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル、(5)ヘテロシクリル、(6)C_3-7シクロアルキルC_1-6アルキル、(7)ヘテロシクリルC_1-6アルキル、(8)アリール、(9)フェニルC_1-6アルキル、(10)ヘテロアリール、および(11)ヘテロアリールC_1-6アルキルからなる群から選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該フェニルC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6ハロアルキル、C_1-6アルコキシル、C_1-6ハロアルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換される）；
またはラセミ体、またはエナンチオマー、またはジアステレオマー、
またはその薬学的に許容される塩、またはそのプロドラッグ。 [2] The compound according to [1], wherein the compound of formula (I) is represented by the following compound of formula (II):

(In the formula,
R ¹ and R ² are (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C _1-6 alkyl, (5) -OC _1-6 alkyl, (6) C _3-7 cycloalkyl , (7) _C3-7 cycloalkoxy, (8) C2-6 alkenyl, (9) -NR ^a R ^b , (10) (R ^a )(R ^b )NC _{1-6 alkyl} , (11) heterocyclyl , (12) aryl, (13) heteroaryl, (14) arylC _1-6 alkyl, (15) heteroarylC _1-6 alkyl, (16) -CN, and (17) C _3-7 cycloalkylC independently selected from the group consisting of _1-6 alkyl; wherein said C _1-6 alkyl, said -OC _1-6 alkyl, said C _3-7 cycloalkyl, said C _3-7 cycloalkoxy, said C _2-6 alkenyl, said heterocyclyl, said aryl, said heteroaryl, said arylC _1-6 alkyl, said heteroarylC _1-6 alkyl, or said C _3-7 cycloalkylC _1-6 alkyl is (1) optionally substituted with 1 to 6 substituents independently selected from the group consisting of hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
Alternatively, R ¹ and R ² may form a 4-7 membered ring that may contain N, O, S, double bonds, or carbonyl; wherein the 4-7 membered ring is (1 optionally substituted with 1 to 6 substituents independently selected from the group consisting of: ) hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
R ^a and R ^b are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) arylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said aryl C _1-6 alkyl, said heteroaryl, or said heteroaryl C _1-6 alkyl is unsubstituted or the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl and -CN substituted with one or more substituents independently selected from;
Alternatively, R ^a and R ^b may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, and C _1-6 alkoxyl;
X is _-CH2- , -NH-, -N(Ci- _6alkyl )-, -O-, or -S-;
R ³ is (1) hydrogen, (2) C _1-6 alkyl, (3) C _2-6 alkenyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) aryl, (7) heteroaryl, (8) phenylC _1-6 alkyl, (9) phenyl-Q-heteroaryl, (10) phenyl-Q-phenyl, (11) heteroaryl-Q-phenyl, (12) heteroaryl-Q- selected from the group consisting of heteroaryl, (13)-(C=O)C _1-6 alkyl, and (14)-(C=O)C _1-6 haloalkyl; wherein said C _1-6 alkyl, said C _2-6 alkenyl, said C _3-7 cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, said phenyl C 1-6 alkyl, said phenyl-Q-heteroaryl, said phenyl-Q-phenyl, said heteroaryl Said -Q-phenyl or said heteroaryl-Q-heteroaryl is (1) hydroxyl, (2) halogen, (3) C _1-6 alkyl, (4) C _1-6 haloalkyl, (5) C _{1 -6} alkoxy, (6) C _1-6 haloalkoxy, (7) C _3-7 cycloalkyl, (8) heterocyclyl, (9) -SF ₅ , (10) -SR ^c , (11) -CN, ( 12) cyano-substituted C _1-6 alkyl, (13) ^-NRcRd , (14) ^-NRe (C=O) ^Rc , (15)-( ^C =O ^{) NRcRd} , (16) -(C=O)Rc, (17) ^-CO2Rc , (18) _-NRe ( ^C =O) ^NRcRd , (19) ^{-NRe ( C} =O) ^ORc , (20 ) ^-NReSO2Rc , ₍ 21) ^-SO2NRcRd , ⁽ 22 ⁾ _-NReSO2NRcRd , ⁽ 23)-S ₍ O ^{) Rc} , ⁽ 24) _-SO2 optionally substituted with 1 to 6 substituents independently selected from the group consisting of R ^c , (25)-O(C═O)R ^c , and (26) nitro;
R ^c and R ^d are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) phenylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl, C _1-6 haloalkyl, substituted with one or more substituents independently selected from the group consisting of C _1-6 haloalkoxyl, and -CN;
Alternatively, R ^c and R ^d may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxyl;
R ^e is independently selected from the group consisting of (1) hydrogen, (2) C _1-6 alkyl, and (3) C _1-6 haloalkyl;
Q is (1) a bond, (2)-( _CH2 ) _n- , (3)-O-, (4)-O-( _CH2 ) _n- , (5)-( _CH2 ) _n -O -, (6)-NH-, and (7)-N(C _1-6 alkyl)-;
n is 1, 2, 3, or 4;

R ⁴ is (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl (5) C _1-6 alkoxyl, (6) C _1-6 haloalkyl ( 7) independently selected from the group consisting of C _1-6 haloalkoxyl, and (8)-CN;
m is 0, 1, 2, 3, or 4;
R ⁵ is (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) C _3-7 cycloalkylC _1- selected from the group consisting of ₆ alkyl, (7) heterocyclylC _1-6 alkyl, (8) aryl, (9) phenylC _1-6 alkyl, (10) heteroaryl, and (11) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclyl C _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, and substituted with one or more substituents independently selected from the group consisting of -CN);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

R⁴は、(1)ハロゲン、(2)ヒドロキシル、(3)C_1-6アルキル、および(8)-CNからなる群から独立して選択され；
mは、0、1、2、3、または4であり；
R⁵は、(1)水素、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル、(5)ヘテロシクリル、(8)アリール、および(10)ヘテロアリールからなる群から選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該アリール、または該ヘテロアリールは、無置換であるか、またはハロゲンおよびヒドロキシルからなる群から独立して選択される1つまたは複数の置換基で置換されている）；
またはラセミ体、またはエナンチオマー、またはジアステレオマー、
またはその薬学的に許容される塩、またはそのプロドラッグ。 [3] The compound according to [1] or [2];
R ¹ and R ² are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) hydroxyl, and (4) C _1-6 alkyl;
X is _-CH2- , -NH-, -N( _C1-6alkyl )-, -O-, or -S-;
R ³ is (6) aryl, (7) heteroaryl, (8) phenylC _1-6 alkyl, (9) phenyl-Q-heteroaryl, (10) phenyl-Q-phenyl, (11) heteroaryl- selected from the group consisting of Q-phenyl, (12)heteroaryl-Q-heteroaryl, (13)-(C=O)Ci- _6alkyl , and (14)-(C=O)Ci- _6haloalkyl wherein said aryl, said heteroaryl, said phenylC _1-6 alkyl, said phenyl-Q-heteroaryl, said phenyl-Q-phenyl, said heteroaryl-Q-phenyl, or said heteroaryl-Q- Heteroaryl is (1) hydroxyl, (2) halogen, (3) _C1-6 alkyl, (4) _C1-6 haloalkyl, (5) _C1-6 alkoxy, (9) _-SF5 , (10 optionally substituted with 1-6 substituents independently selected from the group consisting of )-SR ^c , (11)-CN, and (12) cyano-substituted C _1-6 alkyl;
Q is (1) a bond, (2)-( _CH2 ) _n- , (3)-O-, (4)-O-( _CH2 ) _n- , (5)-( _CH2 ) _n -O -, (6)-NH-, and (7)-N(C _1-6 alkyl)-;
n is 1, 2, 3, or 4;

R ⁴ is independently selected from the group consisting of (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, and (8) -CN;
m is 0, 1, 2, 3, or 4;
R ⁵ is from (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (8) aryl, and (10) heteroaryl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is unsubstituted or from the group consisting of halogen and hydroxyl substituted with one or more independently selected substituents);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

R⁴は、(1)ハロゲン、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル、(5)C_1-6アルコキシル、(6)C_1-6ハロアルキル、(7)C_1-6ハロアルコキシル、および(8)-CNからなる群から独立して選択され；
mは、0、1、2、3、または4であり；
R⁵は、(1)水素、(2)ヒドロキシル、(3)C_1-6アルキル、(4)C_3-7シクロアルキル、(5)ヘテロシクリル、(6)C_3-7シクロアルキルC_1-6アルキル、(7)ヘテロシクリルC_1-6アルキル、(8)アリール、(9)フェニルC_1-6アルキル、(10)ヘテロアリール、および(11)ヘテロアリールC_1-6アルキルからなる群から選択され；ここで、該C_1-6アルキル、該C_3-7シクロアルキル、該ヘテロシクリル、該C_3-7シクロアルキルC_1-6アルキル、該ヘテロシクリルC_1-6アルキル、該アリール、該フェニルC_1-6アルキル、該ヘテロアリール、または該ヘテロアリールC_1-6アルキルは、無置換であるか、またはハロゲン、ヒドロキシル、C_1-6アルキル、C_1-6ハロアルキル、C_1-6アルコキシル、C_1-6ハロアルコキシル、および-CNからなる群から独立して選択される1つまたは複数の置換基で置換されている）；
またはラセミ体、またはエナンチオマー、またはジアステレオマー、
またはその薬学的に許容される塩、またはそのプロドラッグ。 [4] The compound according to [2] or [3];
R ¹ and R ² are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) hydroxyl, and (4) C _1-6 alkyl;
X is _-CH2- , -NH-, -N( _C1-6alkyl )-, -O-, or -S-;
R ³ is selected from the group consisting of (6) aryl and (7) heteroaryl; wherein said aryl, or said heteroaryl is (1) hydroxyl, (2) halogen, (3) C _1-6 alkyl, (4) _C1-6 haloalkyl, (5) _C1-6 alkoxy, (9) _-SF5 , (10) ^-SRc , (11) -CN, and (12) cyano-substituted _C1-6 substituted with substituents independently selected from the group consisting of alkyl;

R ⁴ is (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) C _1-6 alkoxyl, (6) C _1-6 haloalkyl , (7) C _1-6 haloalkoxyl, and (8) -CN;
m is 0, 1, 2, 3, or 4;
R ⁵ is (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) C _3-7 cycloalkylC _1- selected from the group consisting of ₆ alkyl, (7) heterocyclylC _1-6 alkyl, (8) aryl, (9) phenylC _1-6 alkyl, (10) heteroaryl, and (11) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclyl C _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, and substituted with one or more substituents independently selected from the group consisting of -CN);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[5] A compound selected from the group consisting of:
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2,4-dichlorophenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((4-(trifluoromethyl)phenyl)glycyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-phenoxyphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((S)-2-(2,4-dichlorophenoxy)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(4-fluorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((R)-2-(2,4-dichlorophenoxy)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-2-(2-((3-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropylamino)-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((R)-2-phenoxypropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-2-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(benzyloxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2) -oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-cyclopropylphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-((trifluoromethyl)thio)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-((4-chlorophenyl)thio)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-((2,4-dichlorophenyl)thio)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(2-chloro-4-isopropylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-bromo-2-chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(2-cyanopropan-2-yl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(tert-butyl)-2-methylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(2-phenylpropan-2-yl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(tert-butyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(trifluoromethyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((4-(trifluoromethyl)phenyl)glycyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-Chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine) -3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2,4-dichloro-6-methylphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((S)-2-phenoxypropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(pentafluoro-16-sulphanyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-( 2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(2S,4S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)- 1-(2-(2,4-dichlorophenoxy)acetyl)-4-phenylpyrrolidine-2-carboxamide;
(S)-2-(2-(2-chloro-4-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2-(trifluoromethyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,3S,4S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2,4-dichlorophenoxy)acetyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide;
(S)-6-Chloro-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-phenoxyphenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(S)-6-Chloro-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-cyclopropylphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-benzylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine) -3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(naphthalen-2-yloxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(phenoxymethyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(4-chlorophenoxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S) -2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide ;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2-azaspiro[4.4]nonane-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-5- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-5-azaspiro[2.4]heptane-6-carboxamide;
(2S,3aS,7aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-indole-2-carboxamide;
(3S,4aS,8aS)-N-((2S)-4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)decahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((2S)-4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((2,2,2-trifluoroacetyl)-L-phenylalanyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-((S)-3-cyclohexyl-2-(2,2,2-trifluoroacetamido)propanoyl)-N-((S)-4-(cyclopropylamino)- 3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((5-phenylthiazol-2-yl)oxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((5-(phenoxymethyl)thiazol-2-yl)oxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((2-fluorobenzyl)oxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((3-fluorobenzyl)oxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((4-fluorobenzyl)oxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((2-fluorophenoxy)methyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((3-fluorophenoxy)methyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((4-fluorophenoxy)methyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((6-(trifluoromethyl)pyridin-3-yl)-L-valyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((R)-2-phenoxypropanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)- 3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)- 3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(3S,4aS,8aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)decahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((4-(trifluoromethyl)phenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((2,4-dichlorophenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-((2-Chloro-4-fluorophenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S )-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -2-((4-(trifluoromethyl)phenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((4-fluorophenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1 - carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((4-isopropylphenyl)glycyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(phenylcarbamoyl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((4'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide;
(1R,2S,5S)-3-((2-Chloro-4-fluorophenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S )-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-4-cyclopropylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((2,4-dichlorophenyl)glycyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-5-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(2,2,2-trifluoroethoxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-(4-chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((4-isopropylphenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(trifluoromethoxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((4'-ethoxy-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-(4-(benzyloxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-(( S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-ethoxy-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((4-fluorophenyl)glycyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-phenoxyphenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(4-(benzyloxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-(( S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(phenylcarbamoyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(trifluoromethyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2-fluoro-4-(trifluoromethyl)phenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-5-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-fluorophenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-4-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(2,2,2-trifluoroethoxy)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-((3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-4-cyclopropylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(4-(furan-3-yl)phenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(2,2,2-trifluoroacetyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2-fluoro-4-methoxyphenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(4-chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-3-azabicyclo[3.1.0]hexane -2-carboxamide;
(1R,2S,5S)-3-(2-((4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2-fluoro-4-methoxyphenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(trifluoromethyl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(trifluoromethoxy)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((R)-2-(4-fluorophenoxy)-3-methylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2-methoxy-4-(trifluoromethyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(((1H-imidazol-5-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidine -3-yl)butan-2-yl)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-3-azabicyclo[3.1.0] hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-N-((S)-3,4-dioxo-1-((S)-2-oxopyrrolidine-3) -yl)-4-((thiazol-2-ylmethyl)amino)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-N-((S)-4-((isoxazol-3-ylmethyl)amino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-pyrazole-) 3-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-pyrazole-) 4-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(3-fluoro-4-(trifluoromethyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(2,2,2-trifluoroacetyl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-2-(4-fluorophenoxy)-3-methylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-pyrazole-) 5-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(((1H-imidazol-2-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidine -3-yl)butan-2-yl)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(Cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2-methoxy-4-(trifluoromethyl)phenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-imidazole- 2-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-2-(4-fluorophenoxy)propanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-((S)-2-(4-fluorophenoxy)propanoyl)-N-((S)-4-(methylamino)-3,4-dioxo-1-(( S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-3',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-3',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -2-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(methylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-N-( (S)-4-(Methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide;
(1R,2S,5S)-3-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4- (Ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(ethylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-fluorophenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S) -2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -2-(2-(4-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(ethylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2,4-dichlorophenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-((2,4-dichlorophenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-((2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-(( S)-4-(Methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide ;
(1S,3aR,6aS)-2-(2-((3-methyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-(( S)-4-(Methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide ;
(1S,3aR,6aS)-2-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(methylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(methylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(methylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-( (S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1- carboxamide;
(1S,3aR,6aS)-2-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4- (methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-fluorophenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((2-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((2-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl) butan-2-yl)-3-((4-(trifluoromethyl)phenyl)glycyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -6,6-dimethyl-3-((4-(trifluoromethyl)phenyl)glycyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-N-((S) -4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide ;and
(1R,2S,5S)-3-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(ethylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide ;
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[6] The compound, or the racemate, or the enantiomer of any one of [1] to [5], for the manufacture of a drug for the treatment or prevention of disease states or disorders caused by viruses; or use of diastereomers, or pharmaceutically acceptable salts, prodrugs, solvates, or compositions thereof.

[7] The virus is a coronavirus selected from the group consisting of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS coronavirus, MARS coronavirus, and COVID-19 coronavirus, [ 6].

[8] The condition or disorder is headache, olfactory disorder, loss of taste, stuffy nose, nasal congestion, rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, dyspnea, acute respiratory distress syndrome, sepsis, multiple Organ failure, cold-like symptoms, pneumonia, hypoxia, high fever, bronchitis, shortness of breath, systemic illness, nausea, viral encephalitis, meningitis, liver failure, renal failure, heart failure, hair loss, alopecia areata, and combinations thereof.

[9] A method for treating or preventing a condition or disorder caused by a virus in an animal, comprising a therapeutically effective amount of any of [1] to [5] for the animal in need of such treatment or prevention A method comprising administering a compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof.

[10] The condition or disorder is headache, olfactory disturbance, loss of taste, stuffy nose, nasal congestion, rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, dyspnea, acute respiratory distress syndrome, sepsis, multiple Organ failure, cold-like symptoms, pneumonia, hypoxia, high fever, bronchitis, shortness of breath, generalized nausea, nausea, viral encephalitis, meningitis, liver failure, renal failure, heart failure, hair loss, alopecia areata, and combinations thereof.

[11] A method for the treatment or prevention of a condition or disorder caused by a virus in an animal, comprising a therapeutically effective amount of PF-07304814, PF-07321332, PF-07304814, PF-07321332, PF- A method comprising administering a compound selected from the group consisting of MI-09, and MI-30, or a pharmaceutically acceptable salt or prodrug thereof.

[12] said condition or disorder is selected from the group consisting of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS coronavirus, MARS coronavirus, and COVID-19 coronavirus, [9] ~ The method according to [11].

[13] A pharmaceutical composition comprising the compound according to any one of [1] to [5], a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient thing.

[14] The pharmaceutical composition of [13], further comprising other pharmacologically active agents.

[15] The compound of any one of [1] to [5], wherein the compound inhibits the main protease (M ^pro ), for use in treating or preventing a condition or disorder caused by a virus or a pharmaceutically acceptable salt or prodrug thereof, characterized in that

(式中：R¹およびR²は、(1)水素であり；
Xは、-NH-または-O-であり；
R³は、(6a)2,4-置換フェニルであり；ここで、該フェニルの置換基は、(2)ハロゲンおよび(4)C_1-6ハロアルキルからなる群から独立して選択され；

R⁵は、(1)水素、(3)C_1-6アルキル、および(4)C_3-7シクロアルキルからなる群から選択される)；
またはその薬学的に許容される塩。
［ｂ］(1S,3aR,6aS)-N-((S)-4-(シクロプロピルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)-2-(2-(2,4-ジクロロフェノキシ)アセチル)オクタヒドロシクロペンタ[c]ピロール-1-カルボキサミド；
またはその薬学的に許容される塩。
［ｃ］(1S,3aR,6aS)-2-((2-クロロ-4-フルオロフェニル)グリシル)-N-((S)-4-(シクロプロピルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)オクタヒドロシクロペンタ[c]ピロール-1-カルボキサミド；
またはその薬学的に許容される塩。
［ｄ］(1S,3aR,6aS)-2-((2-クロロ-4-(トリフルオロメチル)フェニル)グリシル)-N-((S)-4-(シクロプロピルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)オクタヒドロシクロペンタ[c]ピロール-1-カルボキサミド；
またはその薬学的に許容される塩。
［ｅ］(1S,3aR,6aS)-N-((S)-4-(シクロプロピルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)-2-((2,4-ジクロロフェニル)グリシル)オクタヒドロシクロペンタ[c]ピロール-1-カルボキサミド；
またはその薬学的に許容される塩。
［ｆ］(1R,2S,5S)-3-((2-クロロ-4-(トリフルオロメチル)フェニル)グリシル)-6,6-ジメチル-N-((S)-4-(メチルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)-3-アザビシクロ[3.1.0]ヘキサン-2-カルボキサミド；
またはその薬学的に許容される塩。
［ｇ］(1R,2S,5S)-3-((2-クロロ-4-(トリフルオロメチル)フェニル)グリシル)-N-((S)-4-(エチルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)-6,6-ジメチル-3-アザビシクロ[3.1.0]ヘキサン-2-カルボキサミド；
またはその薬学的に許容される塩。
［ｈ］(1R,2S,5S)-3-((2,4-ジクロロフェニル)グリシル)-6,6-ジメチル-N-((S)-4-(メチルアミノ)-3,4-ジオキソ-1-((S)-2-オキソピロリジン-3-イル)ブタン-2-イル)-3-アザビシクロ[3.1.0]ヘキサン-2-カルボキサミド；
またはその薬学的に許容される塩。
［ｉ］前記［ａ］～［ｈ］のいずれかに記載の化合物、その薬学的に許容される塩、および薬学的に許容される担体または賦形剤を含む医薬組成物。 [16] Mixing the compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, or a prodrug thereof, with a pharmaceutically acceptable carrier or excipient A method of making a pharmaceutical composition, comprising:
[a] a compound of formula (II):

(wherein R ¹ and R ² are (1) hydrogen;
X is -NH- or -O-;
R ³ is (6a) 2,4-substituted phenyl; wherein the substituents of said phenyl are independently selected from the group consisting of (2) halogen and (4) C _1-6 haloalkyl;

R ⁵ is selected from the group consisting of (1) hydrogen, (3) C _1-6 alkyl, and (4) C _3-7 cycloalkyl);
or a pharmaceutically acceptable salt thereof.
[b] (1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butane- 2-yl)-2-(2-(2,4-dichlorophenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
or a pharmaceutically acceptable salt thereof.
[c] (1S,3aR,6aS)-2-((2-chloro-4-fluorophenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
or a pharmaceutically acceptable salt thereof.
[d] (1S,3aR,6aS)-2-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4- dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
or a pharmaceutically acceptable salt thereof.
[e] (1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butane- 2-yl)-2-((2,4-dichlorophenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
or a pharmaceutically acceptable salt thereof.
[f] (1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino) -3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
[g] (1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
[h] (1R,2S,5S)-3-((2,4-dichlorophenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
[i] A pharmaceutical composition comprising the compound according to any one of [a] to [h], a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Advantageous effects of the invention

The compounds of the invention exhibited main protease (M ^pro ) inhibitory activity. In particular, the ketoamide derivatives of the present invention exhibit superior inhibition of coronavirus main protease (M ^pro ) than the prior art, better pharmacological profile, favorable absorption and distribution, favorable solubility, favorable plasma protein binding. , and favorable metabolic or chemical stability, leading to reduced inhibitory activity at the hERG channel and/or improved side effect profile such as QT prolongation. Accordingly, the ketoamide derivatives of the present invention are useful in treating or preventing a wide range of disorders, diseases, or their sequelae caused by viruses, including coronaviruses.

Therefore, according to a further ^aspect of the present invention, the compounds of formula (I) and Provided are compounds of (II), their racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof.

The compounds of the invention are particularly useful for treating or preventing diseases, disorders or sequelae caused by viruses, including coronaviruses. The coronaviruses include HCOV-229E, HCOV-OC43, HCOV-NL63, HCOV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2 (COVID-19), and the like.

The compounds of the invention are also useful in the treatment or prevention of disorders, diseases, or their sequelae caused by viruses, particularly coronaviruses. Such disorders, diseases, or sequelae include headache, loss of smell, loss of taste, stuffy nose, stuffy nose, rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, difficulty breathing, acute respiratory distress syndrome, Sepsis, multiple organ failure, cold-like symptoms, pneumonia, hypoxia, high fever, bronchitis, shortness of breath, systemic illness, nausea, viral encephalitis, meningitis, liver failure, renal failure, heart failure, hair loss, rounds alopecia and the like.

Further, the present invention provides a method of treating or preventing a condition or disorder caused by a virus, including coronaviruses, in animals, including humans, wherein the animal in need of such treatment is treated with PF-07304814, PF- Also provided are methods comprising administering a therapeutically effective amount of a compound selected from the group consisting of 07321332, PF-00835231, MI-09, and MI-30.

Historically, Pfizer has published in WO2005/113580 and WO2006/061714 a main protease (M ^pro ) inhibitor or 3C-like protease targeting SARS-CoV and MERS-CoV. Anti-coronavirus compounds are disclosed as inhibitors.

Recently, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SHANGHAI INSTITUTE OF MATERIAMEDICA, CHINESE ACADEMY OF SCIENCES) has published in WO2020/030143 (Patent Document 3) the prevention or treatment of coronavirus-related diseases and Ebola virus-related diseases. discloses ketoamide compounds for A representative compound is considered A9, showing an IC ₅₀ of 4.8 μM in the SARS-CoV2 M ^pro assay (by the main protease (M ^pro ) assay).

さらに最近では、スタンフォード大学がWO2021/226546（特許文献４）で、コロナウイルス疾患に関連する疾患の治療または予防のためのM^pro阻害剤としてケトアミド化合物を開示している。
本発明の化合物とWO2021/226546に開示された化合物は、ケトアミド部分が同じであるものの、左側が異なっている。WO2021/226546のML104m（2,4,6-トリハロ置換フェニル部位）は、本発明と最も構造的に近い化合物であると考えられる。特に、本発明における2,4-ジ置換フェニル誘導体を左側に有する化合物は、驚くべきことに、M^pro阻害アッセイにおいてML104mよりも3倍以上強い活性を示す（社内データ、表2参照）。本願発明者らは、2,4-ジ置換フェニル誘導体が顕著な強い活性向上効果を有することを見出した。
さらに、本発明のビフェニル誘導体は、WO2021/226546に開示された2,4,6-トリハロ置換フェニル（ML104m）よりも2.5倍以上活性が高いことが示された。本発明の研究者は、ビフェニルが顕著な強い活性向上効果を有することを見出した（表２－１および表２－２）。

また、本発明の2,4-ジ置換フェニル誘導体の薬物動態は、現在SARS-CoV-2（COVID-19）の代表的な経口治療薬であるファイザー社のPF-07321332に対して総曝露量（AUCinf）および半減期（t_1/2）の面で優れていることが確認された。薬物代謝の懸念から現在ファイザー社のPF-07321332がリトナビルとの併用で開発されているが、この結果は、2,4-ジ置換フェニル誘導体がリトナビルの効能促進剤（Ritonavir booster）を必要とせず、単剤で開発できることを示している（表３）。

On the one hand, the compounds of the present invention have excellent inhibitory activity against the main proteases. For example, the compound of Example 7 exhibits an IC ₅₀ of 0.16 μM in the SARS-CoV2 M ^pro assay. Surprisingly, the M ^pro inhibitory activity of the compound of Example 7 is 30 times stronger than A9 of WO2020/030143.

More recently, Stanford University in WO2021/226546 discloses ketoamide compounds as ^Mpro inhibitors for the treatment or prevention of diseases associated with coronavirus disease.
The compounds of the present invention and the compounds disclosed in WO2021/226546 have the same ketoamide moiety, but differ on the left side. ML104m (2,4,6-trihalo-substituted phenyl moiety) of WO2021/226546 is believed to be the compound structurally closest to the present invention. In particular, compounds with a 2,4-disubstituted phenyl derivative on the left side of the present invention surprisingly show more than 3-fold stronger activity than ML104m in the M ^pro inhibition assay (in-house data, see Table 2). The inventors of the present application have found that 2,4-disubstituted phenyl derivatives have a markedly strong activity-enhancing effect.
Furthermore, the biphenyl derivative of the present invention was shown to be more than 2.5 times more active than the 2,4,6-trihalo-substituted phenyl (ML104m) disclosed in WO2021/226546. The researchers of the present invention found that biphenyl has a remarkable and strong activity-enhancing effect (Tables 2-1 and 2-2).

In addition, the pharmacokinetics of the 2,4-disubstituted phenyl derivatives of the present invention show that the total exposure to PF-07321332 from Pfizer, Inc., which is currently the leading oral treatment for SARS-CoV-2 (COVID-19). (AUCinf) and half-life (t _1/2 ) were confirmed to be excellent. Pfizer's PF-07321332 is currently being developed in combination with ritonavir due to drug metabolism concerns, but this result suggests that the 2,4-disubstituted phenyl derivative does not require a ritonavir booster. , indicating that it can be developed as a single agent (Table 3).

The usefulness of the agents of the invention in the diseases indicated above is confirmed by a series of standard tests. Examples of such tests include, but are not limited to:
(1) The anxiolytic activity of the agents of the invention can be confirmed in the mouse elevated plus maze [see, eg, Rodgers RJ, Behavioral Pharmacology 8:477-496 (1997). The relevance of the elevated plus maze is described here at page 486; methods are described in Rodgers RJ et al., Ethology and Psychopharmacology (Eds SJ Cooper and CA Hendrie), pp 9-44 (1994), J. Wiley, Chichester]. (2) The analgesic activity of the agents of the invention can be confirmed in a rat model of visceral hyperalgesia after colorectal dilation [see, for example, Schwetz I, Am J Physiology 286: G683-G691 (2004); See TJ, Brain Research 450: 153-169 (1988)]. (3) The anti-diarrheal activity of the agents of the invention can be confirmed in stress- or CRF-induced rat defecation models [see, eg, Maillot C., Gastroenterology 119: 1569-1579 (2002)]. (4) The hair growth activity of the agent of the present invention can be confirmed by the method described in WO 2007/149938. (5) The anticardiac activity of the agent of the present invention can be confirmed by the methods described herein and in the literature, eg, Drug Discovery Today Volume 20, Number 7, 906-914 (2015). (6) Other activities of the agents of the present invention can be confirmed by methods described in literature known to those skilled in the art, including well-known techniques and general techniques.

As will be appreciated by those of skill in the art, "halogen" as used herein is intended to include fluoro, chloro, bromo and iodo. Similarly, _1-6 in C 1-6 are defined as numbers having 1, 2, 3, 4, 5 or 6. According to this definition, for example, C _1-6 in C _1-6 alkyl is defined to refer to an alkyl group having 1, 2, 3, 4, 5 or 6 carbons. Similarly, C _2-6 alkenyl is defined to refer to alkenyl groups having 2, 3, 4, 5 or 6 carbons. A group that is defined as being independently substituted with substituents may be independently substituted multiple times with substituents.

As used herein, the term “alkyl” means a straight chain saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms, for example Methyl, ethyl, propyl, 2-propyl, butyl (including all isomers), pentyl (including all isomers), and the like.

As used herein, the term "alkoxy" means an -O-alkyl group, including but not limited to methoxy, ethoxy, propoxy, 2-propoxy, butoxy (including all isomers), and the like. is not.

As used herein, the term "haloalkyl" means an alkyl radical substituted with halogen atom(s) as defined above, including fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl group, 4-fluorobutyl group, chloromethyl group, trichloromethyl group , an iodomethyl group, a bromomethyl group, and the like, but are not limited to these.

As used herein, the term "haloalkoxy" means haloalkyl-O-, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro Examples include, but are not limited to, ethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy, iodomethoxy, bromomethoxy groups and the like.

As used herein, the term "cycloalkyl" means a monocyclic or bicyclic ring and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl groups, and the like. does not mean As used herein, preferred cycloalkyl is C _3-7 monocycloalkyl, more preferred cycloalkyl is C _3-6 monocycloalkyl, and even more preferred cycloalkyl is C _3-5 monocycloalkyl.

As used herein, the term "aryl" means an unsaturated or partially saturated monocyclic or bicyclic 5- to 15-membered ring composed of carbon atoms. Examples of such aryls include phenyl, naphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, 2,3-dihydro-1H-indenyl, cyclohexenyl, cyclopentenyl. , (1S,4S)-bicyclo[2.2.2]oct-2-enyl, (1R,4S)-bicyclo[2.2.1]hept-2-enyl, etc. . Preferred aryls herein are 6- to 10-membered unsaturated aryls, and more preferred aryls are phenyl or naphthyl.

As used herein, the term "heteroaryl" refers to an unsaturated or partially saturated monocyclic or bicyclic ring having 1 to 4 heteroatoms independently selected from O, N, S, and carbonyl. means a 5- to 15-membered ring of the formula. preferably an unsaturated or partially saturated monocyclic or bicyclic 5-10 membered ring having 1-4 heteroatoms independently selected from O, N, S and carbonyl; More preferably, an unsaturated or partially saturated 5- to 6-membered ring having 1-4 heteroatoms independently selected from O, N, S, and carbonyl, or O, N, S, and It is an unsaturated or partially saturated 9-10 membered ring having 1-4 heteroatoms independently selected from carbonyl.

Examples of such heteroaryl include, but are not limited to, thiophenyl, thiazolyl, isoxazolyl, pyrazolyl, pyrazyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyranyl, triazinyl, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridyl, benzofuranyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridyl, 2 ,3-dihydro-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazopyridinyl, furopyridyl , benzoisoxazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, quinolyl, isoquinolyl, quinoxalyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, 2,3-dihydro-[1,4] Dioxyno[2,3-b]pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridyl, 1H-indolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-pyrrolo [2,3-c]pyridyl, 1H-pyrrolo[3,2-c]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 7H-pyrrolo[2,3-d]pyrimidyl, 7H-pyrrolo[2 ,3-c]pyridazinyl, 1H-indazolyl, 2H-indazolyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[3,4-c]pyridyl, 1H-pyrazolo[4,3-c]pyridyl , 1H-pyrazolo[4,3-b]pyridyl, 1H-pyrazolo[3,4-d]pyrimidyl, 1H-benzo[d]imidazolyl, 3H-imidazo[4,5-b]pyridyl, 1H-imidazo[4 ,5-b]pyridyl, 9H-purinyl, 1H-imidazo[4,5-d]pyridazinyl, 1H-imidazo[4,5-b]pyrazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5 -a]pyridyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, furo[3,2 -c]pyridyl, benzo[d]isoxazolyl, 2,3-dihydro-1H-yne denyl, indolinyl, isoindolinyl, indolin-2-one-yl, isoindolin-1-one-yl, 1H-benzo[d]imidazol-2(3H)-ones-yl, benzo[d]oxazol-2(3H )-one-yl, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one-yl, 1H-imidazo[4,5-b]pyridin-2(3H)-one-yl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, quinoxalinyl, pyrido[3,4-d]pyrimidyl, pyrido[2,3-d]pyrimidyl, 1,2,3,4-tetrahydroquino lyl, 1,2,3,4-tetrahydroisoquinolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 2,3-dihydro-[1,4]dioxino[2,3 -b]pyridyl, 3,4-dihydroquinolin-2(1H)-one-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-yl, quinolin-2(1H)- on-yl, or 4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-yl, its N-oxide, its S-oxide and the like.

Preferred heteroaryls herein are 5- to 6-membered heteroaromatic rings having 1-4 heteroatoms independently selected from O, N, and S, or is a 9-10 membered heteroaromatic ring having 1-4 heteroatoms selected as . More preferred heteroaryls are 5-6 membered N-containing heteroaromatic rings, more preferred heteroaryls are benzimidazolyl, dihydroisoquinolyl, indolyl, indazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, isoquinolyl, and thiazolyl.

As used herein, the term "heterocyclyl" includes both unsaturated and saturated heterocyclic moieties, where unsaturated heterocyclic moieties (i.e., "heteroaryl") include benzofuranyl, benzofurazanyl, benzimidazolonyl, Benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrryl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indrazinyl, indolinyl, indolyl, isobenzofura nyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl , pyrazolopyrimidinyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolo pyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquino Ryl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, 3,6-dihydro-2H-pyranyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydro-2H-thiopyran 1,1-dioxide, and their N-oxides, and saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, triazolopyrimidyl, tetra tetrahydrothienyl, pyrrolidinonyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4 ,5,6,7-tetrahydro-indazolyl, 5,6,7,8-tetrahydro-1,6-naphthyridyl, 1,4-oxazepanyl, and their N- and S-oxides. It is not limited. Preferred heterocyclyls herein are 3- to 8-membered heterocyclyls having 1-4 heteroatoms independently selected from O, N, S, and carbonyl; more preferred heterocyclyls are O, N 4- to 6-membered saturated monoheterocyclyl having 1-4 heteroatoms selected from , S, and carbonyl; more preferred heterocyclyls have 1-3 heteroatoms selected from O, N, S, and carbonyl is a 5- to 6-membered saturated monoheterocyclyl having a heteroatom of
As used herein, the term “spiroheterocyclyl” means a two-ring twisted structure (ring system) in which the two rings are joined by one common carbon atom, examples of which include the following azaspiro Examples include, but are not limited to, [4.5]decane, azaspiro[4.4]nonane, azaspiro[2.4]heptane, and the like.

As used herein, the term "2,4-substituted" or "4-substituted" means, but is not limited to:

As used herein, the term "protecting group" means a hydroxy or amino protecting group selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis by T.W. Greene et al. John Wiley & Sons, 2007).

As used herein, the term "treating" or "treatment" includes preventing, inhibiting, slowing, halting, or reversing the progression or severity of symptoms or disorders. As used herein, the term "preventing" or "to prevent" includes preventing, suppressing or inhibiting the appearance or occurrence of a symptom or disorder.

As used herein, the articles "a" or "an" refer to both the singular and plural to which they refer, unless otherwise indicated.

Also included within the scope of "compounds of the invention" are any salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled compounds of formula (I) and formula (II). Derivatives, stereoisomers and optical isomers are included.

Compounds of formula (I) and formula (II) can form acid addition salts. It will be appreciated that for use in medicine the salts of the compounds of formula (I) and formula (II) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art, and such salts include salts described in J. Pharm. Sci, 1977, 66, 1-19, e.g. acid addition salts formed with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric; and, but not limited to, succinic, maleic, formic, acetic, Acid addition salts formed with organic acids such as trifluoroacetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid are included. Compounds of formula (I) and formula (II) may include those that form acid addition salts with one or more equivalents of the above acids. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In addition, for compounds containing acidic functional groups such as carboxy groups, the counterions are choline, arginine, benzathine, diethylamine, glycine, lysine, meglumine, olamine, 2-amino-2-methylpropan-1-ol, benetamine. , tert-butylamine, epolamine, ethylenediamine, hydrabamine, morpholine, piperazine, procaine, triethanolamine, diethanolamine, monoethanolamine, triisopropanolamine, and tromethamine, as well as from organic bases such as sodium, potassium, lithium, calcium, Also included are those that can be isolated in the form of inorganic salts that can also be selected from magnesium and the like.

Also within the scope of the invention are so-called "prodrugs" of the compounds of formula (I) and formula (II). For example, certain derivatives of compounds of formulas (I) and (II), which themselves may have little or no pharmacological activity, may, when administered to the body, produce the desired It can be converted into active compounds of formula (I) and formula (II). Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (E.B. Association).

As used herein, the term "animal" includes mammals or non-mammals. Examples of suitable mammals include, but are not limited to, humans, rodents, companion animals, farm animals, and primates. Suitable rodents include, but are not limited to mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals include, but are not limited to, cats, dogs, rabbits, ferrets. Suitable farm animals include, but are not limited to, horses, goats, sheep, pigs, cows, llamas, alpacas. Suitable primates include, but are not limited to, chimpanzees, lemurs, rhesus monkeys, marmosets, spider monkeys, squirrel monkeys, vervet monkeys. Examples of suitable non-mammals include, but are not limited to, birds, reptiles, amphibians, and fish. Examples of birds include, but are not limited to, chickens, turkeys, ducks, and geese.

Prodrugs according to the present invention are suitable functional groups present in compounds of formula (I) and formula (II), for example as described in H Bundgaard, Design of Prodrugs (Elsevier, 1985), They can be produced interchangeably with certain moieties known to those skilled in the art as "pro-moieties." Some examples of prodrugs according to the present invention include:
(i) When compounds of formulas (I) and (II) contain an alcohol functional group (-OH), the hydroxyl group is replaced with a moiety convertible in vivo to a hydroxyl group. Said moiety convertible in vivo into a hydroxyl group means a moiety that can be transformed into a hydroxyl group in vivo by hydrolysis and/or enzymes such as esterases. Examples of such moieties include, but are not limited to, esters, ethers, phosphate groups, etc., which can be easily hydrolyzed in vivo. Preferred are moieties that can replace the hydrogen of the hydroxyl group with acyloxyalkyloxycarbonyl, such as acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl, and pivaloyloxymethyloxycarbonyl; and
(ii) When the compounds of formula (I) and formula (II) contain an amino group, 3-hydroxyoxindole derivatives obtained by reaction with suitable acid halides or suitable acid anhydrides are mentioned as prodrugs. be done. Particularly preferred 3-hydroxyoxindole derivatives as prodrugs are -NHCO( _CH2 ) _2OCH3 , -NHCOCH( _NH2 ) _{CH3 ,} and the like.

Further examples of substituents in accordance with the examples above, as well as examples of other types of prodrugs, can be found in the above references.

Salts and solvates with non-pharmaceutically acceptable counterions or associated solvents are also included within the scope of this invention, e.g., other compounds of formula (I) and formula (II) and pharmaceutically acceptable It may be used as an intermediate in the production of its salt.

The compounds of formula (I) and formula (II) may have crystalline forms, including polymorphs, which are also within the scope of the invention.

Additionally, compounds of Formula (I) and Formula (II) may be administered as prodrugs. As used herein, "prodrugs" of compounds of formula (I) and formula (II) are compounds of formula (I) and formula (II) that ultimately form compounds of formula (I) and formula (II) in vivo after administration to a patient. is a functional derivative of a compound that releases into Administering the compounds of Formula (I) and Formula (II) as prodrugs allows one of ordinary skill in the art to do one or more of the following: (a) alter the onset of action of the compound in vivo; (b) altering the duration of action of the compound in vivo; (c) altering the delivery or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) use of the compound. Overcome side effects or other problems caused by Typical functional derivatives used to produce prodrugs include modified compounds that are cleaved chemically or enzymatically in vivo. Such modifications are well known to those skilled in the art, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates.

Some compounds of formula (I) and formula (II) have one or more chiral carbon atoms. For such compounds, compounds of formula (I) and formula (II) exist in racemic or stereoisomeric forms. The present invention includes all optical isomers, such as stereoisomers, of compounds of formula (I) and formula (II), including enantiomers, diastereomers, and mixtures thereof. The various stereoisomeric forms may be separated or resolved from one another by conventional methods, and any isomer may be obtained by conventional stereoselective or asymmetric synthetic methods.

Some of the compounds herein may exist in various tautomeric forms and the present invention is intended to include all such tautomers.

The invention also provides the compounds described herein, except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. including isotopically labeled compounds that are identical to Isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, for example ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁸ F, ¹²³ I and ¹²⁵ I are included. Compounds of the invention containing these isotopes and/or other isotopes of atoms are within the scope of the invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H, ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. The tritiated ( ³ H) and carbon-14 isotopes ( ¹⁴ C) are particularly preferred for their ease of preparation and detectability. The ¹¹ C and ¹⁸ F isotopes are particularly useful in PET (Positron Emission Tomography) and the ¹²³ I isotope is particularly useful in SPECT (Single Photon Emission CT), all of which are useful for brain imaging. is useful in Furthermore, substitution with heavy isotopes such as deuterium ( ² H), due to their greater metabolic stability, offers therapeutic advantages, e.g., increased in vivo half-life and reduced dosage requirements. Such substitutions may be preferred in some cases. Isotopically-labeled compounds of the invention are generally prepared by following the procedures described in the Schemes and/or Examples below and then substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents. can be produced by using

Certain compounds exhibit unexpected properties, such as increased duration of action and/or metabolic stability, enhanced oral bioavailability or absorption, and/or relative to other compounds disclosed in the art. Or show a decrease in drug interactions.

Self-replication of coronaviruses requires the main protease (M ^pro ). This suggests an important role for the main protease (M ^pro ) in the coronavirus life cycle. Therefore, main protease (M ^pro ) inhibitors are attracting attention as potential therapeutic agents for coronavirus infections. The compounds of the present invention are at risk of various disorders or sequelae caused by coronavirus infection, including the following conditions or diseases: headache, olfactory disturbance, loss of taste, nasal congestion, nasal congestion, rhinorrhea, cough, myalgia. , sore throat, fever, diarrhea, dyspnea, acute respiratory distress syndrome, sepsis, multiple organ failure, cold-like symptoms, pneumonia, hypoxia, high fever, bronchitis, shortness of breath, generalized nausea, nausea, viral encephalitis, meningitis, liver failure, renal failure, heart failure, alopecia, alopecia areata, etc.).

Although the dosage of active ingredient in the compositions of the invention may vary, the amount of active ingredient should be such that a suitable dosage form will be obtained. The active ingredient can be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical effect.

The dose selected will depend on the desired therapeutic effect, route of administration and duration of treatment. Dosages will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the diet the patient is following, concomitant medications, and other factors that those skilled in the art will recognize.

For administration to human patients, the total daily dose of the compounds of the invention will typically be in the range 0.1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of 1 mg to 1000 mg, whereas intravenous administration may require only 0.1 mg to 100 mg. The total daily dosage may be administered in single or divided doses and, at the physician's discretion, may fall outside of the typical ranges given herein.

These dosages are based on an average human subject having a body weight of approximately 60-70 kg. A physician will readily be able to determine dosages to administer for subjects whose weight falls outside this range (eg, infants and the elderly).

In one embodiment, the dosage range is from about 0.5 mg to 500 mg per patient per day, and in another embodiment from about 0.5 mg to 200 mg per patient per day. In embodiments, about 1 mg to 100 mg per patient per day, in another embodiment about 5 mg to 50 mg per patient per day, and in yet another embodiment about 1 mg per patient per day. About 1 mg to 30 mg per person. Pharmaceutical compositions of the invention may be provided in solid dosage formulations containing, for example, from about 0.5 mg to 500 mg of active ingredient, or containing from about 1 mg to 250 mg of active ingredient. Pharmaceutical compositions may be provided in solid dosage formulations containing about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg of active ingredient. For oral administration, the composition contains 1.0 to 1000 mg of active ingredient, for example 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 100, 150, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000, 1000 It can be provided in tablet dosage form containing 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg. The compound can be administered from 1 to 4 times per day, eg, once or twice per day.

Compounds of the invention may be used in combination with one or more other agents in treating, preventing, suppressing, alleviating or reducing the risk of diseases or conditions for which compounds of the invention or other agents are useful. , in combination with other agents, is safer or more effective than either agent alone. Such other agents can be administered, by routes and in amounts conventionally used therefor, concurrently or sequentially with the compounds of this invention. When a compound of the invention is used contemporaneously with one or more other agents, pharmaceutical compositions in unit dose form containing such other agents and the compound of the invention are envisioned. However, combination therapy can also include therapy in which the compounds of this invention and one or more other agents are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and other active ingredients can be used at lower doses than when used alone.

Accordingly, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to a compound of the present invention. The above combinations include not only combinations of a compound of the present invention with one other active compound, but also combinations of a compound of the present invention with two or more other active compounds.

Similarly, the compounds of the invention can be used in combination with other agents that are used to prevent, treat, suppress, alleviate, or reduce the risk of the diseases or conditions for which the compounds of the invention are useful. Such other agents can be administered, by any route and in amounts commonly used, concurrently or sequentially with the compounds of this invention. When a compound of the invention is used contemporaneously with one or more other agents, pharmaceutical compositions containing such other agents in addition to the compound of the invention are envisioned. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients in addition to a compound of the present invention.

The weight ratio of the compound of the invention to the second active ingredient can be varied and is determined according to the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is combined with another drug, the weight ratio of the compound of the invention to the other drug will generally range from about 1000:1 to about 1:1000, and from about 200:1 to about 1:1000. Including about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active ingredients may be administered separately or together. In addition, administration of one component can occur before, concurrently with, or after administration of another agent.

A main protease (M ^pro ) inhibitor is one other pharmacologically active compound or two or more other pharmacological agents, especially in the treatment of pneumonia, acute respiratory distress syndrome, and dyspnea diseases or disorders. may be beneficially combined with active compounds. For example, main protease (M ^pro ) inhibitors, as defined above, in particular compounds of formula (I) and formula (II) above, racemates, enantiomers, diastereomers, or mixtures thereof, or A prodrug or a pharmaceutically acceptable salt or solvate thereof may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:

- remdesivir, dexamethasone, heparin, favipiravir, tocilizumab, sarilumab, baricitinib, nelfinavir, ivermectin, ADM-L1-01, camostat, ciclesonide, or nafamostat;

Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, or pentazocine;

non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

- barbiturate sedatives such as amobarbital, aprobarbital, butabarbital, butalbital, mefobarbital, metalbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

benzodiazepines with sedative properties, such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

sedating H1 antagonists such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclidine;

Dzong;

- Skeletal muscle relaxants such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan) finan), ketamine, memantine, pyrroloquinoline quinone, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®: a combination preparation of morphine and dextromethorphan), topiramate, Neramexane, or perzinfotel with NR2B antagonists, e.g., ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl] -1-hydroxyethyl}-3,4-dihydro-2(1H)-quinolinone;

- alpha adrenergic agonists such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamide-1,2,3,4- Tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;

- tricyclic antidepressants such as desipramine, imipramine, amitriptyline, or nortriptyline;

- anticonvulsants such as carbamazepine, lamotrigine, topiramate, or valproate;

tachykinin (NK) antagonists, such as NK-3, NK-2, or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8, 9,10,11-Tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6,13-dione ( TAK-637), 5-[[(2R,3S)-2[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl ]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, ranepitant, dapitant, or 3-[[2-methoxy-5-(trifluoro methoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

- Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine, or ipratropium;

- COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

- Coal tar analgesics, such as paracetamol;

Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserine, iloperidone , perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, valaperidone, palindre, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion®, or sarizotan;

- vanilloid receptor agonists (e.g. resiniferatoxin) or antagonists (e.g. capsazepine);

- transient receptor potential cation channel subtypes (V1, V2, V3, V4, M8, M2, A1) agonists or antagonists;

- beta-adrenergic agonists, such as propranolol;

- local anesthetics, such as mexiletine;

- corticosteroids, such as dexamethasone;

- 5-HT receptor agonists or antagonists, such as 5-HT1B/1D agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

5-HT2A receptor antagonists, e.g. R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907 )；

Cholinergic (nicotine) analgesics such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R )-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine;

Tramadol®;

PDEV inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[ 4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl ) pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl- Piperazin-1-yl-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-( 5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one , 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine -7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro -7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidine-1- yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide or 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d] pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

α-2-δ ligands, e.g. gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(amino Methyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-( 3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl] Acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-yl)methyl) Cycloheptyl]methylamine, (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid, (3S ,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, or (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;

- cannabinoids;

- metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

Serotonin reuptake inhibitors, e.g., sertraline, desmethylsertraline, a metabolite of sertraline, fluoxetine, norfluoxetine (desmethyl metabolite of fluoxetine), fluvoxamine, paroxetine, citalopram, desmethylcitalopram, a metabolite of citalopram, escitalopram , d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, lithoxetine, dapoxetine, nefazodone, cericlamine, or trazodone;

Noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, hydroxybupropion, a metabolite of bupropion, nomifensine, or viloxazine (Vivalan®) , in particular selective noradrenaline reuptake inhibitors such as reboxetine, e.g. (S,S)-reboxetine;

Dual serotonin-noradrenaline reuptake inhibitors, e.g., venlafaxine, O-desmethylvenlafaxine, a metabolite of venlafaxine, clomipramine, desmethylclomipramine, a metabolite of clomipramine, duloxetine, milnacipran, or imipramine;

Inducible nitric oxide synthase (iNOS) inhibitors, e.g. S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino ]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2- Methyl-7-[{1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5 -chloro-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R) -2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1- (5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl ]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;

- Acetylcholinesterase inhibitors, such as donepezil;

- Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine-1 -yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl ]carbonyl}amino)ethyl]benzoic acid;

Leukotriene B4 antagonists, e.g. 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl) )-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870;

5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1 -methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

- sodium channel blockers, such as lidocaine;

- a calcium channel blocker, such as ziconotide, zonisamide, or mibefradil;

- 5-HT3 antagonists, such as ondansetron;
chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, leucovorin, or paclitaxel;
- Calcitosin gene-related protein (CGRP) antagonists;
- Bradykinin (BK1 and BK2) antagonists;
- voltage-gated sodium-gated channel blockers (Nav1.7, Nav1.8);
・Voltage-gated calcium channel blockers (N-type, T-type);
- P2X (ionotropic ATP receptor) antagonists;
- Acid-sensitive ion channel (ASIC1a, ASIC3) antagonists;
- Angiotensin-converting enzyme (ACE) inhibitors such as AT2 antagonists;
- angiotensin receptor blockers (ARBs);
- direct renin inhibitors (DRIs);
- mineralocorticoid receptor antagonists (MRAs);
- funny channel (If channel) inhibitors, such as ivabradine;
- chemokine CCR2B receptor antagonists;
- Cathepsin (B, S, K) inhibitors;
- a sigma 1 receptor agonist or antagonist;
Cardiac muscle node modulators such as omecamtivemecavir (OM), MYK-491, mabacamtene Soluble guanylate cyclase (sGC) stimulators such as vericiguat;
- an apelin receptor agonist;
- sodium/glucose cotransporter protein 2 (SGLT2) inhibitors, such as dapagliflozin, empagliflozin - heart failure drugs, such as Entresto®, a combination of sacubitril and valsartan;

Or a pharmaceutically acceptable salt or solvate thereof.

Such combination provides excellent therapeutic effects, including synergistic effects.

The pharmaceutical compositions of the invention, which may be prepared by mixing, preferably at room temperature and atmospheric pressure, are generally suitable for oral, parenteral or rectal administration and are tablets, capsules, oral liquid formulations, powders. , granules, buccal preparations, inhalants, reconstitutable powder formulations, injectable or injectable solutions or suspensions, or suppositories. Compositions for oral administration are generally preferred. Tablets and capsules for oral administration may be in unit dose form and contain binders such as pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose; fillers such as lactose, microcrystalline cellulose or phosphorous; tableting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); acceptable wetting agents (e.g. sodium lauryl sulfate), etc. of conventional excipients. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of dry formulations for reconstitution with water or other suitable vehicle before use. . Such liquid formulations may contain conventional additives such as suspending agents (eg sorbitol syrup, cellulose derivatives or hardened edible fats), emulsifiers (eg lecithin or acacia), non-aqueous vehicles (eg almond oil, edible oils such as oily esters, ethyl alcohol, refined vegetable oils), preservatives (eg, methyl or propyl p-hydroxybenzoate, or sorbic acid), and optionally conventional flavoring or coloring agents. , and optionally buffer salts and sweeteners. Formulations for oral administration may suitably be formulated to provide controlled release of the active compound or its pharmaceutically acceptable salts.

Fluid unit dosage forms for parenteral administration include compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutical compounds. manufactured using a pharmaceutically acceptable salt thereof and a sterile vehicle. Injectable formulations are compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable They may be presented in unit-dose form, such as in ampoules, or in multi-dose form, using a sterile vehicle and optionally an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. . Alternatively, the active ingredient of the invention may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use. The compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into vials and the water removed in vacuo. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in a sterile vehicle. Advantageously, including a surfactant or wetting agent in the composition facilitates uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Drops may be formulated with an aqueous or non-aqueous base comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. These lotions and drops may also contain a preservative.

The compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, are also, for example, They may also be formulated in rectal compositions such as suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides.

Compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, are also available in depot formulations. It may be formulated as Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof , suitable polymeric or hydrophobic materials (eg, may be formulated as an emulsion in an acceptable oil) or ion-exchange resins, such as sparingly soluble salts. It may be formulated as a sparingly soluble derivative.

Compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable compounds thereof, for intranasal administration A salt of may be formulated as a liquid formulation to be administered via a suitable metered dose or unit dose device, or as a mixed powder with a suitable carrier to be administered using a suitable delivery device. Accordingly, compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, may be administered orally Agents suitable for administration, buccal administration, parenteral administration, topical administration (including ophthalmic and nasal), depot administration, or rectal administration, or administration by inhalation or insufflation (via the mouth or nose). It may be formulated in the form The compounds of formula (I) and formula (II), or racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, and pharmaceutically acceptable salts thereof, are formulated into ointments, Formulated for topical administration in the form of creams, gels, lotions, packs, tapes, pessaries, aerosols, or drops (e.g., eye drops, ear drops, or nose drops) may be Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured under sterile conditions using sterile ingredients.

General Synthesis The term "base" is likewise not limited to the nature of the base used, and bases commonly used in reactions of this type are equally used here. Such bases include, but are not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and barium hydroxide; alkali metal hydrides such as sodium chloride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate. Alkali metals; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4- pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, N,N-dimethyl-4-aminopyridine (DMAP ), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7- Amines such as ene (DBU), lutidine, and collidine; lithium amide, sodium amide, potassium amide, lithium diisopropylamide, potassium diisopropylamide, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide, etc. of alkali metal amides. Of these, triethylamine, diisopropylethylamine, DMAP, DBU, DBN, DABCO, pyridine, lutidine, collidine, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium phosphate, water Barium oxide and cesium carbonate are preferred.

This reaction is usually and preferably carried out in an inert solvent. There are no particular restrictions as to the nature of the solvent used as long as it does not adversely affect the reaction or the reagents used and dissolves the reagents at least to some extent. Suitable solvents include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; ethers such as diethyl ether, diisopropyl ether, THF, and 1,4-dioxane; Aromatic hydrocarbons; amides such as DMF, DMA, and hexamethylphosphoric acid triamide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine , N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as acetonitrile and benzonitrile; dimethylsulfoxide (DMSO). , and sulfoxides such as sulfolane; acetone, and ketones such as diethyl ketone. Among these solvents, DMF, DMA, DMSO, THF, diethyl ether, diisopropyl ether, dimethoxyethane, acetonitrile, dichloromethane, dichloroethane, and chloroform are preferred, but not limited thereto.

The invention is illustrated in the following non-limiting examples, unless otherwise noted, all reagents are commercially available and all operations are carried out at room or ambient temperature, ie, in the range of about 18-25°C. Microwave reactions are performed using a Biotage Initiator or Biotage Initiator+. Evaporation of the solvent is carried out using a rotary evaporator at a bath temperature of about 60° C. or less under reduced pressure. Reactions are monitored by thin layer chromatography (TLC) and reaction times are exemplary only. The structure and purity of all isolated compounds are confirmed by at least one technique: TLC (Merck silica gel 60F ₂₅₄ precoated TLC plates or Merck _NH2F254 precoated _HPTLC plates), mass spectrometry, or NMR. . Yields are given for illustration only. Flash column chromatography is performed using Biotage SNAP KP-Sil, Biotage SNAP Isolute NH2, Merck silica gel 60 (230-400 mesh (ASTM)), Fuji Silysia Chromatorex® NH-DM1020 and NH-DM2035. Pre-purification for HPLC (preparative LC-MS) was performed using strong cation exchange cartridges (ISOLUTE® SCX-2, 1 g/6 mL, Biotage) or strong anion exchange cartridges (ISOLUTE® ) PE-AX, 1 g/6 mL, Biotage). Purification of compounds using HPLC (preparative LC-MS) or SFC (preparative SFC-MS) is performed using the following apparatus and conditions.

HPLC:
Instrument: Waters MS-trigger AutoPurification® System Column: Waters XBridge C8, 19 mm x 50 mm, 5 µm particles or Waters XBridge C18, 19 mm x 50 mm, 5 µm particles Mobile phase 1: (A) 0.05% (v /v) aqueous ammonia solution, (B) MeOH or MeCN
Mobile phase 2: (A) 0.05% (v/v) formic acid aqueous solution, (B) MeOH or MeCN
Mobile phase 3: (A) 10 mM ammonium formate aqueous solution, (B) MeCN/water = 90/10 (v/v)
Flow rate: 20 mL/min Gradient: A/B(95/5) to A/B(5/95) in 5, 7 or 10 minutes

SFCs:
Instrument: Waters Prep15 SFC system with ACQUITY QDa detector Columns: Waters Torus 2-PIC, 10 mm x 150 mm, 5 μm particles; Waters Torus DEA, 10 mm x 150 mm, 5 μm particles; Waters Torus DIOL, 10 mm x 150 mm, 5 μm particles; Waters Torus 1-AA, 10 mm x 150 mm, 5 μm particles Mobile phase: (A) carbon dioxide (CO ₂ ), (B) MeOH or 10 mM ammonia in MeOH Flow rate: 15 mL/ Minute Gradient: A/B (95/5) to A/B (60/40) in 7 or 10 minutes
Temperature: 40℃
Pressure: 120 bar (1740 psi)

Mass spectral data (ESI) are acquired on a Waters Alliance HPLC system equipped with a ZQ mass spectrometer and UV detector. NMR data were measured on a 400 MHz (JEOL JNM-ECZ400S) using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvents, unless otherwise stated; It is given in parts per million (ppm) relative to tetramethylsilane (TMS) as a standard. Common abbreviations used are s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc. Chemical symbols give their usual meanings of M (mol/liter), L (liter), mL (milliliter), g (gram), mg (milligram), mol (mole), mmol (millimoles).

Each compound prepared is generally named by ChemBioDraw (version 18.1, PerkinElmer Informatics).

General Synthesis In this application, the following abbreviations are used with the following meanings:

AcOH: Dess-Martin acetate Periodinane: 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one
DMAP: 4-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMSO: dimethyl sulfoxide
DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
EtOAc: ethyl acetate
EtOH: ethanol
ESI: electrospray ionization
Ex: example
h: hours
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HBTU: N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
HPLC: high performance liquid chromatography
(M)Hz: (Mega) Hertz
IM: Intermediate
MAC Reagent: Dicyanomethyl Acetate
MAC-TBS reagent: (tert-butyldimethylsilyloxy)malononitrile
MeCN: acetonitrile
MeOH: methanol
min: minutes
MS: mass spectrometry
NMM: N-methylmorpholine
NMR: nuclear magnetic resonance
_NaBH4 : sodium borohydride
NH gel: amino-bonded silica gel
PE-AX: anion exchange resin
rt.: room temperature
SCX: super cation exchange resin
TBSCl: tert-butyldimethylsilyl chloride
TFA: trifluoroacetic acid
THF: Tetrahydrofuran
TLC: thin layer chromatography
TMSCl: trimethylsilyl chloride
tR: retention time
UV: Ultraviolet

The compounds described herein are prepared using techniques known to those skilled in the art through the reaction sequences shown in Schemes 1-8, as well as by other methods. Further, although the schemes below refer to specific acids, bases, reagents, coupling agents, solvents, etc., other suitable acids, bases, reagents, coupling agents, solvents, etc. may be used, It is understood that these are included within the scope of the present invention.

The use of "protecting groups" (PG) is well known in the art (see, eg, "Protective Groups in Organic Synthesis," T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups are used where appropriate.

All starting materials in the general syntheses below are either commercially available or obtained by routine methods well known to those skilled in the art.

All compounds of formula (II) are prepared by the methods described in the general methods set forth below, the specific methods described in the Examples section and the Preparations section, or conventional variations thereof. be able to. The present invention also includes any one or more of the processes for the preparation of compounds of formula (II), and any novel intermediates used in these processes.

In the general methods below, X, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined above for the ketoamide derivatives of Formula II unless otherwise stated.

Sequentially detailed preparations of compounds of Formula II are shown in the reaction schemes below. The term "amidation" is used here, which refers to the coupling of HATU, HBTU or common amide coupling reagents in an inert solvent such as DMF or dichloromethane in the presence of a base such as a trialkylamine. carboxylic acid and amine at a temperature of 0-50° C. using an agent.

Scheme 1 shows a general synthesis of compounds of Formula I, and definitions of A, X, ^R1 , ^R2 , R3 ^, and ^R4 are provided herein.

Compounds of formula II can be prepared by treating compounds of formula 1 with an oxidizing agent such as Dess-Martin periodinane in a solvent such as a halogenated hydrocarbon or EtOAc at temperatures between -10 and 40°C. can be prepared by oxidation using

Compounds of Formula 1 used in the synthesis of compounds of the invention are prepared as described in Schemes 2 and 3. ^R2 , R3 ^{, R5} , X and A are as defined above and PG is a suitable protecting group. Compounds of formula 4 are prepared by amidation of selectively deprotected compounds of formula 2 and carboxylic acid 3 (step 1). Selective deprotection is performed using standard conditions known in the art (see Protective Groups in Organic Synthesis, Green & Wuts, Wiley- ^interscience , New York, 3rd edition, 1999). Provide the corresponding amino acids. Compounds of formula 5 are prepared by reduction of ester ₄ with a suitable reducing reagent such as NaBH4 with or without LiCl in a suitable solvent such as an alcohol with or without THF (Step 2). Compounds of formula 6 can be obtained by oxidation of compounds of formula 5 with an oxidizing agent such as Dess-Martin periodinane in an inert solvent or by DMSO oxidation (The Fifth Series of Experimental Chemistry, Vol. 17 Synthesis of Organic Compounds V, 223- 260, 2004) (Step 3). Compounds of formula 7 are prepared by nucleophilic addition of isonitriles in the presence of the appropriate carboxylic acid (Step 4). Compounds of formula 1 are prepared by the following steps: selective deprotection of the nitrogen atom protecting group, amidation with carboxylic acid 8 under suitable conditions (step 5), and hydrolysis of compounds of formula 9 (step 6). do. Compounds of formula 1 can be prepared from formula 7 without isolation of compounds of formula 9 (step 7).

Compounds of Formula 1 are prepared by the following steps (Scheme 3). Hydrolysis of ester 7 (step 1) and deprotection of PG (steps 2, 1) use standard conditions known in the art. Compounds of formula 1 are then prepared by amidation with carboxylic acids 8 (steps 2, 2).

Compounds of formula 1 are prepared by an alternative synthetic route (step 4). Compounds of formula 4 can be prepared by the following steps: selective deprotection of the nitrogen atom, amidation with carboxylic acid 8 (step 1), ester reduction of formula 11 (step 2), alcohol oxidation of formula 12 (step 3), carboxylic acid Compounds of formula (Ia) can be converted to compounds of formula 1 by nucleophilic addition to compounds of formula (Ia) with isonitrile in the presence of acid and hydrolysis with base (step 4).

Scheme 5 shows the preparation of compounds of formula 1b. Compounds of Formula 1b can be prepared in the same manner as described in Scheme 2. Compounds of formula 9a and 1a are prepared by the following sequential procedures (step 1): 1) selective deprotection by conventional methods, 2) amidation with compounds of formula 8a, and/or 3) hydration of substituent Y. Prepared following resolution (substituent Y is acyl). The resulting compounds of formulas 9a and 1a can be converted to acid halides, acid anhydrides after deprotection of PG and then in the presence of an aldehyde using a suitable base or alkyl halide, reducing reagent in an inert solvent. Amidation or alkylation with an amidating reagent such as an acid (R ³ -LvG is the leaving group to which R ³ is attached) can lead to compounds of Formula 1b. The resulting product, with or without hydrolysis, provides compounds of formula 1b (step 2).

Compounds of Formula IIc can be prepared from compounds of Formula 1c by the following procedure; oxidation as described in Scheme 1, Step 1, followed by deprotection of PG (Step 3) using conventional procedures.

Compounds of formula 2 are prepared by the following steps (Scheme 6); ester reduction of formula 2 (step 1), alcohol oxidation of formula 14 (step 2), nucleophilic addition of formula 15 (step 3), and selection of the nitrogen atom can be converted to compounds of formula 7 by selective deprotection, amidation with carboxylic acid 3 (step 4). Compounds of formula 10 can be prepared from compounds of formula 16 without isolation of compounds of formula 7 (step 5).

Compounds of Formula 1 can be prepared by an alternative synthetic route (Scheme 7). Aldehydes 15, 6, and 13 react with MAC (masked acyl cyanide) reagent 17a to provide the corresponding α-acetoxy esters 18, 19, and 21 (step 1). This nucleophilic addition is carried out in an inert solvent such as THF in the presence of a trialkylamine, a catalyst and an alcohol such as NMM, DMAP or imidazole, and methanol or ethanol. Compounds of formula 1 can be prepared from the α-acetoxy ester 18 by the following amide synthesis sequence: selective deprotection of the nitrogen atom and amidation according to formula 3 (step 2), selective deprotection of the nitrogen atom and amidation according to formula 8 ( Prepared by following step 3), and deprotection of PG and amidation according to formula 20 (step 4).

Compounds of formula 1 can also be prepared by direct amide synthesis using MAC-TBS reagent (17b) in the presence of the corresponding amine 20 (Scheme 8). Aldehydes 15, 6, and 13 are reacted with the MAC-TBS reagent (17b) in the presence or absence of a catalyst such as DMAP in an inert solvent such as MeCN to provide compounds of formula 21. . An optional TBS deprotection step is then performed to provide compounds of Formula 10 and Formula 1 (Step 1). Compounds of formula 10 are prepared from compounds of formula 21 by the following steps; selective or non-selective deprotection of the PG group (including/excluding TBS) followed by amidation with carboxylic acid 3. An optional deprotection step is required if the TBS group remains (steps 2-3). Compounds of formula 1 can be prepared by the usual sequence, deprotection of PG and amidation with the corresponding carboxylic acid (8).

Compounds of formula 8, if not commercially available, can be prepared by known procedures such as t-butyl 2-bromoacetate and the corresponding alcohol, amine, or thiol in the presence of a suitable base in a suitable solvent. .

The invention is illustrated in the following non-limiting examples, unless otherwise noted, all reagents are commercially available and all manipulations are carried out at room or ambient temperature, ie, in the range of about 18-25°C. Evaporation of the solvent is carried out using a rotary evaporator at a bath temperature of about 60° C. or less under reduced pressure. Reactions are monitored by thin layer chromatography (TLC) and reaction times are exemplary only. The structure and purity of all isolated compounds were determined by at least one of TLC (Merck silica gel 60F ₂₅₄ precoated TLC plates or Merck _{NH2F 2548} precoated HPTLC plates), mass spectrometry, or nuclear magnetic resonance (NMR). technique. Yields are given for illustration only. Flash column chromatography was performed using Fuji Silysia Chromatorex® DU3050 (amino type, 30-50 μm) or Biotage silica (32-63 mm, KP-Sil) or Biotage amino-bonded silica (35-75 mm, KP-NH). do. PE-AX and SCX cartridge column chromatography is performed using Biotage ISOLUTE® PE-AX and SCX-2 (1 g, 6 mL) SPE columns. Purification of compounds using HPLC was performed using the following equipment and conditions: Equipment; Waters MS-trigger AutoPurification™ system column; Waters XTerra C18, 19 x 50 mm, 5 mm particles, solvent system; methanol or acetonitrile/0.05%. (v/v) aqueous formic acid, or; methanol or acetonitrile/0.01% (v/v) aqueous ammonia. Low-resolution mass spectral data (ESI) are obtained on a Waters Alliance HPLC system equipped with the following equipment and conditions: Instrument; ZQ or ZMD mass spectrometer and UV detector. NMR data were measured on a 400 MHz (JEOL JNM-ECZ400S) using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvents, unless otherwise stated; It is given in parts per million (ppm) relative to tetramethylsilane (TMS) as a standard. Common abbreviations used are s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc. The chemical symbols are µL (microliter), µg (microgram), M (mol/liter), L (liter), mL (milliliter), g (gram), mg (milligram), mol (mol), mmol ( millimolar) gives the usual meaning.

LC-MS analysis of intermediates and examples is performed using a Waters 2695 Alliance HPLC equipped with a ZQ 2000 mass spectrometer and a 2996 PDA detector. Analysis conditions (Method-A, Method-B, Method-C, Method-D, Method-E, Method-F, Method-G, and Method-H) are as follows.

UPLC-MS analysis of intermediates and examples is performed on a Waters ACQUITY UPLC H-Class equipped with a QDa mass spectrometer and an ACQUITY PDA detector. The analysis conditions (Method-I, Method-J, and Method-K) are as follows.

Pre-purification for HPLC (preparative LC-MS) was performed using strong cation exchange cartridges (ISOLUTE® SCX-2, 1 g/6 mL, Biotage) or strong anion exchange cartridges (ISOLUTE® ) PE-AX, 1 g/6 mL, Biotage).

Purification of compounds using HPLC (preparative LC-MS) or SFC (preparative SFC-MS) is performed using the following apparatus and conditions.

HPLC:
Instrument: Waters MS-trigger AutoPurification® System Column: Waters XBridge C8, 19 mm x 50 mm, 5 µm particles or Waters XBridge C18, 19 mm x 50 mm, 5 µm particles Mobile phase 1: (A) 0.05% (v /v) aqueous ammonia solution, (B) MeOH or MeCN
Mobile phase 2: (A) 0.05% (v/v) formic acid aqueous solution, (B) MeOH or MeCN
Mobile phase 3: (A) 10 mM ammonium formate aqueous solution, (B) MeCN/water = 90/10 (v/v)
Flow rate: 20 mL/min Gradient: A/B(95/5) to A/B(5/95) in 5, 7 or 10 minutes

SFCs:
Instrument: Waters Prep15 SFC system with ACQUITY QDa detector Columns: Waters Torus 2-PIC, 10 mm x 150 mm, 5 μm particles; Waters Torus DEA, 10 mm x 150 mm, 5 μm particles; Waters Torus DIOL, 10 mm x 150 mm, 5 μm particles; Waters Torus 1-AA, 10 mm x 150 mm, 5 μm particles Mobile phase: (A) carbon dioxide (CO ₂ ), (B) MeOH or 10 mM ammonia in MeOH Flow rate: 15 mL/ Minute Gradient: A/B (95/5) to A/B (60/40) in 7 or 10 minutes
Temperature: 40℃
Pressure: 120 bar (1740 psi)

HPLC retention time measurement conditions:

QC method:
QC method-1:
Instrument: Waters ACQUITY UPLC H-Class PLUS with PDA detector and SQ detector 2 mass spectrometer
Column: YMC Triart C18, 2.1 x 100 mm, 1.9 μm particle Column temperature: 60°C
PDA detection: 200-400 nm scanning
MS detection: ESI positive/negative mode mobile phase:
A: 0.05% (v/v) aqueous ammonia solution
B: Acetonitrile

QC方法-2:
装置：2996 PDA 検出器およびZQ 2000 質量分析計を備えたWaters 2795 Alliance HPLC
カラム：Waters XBridge C18 2.1 x 50 mm, 3.5 μm粒子
カラム温度：45℃
PDA 検出：210～400 nm 走査
MS 検出：ESI ポジティブ／ネガティブ モード
移動相：
A：H₂O (Milli-Q 水)
B：アセトニトリル
C：1% (v/v) アンモニア水溶液

QC method-2:
Instrument: Waters 2795 Alliance HPLC with 2996 PDA detector and ZQ 2000 mass spectrometer
Column: Waters XBridge C18 2.1 x 50 mm, 3.5 μm particle Column temperature: 45°C
PDA detection: 210-400 nm scanning
MS detection: ESI positive/negative mode mobile phase:
A: _H2O (Milli-Q water)
B: Acetonitrile
C: 1% (v/v) aqueous ammonia solution

Scheme 2 for the preparation of intermediate 1, step 1

IM 4-1:
(S)-3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3,4-dihydro tert-Butyl isoquinoline-2(1H)-carboxylate
To a stirred solution of methyl (S) _-2 -((tert-butoxycarbonyl)amino)-3-((S) _-2 -oxopyrrolidin-3-yl)propanoate (1.0 eq.) in CH2Cl2 was stirred with N ₂ Add 4M HCl-dioxane (2.8 eq) at 0°C. After stirring at 0° C. to room temperature for 3 hours, the reaction mixture is concentrated under reduced pressure to give the HCl salt. A mixture of HCl salt (1.0 eq.) and (S)-2-(tert-butoxycarbonyl)-1,2,3,4 _- tetrahydroisoquinoline-3-carboxylic acid (1.1 eq.) in CH2Cl2 was stirred at ₀ °C. HATU (1.2 eq.) and _Et3N (1.5 eq.) are added at . After stirring for 16 hours at 0° C. to room temperature, the reaction mixture is diluted with EtOAc and washed with saturated aqueous NaHCO ₃ and brine. The organic layer is dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.
LCMS: Method-A, tR 1.93 min, MS (ESI) m/z: 446.13 (M+H) ⁺ .

IM 4
The following compounds are prepared from the corresponding commercially available Boc-amino acids following the same procedure as for the preparation of IM 4-1 (Table 4).

Scheme 2, process 2

IM5-1:
(S)-3-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2 ( 1H)-tert-Butyl carboxylate
(S)-3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane- in 150 mL THF-MeOH (2:1)) NaBH ₄ (3.51 g, 93.00 mmol) was added to a stirred solution of tert-butyl 2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (IM4-1, 6.56 g, 14.72 mmol) at 0 °C. ). After stirring at 0° C. to room temperature for 3.5 hours, MeOH is added to the reaction mixture and stirred at room temperature for 30 minutes. The resulting mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.
LCMS: Method-A, tR 1.82 min, MS (ESI) m/z: 418.09 (M+H) ⁺ .

IM5
The following compounds are prepared from the corresponding IM 4 following the same procedure as for the preparation of IM 5-1 (Table 5).

Scheme 2, process 3

IM6-1:
(S)-3-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2 ( 1H)-tert-Butyl carboxylate To a stirred suspension of SO ₃ Py (6.75 g, 42.4 mmol) in dry CH ₂ Cl ₂ and DMSO was added iPr ₂ NEt (13.0 mL, 74.6 mmol) at 0 °C under N ₂ . Add After stirring for 35 min at 0° C. under N ₂ , the mixture was treated with (S)-3-(((S)-1-hydroxy-3-((S)-2-oxo) in dry CH ₂ Cl ₂ -DMSO solution. Pyrrolidin-3-yl)propan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (IM 5-1, 5.71 g, 13.68 mmol) was added at 0°C, Stir at 0°C for 2 hours. The reaction mixture is quenched with 10% citric acid and extracted with EtOAc. The organic layer is washed with _brine , dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound.
LCMS: Method-A, tR 1.87 min, MS (ESI) m/z: 416.08 (M+H) ⁺ .

IM6
The following compounds are prepared from the corresponding IM 5 following the same procedure as for the preparation of IM 6-1 (Table 6).

Preparation of intermediate 7

General Procedure, Scheme 2, Step 4
To a stirred solution of aldehyde (IM ₆ , 1.0 eq) and AcOH ( _2.0 eq) in CH2Cl2 at room temperature isonitrile (1.2 eq) is added. After stirring for 2 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with brine. The organic layer is dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain Intermediate 7 below (Table 7-1 to Table 7-3).

IM 7-1
LCMS: Method-F, tR 0.49 min, MS (ESI) m/z = 543.2 (M+H) ⁺ .
IM7-2
LCMS: Method-A, tR 2.12 min, MS (ESI) m/z = 592.98 (M+H) ⁺ .
IM7-3
LCMS: Method-F, tR 0.51 min, MS (ESI) m/z: 521.3 (M+H) ⁺ .
IM 7-4
LCMS: Method-H, tR 0.54 min, MS (ESI) m/z: 571.3 (M+H) ⁺ .
IM7-5
LCMS: Method-F, tR 0.51 min, MS (ESI) m/z = 507.3 (M+H) ⁺ .
IM7-6
LCMS: Method-F, tR 0.54 min, MS (ESI) m/z = 557.3 (M+H) ⁺ .
IM 7-7
LCMS: Method-F, tR 0.52 min, MS (ESI) m/z = 535.4 (M+H) ⁺ .
IM7-8
LCMS: Method-F, tR 0.53 min, MS (ESI) m/z = 535.3 (M+H) ⁺ .
IM7-9
LCMS: Method-F, tR 0.51 min, MS (ESI) m/z = 549.3 (M+H) ⁺ .
IM 7-10
LCMS: Method-A, tR 2.27 min, MS (ESI) m/z = 599.3 (M+H) ⁺ .

General Procedure for Preparation of Intermediate 9: Scheme 2, Step 5 and Scheme 5, Step 1 (No Hydrolysis)

To a stirred solution of intermediate 7 in CH2Cl2 at ₀ ° _C under _N2 is added 4M HCl-dioxane (5 eq). After stirring at 0° C. to room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure to give the HCl salt.

To a stirred mixture of HCl salt (1.0 eq.), HATU (1.5 eq.) and Formula 8 (1.2 eq.) in CH ₂ Cl ₂ is added NMM (3.0 eq.) at 0°C. After stirring for 4 hours at 0° C., the mixture is quenched with brine. The mixture is extracted 3 times with EtOAc. The organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain Intermediate 9 below (Table 8-1 to Table 8-7).

MeOH中の酢酸塩(IM 9)の撹拌溶液に、0℃で2M NaOH(2.0当量)を加える。0℃で15分間撹拌した後、反応混合物を2M塩酸で中和する。混合物をN₂吹き付けで濃縮する。残渣をシリカゲルカラムクロマトグラフィーで精製し、以下の中間体1を得る(表９)。 General Procedure for Preparation of Intermediate 1: Scheme 2, Step 6

To a stirred solution of acetate salt (IM 9) in MeOH at 0° C. is added 2M NaOH (2.0 eq). After stirring for 15 min at 0° C., the reaction mixture is neutralized with 2M hydrochloric acid. Concentrate the mixture with a _N2 blow. The residue is purified by silica gel column chromatography to give Intermediate 1 below (Table 9).

General Procedure: Scheme 2, Step 7
To a stirred solution of intermediate ₇ in CH2Cl2 at ₀ °C is added 4M HCl-dioxane (5 eq). After stirring at 0° C. to room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure to give the HCl salt. To a stirred mixture of HATU (1.5 eq.), Formula 8 (1.5 eq.) and NMM (5.0 eq.) in CH ₂ Cl ₂ is added HCl salt (1.0 eq.) at 0°C. After stirring for 4 hours at 0° C. to room temperature, the solvent is removed by blowing N ₂ . To a stirred solution of crude product (step 7-1) in MeOH at 0° C. is added 2M NaOH (5.0 eq.). After stirring for 1 hour at 0° C. to room temperature, the reaction mixture is neutralized with 2M hydrochloric acid. The reaction mixture is extracted with EtOAc. The organic layer is washed with _brine , dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain intermediates 1 and 1c below (Table 9-1 to Table 9-13).

Scheme 5, step 1 (with hydrolysis)
IM 1a-1:
((2S)-1-((6S)-6-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidine-3- yl)butan-2-yl)carbamoyl)-5-azaspiro[2.4]heptan-5-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate tert-butyl

(6S)-6-(((2S)-3-acetoxy-4-(cyclopropylamino)-4-oxo-1-((S) _-2 -oxopyrrolidine-) in CH2Cl2 ( _2.0 mL) A mixture of tert-butyl 3-yl)butan-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (IM 7-5, 54 mg, 0.107 mmol) and TFA (0.5 mL) was added to room temperature. Stir for 2 hours at The mixture is purified on a CX-2 cartridge column (2N _NH3 /MeOH). The filtrate is concentrated under reduced pressure to give an oil. Residual oil is dissolved in 2.0 mL of DMF. (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (37 mg, 0.160 mmol), HATU (81 mg, 0.213 mmol), and NMM (0.059 mL, 0.533 mmol) Add to the DMF solution at room temperature. After stirring for 18 hours at room temperature, the mixture is concentrated under reduced pressure and the resulting residue is dissolved in MeOH. The solution is filtered through a PE-AX cartridge column. The filtrate is cooled to 0° C. and 4M LiOH aqueous solution (0.053 mL, 0.213 mmol) is added to the mixture. The mixture is stirred at 0° C. for 2 hours, 2N aqueous hydrochloric acid (0.11 mL, 0.22 mmol) is added to the mixture and concentrated under reduced pressure to give a glass. Purify the remaining glass by silica gel column chromatography (70-100% EtOAc/hexanes, 0-15% MeOH/EtOAc) to give 55 mg (89%) of the title compound.
LCMS: Method-F, tR 0.47 min, m/z = 578.3 (M+H) ⁺

The following compounds are prepared from the corresponding IM 7 following the same procedure as for the preparation of IM 1a-1 (Table 10).

Scheme 5, step 2 (no hydrolysis)
IM 1b-1:
(6S)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)- 5-( (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-5-azaspiro[2.4]heptane-6-carboxamide

((2S)-1- _{( (} 6S)-6-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((( S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-5-azaspiro[2.4]heptan-5-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamic acid A mixture of tert-butyl (IM 1a-1, 55 mg, 0.095 mmol) and TFA (0.5 mL) is stirred at room temperature. After stirring at room temperature for 2 hours, the mixture is purified by SCX-2 cartridge column ( _NH3 -MeOH) to give the amine. The resulting amine is dissolved in 2.0 mL of CH ₂ Cl ₂ and NMM (0.052 mL, 0.476 mmol) and trifluoroacetic anhydride (0.020 mL, 0.143 mmol) are added to the mixture at room temperature. After stirring for 2 hours at room temperature, the mixture is purified by PE-AX and SCX-2 cartridge columns (MeOH) to give 19 mg (35%) of the title compound.
LCMS: Method-F, tR 0.53 min, m/z = 574.3 (M+H) ⁺

The following compounds are prepared from the corresponding IM 1a following the same procedure as for the preparation of IM 1b-1 (Table 11).

(3S)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)- 2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1b-4), and (1R,2S,5S)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butane- 2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-Carboxamides (1b-5) were obtained by hydrolysis of aqueous LiOH (4 M, 2.0 equiv.) in MeOH following the same procedure as for the preparation of IM 1b to give acetic acid (3S)-3-((S )-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)-1-(cyclopropylamino)-1-oxo -4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl (IM 9-32), and acetic acid (3S)-3-((1R, 2S,5S)-3-(( S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamido)-1-(cyclopropyl Prepared from amino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl (IM 9-34) (Tables 11-1 and 11-2).

General Procedure, Scheme 5, Step 3-1
To a mixture of the alcohol derivative (IM 1c, 1.0 eq) in CH2Cl2 at ₀ ° C. was added Dess-Martin periodinane (8.2 eq) and _NaHCO3 (2.2 eq) and stirred at room temperature for ₃ h. do. The mixture is quenched at room temperature with aqueous sodium thiosulfate and aqueous NaHCO ₃ (1 mL) and stirred for 10 minutes. Brine is added to the mixture, extracted with EtOAc and passed through a pad of sodium sulfate. The filtrate is removed by concentration under reduced pressure and the crude product is purified by silica gel column chromatography to obtain intermediate IIc with protected nitrogen atom (Table 12).

General Procedure, Scheme 5, Step 3-2
Intermediate IIc is added to 4M hydrochloric acid in 1,4-dioxane (1 mL) and stirred at room temperature for 30 minutes. Solvents are removed by _N2 gas blowing and the crude products are purified by preparative LC-MS to give the following examples (Table 13).

実施例29および3のLCMSデータを表17-1に示す。

LCMS data for Examples 29 and 3 are shown in Table 17-1.

Scheme 6 for the preparation of intermediate 7, step 1

IM 14-1
tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate
To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (1 equivalent) in MeOH, at 0 °C Add NaBH ₄ (5 eq) and stir overnight at room temperature. Aqueous NH ₄ Cl solution and brine are added to the mixture, extracted with EtOAc/MeOH=10/1, and dried over sodium sulfate. Remove the solvent by concentration under reduced pressure to obtain the title compound. This product is used in the next step without further purification.
LCMS: Method-F, tR 0.43 min, m/z = 281.2 (M+Na) ⁺ .

Scheme 6, step 2
IM 15-1
tert-Butyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate
tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- ₂ -yl)carbamate ( _IM14 ) in CH2Cl2/EtOAc = 1/1 -1, 1 eq.) to a mixture of Dess-Martin periodinane (1.3 eq.) and NaHCO ₃ (1.3 eq.) at 0° C. and stirred at room temperature for 4 h. Filter the solvent, wash with 10% MeOH in CH ₂ Cl ₂ and collect the filtrate. The solvent is removed by vacuum concentration and the crude product is purified by silica gel column chromatography to give the title compound.
LCMS: Method-I, tR 0.17 min, m/z = 279.0 (M+Na) ⁺ .

Scheme 6, Step 3
IM 16-1
(3S)-3-((tert-Butoxycarbonyl)amino)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate
tert-Butyl ((S)-1-oxo-3-((S) _-2 -oxopyrrolidin-3-yl)propan- ₂ -yl)carbamate (IM 15-1, 1 etc.) in CH2Cl2 amount, 1.3 g, 5.1 mmol) and AcOH (1.5 eq) is added dropwise at 0° C. with isocyanocyclopropane (1.5 eq) and stirred at room temperature for 4 h. Solvent is removed by _N2 gas blowing and the crude product is purified by silica gel column chromatography to give the title compound.
LCMS: Method-I, tR 0.17 min, m/z = 384.2 (M+H) ⁺ .

General Procedure, Scheme 6, Step 4-1
(3S)-3-((tert-butoxycarbonyl)amino)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidine-3-acetic acid in 1,4-dioxane) A mixture of yl)butan-2-yl (IM16-1) and 4M hydrochloric acid is stirred at room temperature for 1 hour. Remove the solvent by flushing with _N2 to obtain the hydrochloride salt.

General Procedure, Scheme 6, Step 4-2
A mixture of HCl salt (1.5 eq), HATU (1.5 eq) and NMM (5.0 eq) in CH ₂ Cl ₂ is stirred at 0° C. for 10 min. Carboxylic acid (1 eq.) is added to the mixture at 0° C. and stirred overnight at room temperature. NaHCO ₃ aqueous solution and brine are added to the mixture, extracted with EtOAc and dried over sodium sulfate. The solvent is removed by concentration under reduced pressure and the crude product is purified by silica gel column chromatography to give Intermediate 7 below (Table 14).

IM 7-5
LCMS: Method-F, tR 0.50 min, m/z = 521.4 (M+H) ⁺ .
IM7-6
LCMS: Method-I, tR 0.20 min, m/z = 543.3 (M+H) ⁺ .
IM 7-7
LCMS: Method-F, tR 0.51 min, m/z = 557.3 (M+H) ⁺ .
IM 7-8
LCMS: Method-F, tR 0.50 min, m/z = 507.3 (M+H) ⁺ .
IM-7-9
LCMS: Method-F, tR 0.54 min, m/z = 577.3 (M+H) ⁺ .

Preparation of Intermediate 10 Scheme 6, Step 5-1
The following intermediates are prepared following the same procedure as described in Scheme 2, Step 7, using intermediate 16 and carboxylic acid 3 instead of intermediate 7 and carboxylic acid 8 (Table 15-1 to Table 15-1). 24).

General procedure for the preparation of the examples: Scheme 1
A mixture of Intermediate 1 (1.0 eq.) and Dess-Martin periodinane (2.0 eq.) in dichloromethane was stirred at 0° C. for 1 hour and the mixture was quenched with saturated aqueous sodium thiosulfate and washed with CH ₂ Cl ₂ . Extract. The extract was concentrated by blowing N ₂ , and the resulting residue was filtered through silica gel column chromatography and/or PE-AX cartridge column, purified by preparative HPLC, and subjected to the following examples (Table 16-1 to Table 16- 29) is obtained.

参考文献
工程1：Zhongら、Bioorganic & Medicinal Chemistry Letters (2016), 26(10), 2526-2530
工程2：Miyataら、世界知的所有権機関, WO2010113022 A1
工程3：Shimizuら、Bioorganic & Medicinal Chemistry Letters (2010), 20(4), 1453-1456；
さらに、大部分のビフェニル置換カルボン酸8は、市販の試薬（例えば、Combi-Blocks (4-ブロモフェノキシ)酢酸エチルエステル(cas#.6964-29-0))から合成できる。 Some examples are prepared by using a biphenyl-substituted carboxylic acid 8 as the left side unit, which is prepared as follows.

Reference step 1: Zhong et al., Bioorganic & Medicinal Chemistry Letters (2016), 26(10), 2526-2530
Step 2: Miyata et al., World Intellectual Property Organization, WO2010113022 A1
Step 3: Shimizu et al., Bioorganic & Medicinal Chemistry Letters (2010), 20(4), 1453-1456;
Additionally, most biphenyl-substituted carboxylic acids 8 can be synthesized from commercially available reagents such as Combi-Blocks (4-bromophenoxy)acetic acid ethyl ester (cas#.6964-29-0).

All examples are analyzed by LCMS under the QC methods described in Tables 17-1, 17-2 and 17-3 below.

Pharmacological Assay Main Protease (M ^pro ) Assay:
The ability of compounds to inhibit the protease activity of the SARS-CoV-2 main protease ( ^Mpro ) is measured by an enzymatic assay using a fluorescence resonance energy transfer (FRET)-based substrate. A FRET-based synthetic fluorescent peptide, Dabcyl-KTSAVLQSGFRKME-Edans (Peptide Institute), is designed such that cleavage between Gln and Ser by a protease results in an increase in its fluorescence signal of Edans. In this assay, recombinant SARS-CoV-2 M ^pro protein (Boston Biochem) is used as protease at a final concentration of 50 nM. Assays are performed in 384-well plates and the total assay volume is 18 μL. Recombinant SARS-CoV-2 M ^pro and various concentrations of compounds are pre-incubated at 30°C for 30 min. The assay is initiated by adding substrate to a final concentration of 5 μM and the plates are incubated at 30° C. for 15 minutes. Fluorescent signals are measured at 490 nm with excitation at 340 nm using a PHERAstar Microplate Reader (Molecular Devices). Fluorescence intensity is normalized with background signal and calculated as percent inhibition. At this time, 0% inhibition is the normal fluorescence intensity without compound, and 100% inhibition is the normal fluorescence intensity without recombinant SARS-CoV-2 M ^pro . Compound IC ₅₀ values are calculated by fitting percent inhibition using XLfit (ID Business Solutions).
All tested compounds of the invention exhibit IC ₅₀ values <1 μM.

Cell-based viral infection assay:
Antiviral activity against SARS-CoV-2 of compounds is determined by reference to the method described in Example 2 of WO2021/215517. See also Sakurai et al., Biochemical and Biophysical Research Communication, 545, (2021), 203-207, Imamura et al., FEBS Open Bio, 11, (2021), 1452-1464 for this method.
These methods can be performed using Calu-3 cells (human airway epithelial cells) instead of VeroE6 cells or Caco-2 cells. Calu-3 cells are plated and incubated with appropriate concentrations of each compound. The cells are then infected with SARS-CoV-2 and incubated at 37°C in the presence of compounds. After 3 days, cells are fixed overnight with 4% paraformaldehyde. Viral infection is determined by immunofluorescence using an anti-SARS-CoV N antibody as the primary antibody and detected with Alexa Fluor 488-conjugated IgG. Cells are imaged on a plate reader. _EC50 values for compounds are calculated by non-linear regression fitting. All test compounds of the invention show favorable inhibition of SARS-CoV-2 infection.

Human dofetilide binding assay:
hERG-expressing HEK293S cells are prepared and grown in-house. Harvested cells are suspended in 50 mM Tris-HCl (pH 7.4 at 4° C.) and homogenized for 20 seconds on ice using a handheld Polytron PT 1200 disruptor set at full power. The homogenate is centrifuged at 48000 xg for 20 minutes at 4°C. The pellet is then similarly resuspended, homogenized and similarly centrifuged once again. The final pellet is resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl2 ₍ pH 7.4 at 4°C), homogenized, aliquoted and stored at -80°C until use. . This aliquoted membrane fraction is used for protein concentration quantification using the BCA protein assay kit (PIERCE) and an ARVOsx plate reader (Wallac). Binding assays are performed in a total volume of 30 μL in 384-well plates. Binding activity is measured using fluorescence polarization technology on a PHERAstar (BMG LABTECH). 10 μL of test compound is incubated with 10 μL of fluorescent ligand (6 nM dofetilide derivative labeled with Cy3B) and 10 μL of membrane homogenate (6 μg protein) for 120 minutes at room temperature. Non-specific binding is determined with 10 μM E4031 at final concentration.

All tested compounds of the invention exhibit IC ₅₀ values for human dofetilide binding that are greater than the IC ₅₀ values for the M ^pro assay. A large IC ₅₀ value for human dofetilide binding activity reduces the risk of adverse cardiovascular events.

Metabolic stability assay:
Half-Life in Human Liver Microsomes (HLM) Test compounds (1 μM) in 100 mM potassium phosphate buffer (pH 7.4) in 1 mM MgCl ₂ and 0.61 mg/mL HLM (Xenotech Xtreme200 ) at 37°C. Add nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) to the reaction mixture (a NADPH generation system can be used instead of NADPH). Aliquots of samples are taken at 0, 10, 30 and 60 minutes, where 0 minutes indicates when NADPH was added to the reaction mixture. A sampled portion is extracted with an acetonitrile solution containing an internal standard. The precipitated proteins are sedimented in a centrifuge (2000 rpm, 15 min). The compound concentration in the supernatant is measured with an LC/MS/MS system.

Half-life values are obtained by plotting the natural logarithm of the compound/internal standard peak area ratio versus time. Through each time point, the metabolic rate (k) is obtained from the slope of the best-fit line. Convert this to a half-life value from the following formula: half-life = ln2/k.
The compounds of the invention exhibit favorable stability, which demonstrates the utility described above.

CYP3A inhibitory effect on HLM-mediated metabolism Test article (1 μM) in 100 mM potassium phosphate buffer (pH 7.4) with 1 mM MgCl ₂ and 1 mg/mL HLM (Xenotech Xtreme200) on 96 deep well plate Incubate at 37°C. Ketoconazole (1 μM) is also added to the reaction mixture for the CYP3A inhibition group. The metabolic reaction is initiated by the addition of the nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) generating system. Aliquots of samples are taken at 0, 10, 30 and 60 minutes. Here, 0 min indicates the time when the NADPH generating system was added to the reaction mixture. A sampled portion is extracted with an acetonitrile solution containing an internal standard. The precipitated proteins are spun down in a centrifuge (2000 rpm, 15 min). The compound concentration in the supernatant is measured with an LC/MS/MS system. Calculate the half-life as in the HLM assay. The half-lives of the CYP3A inhibition group (compounds to which ketoconazole was added) and the control group (only compounds to which ketoconazole was not added) were compared, and the contribution of CYP3A to the metabolism of each compound was determined.
The compounds of the present invention exhibit favorable CYP3A inhibitory activity, which demonstrates the utility described above.

Drug Interaction Assay This method uses probes (Tacrine (Sigma A3773-1G) 2 μM, Dextromethorphan (Sigma, D-9684) 5 μM, Diclofenac (Sigma D-6899-10G) 5 μM, and Percent inhibition of metabolite formation from midazolam (Ultrafine UC-429) 2 μM) is determined virtually.

More specifically, the assay is performed as follows. Compounds (60 μM, 10 μL) were added in 170 μL of a mixture containing 0.1 mg protein/mL human liver microsomes, 100 mM potassium phosphate buffer (pH 7.4), 1 mM MgCl ₂ , and probe as substrate for 5 min. Pre-incubate. Reactions are initiated by the addition of NADPH (20 μL of NADPH generating system consisting of 10 mM NADP ⁺ , 50 mM DL-isocitrate and 10 U/mL isocitrate dehydrogenase is also used). Incubate the assay plate at 37°C. Acetonitrile is added to the incubation solution for an appropriate time (eg 8 minutes).
Concentrations of metabolites in supernatants are measured by an LC/MS/MS system. The extent of drug-drug interaction is interpreted based on % formation of metabolites in the presence or absence of test compound.

The compounds of the invention exhibit favorable stability, which demonstrates the utility described above.

Plasma protein binding assay:
Plasma protein binding of test compounds (1 μM) is determined by equilibrium dialysis using a 96-well plate type apparatus. HTD96a™, a regenerated cellulose membrane (molecular weight cutoff 12000-14000, 22 mm x 120 mm) was soaked overnight in distilled water, then in 30% ethanol for 15 minutes and finally in dialysis buffer (Dulbecco's phosphate buffer). Soak in physiological saline, pH 7.4) for 20 minutes. Human, Sprague-Dawley rat, and beagle dog frozen plasma are used. Assemble the dialyzer and add 150 μL compound-laden plasma to one side of each well and 150 μL dialysis buffer to the opposite well. After 4 hours of incubation at 150 rpm and 37° C., aliquots of plasma and buffer are harvested. Compounds in plasma and buffer are extracted with 300 μL of acetonitrile containing internal standard compounds for analysis. Compound concentrations are determined by LC/MS/MS analysis.
The unbound fraction (fu) of a compound is calculated by the following formula (A) or (B):

式中、[血漿]_eqおよび[緩衝液]_eqは、それぞれ血漿および緩衝液中の化合物濃度を示す。

where [plasma] _eq and [buffer] _eq indicate the concentration of the compound in plasma and buffer, respectively.

式中、Cpは、血漿試料中の化合物のピーク面積であり；
Cis,pは、血漿試料中の内部標準のピーク面積であり；
Cbは、緩衝液試料中の化合物のピーク面積であり；
Cis,bは、緩衝液試料の内部標準のピーク面積であり；
4および4/3は、それぞれ血漿および緩衝液で希釈率の逆数である。
本発明の化合物は、好ましい血漿タンパク結合を示し、これは上述の実用性を示す。

where Cp is the peak area of the compound in the plasma sample;
Cis,p is the peak area of the internal standard in the plasma sample;
Cb is the peak area of the compound in the buffer sample;
Cis,b is the peak area of the internal standard of the buffer sample;
4 and 4/3 are the reciprocal dilution ratios in plasma and buffer respectively.
The compounds of the invention exhibit favorable plasma protein binding, which demonstrates the utility described above.

Water solubility test at equilibrium:
A DMSO solution (2 μL, 30 mM) of each compound is dispensed into each well of a 96-well glass bottom plate. Potassium phosphate buffer (50 mM, 198 μL, pH 6.5) is added to each well and the mixture is incubated for 24 hours at 37° C. with rotary shaking. After centrifugation at 2000×g for 5 minutes, the supernatant is filtered through a polycarbonate iso-pore membrane. Sample concentrations are determined by a conventional gradient HPLC method (J. Pharm. Sci., 2006, 95, 2115-2122).
The compounds of the invention exhibit favorable water solubility, which demonstrates the utility described above.

Pharmacokinetics (PK) in animals:
Male RccHan®: Compounds are administered intravenously or orally to animals such as WIST rats. After dosing, blood is drawn from a vein with a heparinized syringe at each of the predetermined time points. After centrifugation at 4,000 g for 5 minutes at 4°C, the concentration of each compound in plasma is quantified by an LC/MS/MS system after an extraction process. Pharmacokinetic parameters are calculated by non-compartmental analysis.
The compounds of the invention exhibit favorable PK results and demonstrate the utility described above.

Parallel artificial membrane permeation assay (PAMPA):
A DMSO solution of each compound was dispensed into each well of the donor plate of the MultiScreen (registered trademark) 96-well plate (MultiScreen IP/MultiScreen 96-well Transport Receiver Plate, Merck Millipore), and added with phosphate buffer (50 mM, pH 6.0). ) was added for dilution. Phospholipid dissolved in an organic solvent (e.g., DOPC:stearic acid (80:20, w/w) in dodecane containing 1% ethanol, Avanti) was added to the filter membrane at the bottom of each well of the acceptor plate to form an artificial lipid membrane. to make. Phosphate buffer (50 mM, pH 6.0) containing 0.5% DMSO is then added to each well of the acceptor plate. Overlay the acceptor plate on the donor plate to bring the filter membranes into contact with the liquid in each well. After incubating for a certain period of time (30° C., about 400 rpm for 18 hours), the buffer solution is collected from each well of the acceptor plate and the donor plate, and the concentration of each compound is measured by UPLC (manufactured by Waters).
The membrane permeability of a compound is calculated by the following formula.

ここで
Pe＝透過率［cm／s］
C_A = インキュベーション時間後のアクセプターウェル中の化合物濃度[mM]
C_D = インキュベーション時間後のドナーウェル中の化合物濃度[mM]
V_A＝アクセプターウェルの容量＝0.2［mL］
V_D = ドナーウェルの容量 = 0.3 [mL]
C_equiv = (C_D×V_D+C_A×V_A) / (V_D+V_A) [mM]
A = フィルター面積 = 0.3 [cm²］
t = インキュベーション時間 = 64800 [s] (= 18時間)
本発明の化合物は、好ましい透過性を示し、これは上記の実用性を示す。

here
Pe = transmittance [cm/s]
C _A = compound concentration in acceptor wells after incubation time [mM]
C _D = compound concentration in donor wells after incubation time [mM]
V _A = Volume of acceptor well = 0.2 [mL]
V _D = volume of donor well = 0.3 [mL]
C _equiv = (C _D ×V _D +C _A ×V _A ) / (V _D +V _A ) [mM]
A = filter area = 0.3 [cm ² ]
t = incubation time = 64800 [s] (= 18 hours)
The compounds of the invention exhibit favorable permeabilities, which demonstrate the utility described above.

All publications (including, but not limited to, issued patents, patent applications, and scholarly articles) cited in this application are each hereby incorporated by reference in their entirety. Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It is understood that various modifications may be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

The ketoamide derivatives of the invention are useful in the treatment or prevention of ^Mpro -related conditions or disorders that are disorders, diseases, or sequelae caused by viruses, including coronaviruses.

Claims (15)

Compounds of formula (I):

(in the formula:
R ¹ and R ² are (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C _1-6 alkyl, (5) -OC _1-6 alkyl, (6) C _3-7 cycloalkyl , (7) _C3-7 cycloalkoxy, (8) C2-6 alkenyl, (9) -NR ^a R ^b , (10) (R ^a )(R ^b )NC _{1-6 alkyl} , (11) heterocyclyl , (12) aryl, (13) heteroaryl, (14) arylC _1-6 alkyl, (15) heteroarylC _1-6 alkyl, (16) -CN, and (17) C _3-7 cycloalkylC independently selected from the group consisting of _1-6 alkyl; wherein said C _1-6 alkyl, said -OC _1-6 alkyl, said C _3-7 cycloalkyl, said C _3-7 cycloalkoxy, said C _2-6 alkenyl, said heterocyclyl, said aryl, said heteroaryl, said arylC _1-6 alkyl, said heteroarylC _1-6 alkyl, or said C _3-7 cycloalkylC _1-6 alkyl is (1) optionally substituted with 1 to 6 substituents independently selected from the group consisting of hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
Alternatively, R ¹ and R ² may form a 4- to 7-membered ring that may contain N, O, S, double bonds, or carbonyl; wherein the 4- to 7-membered ring is (1 optionally substituted with 1 to 6 substituents independently selected from the group consisting of: ) hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
R ^a and R ^b are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) arylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said aryl C _1-6 alkyl, said heteroaryl, or said heteroaryl C _1-6 alkyl is unsubstituted or the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl and -CN substituted with one or more substituents independently selected from;
Alternatively, R ^a and R ^b may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, and C _1-6 alkoxyl;
X is _-CH2- , -NH-, -N( _C1-6alkyl )-, -O-, or -S-;
R ³ is (1) hydrogen, (2) C _1-6 alkyl, (3) C _2-6 alkenyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) aryl, (7) heteroaryl, (8) phenylC _1-6 alkyl, (9) phenyl-Q-heteroaryl, (10) phenyl-Q-phenyl, (11) heteroaryl-Q-phenyl, (12) heteroaryl-Q- selected from the group consisting of heteroaryl, (13)-(C=O)C _1-6 alkyl, and (14)-(C=O)C _1-6 haloalkyl; wherein said C _1-6 alkyl, said C _2-6 alkenyl, said C _3-7 cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, said phenyl C _1-6 alkyl, said phenyl-Q-heteroaryl, said phenyl-Q-phenyl, said hetero Aryl-Q-phenyl or said heteroaryl-Q-heteroaryl is (1) hydroxyl, (2) halogen, (3) C _1-6 alkyl, (4) C _1-6 haloalkyl, (5) C _{1 -6} alkoxy, (6) C _1-6 haloalkoxy, (7) C _3-7 cycloalkyl, (8) heterocyclyl, (9) -SF ₅ , (10) -SR ^c , (11) -CN, ( 12) cyano-substituted C _1-6 alkyl, (13) ^-NRcRd , (14) ^-NRe (C=O) ^Rc , (15)-( ^C =O ^{) NRcRd} , (16) -(C=O)Rc, (17) ^-CO2Rc , (18) _-NRe ( ^C =O) ^NRcRd (19) ^{-NRe ( C} =O) ^ORc , (20) ^-NReSO2Rc , ₍ 21) _-SO2NRcRd , ₍ 22 ^{) -NReSO2NRcRd} , ⁽ 23)-S ₍ O ^{) Rc} , ⁽ 24) ^-SO2R optionally substituted with 1 to 6 substituents independently selected from the group consisting of ^c , (25)-O(C=O)R ^c , and (26) nitro;
R ^c and R ^d are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) phenylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl, C _1-6 haloalkyl, substituted with one or more substituents independently selected from the group consisting of C _1-6 haloalkoxyl, and -CN;
Alternatively, R ^c and R ^d may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxyl;
R ^e is independently selected from the group consisting of (1) hydrogen, (2) C _1-6 alkyl, and (3) C _1-6 haloalkyl;
Q is (1) a bond, (2)-( _CH2 ) _n- , (3)-O-, (4)-O-( _CH2 ) _n- , (5)-( _CH2 ) _n -O -, (6)-NH-, and (7)-N(C _1-6 alkyl)-;
n is 1, 2, 3, or 4;
Ring A is N-containing heterocyclyl, N-containing heteroaryl, N-containing bicyclic heterocyclyl, N-containing spiroheterocyclyl, N-containing heterocyclyl substituted with phenyl, and N-containing bicyclic saturated or is selected from the group consisting of partially saturated heteroaryl; wherein said A is optionally substituted with 1 to 4 substituents independently selected from R ⁴ ;
R ⁴ is (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl (5) C _1-6 alkoxyl, (6) C _1-6 haloalkyl, (7) C _1-6 haloalkoxyl, and (8) independently selected from the group consisting of -CN;
Y is -CN, -(C=O)H, -(C=O) _CH2OH , or -(C=O)(C=O) ^NHR5 ;
R ⁵ is (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) C _3-7 cycloalkylC _1- selected from the group consisting of ₆ alkyl, (7) heterocyclylC _1-6 alkyl, (8) aryl, (9) phenylC _1-6 alkyl, (10) heteroaryl, and (11) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclyl C _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, and substituted with one or more substituents independently selected from the group consisting of -CN);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 2. A compound according to claim 1, wherein the compound of formula (I) is represented by the compound of formula (II):

(in the formula:
R ¹ and R ² are (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C _1-6 alkyl, (5) -OC _1-6 alkyl, (6) C _3-7 cycloalkyl , (7) _C3-7 cycloalkoxy, (8) C2-6 alkenyl, (9) -NR ^a R ^b , (10) (R ^a )(R ^b )NC _{1-6 alkyl} , (11) heterocyclyl , (12) aryl, (13) heteroaryl, (14) arylC _1-6 alkyl, (15) heteroarylC _1-6 alkyl, (16) -CN, and (17) C _3-7 cycloalkylC independently selected from the group consisting of _1-6 alkyl; wherein said C _1-6 alkyl, said -OC _1-6 alkyl, said C _3-7 cycloalkyl, said C _3-7 cycloalkoxy, said C _2-6 alkenyl, said heterocyclyl, said aryl, said heteroaryl, said arylC _1-6 alkyl, said heteroarylC _1-6 alkyl, or said C _3-7 cycloalkylC _1-6 alkyl is (1) optionally substituted with 1 to 6 substituents independently selected from the group consisting of hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
Alternatively, R ¹ and R ² may form a 4-7 membered ring that may contain N, O, S, double bonds, or carbonyl; wherein the 4-7 membered ring is (1 optionally substituted with 1 to 6 substituents independently selected from the group consisting of: ) hydroxyl, (2) halogen, and (3) C _1-6 alkyl;
R ^a and R ^b are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) arylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said aryl C _1-6 alkyl, said heteroaryl, or said heteroaryl C _1-6 alkyl is unsubstituted or the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl and -CN substituted with one or more substituents independently selected from;
Alternatively, R ^a and R ^b may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, and C _1-6 alkoxyl;
X is _-CH2- , -NH-, -N(Ci- _6alkyl )-, -O-, or -S-;
R ³ is (1) hydrogen, (2) C _1-6 alkyl, (3) C _2-6 alkenyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) aryl, (7) heteroaryl, (8) phenylC _1-6 alkyl, (9) phenyl-Q-heteroaryl, (10) phenyl-Q-phenyl, (11) heteroaryl-Q-phenyl, (12) heteroaryl-Q- selected from the group consisting of heteroaryl, (13)-(C=O)C _1-6 alkyl, and (14)-(C=O)C _1-6 haloalkyl; wherein said C _1-6 alkyl, said C _2-6 alkenyl, said C _3-7 cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, said phenyl C 1-6 alkyl, said phenyl-Q-heteroaryl, said phenyl-Q-phenyl, said heteroaryl Said -Q-phenyl or said heteroaryl-Q-heteroaryl is (1) hydroxyl, (2) halogen, (3) C _1-6 alkyl, (4) C _1-6 haloalkyl, (5) C _{1 -6} alkoxy, (6) C _1-6 haloalkoxy, (7) C _3-7 cycloalkyl, (8) heterocyclyl, (9) -SF ₅ , (10) -SR ^c , (11) -CN, ( 12) cyano-substituted C _1-6 alkyl, (13) ^-NRcRd , (14) ^-NRe (C=O) ^Rc , (15)-( ^C =O ^{) NRcRd} , (16) -(C=O)Rc, (17) ^-CO2Rc , (18) _-NRe ( ^C =O) ^NRcRd , (19) ^{-NRe ( C} =O) ^ORc , (20 ) ^-NReSO2Rc , ₍ 21) ^-SO2NRcRd , ⁽ 22 ⁾ _-NReSO2NRcRd , ⁽ 23)-S ₍ O ^{) Rc} , ⁽ 24) _-SO2 optionally substituted with 1 to 6 substituents independently selected from the group consisting of R ^c , (25)-O(C═O)R ^c , and (26) nitro;
R ^c and R ^d are (1) hydrogen, (2) C _1-6 alkyl, (3) C _3-7 cycloalkyl, (4) heterocyclyl, (5) C _3-7 cycloalkylC _1-6 alkyl , (6) heterocyclylC _1-6 alkyl, (7) aryl, (8) phenylC _1-6 alkyl, (9) heteroaryl, and (10) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclylC _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxyl, C _1-6 haloalkyl, substituted with one or more substituents independently selected from the group consisting of C _1-6 haloalkoxyl, and -CN;
Alternatively, R ^c and R ^d may form a 4- to 7-membered ring that may contain N, O, S, a double bond, or a carbonyl; wherein the 4- to 7-membered ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxyl;
R ^e is independently selected from the group consisting of (1) hydrogen, (2) C _1-6 alkyl, and (3) C _1-6 haloalkyl;
Q is (1) a bond, (2)-( _CH2 ) _n- , (3)-O-, (4)-O-( _CH2 ) _n- , (5)-( _CH2 ) _n -O -, (6)-NH-, and (7)-N(C _1-6 alkyl)-;
n is 1, 2, 3, or 4;

R ⁴ is (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl (5) C _1-6 alkoxyl, (6) C _1-6 haloalkyl ( 7) independently selected from the group consisting of C _1-6 haloalkoxyl, and (8)-CN;
m is 0, 1, 2, 3, or 4;
R ⁵ is (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (6) C _3-7 cycloalkylC _1- selected from the group consisting of ₆ alkyl, (7) heterocyclylC _1-6 alkyl, (8) aryl, (9) phenylC _1-6 alkyl, (10) heteroaryl, and (11) heteroarylC _1-6 alkyl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said C _3-7 cycloalkylC _1-6 alkyl, said heterocyclyl C _1-6 alkyl, said aryl, said phenyl C _1-6 alkyl, said heteroaryl, or said heteroarylC _1-6 alkyl is unsubstituted or halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, and substituted with one or more substituents independently selected from the group consisting of -CN);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof. A compound according to claim 1 or claim 2;
R ¹ and R ² are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) hydroxyl, and (4) C _1-6 alkyl;
X is _-CH2- , -NH-, -N( _C1-6alkyl )-, -O-, or -S-;
R ³ is (6) aryl, (7) heteroaryl, (8) phenylC _1-6 alkyl, (9) phenyl-Q-heteroaryl, (10) phenyl-Q-phenyl, (11) heteroaryl- selected from the group consisting of Q-phenyl, (12)heteroaryl-Q-heteroaryl, (13)-(C=O)Ci- _6alkyl , and (14)-(C=O)Ci- _6haloalkyl wherein said aryl, said heteroaryl, said phenylC _1-6 alkyl, said phenyl-Q-heteroaryl, said phenyl-Q-phenyl, said heteroaryl-Q-phenyl, or said heteroaryl-Q- Heteroaryl is (1) hydroxyl, (2) halogen, (3) _C1-6 alkyl, (4) _C1-6 haloalkyl, (5) _C1-6 alkoxy, (9) _-SF5 , (10 optionally substituted with 1-6 substituents independently selected from the group consisting of )-SR ^c , (11)-CN, and (12) cyano-substituted C _1-6 alkyl;
Q is (1) a bond, (2)-( _CH2 ) _n- , (3)-O-, (4)-O-( _CH2 ) _n- , (5)-( _CH2 ) _n -O -, (6)-NH-, and (7)-N(C _1-6 alkyl)-;
n is 1, 2, 3, or 4;

R ⁴ is independently selected from the group consisting of (1) halogen, (2) hydroxyl, (3) C _1-6 alkyl, and (8) -CN;
m is 0, 1, 2, 3, or 4;
R ⁵ is from (1) hydrogen, (2) hydroxyl, (3) C _1-6 alkyl, (4) C _3-7 cycloalkyl, (5) heterocyclyl, (8) aryl, and (10) heteroaryl wherein said C _1-6 alkyl, said C _3-7 cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is unsubstituted or from the group consisting of halogen and hydroxyl substituted with one or more independently selected substituents);
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof. A compound selected from the group consisting of:
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2,4-dichlorophenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((4-(trifluoromethyl)phenyl)glycyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-phenoxyphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((S)-2-(2,4-dichlorophenoxy)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(4-fluorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((R)-2-(2,4-dichlorophenoxy)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-2-(2-((3-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropylamino)-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((R)-2-phenoxypropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-2-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(benzyloxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2) -oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-cyclopropylphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-((trifluoromethyl)thio)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-((4-chlorophenyl)thio)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-((2,4-dichlorophenyl)thio)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(2-chloro-4-isopropylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-bromo-2-chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (3-(2-fluoro-4-(trifluoromethyl)phenyl)propanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(2-cyanopropan-2-yl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(tert-butyl)-2-methylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(2-phenylpropan-2-yl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(tert-butyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(trifluoromethyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((4-(trifluoromethyl)phenyl)glycyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-Chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine) -3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2,4-dichloro-6-methylphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((S)-2-phenoxypropanoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(pentafluoro-16-sulphanyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-( 2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(2S,4S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)- 1-(2-(2,4-dichlorophenoxy)acetyl)-4-phenylpyrrolidine-2-carboxamide;
(S)-2-(2-(2-chloro-4-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(2-(trifluoromethyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,3S,4S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2,4-dichlorophenoxy)acetyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide;
(S)-6-Chloro-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2,4-dichlorophenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-phenoxyphenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(S)-6-Chloro-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-cyclopropylphenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-benzylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine) -3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(naphthalen-2-yloxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- (2-(4-(phenoxymethyl)phenoxy)acetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(S)-2-(2-(4-(4-chlorophenoxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S) -2-oxopyrrolidin-3-yl)butan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide ;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2-azaspiro[4.4]nonane-3-carboxamide;
(S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-5- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-5-azaspiro[2.4]heptane-6-carboxamide;
(2S,3aS,7aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-indole-2-carboxamide;
(3S,4aS,8aS)-N-((2S)-4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)decahydroisoquinoline-3-carboxamide; and
(1S,3aR,6aS)-N-((2S)-4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-((2,2,2-trifluoroacetyl)-L-phenylalanyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-((S)-3-cyclohexyl-2-(2,2,2-trifluoroacetamido)propanoyl)-N-((S)-4-(cyclopropylamino)- 3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((5-phenylthiazol-2-yl)oxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((5-(phenoxymethyl)thiazol-2-yl)oxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((2-fluorobenzyl)oxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((3-fluorobenzyl)oxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((4-fluorobenzyl)oxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((2-fluorophenoxy)methyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((3-fluorophenoxy)methyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-((4-fluorophenoxy)methyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((6-(trifluoromethyl)pyridin-3-yl)-L-valyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((R)-2-phenoxypropanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)- 3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)- 3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(3S,4aS,8aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)decahydroisoquinoline-3-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((4-(trifluoromethyl)phenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((2,4-dichlorophenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-((2-Chloro-4-fluorophenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S )-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -2-((4-(trifluoromethyl)phenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((4-fluorophenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1 -((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1 - carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((4-isopropylphenyl)glycyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(phenylcarbamoyl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((4'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide;
(1R,2S,5S)-3-((2-Chloro-4-fluorophenyl)glycyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S )-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-4-cyclopropylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((2,4-dichlorophenyl)glycyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-5-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(2,2,2-trifluoroethoxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-(4-chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((4-isopropylphenyl)glycyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(trifluoromethoxy)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((4'-ethoxy-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-(4-(benzyloxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-(( S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-((4'-ethoxy-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-((4-fluorophenyl)glycyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-phenoxyphenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(4-(benzyloxy)phenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-(( S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(phenylcarbamoyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(trifluoromethyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2-fluoro-4-(trifluoromethyl)phenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-5-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-fluorophenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-4-fluorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(2,2,2-trifluoroethoxy)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-((3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(2-chloro-4-cyclopropylphenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(4-(furan-3-yl)phenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(4-(2,2,2-trifluoroacetyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2-fluoro-4-methoxyphenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(4-chlorophenoxy)acetyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)- 2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-3-azabicyclo[3.1.0]hexane -2-carboxamide;
(1R,2S,5S)-3-(2-((4'-cyano-3'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2-fluoro-4-methoxyphenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(cyclopropyl) amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(trifluoromethyl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(trifluoromethoxy)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((R)-2-(4-fluorophenoxy)-3-methylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(2-methoxy-4-(trifluoromethyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(((1H-imidazol-5-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidine -3-yl)butan-2-yl)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)- 4-(Cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-3-azabicyclo[3.1.0] hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-N-((S)-3,4-dioxo-1-((S)-2-oxopyrrolidine-3) -yl)-4-((thiazol-2-ylmethyl)amino)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-N-((S)-4-((isoxazol-3-ylmethyl)amino)-3,4-dioxo -1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-pyrazole-) 3-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-pyrazole-) 4-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-(2-(3-fluoro-4-(trifluoromethyl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-6,6-dimethyl-3-(2-(4-(2,2,2-trifluoroacetyl)phenoxy)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-2-(4-fluorophenoxy)-3-methylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-pyrazole-) 5-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1R,2S,5S)-N-((S)-4-(((1H-imidazol-2-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidine -3-yl)butan-2-yl)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(Cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-3-(2-(2-methoxy-4-(trifluoromethyl)phenoxy)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-(2,4-dichlorophenoxy)acetyl)-6,6-dimethyl-N-((S)-4-(((1-methyl-1H-imidazole- 2-yl)methyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2- carboxamide;
(1S,3aR,6aS)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl )-2-((S)-2-(4-fluorophenoxy)propanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-((S)-2-(4-fluorophenoxy)propanoyl)-N-((S)-4-(methylamino)-3,4-dioxo-1-(( S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-3',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-3',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S )-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -2-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(methylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-N-( (S)-4-(Methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxamide;
(1R,2S,5S)-3-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4- (Ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide;
(1S,3aR,6aS)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-N-((S)-4-(ethylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-fluorophenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S) -2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -2-(2-(4-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)acetyl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(ethylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2,4-dichlorophenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-((2,4-dichlorophenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo-1-( (S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-((2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-(( S)-4-(Methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide ;
(1S,3aR,6aS)-2-(2-((3-methyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-(( S)-4-(Methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide ;
(1S,3aR,6aS)-2-(2-([1,1'-biphenyl]-4-yloxy)acetyl)-N-((S)-4-(methylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(ethylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3, 4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-((2-chloro-4-(trifluoromethyl)phenyl)glycyl)-N-((S)-4-(methylamino)-3,4-dioxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(methylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-( (S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1- carboxamide;
(1S,3aR,6aS)-2-(2-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4- (methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-3-((2-chloro-4-fluorophenyl)glycyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1S,3aR,6aS)-2-(2-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((2-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((3,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((2,4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-( ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1S,3aR,6aS)-2-(2-((2-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4 -(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide;
(1R,2S,5S)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl) butan-2-yl)-3-((4-(trifluoromethyl)phenyl)glycyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-N-((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl) -6,6-dimethyl-3-((4-(trifluoromethyl)phenyl)glycyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;
(1R,2S,5S)-3-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-6,6-dimethyl-N-((S) -4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide ;and
(1R,2S,5S)-3-(2-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)acetyl)-N-((S)-4-(ethylamino )-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide ;
or racemate, or enantiomer, or diastereomer,
or a pharmaceutically acceptable salt thereof, or a prodrug thereof. A compound, or a racemate, or an enantiomer, or a diastereomer, according to any one of claims 1 to 4, for the manufacture of a medicament for the treatment or prevention of a disease state or disorder caused by a virus. use of mers, or pharmaceutically acceptable salts, prodrugs, solvates, or compositions thereof. 6. The virus of claim 5, wherein the virus is a coronavirus selected from the group consisting of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS coronavirus, MARS coronavirus, and COVID-19 coronavirus. Use as indicated. said condition or disorder is headache, dysosmia, loss of taste, stuffy nose, stuffy nose, rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, dyspnea, acute respiratory distress syndrome, sepsis, multiple organ failure, Cold-like symptoms, pneumonia, hypoxia, high fever, bronchitis, shortness of breath, systemic illness, nausea, viral encephalitis, meningitis, liver failure, renal failure, heart failure, hair loss, alopecia areata, and any of these 6. Use according to claim 5, selected from the group consisting of combinations. A method for treating or preventing a disease state or disorder caused by a virus in an animal, wherein a therapeutically effective amount of any one of claims 1 to 4 is applied to the animal in need of such treatment or prevention. A method comprising administering a compound as described, or a pharmaceutically acceptable salt or prodrug thereof. said condition or disorder is headache, dysosmia, loss of taste, stuffy nose, stuffy nose, rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, dyspnea, acute respiratory distress syndrome, sepsis, multiple organ failure, Cold-like symptoms, pneumonia, hypoxia, high fever, bronchitis, shortness of breath, generalized nausea, nausea, viral encephalitis, meningitis, liver failure, renal failure, heart failure, hair loss, alopecia areata, and any of these 9. The method of claim 8, selected from the group consisting of combinations. A method for the treatment or prevention of a condition or disorder caused by a virus in an animal comprising a therapeutically effective amount of PF-07304814, PF-07321332, PF-00835231, MI in the animal in need of such treatment or prevention. -09, and MI-30, or a pharmaceutically acceptable salt or prodrug thereof. 8-claim wherein said condition or disorder is selected from the group consisting of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS coronavirus, MARS coronavirus, and COVID-19 coronavirus 10. The method according to 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient. 13. A pharmaceutical composition according to claim 12, further comprising other pharmacologically active agents. A compound according to any one of claims 1 to 4 for use in treating or preventing a condition or disorder caused by a virus, wherein said compound inhibits the main protease (M ^pro ). A featured compound, or a pharmaceutically acceptable salt or prodrug thereof. mixing the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, with a pharmaceutically acceptable carrier or excipient A method of making a pharmaceutical composition, comprising: