Protease inhibitors as antiviral drugs

Abstract

Provided herein are, inter alia, compounds, pharmaceutical compositions and methods relating to the treatment of viral infections caused by coronaviruses or enteroviruses. Provided herein are compounds of formula (I), (II) and (III) and methods of using the compounds for treatment. TIFF2024522990000358.tif34119These compounds are peptidomimetics that inhibit coronavirus protease 3CL and are useful for treating conditions caused by viral infections, including COVID-19.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 195,930, filed June 2, 2021, and U.S. Provisional Application No. 63 / 275,113, filed November 3, 2021, the disclosures of both of which are incorporated herein by reference in their entireties. Technical Field The field of this invention is pharmaceutical compounds, compositions, and methods for preventing, treating, and / or curing viral diseases, including coronavirus and enterovirus infections. More particularly, the present invention provides specifically designed peptidomimetics, and pharmaceutically acceptable salts and other derivatives thereof, that are believed to act through the inhibition of proteases, as well as methods of administering these compounds and compositions for the treatment of viral infections. [Background technology]

[0002] background Coronaviruses (CoVs) are a group of related RNA viruses that cause disease in a wide range of vertebrates, including humans and domestic animals. COVID-19 is a relatively new, potentially fatal respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses a serious threat to global public health. The SARS-CoV-2 main protease (M pro , also known as 3CL protease, is believed to play a central role in viral replication. pro (or 3CL), which can be used to treat COVID-19 disease. Several inhibitors of 3CL protease have been reported that exhibit antiviral activity against the COVID-19 virus. Pfizer has described two different peptidomimetic compounds, PF-07321332 (Chem. Eng. News, April 12, 2021) and PF-00835231 (J. Med. Chem. July 2020 (pp. AW)), which appear to form reversible covalent bonds to cysteine ​​residues in 3CL, thus achieving tight binding and potent inhibition. Chinese researchers have similarly reported another inhibitor of 3CL protease that acts by binding to cysteine ​​residues using an aldehyde group (Science, vol. 371, 1374-8, 26 March 2021). See also WO2020 / 030143 and WO2020 / 2475665. While these reports demonstrate that small molecule peptidomimetic inhibitors can achieve antiviral activity for treating COVID-19, there remains a need for alternative compounds with suitable medicinal chemistry properties to help control the spread of COVID-19. The present invention provides such compounds, and methods of making and using them, for treating viral infections such as COVID-19. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2020 / 030143 [Patent Document 2] International Publication No. 2020 / 2475665 [Non-patent literature]

[0004] [Non-Patent Document 1] Chem. Eng. News, April 12, 2021 [Non-patent document 2] J. Med. Chem. July 2020 (pp. AW) [Non-patent document 3] Science, vol. 371, 1374-8, 26 March 2021 Summary of the Invention [Means for solving the problem]

[0005] Brief Summary of the Invention In one aspect, the present disclosure provides a compound having a structure according to Formula I: [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein Z is -CHO, -CN, -CH2CN, -C(=O)-CH=CH2, -NH-C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] , -CH(OH)SO3 - (and Na + (associated cations such as -CO2-C 1~3 Alkyl, -CH2OH, -C(=O)OH, -CH(OCH3)2 and - C(=O)-C 1~3 haloalkyl; L is a bond, -(CR2) 1~2 -, -(CR2) 0~2 -NR-, -NR-(CR2) 0~2 , -(CR2) 0~2 -O-, -O-(CR2) 0~2 , -(CR2) 0~2 -C(=O)-NR-, -NR-C(=O)-(CR2) 0~2 -, -NR-C(=O)-CHR 2 -NR-C(=O)-(CR2) 0~2-, -NR-C(=O)-CHR 2 -NR-C(=O)-O-(CR2) 0~2 -, -(CR2) 0~2 -C(=O)-NR-CHR 2 -C(=O)-NR-, -(CR2) 0~2 -OC(=O)-NR-CHR 2 -C(=O)-NR-, -NR-C(=O)-O-(CR2) 0~2 -and-(CR2) 0~2 -OC(=O)-NR-; R 1 is selected from -CF3, -CHF2, -CH2F, phenyl, naphthyl, and 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O, and S as ring members, wherein phenyl, naphthyl, and 5-10 membered heteroaryl are each selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; R 2 are respectively, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with up to three groups selected from haloalkoxy; R 3 is H or C 1~4 is alkyl, R * are respectively, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 independently selected from haloalkyl, CN, halo, and —OH; m is an integer from 0 to 2, n is an integer from 0 to 4, R is H and C 1~4 alkyl).

[0006] In another aspect, the present invention provides a compound of formula (II): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein Ring A is C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 cycloalkyl of 5 to 9 atoms optionally substituted with up to three groups selected from haloalkoxy; Z is -CO2-C 1~3 Alkyl, -CHO, -CH2CN, -C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)-C 1~3 Haloalkyl, -NH-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] and -CH(OH)SO3 - (and Na + or an associated cation such as or Z may be -CN, provided that when n=1, R 2 is not t-butyl, R 1 is H, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy or C 1~4 alkyl, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy and C 1~4 Alkyl is a group that includes halo, CN, C 3~6 Cycloalkyl, C1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy, or R 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, and the 5-10 membered heteroaryl is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; R 2 is C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with up to three groups selected from haloalkoxy; R 3 is H or C 1~4 is alkyl, R * are respectively, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 independently selected from haloalkyl, CN, halo, and —OH; m is an integer from 0 to 2, and n is an integer from 0 to 4.

[0007] Furthermore, in another aspect, the present invention provides a compound of formula (III): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein Ring A is C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 cycloalkyl of 5 to 9 atoms optionally substituted with up to three groups selected from haloalkoxy; Z is -CO2-C 1~3 Alkyl, -CHO, -CN, -CH2CN, -C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)-C 1~3 Haloalkyl, -NH-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] and -CH(OH)SO3 - (and Na + and associated cations such as R 1 is H, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy, C 1~4 Alkyl (halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 haloalkoxy), or a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S as ring members, wherein the 5-10 membered heteroaryl is halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; R 2 is C1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with up to three groups selected from haloalkoxy; R 3 is H or C 1~4 is alkyl, R 6 is hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl or C 1~3 haloalkoxy).

[0008] The compounds described herein can be used for any suitable purpose. In some embodiments, the compounds can be used in therapeutic methods to treat viral infections, such as COVID-19.

[0009] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I, Formula II, or Formula III.

[0010] In another aspect, the present invention provides methods of using the compounds and compositions to treat viral infections, particularly COVID-19.

[0011] In yet another aspect, the disclosure provides pharmaceutical compositions comprising the compounds described above in admixture with at least one pharmaceutically acceptable carrier or excipient.

[0012] In yet another aspect, the present disclosure provides methods for treating and / or preventing viral infections, comprising administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition comprising such compound(s). The compounds and compositions are useful for treating or preventing coronavirus and enterovirus infections, including COVID-19.

[0013] In yet another aspect, the present disclosure provides for the use of a compound described herein for the manufacture of a medicament, particularly a medicament useful for the treatment or prevention of coronavirus and enterovirus infections, including COVID-19.

[0014] In yet another aspect, the disclosure provides a combination for treating and / or preventing a coronavirus or enterovirus infection, including a COVID-19 infection, in a subject, comprising an effective amount of a compound of Formula I, Formula II, or Formula III, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and an effective amount of a second prophylactic or therapeutic agent to treat and / or prevent the viral infection.

[0015] In yet another aspect, the present disclosure provides a method of treating and / or preventing a viral infection in a subject, comprising administering to a subject in need thereof an effective amount of the combination described above.

[0016] In yet another aspect, the present disclosure provides a method of inhibiting viral protease activity in a cell or a subject in need thereof, comprising contacting a cell or administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutical composition comprising such a compound, or a combination comprising such a compound of Formula (I), (II) or (III). DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention General definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.All patents, applications, published applications and other publications mentioned herein are incorporated by reference in their entirety.If the definitions set forth in this section are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications or other publications incorporated herein by reference, the definitions set forth in this section shall prevail over the definitions incorporated herein by reference.

[0018] As used herein, "a" or "an" means "at least one" or "one or more."

[0019] The term "alkyl," as used herein, refers to saturated hydrocarbon groups of a linear or branched configuration or combinations thereof; specifically contemplated alkyl groups include those having 10 or fewer carbon atoms, particularly those having 1 to 6 carbon atoms, and lower alkyl groups having 1 to 4 carbon atoms. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, and the like.

[0020] Alkyl groups can be unsubstituted or they can be substituted to the extent that such substitution is chemically justified. Typical substituents include, but are not limited to, halo, ═O, ═N—CN, ═N—OR a , =NR a , -OR a , -NR a 2, -SR a , -SO2R a , -SO2NR a 2, -NR a SO2Ra , -NR a CONR a 2, -NR a COOR a , -NR a COR a , -CN, -COOR a , -CONR a 2. -OOCR a , -COR a and -NO2, R a are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C 10 Heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C 10 Aryl or C5-C 10 heteroaryl, and R a are halo, =O, =N-CN, and =N-OR, respectively. b , =NR b , OR b , N.R. b 2. SR b , SO2R b , SO2NR b 2. NR b SO2R b , N.R. b CONR b 2. NR b COOR b , N.R. b COR b ,CN,COOR b ,CONR b 2. OOCR b , C.O.R. b and optionally substituted by NO2, R b are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C 10 Heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C 10 Aryl or C5-C 10The alkyl, alkenyl and alkynyl groups are also C1-C8 acyl, C2-C8 heteroacyl, C6-C 10 Aryl or C5-C 10 The substituents may be two R groups on the same atom or adjacent atoms. a group or R b When the group contains a -NR b 2 or -NR b -C(O)R b ), these two R a group or R b Groups can optionally be joined together with atoms in the substituent to which they are attached to form a ring having 5 to 8 ring members, which ring can be joined by R a or R b It may be substituted as allowed by itself and may contain additional heteroatoms (N, O or S) as ring members.

[0021] The term "alkenyl," as used herein, refers to an alkyl, as defined above, having at least two carbon atoms and at least one carbon-carbon double bond. Thus, particularly contemplated alkenyl groups include straight-chain, branched, or cyclic alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, etc.) having 2 to 10 carbon atoms, or, in the case of cyclic alkenyl groups, 5 to 10 atoms. Alkenyl groups are optionally substituted with groups suitable for alkyl groups, as described herein.

[0022] Similarly, the term "alkynyl," as used herein, refers to an alkyl or alkenyl, as defined above, having at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond. Particularly contemplated alkynyls include straight-chain, branched, or cyclic alkynes having a total of 2 to 10 carbon atoms (e.g., ethynyl, propynyl, butynyl, cyclopropylethynyl, etc.). Alkynyl groups are optionally substituted with groups suitable for alkyl groups, as described herein.

[0023] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, refer, unless otherwise stated, to cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyls and heterocycloalkyls are not aromatic. Furthermore, for heterocycloalkyls, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyls include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0024] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, and such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring.

[0025] In embodiments, a bridged monocyclic ring is a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., (CH) w where w is 1, 2, or 3. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, a fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, a bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.

[0026] In embodiments, the cycloalkyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either of (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl.

[0027] In embodiments, a polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either of (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0028] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, where such group is unsaturated (i.e., contains at least one ring carbon-carbon double bond), but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is a monocyclic cycloalkenyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., (CH)) of between 1 and 3 additional carbon atoms. wwhere w is 1, 2, or 3. Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, a fused bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, a bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, a cycloalkenyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either of (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0029] In embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic heterocycle, a bicyclic heterocycle, or a polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, wherein the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Heterocyclyl monocyclic heterocycles are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl. Heterocyclyl bicyclic heterocycles include phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyl include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl.

[0030] In embodiments, the heterocyclyl group is optionally substituted with one or two groups, independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted with one or two groups, independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either of (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0031] The term "aryl" or "aromatic moiety," as used herein, refers to an aromatic ring system that may further contain one or more non-carbon atoms. These are typically 5- to 6-membered isolated rings or 8- to 10-membered bicyclic groups, which may be substituted. Thus, contemplated aryl groups include (e.g., phenyl, naphthyl, etc.) and pyridyl. Additionally, contemplated aryl groups may be fused (i.e., covalently bonded to two atoms on the first aromatic ring) with one or two 5- or 6-membered aryl or heterocyclic groups, and thus are referred to as "fused aryls" or "fused aromatics."

[0032] Aromatic groups containing one or more heteroatoms (usually N, O, or S) as ring members can be referred to as heteroaryl or heteroaromatic groups. Typical heteroaromatic groups include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazolyl, as well as C8-C6 heteroaromatic groups in which one of these monocyclic groups is fused to either a phenyl ring or a heteroaromatic monocyclic group, such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidyl, quinazolinyl, quinoxalinyl, and cinnolinyl. 10 This definition includes fused bicyclic moieties formed by forming a bicyclic group. Included within this definition are bicyclic systems of either monocyclic or fused rings that have the character of aromaticity in terms of electron distribution throughout the ring system. It also includes bicyclic groups in which at least the ring directly attached to the rest of the molecule has the character of aromaticity. Typically, ring systems contain 5 to 12 ring atoms.

[0033] As also used herein, the terms "heterocycle," "cycloheteroalkyl," and "heterocyclic moiety" are used interchangeably herein and refer to any compound in which atoms form a ring through multiple covalent bonds, where the ring contains at least one atom other than a carbon atom as a ring member. Particularly contemplated heterocyclic rings include 5- and 6-membered rings having nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, thiazole, tetrazole, etc.). Typically, these rings contain 0 to 1 oxygen or sulfur atom, at least 1, and usually 2 to 3 carbon atoms, and up to 4 nitrogen atoms as ring members. Further contemplated heterocycles may be fused to one or two carbocyclic or heterocyclic rings (i.e., covalently bonded to two atoms on the first heterocyclic ring), i.e., as used herein, are referred to as "fused heterocycles" or "fused heterocyclic rings" or "fused heterocyclic moieties." When the rings are aromatic, they may be referred to herein as "heteroaryl" or heteroaromatic groups.

[0034] Heterocyclic groups that are not aromatic may be substituted with groups suitable for substituting alkyl groups, as described above.

[0035] The aryl and heteroaryl groups can be substituted where permissible. Suitable substituents include, but are not limited to, halo, -OR a , -NR a 2, -SR a , -SO2R a , -SO2NR a 2, -NR a SO2R a , -NR a CONR a 2, -NR a COOR a , -NR a COR a , -CN, -COOR a , -CONR a 2. -OOCR a , -COR aand -NO2, R a are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C 10 Heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C 10 Aryl or C5-C 10 heteroaryl, and R a are halo, =O, =N-CN, and =N-OR, respectively. b , =NR b , OR b , N.R. b 2. SR b , SO2R b , SO2NR b 2.NR b SO2R b , N.R. b CONR b 2.NR b COOR b , N.R. b COR b , CN, COOR b ,CONR b 2. OOCR b , C.O.R. b and optionally substituted by NO2, R b are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C 10 Heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C 10 Aryl or C5-C 10 The alkyl, alkenyl and alkynyl groups are also C1-C8 acyl, C2-C8 heteroacyl, C6-C 10 Aryl or C5-C 10 The substituents may be two R groups on the same atom or adjacent atoms. a group or R b When the group contains a -NR b 2 or -NRb -C(O)R b ), these two R a group or R b The groups can optionally be joined together with atoms in the substituent to which they are both attached to form a ring having 5 to 8 ring members, which ring can be joined by R a or R b It may be substituted as allowed by itself and may contain additional heteroatoms (N, O or S) as ring members.

[0036] The term "alkoxy" as used herein refers to a hydrocarbon group linked via an oxygen atom, e.g., -O-Hc, where the hydrocarbon portion Hc can have any number of carbon atoms in the alkyl chain, typically 1 to 10 carbon atoms, and may further contain double or triple bonds, one or two oxygen, sulfur, or nitrogen atoms, and may be substituted with aryl, heteroaryl, cycloalkyl, and / or heterocyclyl groups. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term "alkylthio" refers to an alkyl sulfide of the general formula -S-Hc, where the hydrocarbon portion Hc is as described for an alkoxy group. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.

[0037] The term "amino," as used herein, refers to the group -NH. The term "alkylamino" refers to an amino group in which one or both hydrogen atoms have been replaced by a hydrocarbon group, Hc, as described above, where the amino nitrogen "N" may be substituted by one or two Hc groups as described above for the alkoxy group. Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, and the like. Similarly, the term "substituted amino" refers to an amino group in which one or both hydrogen atoms have been replaced by a hydrocarbon group, Hc, as described above, where the amino nitrogen "N" may be substituted by one or two Hc groups as described above for the alkoxy group.

[0038] The term "acyl," as used herein, refers to a group of formula -C(=O)-D, where D represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle as defined above. Typical examples are those where D is a C1-C 10 Alkyl, C2-C 10 is an alkenyl or alkynyl, or phenyl, each of which is optionally substituted. In some embodiments, D can be H, Me, Et, isopropyl, propyl, butyl, C1-C4 alkyl (substituted with -OH, -OMe, or NH2), phenyl, halophenyl, alkylphenyl, etc.

[0039] The term "aryloxy," as used herein, refers to an aryl group linked to an oxygen atom, which may be further substituted. For example, suitable aryloxy groups include phenyloxy and the like. Similarly, the term "arylthio," as used herein, refers to an aryl group linked to a sulfur atom, which may be further substituted. For example, suitable arylthio groups include phenylthio and the like.

[0040] Each hydrocarbon moiety of alkoxy, alkylthio, alkylamino, aryloxy, etc. may be appropriately substituted for the associated hydrocarbon moiety.

[0041] The term "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine. Halogen or halo, when present as a substituent, typically refers to F or Cl or Br, more typically F or Cl.

[0042] The term "haloalkyl" refers to the alkyl group described above, in which one or more hydrogen atoms on the alkyl group are replaced by a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0043] The term "haloalkoxy" refers to the group alkyl-O-, in which one or more hydrogen atoms on the alkyl group are replaced by a halo group, and includes, by way of example, groups such as trifluoromethoxy.

[0044] The term "lactam," as used herein, refers to a cyclic amide, usually a saturated ring having from 4 to 8 ring atoms.

[0045] The term "sulfonyl" refers to the groups SO-alkyl, SO-substituted alkyl, SO-alkenyl, SO-substituted alkenyl, SO-cycloalkyl, SO-substituted cycloalkyl, SO-cycloalkenyl, SO-substituted cycloalkenyl, SO-aryl, SO-substituted aryl, SO-heteroaryl, SO-substituted heteroaryl, SO-heterocyclic, and SO-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are each as defined herein. Sulfonyl includes, by way of example, methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0046] The term "sulfonylamino" refers to the group -NR 21 SO2R 22 refers to R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally joined together with the atoms to which they are bound to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0047] The term "aminosulfonyl" refers to the group -SO2NR 21 R 22 refers to R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally, together with the nitrogen to which they are bound, form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0048] The term "acylamino" refers to the group -NR20 C(O) alkyl, -NR 20 C(O) substituted alkyl, -NR 20 C(O)cycloalkyl, -NR 20 C(O)-substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)-substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O) substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O) substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O) substituted aryl, -NR 20 C(O)heteroaryl, -NR 20 C(O)-substituted heteroaryl, -NR 20 -C(O) heterocyclic and -NR20C(O) substituted heterocyclic, R 20 is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0049] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0050] The term "aminocarbonylamino" refers to the group -NR 20 C(O)NR 21 R 22 refers to R 20 is hydrogen or alkyl, and R 21 and R 22is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally, together with the nitrogen to which they are bound, form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0051] It should be further recognized that all of the above-defined groups may be further substituted with one or more substituents, which in turn may be substituted with hydroxy, amino, cyano, C1-C4 alkyl, halo, or C1-C4 haloalkyl. For example, a hydrogen atom in an alkyl or aryl may be substituted with amino, halo, or C1-C4 haloalkyl. 1~4 It may be replaced by a haloalkyl or alkyl group.

[0052] The term "substituted," as used herein, refers to the replacement of a hydrogen atom of a non-substituent with a functional group; particularly contemplated functional groups include nucleophilic groups (e.g., -NH, -OH, -SH, -CN, etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., heterocycles, aryls, alkyls, alkenyls, alkynyls, etc.), ionic groups (e.g., -NH, +) and halogens (e.g., -F, -Cl), NHCOR, NHCONH2, OCH2COOH, OCH2CONH2, OCH2CONHR, NHCH2COOH, NHCH2CONH2, NHS02R, OCH2-heterocycle, PO3H, SO3H, amino acids, and all chemically reasonable combinations thereof. Furthermore, the term "substituted" also includes multiple degrees of substitution, and where multiple substituents are disclosed or claimed, the substituted compound may be independently substituted with one or more of the disclosed or claimed substituent moieties.

[0053] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0054] For all of the substituted groups defined above, it is understood that compounds arrived at by defining a substituent that has further substituents thereon (e.g., a substituted aryl having a substituted aryl group as a substituent that is itself substituted by a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended to be encompassed herein. In such cases, the maximum number of such substitutions is 3. For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl.

[0055] Unless otherwise indicated, the naming of substituents not explicitly defined herein is arrived at by naming the terminal portion of that functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0056] With respect to any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include any substitutions or substitution patterns that are sterically impractical and / or synthetically impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0057] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, the compound contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the subject racemate.

[0058] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction in which the plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, or clockwise. However, the optical rotation symbols (+) and (-) do not refer to the absolute configuration of the molecule, i.e., R and S.

[0059] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0060] The phrase "enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referenced herein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a compound referenced herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referenced herein."

[0061] The term "pharmaceutically acceptable salt" refers to a salt (a salt with a counterion having acceptable mammalian safety for a given dosage regimen) that is acceptable for administration to a patient, such as a mammal, such as a human. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound, which is derived from a variety of organic and inorganic counterions well known in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc.

[0062] The term "salt thereof" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation. The salt is optionally a pharmaceutically acceptable salt, although this is not necessary in the case of salts of intermediate compounds that are not intended for administration to patients. For example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation, and the salt contains the conjugate base of the inorganic or organic acid as the anionic component.

[0063] The terms "effective amount," "therapeutically effective amount," or "effective dose," or related terms, may be used interchangeably and refer to an amount of a therapeutic agent sufficient, when administered to a subject, to measurably improve or prevent a disease or disorder associated with coronavirus infection. For example, administration of an effective dose sufficient to inhibit coronavirus growth and / or replication and / or the development of a viral infection in a subject. The therapeutically effective amount of a therapeutic agent provided herein, when used alone or in combination with an antiviral agent, will vary depending on the relative activity of the therapeutic agent, as well as the subject and disease state being treated, the subject's weight, age, and sex, the severity of the disease state in the subject, the method of administration, etc., and can be readily determined by one of skill in the art. In one embodiment, the therapeutically effective amount depends on the particular circumstances of the subject and disorder being treated and can be ascertained by one of skill in the art using known techniques. Furthermore, adjustments may be necessary depending on age, weight, general health, sex, diet, time of administration, drug interactions, and severity of the disease, as is known in the art.

[0064] The terms "subject" and "patient," as used herein, refer to human and non-human animals, including vertebrates, mammals, and non-mammals. In one embodiment, the subject may be a human, non-human primate, monkey, ape, murine (e.g., mouse and rat), bovine, porcine, equine, canine, feline, caprine, wolf, frog, or fish.

[0065] The terms "administering," "administered," and grammatical variations refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary administration routes for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as by injection or infusion. The phrase "parenteral administration," as used herein, refers to a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, intrathecal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. In one embodiment, the formulation is administered by a non-parenteral route, for example, orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, such as nasal, vaginal, rectal, sublingual, or topical. Administration can also be, for example, single, multiple, and / or over one or more extended periods of time.

[0066] "Treating" should be understood broadly and encompasses any beneficial effect, including, for example, delaying, slowing, or halting the worsening of symptoms associated with pulmonary inflammatory disease, or at least partially curing such symptoms. Treatment also encompasses resulting in some form of improvement in patient function, as discussed in more detail below. In some embodiments, treatment also means prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder, as well as those prone to have the disease or disorder, or those in whom the disease or disorder is to be prevented.

[0067] The term "synergistic effect" refers to a situation in which the combination of two or more drugs produces an effect that is greater than the sum of the effects of each of the drugs individually. This term encompasses not only the alleviation of symptoms of the disorder being treated, but also improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improvement in clinical outcome.

[0068] The term "sub-therapeutic amount" of a drug or therapy refers to an amount that is less than the effective amount of that drug or therapy when used alone, but which, when combined with an effective or sub-therapeutic amount of another drug or therapy, can produce the result desired by the physician, for example, due to synergy in the resulting beneficial effect or reduced side effects.

[0069] Combination therapy or "in combination with" refers to the use of more than one therapeutic agent to treat a particular disorder or condition. "In combination with" is not intended to imply that the therapeutic agents must be administered at the same time and / or formulated to be delivered together, although these delivery methods are within the scope of this disclosure. Therapeutic agents can be administered simultaneously with, before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after) one or more other additional agents. Therapeutic agents in combination therapy can also be administered on alternating dosing schedules, with or without rest periods (e.g., no therapeutic agent is administered on some days of the schedule). Administration of a therapeutic agent "in combination with" another therapeutic agent includes, but is not limited to, sequential and simultaneous administration of the two agents. Generally, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent.

[0070] The compounds and compositions described herein can be administered to a subject who needs to treat viral infection.The subject is usually a mammal who has been diagnosed with at least one coronavirus or enterovirus infection and needs to be treated.The method includes administering an effective amount of at least one compound of the present invention.Optionally, the compound can be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful in treating the symptoms suffered by a particular subject or additional antiviral agents. compound

[0071] In an embodiment, a compound of formula (I): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, provided herein, wherein: Z is -CHO, -CN, -CH2CN, -C(=O)-CH=CH2, -NH-C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] , -CH(OH)SO3 - (and Na + (associated cations such as -CO2-C 1~3 Alkyl, -CH2OH, -C(=O)OH, -CH(OCH3)2 and -C(=O)-C 1~3 haloalkyl; L is a bond, -(CR2) 1~2 -, -(CR2) 0~2 -NR-, -NR-(CR2) 0~2 , -(CR2) 0~2 -O-, -O-(CR2) 0~2 , -(CR2) 0~2 -C(=O)-NR-, -NR-C(=O)-(CR2)0~2 -, -NR-C(=O)-CHR 2 -NR-C(=O)-(CR2) 0~2 -, -NR-C(=O)-CHR 2 -NR-C(=O)-O-(CR2) 0~2 -, -(CR2) 0~2 -C(=O)-NR-CHR 2 -C(=O)-NR-, -(CR2) 0~2 -OC(=O)-NR-CHR 2 -C(=O)-NR-, -NR-C(=O)-O-(CR2) 0~2 -and-(CR2) 0~2 -OC(=O)-NR-; R 1 is selected from -CF3, -CHF2, -CH2F, phenyl, naphthyl, and 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O, and S as ring members, wherein phenyl, naphthyl, and 5-10 membered heteroaryl are each selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; R 2 are respectively, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with up to three groups selected from haloalkoxy; R 3 is H or C 1~4 is alkyl, R * are respectively, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3independently selected from haloalkyl, CN, halo, and —OH; m is an integer from 0 to 2, n is an integer from 0 to 4, R is H and C 1~4 alkyl).

[0072] In embodiments, R 1 is -CF3, -CHF2, -CH2F, phenyl, naphthyl or indolyl, and phenyl, naphthyl and 5-10 membered heteroaryl are each halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, R is optionally substituted with one or two groups selected from haloalkoxy. 1 is —CF. In embodiments, R 1 is -CHF2. In an embodiment, R 1 is —CHF. In embodiments, R 1 is unsubstituted phenyl. In embodiments, R 1 is unsubstituted naphthyl. In embodiments, R 1 is an unsubstituted indolyl. In embodiments, R 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is phenyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is naphthyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3In embodiments, R is indolyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is phenyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is naphthyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is an indolyl substituted by two groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is phenyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is naphthyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is an indolyl substituted with three groups independently selected from haloalkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3In one embodiment, R is phenyl substituted with one group selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In an embodiment, R is naphthyl substituted with one group selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with one group selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In one embodiment, R is phenyl substituted with two groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In one embodiment, R is naphthyl substituted with two groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with two groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In one embodiment, R is phenyl substituted with three groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In one embodiment, R is naphthyl substituted with three groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with three groups independently selected from alkoxy. 1 is phenyl substituted with one group selected from fluoro, methyl, and methoxy. 1 is naphthyl substituted with one group selected from fluoro, methyl, and methoxy. 1is indolyl substituted with one group selected from fluoro, methyl, and methoxy. 1 is phenyl substituted with two groups independently selected from fluoro, methyl, and methoxy. 1 is naphthyl substituted with two groups independently selected from fluoro, methyl, and methoxy. 1 is indolyl substituted with two groups independently selected from fluoro, methyl, and methoxy. In embodiments, R 1 is phenyl substituted with three groups independently selected from fluoro, methyl, and methoxy. 1 is naphthyl substituted with three groups independently selected from fluoro, methyl, and methoxy. 1 is indolyl substituted with three groups independently selected from fluoro, methyl and methoxy.

[0073] In embodiments, R 1 is phenyl or a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, and each of the phenyl or 5-10 membered heteroaryl is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 and optionally substituted with 1, 2, or 3 groups independently selected from haloalkoxy.

[0074] In embodiments, R 1 is unsubstituted phenyl or 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is unsubstituted phenyl. In embodiments, R 1is a 5-10 membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom selected from N, O, and S as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing two heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom N as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom O as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom S as a ring member.

[0075] In embodiments, R 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In an embodiment, R is phenyl substituted with 1, 2, or 3 groups independently selected from haloalkyl. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is phenyl substituted with one group independently selected from haloalkyl. 1 is phenyl substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0076] In embodiments, R 1 contains one or two heteroatoms selected from N, O and S as ring members, and is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one or two heteroatoms selected from N, O and S as ring members, and is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl or chloromethyl.

[0077] In embodiments, R 1 contains one heteroatom selected from N, O and S as a ring member and is not limited to halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom selected from N, O and S as a ring member and is not limited to halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from N, O and S as a ring member and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl or chloromethyl.

[0078] In embodiments, R 1 contains one heteroatom N and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom N and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from N and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0079] In embodiments, R 1 contains one heteroatom O and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom O and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1is a 5-10 membered heteroaryl containing one heteroatom selected from O and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0080] In embodiments, R 1 contains one heteroatom S and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom S and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from S and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0081] In embodiments, R 1 are phenyl or indolyl, which are halo, C 1~3 Alkyl and C 1~3 In one embodiment, R is substituted with one group selected from alkoxy. 1 is -CF3, -CHF2, phenyl or indolyl, and phenyl and indolyl are halo, C 1~3 Alkyl and C 1~3 In one embodiment, R is optionally substituted with one group selected from alkoxy. 1is -CF3, -CHF2, phenyl or indolyl, where phenyl and indolyl are optionally substituted with one group selected from fluoro, methyl and methoxy.

[0082] In embodiments, L is -NHC(=O)-, -C(=O)NH-, -NH(C=O)-O-CH-, -CH-OC(=O)NH-, -NHC(=O)-CHR 2 -NHC(=O)-, -C(=O)NH-CHR 2 -C(=O)NH-, -CH2-OC(=O)NH-CHR 2 -C(=O)NH- and -NHC(=O)-CHR 2 In an embodiment, L is selected from -NHC(=O)-, -C(=O)NH-, -NHC(=O)-CHR 2 -NHC(=O)- or -C(=O)NH-CHR 2 In embodiments, L is —NHC(═O)— or —C(═O)NH—.

[0083] In embodiments, L is -NHC(=O)-. In embodiments, L is -C(=O)NH-. In embodiments, L is -NH(C=O)-O-CH-. In embodiments, L is -CH-OC(=O)NH-. In embodiments, L is -NHC(=O)-CHR 2 In embodiments, L is -NHC(=O)-. 2 In embodiments, L is -CH2-OC(=O)NH-CHR 2 In an embodiment, L is -NHC(=O)-CHR 2 -NHC(=O)-O-CH2-.

[0084] In embodiments, R 2 is C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3alkyl, which are halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy and C 1~3 haloalkyl. In embodiments, R 2 is C 1~4 Alkyl, 3-7 membered cycloalkyl, C 1~2 Alkyl-(C 3~6 cycloalkyl) or (C 3~6 Cycloalkyl)C 1~2 alkyl, each of which is C 1~6 In embodiments, R is optionally substituted with alkoxy. 2 is the unsubstituted branch C 1~6 In embodiments, R 2 is an unsubstituted linear C 1~6 In embodiments, R 2 is a 3- to 7-membered unsubstituted cycloalkyl. In embodiments, R 2 is the unsubstituted C 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 is an unsubstituted (3- to 7-membered cycloalkyl)-C 1~3 It is alkyl.

[0085] In embodiments, R 2 is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, or isopentyl. 2 is isopropylmethyl, isobutylmethyl, isobutylethyl, or isopentylmethyl. 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 2 is cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, or cyclohexylethyl. In embodiments, R 2 is methyl. In embodiments, R 2 is ethyl. In embodiments, R 2 is propyl. In embodiments, R2 is butyl. In an embodiment, R 2 is isopropyl. In embodiments, R 2 is isobutyl. In embodiments, R 2 is t-butyl. In embodiments, R 2 is isopentyl. In embodiments, R 2 is isopropylmethyl. In embodiments, R 2 is isobutylmethyl. In embodiments, R 2 is isobutylethyl. In embodiments, R 2 is isopentylmethyl. In embodiments, R 2 is cyclopropyl. In embodiments, R 2 is cyclobutyl. In embodiments, R 2 is cyclopentyl. In embodiments, R 2 is cyclohexyl. In embodiments, R 2 is cycloheptyl. In embodiments, R 2 is cyclopropylmethyl. In embodiments, R 2 is cyclopropylethyl. In embodiments, R 2 is cyclohexylmethyl. In embodiments, R 2 is cyclohexylethyl.

[0086] In embodiments, R 2 , Halo, CN, C 1~3 Alkyl and C 1~6 In an embodiment, R is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, or isopentyl, substituted with one, two, or three groups selected from alkoxy. 2 is trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, trifluorobutyl, fluoroethyl, fluorobutyl, fluoro-t-butyl, fluoroisopentyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, t-butoxyethyl, or 1-methyl-t-butoxyethyl. 2is 1-methyl-t-butoxyethyl.

[0087] In embodiments, R 2 , Halo, CN, C 1~3 Alkyl and C 1~6 In an embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, substituted with one, two, or three groups selected from alkoxy. 2 , Halo, CN, C 1~3 Alkyl and C 1~6 In an embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, substituted with one group selected from alkoxy. 2 , Halo, CN, C 1~3 Alkyl and C 1~6 In an embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, substituted with two groups selected from alkoxy. 2 , Halo, CN, C 1~3 Alkyl and C 1~6 In an embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, substituted with three groups selected from alkoxy. 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, substituted with one, two, or three groups selected from fluoro, CN, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy. 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl substituted by one group selected from fluoro, CN, methyl, ethyl, propyl, methoxy, ethoxy or propoxy.

[0088] In embodiments, R 2is methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, isopropylmethyl, 1-methyl-t-butoxyethyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, or cyclohexylmethyl. 2 is ethyl, propyl, t-butyl, isobutyl, isopropylmethyl, cyclopropyl, cyclohexyl, 1-methyl-t-butoxyethyl, cyclopropylmethyl, or cyclohexylmethyl. 2 is t-butyl, isopropylmethyl, cyclohexylmethyl or 1-methyl-t-butoxyethyl.

[0089] In embodiments, R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 3 is H. In an embodiment, R 3 is methyl. In embodiments, R 3 is ethyl. In embodiments, R 3 is propyl. In embodiments, R 3 is isopropyl. In embodiments, R 3 is butyl. In an embodiment, R 3 is isobutyl. In embodiments, R 3 is t-butyl.

[0090] In embodiments, Z is -CHO, -CN, -CHCN, -C(=O)CH=CH, -C(=O)CHCl, -C(=O)CHF, -C(=O)CHBr, -C(=O)CHI, -NHC(=O)CH=CH, -C(=O)CHOH, [ka] , -CO2CH3, -CH2OH, -C(=O)OH, -CH(OCH3)2 and -CH(OH)SO3 - (and Na +In embodiments, Z is selected from -CN, -CO2CH3, -CH2OH, -C(=O)OH, -NHC(=O)CH=CH2, -C(=O)CH=CH2, -C(=O)CH2OH, -CH(OCH3)2, -CHO, -CH(OH)SO3 - (and Na + or —C(═O)—CHX, where X is F, Cl, Br, or I.

[0091] In embodiments, Z is -CHO. In embodiments, Z is -CN. In embodiments, Z is -CHCN. In embodiments, Z is -C(=O)CH=CH. In embodiments, Z is -C(=O)CHCl. ​​In embodiments, Z is -C(=O)CHF. In embodiments, Z is -C(=O)CHBr. In embodiments, Z is -C(=O)CHI. In embodiments, Z is -NHC(=O)CH=CH. In embodiments, Z is -C(=O)CHOH. In embodiments, Z is [ka] In embodiments, Z is -CO2CH3. In embodiments, Z is -CH2OH. In embodiments, Z is -C(=O)OH. In embodiments, Z is -CH(OCH3)2. In embodiments, Z is -CH(OH)SO3 - (and Na + (associated cations such as

[0092] In embodiments, R * is independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, CN, —OH, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloromethyl, dichloromethyl, chloromethyl, trichloroethyl, dichloroethyl, and chloroethyl. * is independently chloro. In embodiments, R *is independently fluoro. In embodiments, R * is independently bromo. In embodiments, R * is independently iodo. In an embodiment, R * is independently methyl. In an embodiment, R * is independently ethyl. In an embodiment, R * is independently propyl. In embodiments, R * is independently methoxy. In an embodiment, R * is independently ethoxy. In embodiments, R * is independently propoxy. In an embodiment, R * is independently CN. In an embodiment, R * is independently —OH. In an embodiment, R * is independently trifluoromethyl. In an embodiment, R * is independently trifluoroethyl. In an embodiment, R * is independently difluoromethyl. In an embodiment, R * is independently difluoroethyl. In an embodiment, R * is independently fluoromethyl. In an embodiment, R * is independently fluoroethyl. In embodiments, R * is independently trichloromethyl. In an embodiment, R * is independently trichloroethyl. In an embodiment, R * is independently dichloromethyl. In an embodiment, R * is independently dichloroethyl. In an embodiment, R * is independently chloromethyl. In an embodiment, R * is independently chloroethyl.

[0093] In embodiments, m is 0, 1 or 2. In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2.

[0094] In embodiments, n is 0, 1, 2, 3, or 4. In embodiments, n is 1, 2, or 3. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.

[0095] In embodiments, the compound of formula (IA): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , L, R 2 , R 3 , Z, R * , m and n are as described herein, including in the embodiments).

[0096] In embodiments, the compound of formula (IB): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * , m and n are as described herein, including in the embodiments).

[0097] In embodiments, the compound of formula (IC): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * , m and n are as described herein, including in the embodiments).

[0098] In embodiments, the compound of formula (IC1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0099] In embodiments, a compound of formula (IC1A): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0100] In embodiments, a compound of formula (ID): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * , m, and n are as described herein, including in the embodiments. In embodiments, R 2 are respectively, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is independently selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, R 2 are each independently as described herein, including in the embodiments.

[0101] In an embodiment, a compound of formula (ID1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * and n are as described herein, including in the embodiments. In embodiments, R 2 are respectively, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is independently selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, R 2 are each independently as described herein, including in the embodiments.

[0102] In embodiments, the compound of formula (IE): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 5 is hydrogen, halo, -CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 haloalkoxy, p is an integer from 0 to 4, and R 2 , Z, R * , m and n are as described herein, including in the embodiments).

[0103] In embodiments, R 5 is hydrogen, halo, C 1~3 Alkyl and C 1~3 In embodiments, R is independently selected from alkoxy. 5is independently selected from hydrogen, halo, -CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, trifluoethyl, trifluoropropyl, trichloroethyl, and tribromoethyl. 5 is independently selected from hydrogen, —CN, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trichloromethyl, tribromomethyl, trifluoroethyl, trichloroethyl, and tribromoethyl. 5 is independently selected from hydrogen, fluoro, methyl, and methoxy. 5 is hydrogen. In embodiments, R 5 is methyl. In embodiments, R 5 is methoxy.

[0104] In embodiments, p is 0. In embodiments, p is 1. In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4.

[0105] In embodiments, the compound of formula (IF): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 5 , Z and n are as described herein, including in the embodiments.

[0106] In embodiments, the compound of formula (IG): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 5 and Z are as described herein, including in the embodiments).

[0107] In embodiments, a compound of formula (IG1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and R 5 are as described herein, including in the embodiments).

[0108] In embodiments, a compound of formula (IG2): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 are as described herein, including in the embodiments).

[0109] In embodiments, a compound of formula (IH): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * , m, and n are as described herein, including in the embodiments. In embodiments, R 2 are respectively, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is independently selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, R 2 are each independently as described herein, including in the embodiments.

[0110] In an embodiment, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and tautomers, mixtures of two or more tautomers, and isotopic variations thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

[0111] In an embodiment, a compound of formula (II): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, provided herein, wherein: Ring A is C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 cycloalkyl of 5 to 9 atoms optionally substituted with up to three groups selected from haloalkoxy; Z is -CO2-C 1~3 Alkyl, -CHO, -CH2CN, -C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)-C 1~3Haloalkyl, -NH-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] and -CH(OH)SO3 - (and Na + or an associated cation such as or Z may be -CN, provided that when n=1, R 2 is not t-butyl, R 1 is H, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy or C 1~4 alkyl, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy and C 1~4 Alkyl is a group that includes halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy, or R 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, and the 5-10 membered heteroaryl is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; R 2 is C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with up to three groups selected from haloalkoxy; R3 is H or C 1~4 is alkyl, R * are respectively, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 independently selected from haloalkyl, CN, halo, and —OH; m is an integer from 0 to 2, and n is an integer from 0 to 4.

[0112] In embodiments, ring A is a 5-membered ring that can be optionally fused to a cyclopropyl ring to form a bicyclic ring system that is an unsubstituted 3-azabicyclo[3.1.0]hexane ring. In embodiments, ring A is optionally fused to a cyclopropyl ring to form a bicyclic ring system that is an unsubstituted 3-azabicyclo[3.1.0]hexane ring. 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, ring A is a 5-membered ring that can form a bicyclic ring system that is a 3-azabicyclo[3.1.0]hexane ring substituted with one group selected from haloalkoxy. In an embodiment, ring A is optionally fused to a cyclopropyl ring, 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, ring A is a 5-membered ring that can form a bicyclic ring system that is a 3-azabicyclo[3.1.0]hexane ring substituted with two groups independently selected from haloalkoxy. In an embodiment, ring A is optionally fused to a cyclopropyl ring, such as C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 It is a five-membered ring that can form a bicyclic ring system that is a 3-azabicyclo[3.1.0]hexane ring substituted with three groups independently selected from haloalkoxy.

[0113] In embodiments, ring A is a 5-membered ring that can be optionally fused to a cyclopropyl ring to form a bicyclic ring system, which is a 3-azabicyclo[3.1.0]hexane ring substituted with two methyl groups to form a 6,6-dimethyl-3-azabicyclo[3.1.0]hexane ring.

[0114] In embodiments, Z is -CO2CH3, -CHO, -CH2CN, -C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)-C 1~3 Haloalkyl, -NH-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] and -CH(OH)SO3 - (and Na + In embodiments, Z is —CN, provided that when n=1, R 2 is not t-butyl. In embodiments, Z is -CN, -CO2CH3, -CH2CN, NHC(=O)CH=CH2, -C(=O)CH2OH, -CHO, -CH(OH)SO3 - (and Na + or —C(═O)—CHX, where X is F, Cl, Br, or I.

[0104] In embodiments, Z is -CO2CH3. In embodiments, Z is -CHO. In embodiments, Z is -CH2CN. In embodiments, Z is -C(=O)-CH=CH2. In embodiments, Z is -CH2-C(=O)-CH=CH2. In embodiments, Z is -C(=O)-C 1~3 In embodiments, Z is -NH-C(=O)-CH=CH2. In embodiments, Z is -C(=O)CH2OH. In embodiments, Z is [ka] In embodiments, Z is -CH(OH)SO3 - (and Na +In embodiments, Z is -C(=O)-CHX, where X is F, Cl, Br, or I. In embodiments, Z is -C(=O)-CHF. In embodiments, Z is -C(=O)-CHCl. ​​In embodiments, Z is -C(=O)-CHBr. In embodiments, Z is -C(=O)-CHI.

[0115] In embodiments, R 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is indolyl optionally substituted with 1, 2, or 3 groups independently selected from haloalkoxy. 1 is an unsubstituted indolyl. In embodiments, R 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is indolyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is an indolyl substituted by two groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is an indolyl substituted with three groups independently selected from haloalkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with one group selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3In embodiments, R is indolyl substituted with two groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with three groups independently selected from alkoxy. 1 is indolyl substituted with one group selected from fluoro, methyl, and methoxy. 1 is indolyl substituted with two groups independently selected from fluoro, methyl, and methoxy. In embodiments, R 1 is indolyl substituted with three groups independently selected from fluoro, methyl and methoxy.

[0116] In embodiments, R 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, each of which is halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 and optionally substituted with 1, 2, or 3 groups independently selected from haloalkoxy.

[0117] In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom selected from N, O, and S as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing two heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom N as a ring member. In embodiments, R 1is a 5-10 membered unsubstituted heteroaryl containing one heteroatom O as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom S as a ring member.

[0118] In embodiments, R 1 contains one or two heteroatoms selected from N, O and S as ring members, and is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one or two heteroatoms selected from N, O and S as ring members, and is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl or chloromethyl.

[0119] In embodiments, R 1 contains one heteroatom selected from N, O and S as a ring member and is not limited to halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom selected from N, O and S as a ring member and is not limited to halo, CN, C 1~3 Alkyl, C 1~3Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from N, O and S as a ring member and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl or chloromethyl.

[0120] In embodiments, R 1 contains one heteroatom N and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom N and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from N and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0121] In embodiments, R 1 contains one heteroatom O and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl.1 contains one heteroatom O and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from O and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0122] In embodiments, R 1 contains one heteroatom S and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom S and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from S and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0123] In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3In one embodiment, R is a 3- to 7-membered cycloalkyl optionally substituted with 1 to 3 groups independently selected from haloalkoxy. 1 is a 3- to 7-membered unsubstituted cycloalkyl. In embodiments, R 1 is unsubstituted cyclopropyl. In embodiments, R 1 is unsubstituted cyclobutyl. In embodiments, R 1 is unsubstituted cyclopentyl. In embodiments, R 1 is unsubstituted cyclohexyl. In embodiments, R 1 is unsubstituted cycloheptyl. In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopropyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclobutyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopentyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3In one embodiment, R is cyclohexyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopropyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclobutyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopentyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclohexyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopropyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclobutyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopentyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 and cyclohexyl substituted with three groups independently selected from haloalkoxy.

[0124] In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; 1~4 Alkoxy or C 1~4 In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 C optionally substituted with one group selected from haloalkoxy 1~4 Alkoxy or C 1~4 In embodiments, R 1, Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 C optionally substituted with two groups independently selected from haloalkoxy; 1~4 Alkoxy or C 1~4 In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 C optionally substituted with three groups independently selected from haloalkoxy; 1~4 Alkoxy or C 1~4 It is alkyl.

[0125] In embodiments, R 1 is the unsubstituted C 1~4 Alkoxy or C 1~4 In embodiments, R 1 is the unsubstituted C 1~4 In embodiments, R 1 is the unsubstituted C 1~4 In embodiments, R 1 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or t-butoxy. 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 1 is substituted by one group selected from fluoro, chloro, bromo and iodo, C 1~4 Alkoxy or C 1~4 In embodiments, R 1 is substituted by two groups independently selected from fluoro, chloro, bromo and iodo; 1~4 Alkoxy or C 1~4 In embodiments, R 1 is substituted by three groups independently selected from fluoro, chloro, bromo and iodo; 1~4Alkoxy or C 1~4 It is alkyl.

[0126] In embodiments, R 1 is trifluoromethyl, difluoromethyl, cyclopropyl, isopropyl, t-butyl, t-butoxy; or R 1 is indolyl optionally substituted with one or two groups independently selected from fluoro, methyl, and methoxy. In embodiments, R 1 is trifluoromethyl, difluoromethyl, cyclopropyl, isopropyl, t-butyl, or t-butoxy. 1 is trifluoromethyl. In embodiments, R 1 is difluoromethyl. In embodiments, R 1 is cyclopropyl. In embodiments, R 1 is isopropyl. In embodiments, R 1 is t-butyl. In embodiments, R 1 is t-butoxy. In embodiments, R 1 is an unsubstituted indolyl. In embodiments, R 1 is indolyl optionally substituted with one group selected from fluoro, methyl, and methoxy. In embodiments, R 1 is indolyl optionally substituted with two groups independently selected from fluoro, methyl, and methoxy. In embodiments, R 1 is indolyl optionally substituted with three groups independently selected from fluoro, methyl and methoxy.

[0127] In embodiments, R 2 is the unsubstituted C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 is the unsubstituted C 1~6 In embodiments, R2 is a 3- to 7-membered unsubstituted cycloalkyl. In embodiments, R 2 is an unsubstituted (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 is the unsubstituted C 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, or hexyl. 2 is isopropylmethyl, isobutylmethyl, isobutylethyl, or isopentylmethyl. 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 2 is cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, or cyclohexylethyl. 2 is methyl. In embodiments, R 2 is ethyl. In embodiments, R 2 is propyl. In embodiments, R 2 is butyl. In an embodiment, R 2 is isopropyl. In embodiments, R 2 is isobutyl. In embodiments, R 2 is t-butyl. In embodiments, R 2 is pentyl. In embodiments, R 2 is isopentyl. In embodiments, R 2 is t-pentyl. In embodiments, R 2 is hexyl. In an embodiment, R 2 is isopropylmethyl. In embodiments, R 2 is isobutylmethyl. In embodiments, R 2 is isobutylethyl. In embodiments, R 2 is isopentylmethyl. In embodiments, R 2is cyclopropyl. In embodiments, R 2 is cyclobutyl. In embodiments, R 2 is cyclopentyl. In embodiments, R 2 is cyclohexyl. In embodiments, R 2 is cycloheptyl. In embodiments, R 2 is cyclopropylmethyl. In embodiments, R 2 is cyclopropylethyl. In embodiments, R 2 is cyclopentylmethyl. In embodiments, R 2 is cyclopentylethyl. In embodiments, R 2 is cyclohexylmethyl. In embodiments, R 2 is cyclohexylethyl.

[0128] In embodiments, R 2 is selected from ethyl, isopropyl, isobutyl, t-butyl, isopropylmethyl, cyclopropyl, cyclohexyl, and cyclobutyl. 2 is t-butyl, isopropylmethyl or cyclopropyl.

[0129] In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 substituted by one group selected from haloalkoxy, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) or (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 substituted by two groups independently selected from haloalkoxy; 1~6 Alkyl, 3-7 membered cycloalkyl, C1~3 Alkyl-(3- to 7-membered cycloalkyl) or (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 substituted by three groups independently selected from haloalkoxy; 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) or (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by one group selected from haloalkoxy 1~6 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with one group selected from haloalkoxy. 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by one group selected from haloalkoxy 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 (3-7 membered cycloalkyl)-C substituted with one group selected from haloalkoxy 1~3 In embodiments, R 2 , Halo, CN, C 1~3Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by two groups independently selected from haloalkoxy 1~6 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with two groups independently selected from haloalkoxy. 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by two groups independently selected from haloalkoxy 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 (3- to 7-membered cycloalkyl)-C substituted by two groups independently selected from haloalkoxy 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by three groups independently selected from haloalkoxy 1~6 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with three groups independently selected from haloalkoxy. 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C1~3 Haloalkyl and C 1~3 C substituted by three groups independently selected from haloalkoxy 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 (3- to 7-membered cycloalkyl)-C substituted by three groups independently selected from haloalkoxy 1~3 It is alkyl.

[0130] In embodiments, R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 3 is H. In an embodiment, R 3 is methyl. In embodiments, R 3 is ethyl. In embodiments, R 3 is propyl. In embodiments, R 3 is isopropyl. In embodiments, R 3 is butyl. In an embodiment, R 3 is isobutyl. In embodiments, R 3 is t-butyl.

[0131] In embodiments, R * is independently selected from chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, CN, —OH, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloromethyl, dichloromethyl, chloromethyl, trichloroethyl, dichloroethyl, and chloroethyl. * is independently chloro. In embodiments, R * is independently fluoro. In embodiments, R * is independently bromo. In embodiments, R *is independently iodo. In an embodiment, R * is independently methyl. In an embodiment, R * is independently ethyl. In an embodiment, R * is independently propyl. In embodiments, R * is independently methoxy. In an embodiment, R * is independently ethoxy. In embodiments, R * is independently propoxy. In an embodiment, R * is independently CN. In an embodiment, R * is independently —OH. In an embodiment, R * is independently trifluoromethyl. In an embodiment, R * is independently trifluoroethyl. In an embodiment, R * is independently difluoromethyl. In an embodiment, R * is independently difluoroethyl. In an embodiment, R * is independently fluoromethyl. In an embodiment, R * is independently fluoroethyl. In embodiments, R * is independently trichloromethyl. In an embodiment, R * is independently trichloroethyl. In an embodiment, R * is independently dichloromethyl. In an embodiment, R * is independently dichloroethyl. In an embodiment, R * is independently chloromethyl. In an embodiment, R * is independently chloroethyl.

[0132] In embodiments, m is 0, 1 or 2. In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2.

[0133] In embodiments, n is 0, 1, 2, 3 or 4. In embodiments, n is 1 or 2. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.

[0134] In embodiments, the compound of formula (IIA): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * , m and n are as described herein, including in the embodiments).

[0135] In embodiments, the compound of formula (IIA1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z, R * , m and n are as described herein, including in the embodiments).

[0136] In embodiments, the compound of formula (IIB): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 and Z are as described herein, including in the embodiments).

[0137] In embodiments, the compound of formula (IIB1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0138] In embodiments, the compound of formula (IIB1A): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0139] In embodiments, the compound of formula (IIB2): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0140] In embodiments, the compound of formula (IIB2A): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0141] In embodiments, the compound of formula (IIB3): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0142] In embodiments, the compound of formula (IIB4): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0143] In embodiments, the compound of formula (IIB5): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0144] In embodiments, the compound of formula (IIC): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 5 is hydrogen, halo, -CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 haloalkoxy, p is an integer from 0 to 4, and R 2 , Z, R * , m and n are as described herein, including in the embodiments).

[0145] In embodiments, R 5 is hydrogen, halo, C 1~3 Alkyl and C 1~3 In embodiments, R is independently selected from alkoxy. 5 is independently selected from hydrogen, halo, —CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, trifluoroethyl, trifluoropropyl, trichloroethyl, and tribromoethyl. 5 is independently selected from hydrogen, —CN, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trichloromethyl, tribromomethyl, trifluoroethyl, trichloroethyl, and tribromoethyl. 5 is independently selected from hydrogen, fluoro, methyl and methoxy.

[0146] In embodiments, p is 0. In embodiments, p is 1. In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4.

[0147] In embodiments, the compound of formula (IID): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 5 , n and Z are as described herein, including in the embodiments).

[0148] In embodiments, the compound of formula (IID1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 5 and Z are as described herein, including in the embodiments).

[0149] In embodiments, the compound of formula (IID1A): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0150] In embodiments, the compound of formula (IID2): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 5 and Z are as described herein, including in the embodiments).

[0151] In embodiments, the compound of formula (IID2A): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0152] In an embodiment, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0153] In an embodiment, a compound of formula (III): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, provided herein, wherein: Ring A is C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 cycloalkyl of 5 to 9 atoms optionally substituted with up to three groups selected from haloalkoxy; Z is -CO2-C 1~3 Alkyl, -CHO, -CN, -CH2CN, -C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)-C 1~3 Haloalkyl, -NH-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] and -CH(OH)SO3 - (and Na + and associated cations such as R 1 is H, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy or C 1~4 alkyl, 3- to 7-membered cycloalkyl, C 1~4 Alkoxy and C 1~4 Alkyl is a group that includes halo, CN, C 3~6Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy, or R 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, and the 5-10 membered heteroaryl is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; R 2 is C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 alkyl, each of which is selected from halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with up to three groups selected from haloalkoxy; R 3 is H or C 1~4 is alkyl, R 6 is hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl or C 1~3 haloalkoxy).

[0154] In embodiments, ring A is a 5-membered ring that can be optionally fused to a cyclopropyl ring to form a bicyclic ring system that is an unsubstituted 3-azabicyclo[3.1.0]hexane ring. In embodiments, ring A is optionally fused to a cyclopropyl ring to form a bicyclic ring system that is an unsubstituted 3-azabicyclo[3.1.0]hexane ring. 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3In an embodiment, ring A is a 5-membered ring that can form a bicyclic ring system that is a 3-azabicyclo[3.1.0]hexane ring substituted with one group selected from haloalkoxy. In an embodiment, ring A is optionally fused to a cyclopropyl ring, 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In an embodiment, ring A is a 5-membered ring that can form a bicyclic ring system that is a 3-azabicyclo[3.1.0]hexane ring substituted with two groups independently selected from haloalkoxy. In an embodiment, ring A is optionally fused to a cyclopropyl ring, such as C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 It is a five-membered ring that can form a bicyclic ring system that is a 3-azabicyclo[3.1.0]hexane ring substituted with three groups independently selected from haloalkoxy.

[0155] In embodiments, ring A is a 5-membered ring that can be optionally fused to a cyclopropyl ring to form a bicyclic ring system, which is a 3-azabicyclo[3.1.0]hexane ring substituted with two methyl groups to form a 6,6-dimethyl-3-azabicyclo[3.1.0]hexane ring.

[0156] In embodiments, Z is -CO2CH3, -CHO, -CN, -CH2CN, -C(=O)-CH=CH2, -CH2-C(=O)-CH=CH2, -C(=O)-C 1~3 Haloalkyl, -NH-C(=O)-CH=CH2, -C(=O)CH2OH, [ka] and -CH(OH)SO3 - (and Na + In embodiments, Z is selected from the group consisting of -CO2CH3, -CHO, -CN, -C(=O)-C 1~3 Haloalkyl, -NH-C(=O)-CH=CH2 and -CH(OH)SO3- (and Na + In embodiments, Z is selected from -CO2CH3, -CHO, -CN, -NH-C(=O)-CH=CH2, -CH(OH)SO3 - (and Na + and —C(═O)—CHX, where X is F, Cl, Br, or I.

[0157] In embodiments, Z is -CO2CH3. In embodiments, Z is -CHO. In embodiments, Z is -CN. In embodiments, Z is -CH2CN. In embodiments, Z is -C(=O)-CH=CH2. In embodiments, Z is -CH2-C(=O)-CH=CH2. In embodiments, Z is -C(=O)-C 1~3 In embodiments, Z is -NH-C(=O)-CH=CH2. In embodiments, Z is -C(=O)CH2OH. In embodiments, Z is [ka] In embodiments, Z is -CH(OH)SO3 - (and Na + In embodiments, Z is -C(=O)-CHX, where X is F, Cl, Br, or I. In embodiments, Z is -C(=O)-CHF. In embodiments, Z is -C(=O)-CHCl. ​​In embodiments, Z is -C(=O)-CHBr. In embodiments, Z is -C(=O)-CHI.

[0158] In embodiments, R 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is indolyl optionally substituted with 1, 2, or 3 groups independently selected from haloalkoxy. 1 is an unsubstituted indolyl. In embodiments, R 1, Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is indolyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In embodiments, R is an indolyl substituted by two groups independently selected from haloalkoxy. 1 , Halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is an indolyl substituted with three groups independently selected from haloalkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with one group selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with two groups independently selected from alkoxy. 1 Ha, Halo, C 1~3 Alkyl and C 1~3 In embodiments, R is indolyl substituted with three groups independently selected from alkoxy. 1 is indolyl substituted with one group selected from fluoro, methyl, and methoxy. 1 is indolyl substituted with two groups independently selected from fluoro, methyl, and methoxy. In embodiments, R 1 is indolyl substituted with three groups independently selected from fluoro, methyl and methoxy.

[0159] In embodiments, R 1is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members, each of which is halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 and optionally substituted with 1, 2, or 3 groups independently selected from haloalkoxy.

[0160] In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom selected from N, O, and S as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing two heteroatoms selected from N, O and S as ring members. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom N as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom O as a ring member. In embodiments, R 1 is a 5-10 membered unsubstituted heteroaryl containing one heteroatom S as a ring member.

[0161] In embodiments, R 1 contains one or two heteroatoms selected from N, O and S as ring members, and is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one or two heteroatoms selected from N, O and S as ring members, and is selected from halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one or two heteroatoms selected from N, O and S as ring members and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl or chloromethyl.

[0162] In embodiments, R 1 contains one heteroatom selected from N, O and S as a ring member and is not limited to halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom selected from N, O and S as a ring member and is not limited to halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from N, O and S as a ring member and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl or chloromethyl.

[0163] In embodiments, R 1 contains one heteroatom N and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom N and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from N and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0164] In embodiments, R 1 contains one heteroatom O and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom O and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from O and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0165] In embodiments, R 1 contains one heteroatom S and is not a halo, CN, C1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one, two, or three groups independently selected from haloalkyl. 1 contains one heteroatom S and is not a halo, CN, C 1~3 Alkyl, C 1~3 Alkoxy or C 1~3 In one embodiment, R is a 5-10 membered heteroaryl substituted with one group independently selected from haloalkyl. 1 is a 5-10 membered heteroaryl containing one heteroatom selected from S and substituted by one group independently selected from fluoro, chloro, iodo, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, or chloromethyl.

[0166] In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl optionally substituted with 1 to 3 groups independently selected from haloalkoxy. 1 is a 3- to 7-membered unsubstituted cycloalkyl. In embodiments, R 1 is unsubstituted cyclopropyl. In embodiments, R 1 is unsubstituted cyclobutyl. In embodiments, R 1 is unsubstituted cyclopentyl. In embodiments, R 1 is unsubstituted cyclohexyl. In embodiments, R 1 is unsubstituted cycloheptyl. In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopropyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclobutyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopentyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclohexyl substituted with one group selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopropyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclobutyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopentyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclohexyl substituted with two groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclopropyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is cyclobutyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3In one embodiment, R is cyclopentyl substituted with three groups independently selected from haloalkoxy. 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 and cyclohexyl substituted with three groups independently selected from haloalkoxy.

[0167] In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with 1 to 3 groups independently selected from haloalkoxy; 1~4 Alkoxy or C 1~4 In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 C optionally substituted with one group selected from haloalkoxy 1~4 Alkoxy or C 1~4 In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 C optionally substituted with two groups independently selected from haloalkoxy; 1~4 Alkoxy or C 1~4 In embodiments, R 1 , Halo, CN, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 C optionally substituted with three groups independently selected from haloalkoxy; 1~4 Alkoxy or C 1~4 It is alkyl.

[0168] In embodiments, R 1 is the unsubstituted C 1~4 Alkoxy or C 1~4 In embodiments, R 1 is the unsubstituted C 1~4 In embodiments, R 1 is the unsubstituted C 1~4 In embodiments, R 1 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or t-butoxy. 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 1 is substituted by one group selected from fluoro, chloro, bromo and iodo, C 1~4 Alkoxy or C 1~4 In embodiments, R 1 is substituted by two groups independently selected from fluoro, chloro, bromo and iodo; 1~4 Alkoxy or C 1~4 In embodiments, R 1 is substituted by three groups independently selected from fluoro, chloro, bromo and iodo; 1~4 Alkoxy or C 1~4 It is alkyl.

[0169] In embodiments, R 1 is trifluoromethyl, difluoromethyl, cyclopropyl, isopropyl, t-butyl, isopropylmethyl, t-butoxy; or R 1 is indolyl optionally substituted with one or two groups selected from fluoro, methyl, and methoxy. In embodiments, R 1 is trifluoromethyl or indolyl optionally substituted with one or two groups selected from fluoro, methyl, and methoxy. 1is trifluoromethyl, difluoromethyl, cyclopropyl, isopropyl, t-butyl, or t-butoxy. 1 is trifluoromethyl. In embodiments, R 1 is difluoromethyl. In embodiments, R 1 is cyclopropyl. In embodiments, R 1 is isopropyl. In embodiments, R 1 is t-butyl. In embodiments, R 1 is isopropylmethyl. In embodiments, R 1 is t-butoxy.

[0170] In embodiments, R 2 is the unsubstituted C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 is the unsubstituted C 1~6 In embodiments, R 2 is a 3- to 7-membered unsubstituted cycloalkyl. In embodiments, R 2 is the unsubstituted C 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 is an unsubstituted (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, or hexyl. 2 is isopropylmethyl, isobutylmethyl, isobutylethyl, or isopentylmethyl. 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 2is cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, or cyclohexylethyl. 2 is methyl. In embodiments, R 2 is ethyl. In embodiments, R 2 is propyl. In embodiments, R 2 is butyl. In an embodiment, R 2 is isopropyl. In embodiments, R 2 is isobutyl. In embodiments, R 2 is t-butyl. In embodiments, R 2 is pentyl. In embodiments, R 2 is isopentyl. In embodiments, R 2 is t-pentyl. In embodiments, R 2 is hexyl. In an embodiment, R 2 is isopropylmethyl. In embodiments, R 2 is isobutylmethyl. In embodiments, R 2 is isobutylethyl. In embodiments, R 2 is isopentylmethyl. In embodiments, R 2 is cyclopropyl. In embodiments, R 2 is cyclobutyl. In embodiments, R 2 is cyclopentyl. In embodiments, R 2 is cyclohexyl. In embodiments, R 2 is cycloheptyl. In embodiments, R 2 is cyclopropylmethyl. In embodiments, R 2 is cyclopropylethyl. In embodiments, R 2 is cyclopentylmethyl. In embodiments, R 2 is cyclopentylethyl. In embodiments, R 2 is cyclohexylmethyl. In embodiments, R 2 is cyclohexylethyl.

[0171] In embodiments, R2 is selected from ethyl, isopropyl, isobutyl, t-butyl, isopropylmethyl, cyclopropyl, cyclohexyl, and cyclobutyl. 2 is t-butyl, isopropylmethyl or cyclopropyl.

[0172] In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 substituted by one group selected from haloalkoxy, C 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) or (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 substituted by two groups independently selected from haloalkoxy; 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) or (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 substituted by three groups independently selected from haloalkoxy; 1~6 Alkyl, 3-7 membered cycloalkyl, C 1~3 Alkyl-(3- to 7-membered cycloalkyl) or (3- to 7-membered cycloalkyl)-C 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3C substituted by one group selected from haloalkoxy 1~6 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with one group selected from haloalkoxy. 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by one group selected from haloalkoxy 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 (3-7 membered cycloalkyl)-C substituted with one group selected from haloalkoxy 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by two groups independently selected from haloalkoxy 1~6 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with two groups independently selected from haloalkoxy. 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by two groups independently selected from haloalkoxy 1~3alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 (3- to 7-membered cycloalkyl)-C substituted by two groups independently selected from haloalkoxy 1~3 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by three groups independently selected from haloalkoxy 1~6 In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 In one embodiment, R is a 3- to 7-membered cycloalkyl substituted with three groups independently selected from haloalkoxy. 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 C substituted by three groups independently selected from haloalkoxy 1~3 alkyl-(3- to 7-membered cycloalkyl). In embodiments, R 2 , Halo, CN, C 1~3 Alkyl, C 1~6 Alkoxy, C 1~3 Haloalkyl and C 1~3 (3- to 7-membered cycloalkyl)-C substituted by three groups independently selected from haloalkoxy 1~3 It is alkyl.

[0173] In embodiments, R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl. 3 is H. In an embodiment, R3 is methyl. In embodiments, R 3 is ethyl. In embodiments, R 3 is propyl. In embodiments, R 3 is isopropyl. In embodiments, R 3 is butyl. In an embodiment, R 3 is isobutyl. In embodiments, R 3 is t-butyl.

[0174] In embodiments, R 6 is hydrogen. In embodiments, R 6 is halo. In embodiments, R 6 is C 1~6 In embodiments, R 6 is C 1~6 In embodiments, R 6 is C 1~3 In embodiments, R 6 is C 1~3 It is haloalkoxy.

[0175] In embodiments, R 6 is hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, trifluoromethyl, trifluoroethyl, trifluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, fluoromethyl, fluoroethyl, fluoropropyl, trichloromethyl, trichloroethyl, trichloropropyl, dichloromethyl, dichloroethyl, dichloropropyl, chloromethyl, chloroethyl, chloropropyl, tribromomethyl, tribromoethyl, tribromopropyl, dibromomethyl, dibromoethyl, dibromopropyl, bromomethyl, bromoethyl, bromopropyl, triiodomethyl, triiodoethyl, triiodopropyl, diiodomethyl, diiodoethyl, diiodopropyl, iodomethyl, iodoethyl, or iodopropyl. 6is methyl, isopropyl, or t-butyl. 6 is methyl. In embodiments, R 6 is ethyl. In embodiments, R 6 is propyl. In embodiments, R 6 is isopropyl. In embodiments, R 6 is butyl. In an embodiment, R 6 is isobutyl. In embodiments, R 6 is t-butyl.

[0176] In embodiments, the compound of formula (IIIA): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z and R 6 are as described herein, including in the embodiments).

[0177] In embodiments, the compound of formula (IIIB): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 1 , R 2 , Z and R 6 are as described herein, including in the embodiments).

[0178] In embodiments, the compound of formula (IIIC): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 5 is hydrogen, halo, -CN, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 1~3 haloalkoxy, p is an integer from 0 to 4, and R 2 , Z and R 6 are as described herein, including in the embodiments).

[0179] In embodiments, R 5 is hydrogen, halo, C 1~3 Alkyl and C 1~3 In embodiments, R is independently selected from alkoxy. 5 is independently selected from hydrogen, halo, —CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, trifluoroethyl, trifluoropropyl, trichloroethyl, and tribromoethyl. 5 is independently selected from hydrogen, —CN, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trichloromethyl, tribromomethyl, trifluoroethyl, trichloroethyl, and tribromoethyl. 5 is independently selected from hydrogen, fluoro, methyl, and methoxy. 5 is hydrogen. In embodiments, R 5is fluoro. In embodiments, R 5 is methyl. In embodiments, R 5 is methoxy.

[0180] In embodiments, p is 0. In embodiments, p is 1. In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4.

[0181] In embodiments, the compound of formula (IIID): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 5 , Z and R 6 are as described herein, including in the embodiments).

[0182] In embodiments, a compound of formula (IIID1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , Z and R 6 are as described herein, including in the embodiments).

[0183] In embodiments, the compound of formula (IIID1A): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0184] In embodiments, the compound of formula (IIID1B): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0185] In embodiments, the compound of formula (IIID1C): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0186] In embodiments, the compound of formula (IIIE): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 , R 6 and Z are as described herein, including in the embodiments).

[0187] In embodiments, the compound of formula (IIIE1): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0188] In embodiments, the compound of formula (IIIE2): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0189] In embodiments, the compound of formula (IIIE3): [ka] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, provided herein (wherein R 2 and Z are as described herein, including in the embodiments).

[0190] In an embodiment, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and tautomers, mixtures of two or more tautomers, and isotopic variations thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. Pharmaceutical compositions, combinations and other related uses

[0191] In yet another aspect, the disclosure provides pharmaceutical compositions comprising the compounds described above in admixture with at least one pharmaceutically acceptable carrier or excipient.

[0192] The compounds described above can be used for any suitable purpose, for example, the compounds can be used in the treatment and / or testing related to viral infections.

[0193] In yet another aspect, the present disclosure provides methods of treating and / or preventing a viral infection. In embodiments, the viral infection is a coronavirus infection.

[0194] In yet another aspect, the disclosure provides for the use of the compounds described above for the manufacture of a medicament, and the use of the compounds of the invention in therapy, generally for treating a viral infection, such as COVID-19.

[0195] In yet another aspect, the present disclosure provides a combination for treating and / or preventing a viral infection in a subject, comprising an effective amount of the above-described compound, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and / or preventing the viral infection.

[0196] In yet another aspect, the present disclosure provides methods of treating and / or preventing viral infection in a subject who has been exposed to or is likely to be exposed to a coronavirus or enterovirus, particularly the virus that causes COVID-19.

[0197] In yet another aspect, the disclosure provides a method of inhibiting the activity of a coronavirus major viral protease (3CL), comprising contacting the 3CL with an effective amount of a compound of the invention.

[0198] The method can be used for any suitable purpose, hi some embodiments, the method can be used to treat an enterovirus or coronavirus infection, such as COVID-19. formulation

[0199] Any suitable formulation of the compounds described herein can be prepared. Generally, see Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, 20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. The formulation is selected to be suitable for a suitable route of administration. In some embodiments, the compound of formula (I), (II) or (III) is formulated for oral administration. In some embodiments, the compound is formulated for parenteral administration, such as injection or infusion.

[0200] When a compound is sufficiently basic or acidic to the extent that it forms a stable non-toxic acid or base salt, it may be appropriate to administer the compound as a salt.Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate.Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.Pharmaceutically acceptable salts can be obtained by using standard procedures well known in the art, for example, with a sufficiently basic compound, such as an amine, and a suitable acid that provides a physiologically acceptable anion.Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0201] When the contemplated compound is administered in a pharmacological composition, it is contemplated that the compound can be formulated in a mixture with pharmaceutically acceptable excipients and / or carriers. For example, the contemplated compound can be administered orally as a neutral compound or as a pharmaceutically acceptable salt, or intravenously with saline solution. Conventional buffers such as phosphate, bicarbonate, or citrate can be used for this purpose. Of course, those skilled in the art can modify the formulation within the scope of the teachings of this specification to provide a variety of formulations for specific administration routes. In particular, the contemplated compound may be modified to make it more soluble in water or other vehicles, which can be easily achieved by, for example, sufficiently minor modifications (salt formulation, esterification, etc.) within the ordinary skill of the art. It is also well within the skill of the art to modify the administration route and dosage regimen of a particular compound to manage the pharmacokinetics of the compound to maximize the beneficial effect in patients.

[0202] The compounds having Formula I, II, or III described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide (dimethylaceatmide), and dimethyl sulfoxide. In one embodiment, the present invention provides a formulation prepared by combining a compound having Formula I, II, or III with a pharmaceutically acceptable carrier. In one aspect, the formulation may be prepared using a method comprising: a) dissolving the compound described in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a cyclodextrin, a vitamin such as tocopherol, a fatty acid, a fatty acid ester, a phospholipid, or a combination thereof to prepare a solution; and b) adding saline or a buffer containing 1-10% carbohydrate solution. In one example, the carbohydrate comprises dextrose. The pharmaceutical compositions obtained using this method are stable and useful for veterinary and clinical applications.

[0203] Illustrative examples of water-soluble organic solvents for use in the present method include, but are not limited to, polyethylene glycol (PEG), alcohol, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or combinations thereof. Examples of alcohols include, but are not limited to, methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0204] Illustrative examples of water-soluble nonionic surfactants for use in the present methods include, but are not limited to, CREMOPHOR® EL, polyethylene glycol-modified CREMOPHOR® (polyoxyethyleneglyceroltriricinoleat 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated persic oil), LABRASOL® (capryl-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol esters), SOFTIGEN® (PEG 6 caprylic acid glyceride), glycerin, glycol-polysorbate, or combinations thereof.

[0205] Illustrative examples of water-soluble lipids for use in the present methods include, but are not limited to, vegetable oils, triglycerides, plant oils, or combinations thereof. Examples of lipid oils include, but are not limited to, castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, coconut oil triglycerides, palm seed oil and its hydrogenated forms, or combinations thereof.

[0206] Illustrative examples of fatty acids and fatty acid esters for use in the present methods include, but are not limited to, oleic acid, monoglycerides, diglycerides, mono- or di-fatty acid esters of PEG, or combinations thereof.

[0207] Illustrative examples of cyclodextrins for use in the present methods include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutylether-beta-cyclodextrin.

[0208] Illustrative examples of phospholipids for use in the present methods include, but are not limited to, soybean phosphatidylcholine or distearoylphosphatidylglycerol and their hydrogenated forms, or combinations thereof.

[0209] Those skilled in the art can select or modify formulations within the scope of the teachings of this specification to provide various formulations for specific administration routes.In particular, the compounds may be modified to make them more soluble in water or other vehicles.It is also well within the skill of the art to modify the administration route and dosage regimen of a specific compound to manage the pharmacokinetics of the compound to maximize the beneficial effect in patients. Drug combinations

[0210] The method of the embodiment comprises administering an effective amount of at least one exemplary compound of the present disclosure.Optionally, the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful in treating viral infections suffered by the subject, one example of which is remdesivir.

[0211] The additional therapeutic agent may be administered in a separate pharmaceutical composition from at least one exemplary compound of the present disclosure, or may be included in a single pharmaceutical composition with at least one exemplary compound of the present disclosure. The additional therapeutic agent may be administered simultaneously with, before, or after the administration of at least one exemplary compound of the present disclosure. Methods of Using Exemplary Compounds and Pharmaceutical Compositions Thereof

[0212] The present invention also provides pharmaceutical compositions for treating and / or preventing viral infections comprising any compound having Formula I, II, III, or any of the disclosed exemplary compounds.

[0213] To practice the methods of the present invention, the compounds having the formula and pharmaceutical compositions thereof may be administered orally, parenterally, by inhalation, topically, rectally, nasally, bucally, vaginally, via an implanted reservoir, or other modes of drug administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0214] According to the techniques known in the art, suitable dispersing or wetting agents and suspending agents may be used to formulate sterile injectable compositions, such as injectable sterile aqueous or oily suspensions.Sterile injectable preparations may also be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents.Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution and isotonic sodium chloride solution.Suitable carriers and other components of pharmaceutical compositions are usually sterilized.

[0215] In addition, sterile, fixed oils are commonly used as solvents or suspending media (e.g., synthetic monoglycerides or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful for preparing injectables, as are pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants. Various emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0216] Compositions for oral administration may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase together with an emulsifying or suspending agent. If necessary, certain sweeteners, flavorings, or colorings can be added. Nasal aerosol or inhalation compositions can be prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as solutions, for example, in saline, using suitable preservatives (e.g., benzyl alcohol), absorption enhancers to enhance bioavailability, and / or other solubilizers or dispersants known in the art.

[0217] Furthermore, any of the compounds having Formula I, II, or III, or any of the exemplary compounds disclosed herein, may be administered alone or in combination with other therapeutic agents, for example, antiviral agents for the treatment of viral infections such as COVID-19. Combination therapy according to the present invention involves the administration of at least one exemplary compound of the present disclosure and at least one other therapeutic agent, such as an antiviral agent like remdesivir, in a pharmaceutical composition. The at least one exemplary compound of the present disclosure and at least one other therapeutic agent may be administered individually or together as a pharmaceutical composition. The amounts of the at least one exemplary compound of the present disclosure and the at least one other therapeutic agent, as well as the relative timing of administration, are selected to achieve a desired combined therapeutic effect. Biological Testing

[0218] Suitable assays and model systems for evaluating the therapeutic efficacy, e.g., antiviral efficacy, of exemplary compounds of the present invention are well known in the art. "The Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19," Hoffman, et al., J. Med. Chem. July 2020, pp. AW, describes a suitable SARS CoV-2 protease FRET assay for measuring inhibition of 3CL protease, and also describes a suitable antiviral assay using MRC-5 cells infected with hCOV 229e coronavirus. Compounds of the present invention can be tested using these or other known bioassays in cell culture to screen for highly potent inhibitors of 3CL with antiviral activity. Methods for making the compounds of the present invention.

[0219] The compounds of the present invention can be easily prepared using the methods illustrated by Schemes I-X and the examples herein, taking into account the knowledge in the art of making related peptidomimetic compounds.See, for example, the synthetic methods in Hoffman, et al., J. Med. Chem. July 2020; Science vol. 371, 1374-78 (2021); and WO2020 / 247665.

[0220] As used herein, common organic chemistry abbreviations are defined as follows: Ac Acetyl ACN Acetonitrile AcOH acetic acid aq. Water-based BOC or Boc tert-butoxycarbonyl CBZ Benzoxycarbonyl DCM dichloromethane DIEA or DIPEA Diisopropylethylamine DMF N,N'-dimethylformamide DMP Dess-Martin Periodinane DMSO dimethyl sulfoxide EDC or EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc or EA ethyl acetate EtOH ethanol Eq equivalent FA formic acid Fmoc 9-Fluorenylmethoxycarbonyl g grams h time HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl Hydrochloric acid HOBt N-hydroxybenzotriazole HOPO 2-hydroxypyridine-N-oxide HPLC High-Performance Liquid Chromatography IBX 2-iodoxybenzoic acid IPA Isopropyl Alcohol LC / MS Liquid Chromatography-Mass Spectrometry LDA Lithium diisopropylamide mg milligram MeOH Methanol mL milliliter μL / uL microliter mol mole mmol millimole μmol / umol micromol MS mass spectrometry NHS or HOSu N-hydroxysuccinimide NMP N-methyl-2-pyrrolidone PE Petroleum Ether Pip Piperidine RP-HPLC Reversed-Phase HPLC rt room temperature t-Bu tert-butyl TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TEA Triethylamine tert, t third grade TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran Scheme I. General method for making aldehyde intermediates for compounds of formula (I). [ka] [ka] Scheme II. Synthesis of selected precursors. [ka] Scheme III. Synthesis of compounds of formula (II). [ka] [ka] [ka] Scheme IV. Methods for introducing various groups Z into compounds of formula I and II. General conversion of aldehydes to -CN, -CHCN, -C(O)CH=CH, -NHC(O)CH=CH, -CHC(O)CH=CH [ka] [ka] Scheme V. Further synthesis of compounds of formula (I). [ka] [ka] Scheme VI. Synthesis of selected compounds of formula (I). [ka] Scheme VII. Synthesis of selected compounds of formula (I). [ka] Scheme VIII. Synthesis of selected compounds of formula (II). [ka] Scheme IX. Synthesis of selected compounds of formula (I) containing benzo-thiazole ketones. [ka] Scheme X. Synthesis of selected compounds of formula (I). Various synthetic routes to bisulfite adducts [ka] [ka] [Example]

[0221] Example

[0222] The following examples are intended to be illustrative and can be used to further understand embodiments of the present disclosure, and should not be construed as limiting the scope of the present teachings in any way.

[0223] The chemical reactions described in the examples can be easily adapted to prepare some other compounds of the present disclosure, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds not exemplified in the present disclosure can be successfully carried out by modifications obvious to those skilled in the art, for example, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications to reaction conditions, reagents, and starting materials. Alternatively, it will be recognized that other reactions disclosed herein or known in the art have applicability for the preparation of other compounds of the present disclosure. Synthesis Examples (Example S1) Synthesis of Compounds A-1-a, A-1-b, A-1-c, and A-1-d [ka]

[0224] To a solution of 1H-indole-2-carboxylic acid (compound 101) (200 g, 1.24 mol) and N-hydroxysuccinimide (157.1 g, 1.37 mol) in dichloromethane (2.5 L) was added EDCI (286 g, 1.49 mmol) at 0 °C. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The resulting solid was triturated with deionized water, and the solid was collected and evaporated to dryness under reduced pressure to give compound 102 (310 g, 96%) as a light brown solid.1 H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 - 7.35 (m, 3H), 7.19 (t, J = 7.4 Hz, 1H), 2.92 (s, 4H).

[0225] To a stirred mixture of methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound 103) (500 g, 1748.24 mmol) in MeOH (200 mL) was added 4 M HCl in 1,4-dioxane (2000 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate hydrochloride (compound 104) (389 g, 1721 mmol, 98%) as a pale yellow solid, which was used in the next step without further purification. LCMS = [M+H] + :187.1.

[0226] To a stirred mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate hydrochloride (389 g, 1721 mmol) (Compound 104) and DIEA (866.162 mL, 5240.94 mmol) in DCM (1800 mL) and EtOH (500 mL) was added 2,5-dioxopyrrolidin-1-yl(2R)-2-{[(tert-butoxy)carbonyl]amino}-4-methyl-pentanoate (Compound 105) (573.66 g, 1746.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was washed successively with water (1.0 L × 2), 0.5 M HCl (1.1 L), saturated NaHCO3 (1 L), and water (1 L). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 106 (700 g, 1752.23 mmol, >99%) as a pale yellow solid, which was used in the next step without further purification. LCMS = [M+H] +:400.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.40 - 4.28 (m, 1H), 3.94 (dd, J = 15.1, 8.1 Hz, 1H), 3.74 - 3.52 (m, 3H), 3.15 (t, J = 8.8 Hz, 1H), 3.06 (dd, J = 16.4, 9.2 Hz, 1H), 2.33 (t, J = 9.2 Hz, 1H), 2.14 - 2.00 (m, 2H), 1.68 - 1.51 (m, 3H), 1.42 - 1.34 (m, 11H), 0.87 (dd, J = 11.4, 6.6 Hz, 6H).

[0227] A mixture of methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound 106) (590 g, 1476.88 mmol) in HCl / dioxane (3 L) was stirred at room temperature for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound 107 as a yellow solid (490 g, 99%), which was used in the next step without further purification. LCMS = [M+H] + :300.2.

[0228] To a stirred mixture of methyl (S)-2-((S)-2-amino-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (Compound 107) (418 g, 1235 mmol) and TEA (519.020 mL, 3734.03 mmol) in DMF (2500 mL) was added 2,5-dioxopyrrolidin-1-yl 1H-indole-2-carboxylate (Compound 102) (353 g, 1369.15 mmol) at room temperature. The reaction mixture was stirred for 1.5 hours. LCMS showed the reaction was complete. EtOAc (6 L) was added to the reaction mixture, which was then washed with brine (6 L × 6). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to a reduced volume. Compound A-1-a was obtained as an off-white solid (414 g, yield: 76%), which was used in the next step without further purification. LCMS = [M+H] + :443.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.54 (t, J = 12.2 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.24 (t, J = 10.3 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 4.65 - 4.50 (m, 1H), 4.44 - 4.28 (m, 1H), 3.72 - 3.55 (s, 3H), 3.19 - 3.06 (m, 2H), 2.36 (ddd, J = 13.8, 10.3, 4.0 Hz, 1H), 2.16 - 2.03 (m, 2H), 1.79 - 1.49 (m, 5H), 0.92 (dt, J = 14.4, 7.2 Hz, 6H).

[0229] To a stirred solution of methyl (S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound A-1-a) (500 g, 1131 mmol) in THF (20 L) was added LiBH (74 g, 3393 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with saturated aqueous NH Cl until gas generation ceased. The mixture was washed with brine (5 L × 4), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a reduced volume. The resulting residue was purified by silica column chromatography (DCM:MeOH = 15:1) to give the desired product compound A-1-b (310 g, 66%) as a white solid. LCMS=[M+H] + :415.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.50 (td, J = 9.7, 5.0Hz, 1H), 3.80 (s, 1H), 3.40 - 3.28 (m, 1H), 3.28 - 3.20 (m, 1H), 3.15 - 2.99 (m, 2H), 2.33 - 2.20 (m, 1H), 2.12 (dt, J = 17.8, 9.4 Hz, 1H), 1.86 - 1.75 (m, 1H), 1.75 - 1.64 (m, 2H), 1.56 (ddd, J = 19.3, 9.6, 6.9 Hz, 2H), 1.45 - 1.35 (m, 1H), 0.91 (dd, J = 15.6, 6.3 Hz, 6H).

[0230] To a stirred solution of N-((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide (compound A-1-b) (8.3 g, 20 mmol) in DMSO (60 mL) was added 2-iodoxybenzoic acid (IBX) (11.2 g, 40 mmol) at room temperature. The reaction mixture was stirred at 30 °C for 18 h, and LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc (300 mL) and filtered. The filtrate was washed with a mixture of brine and saturated aqueous NaHCO3 (1:1 to 5:1, 200 mL × 5). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to a low volume at room temperature to give the crude product. THF (40 mL) was added, and the mixture was stirred at room temperature overnight. The resulting solid was collected and evaporated to dryness in vacuo to give the desired product N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)-propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) as a white solid (2.5 g, 31%). LCMS = [M+H] + :413.2. 1 H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.64 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.14-7.05 (m, 2H), 7.01 (s, 1H), 6.34 (s, 1H), 4.90 (s, 1H), 4.34 (s, 1H), 3.27-3.22 (m, 2H), 2.43 (s, 1H), 2.30 (s, 1H), 2.01-1.96 (m, 1H), 1.94-1.91 (m, 1H) 1.88 - 1.65 (m, 4H), 1.00-0.98 (m, 6H).

[0231] To a stirred solution of N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) (31 g, 75.25 mmol) in 300 mL of EtOAc was added a solution of NaHSO (27.56 mg, 72.73 mmol) in 100 mL of water at room temperature. The reaction mixture was heated at 50° C. for 3 hours. After the reaction was complete (monitored by LCMS), the organic layer was separated and removed. The aqueous layer was washed with EtOAc (100 mL x 5), concentrated to a small volume to remove residual EtOAc, and then lyophilized to give the desired product sodium (2S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (compound A-1-d) as an off-white solid (32 g, 85%). LCMS = [M-Na+2H] + :495.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.45 (dd, J = 20.7, 8.2 Hz, 1H), 7.72 (dd, J = 48.9, 9.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.25 (dd, J = 5.1, 1.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 5.43 (dd, J = 50.7, 5.9 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.33 - 4.03 (m, 1H), 4.01 - 3.82 (m, 1H), 3.19 - 2.92 (m, 2H), 2.29 - 2.08 (m, 2H), 2.06 - 1.90 (m, 1H), 1.83 - 1.51 (m, 5H), 1.00 - 0.83 (m, 6H). (Example S2) Synthesis of compounds A-1-e and A-1-f [ka]

[0232] To a stirred solution of methyl (2S)-2-[(2S)-2-[(1H-indol-2-yl)formamido]-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound A-1-a) (150 mg, 0.34 mmol) in THF (3.5 mL) and HO (3.5 mL) was added LiOH (0.01 mL, 0.68 mmol). The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed (monitored by TLC), the pH of the reaction mixture was adjusted to approximately 3–4 with citric acid. The resulting mixture was extracted with DCM (20 mL × 2) and washed with brine (5 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The solvent was removed under reduced pressure to give compound A-1-e as an off-white solid, which was used in the next step without further purification. LCMS=[M+H] + :429.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.57 (s, 1H), 8.43-8.40 (m, 2H), 7.62 (d, J = 8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.60-4.54 (m, 1H), 4.31 - 4.25(m, 1H), 3.15 - 3.05 (m, 2H), 2.37-2.29 (m, 1H), 2.16 - 2.02 (m, 2H), 1.78 - 1.53 (m, 5H), 0.94-0.89 (m, 6H).

[0233] To a stirred solution of (2S)-2-[(2S)-2-[(1H-indol-2-yl)formamido]-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoic acid (Compound A-1-e) (110 mg, 0.26 mmol) in DMF (5 mL) was added NH4Cl (68 mg, 1.28 mmol), HATU (146 mg, 0.39 mmol), and DIEA (0.129 mL, 0.78 mmol) at room temperature. The reaction mixture was stirred at room temperature under N2 for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was extracted with EtOAc (50 mL x 3), the organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The resulting crude product was purified using preparative TLC (DCM:MeOH=10:1) to give compound 108 (40 mg, 0.09 mmol, 36.45%) as an off-white solid. LCMS=[M+H] + :428.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.47 (d, J = 8 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.63 - 7.60 (m, 2H), 8.43 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J = 1.2 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.05 - 7.02 (m, 2H), 4.54-4.49 (m, 1H), 4.31 - 4.25 (m, 1H), 3.14-3.03 (m, 2H), 2.33-2.26 (m, 1H), 2.18-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.74 - 1.48 (m, 5H), 1.01-0.83 (m, 6H).

[0234] To a stirred solution of N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide (compound 108) (30 mg, 0.070 mmol) in DMF (0.5 mL) was added 2,4,6-trichloro-1,3,5-triazine (20 mg, 0.105 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and, upon completion (monitored by LCMS), concentrated to a low volume. The crude material was purified by preparative HPLC to give compound A-1-f as an off-white solid (2 mg, 7%). LCMS = [M+H] + :410.2. 1 H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.14 (t, J = 6.9 Hz, 1H), 6.98 (d, J = 9.7 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.22 (d, J = 8.2 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.85 - 4.80 (m, 1H), 2.84 - 2.80 (m, 2H), 1.90 - 1.88 (m, 1H), 1.80 - 1.76 (m, 2H), 1.36 - 1.19 (m, 5H), 0.99 (d, J = 5.8 Hz, 6H). (Example S3) Synthesis of compound A-1-g [ka]

[0235] A solution of lithium diisopropylamide (LDA) in THF (14.124 mL, 28.25 mmol) was added dropwise to a solution of methyl (2S)-2-[(2S)-2-[(1H-indol-2-yl)formamido]-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (Compound A-1-a) (500 mg, 1.13 mmol) and chloroiodomethane (0.850 mL, 11.30 mmol) in THF (3 mL) at −78 °C with stirring under N. The mixture was gradually warmed to room temperature and continuously stirred under N for 2 h. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL x 2) and the solvent was removed under reduced pressure to give the crude product, which was further purified by preparative HPLC (ACN / water (0.1% FA)) to give compound A-1-g as an off-white solid (96 mg, 0.21 mmol, 18.43%). LCMS = [M+H] + :461.2. HPLC=95% 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.65 (d, J = 7.7 Hz, 1H), 8.51 (d, J = 7.7 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 1.4 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.03 (dd, J = 11.0, 4.0 Hz, 1H), 4.61 (t, J = 9.4 Hz, 2H), 4.54 - 4.40 (m, 2H), 3.18 - 3.04 (m, 2H), 2.27-2.28 (m, 1H), 2.31 - 2.28 (m, 1H), 2.15 - 2.05 (m, 1H), 1.77 - 1.68 (m, 2H), 1.67 - 1.53 (m, 3H), 0.95 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 6.3Hz, 3H). (Example S4) Synthesis of compound A-1-h [ka]

[0236] To a solution of (2S)-N-[(2S)-4-chloro-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[(1H-indol-2-yl)formamido]-4-methylpentanamide (Compound A-1-g) (454 mg, 0.98 mmol) and 2-oxo-2-phenyl-acetic acid (0.139 mL, 1.28 mmol) in DMF (9 mL) was added CsF (342.06 mg, 2.27 mmol). The reaction mixture was stirred at 65 °C under N for 2 h. LCMC indicated the reaction was complete. The reaction mixture was diluted with EtOAc (60 mL) and washed with brine (30 mL × 2). The organic layer was dried over anhydrous NaSO and concentrated to a low volume. The resulting residue was purified by reverse-phase column chromatography (ACN / water (0.1% FA) 60 / 40 to 70 / 30) to give compound 109 (150 mg, 0.26 mmol, 26.5%) as a brown solid. LCMS = [M+H] + :575.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.70 (d, J = 7.9 Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 8.21 - 8.03 (m, 2H), 7.82 (t, J = 7.4 Hz, 1H), 7.74 - 7.54 (m, 3H), 7.43 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 5.28 (q, J = 17.1 Hz, 2H), 4.73 - 4.32 (m, 2H), 3.21 - 3.00 (m, 2H), 2.42 - 2.26 (m, 1H), 2.22 - 1.98 (m, 2H), 1.87 - 1.45 (m, 5H), 1.06 - 0.81 (m, 6H).

[0237] To a solution of (3S)-3-[(2S)-2-[(1H-indol-2-yl)formamido]-4-methylpentanamido]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl 2-oxo-2-phenylacetate (compound 109) (210 mg, 0.37 mmol) in MeOH (8 mL) was added NaHCO (6.14 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated to a reduced volume. The resulting residue was purified by preparative HPLC to give compound A-1-h (38.79 mg, 0.09 mmol, 23.99%) as a white solid. LCMS=[M+H] + :443.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.74 - 8.21 (m, 2H), 7.70 - 7.47 (m, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.26 (s, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 5.02 (d, J = 5.9 Hz, 1H), 4.67 - 4.36 (m, 2H), 4.32 - 4.20 (m, 1H), 4.19 - 4.09 (m, 1H), 3.22 - 2.91 (m, 2H), 2.37 - 2.21 (m, 1H), 2.17 - 2.01 (m, 1H), 2.00 - 1.85 (m, 1H), 1.79 - 1.46 (m, 5H), 0.96 - 0.89 (m, 6H). (Example S5) Synthesis of Compound A-1-i [ka]

[0238] A mixture of N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) (1 g, 2.42 mmol) and 4-methylbenzenesulfonic acid hydrate (46 mg, 0.24 mmol) in MeOH (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to a reduced volume, and the resulting residue was purified by preparative HPLC to give compound A-1-i (300 mg, 0.65 mmol, 27.03%) as a white solid. LCMS = [M+Na] + :482.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 9.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.18 - 7.15 ( m, 1H), 7.08 - 6.97 (m, 1H), 4.54 - 4.43 (m, 1H), 4.19 (d, J = 5.8 Hz, 1H), 4.01 - 3.86 (m, 1H), 3.29 (s, 3H), 3.24 (s, 3H), 3.12 - 2.98 (m, 2H), 2.29 - 2.19 (m, 1H), 2.15 - 2.05 (m, 1H), 1.89 - 1.81 (m, 1H), 1.78 - 1.62 (m, 2H), 1.60 - 1.45 (m, 2H), 1.40 - 1.27 (m, 1H), 0.99 - 0.84 (m, 6H). (Example S6) Synthesis of Compound A-1-j [ka]

[0239] The synthesis of compound A-1-j was similar to that of compound A-1-d. The aqueous layer was washed with ethyl acetate (5 mL x 5). After removing the remaining organic solvent, the residue was lyophilized to give compound A-1-j (50 mg, 49.91%). LCMS = [M-Na + 2H] + :495.2, HPLC:81.36%. 1 H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 8.64 - 8.30 (m, 1H), 7.97 - 7.56 (m, 2H), 7.49 - 7.38 (m, 2H), 7.28 - 7.21 (m, 1H), 7.21 - 7.13 (m, 1H), 7.06 - 6.96 (m, 1H), 5.76 - 5.25 (m, 1H), 4.62 - 4.38 (m, 1H), 4.31 - 3.86 (m, 2H), 3.18 - 3.09 (m, 1H), 3.07 - 2.95 (m, 1H), 2.22 - 1.91 (m, 3H), 1.77 - 1.49 (m, 5H), 0.97 - 0.80 (m, 6H). (Example S7) Synthesis of compounds B-2-a, A-2-a, A-2-b and A-2-c [ka]

[0240] To a solution of compound 110 (5 g, 16.40 mmol) in anhydrous DMF (40 mL) was added HATU (5.7 g, 15.03 mmol) and DIEA (8.3 mL, 50.15 mmol) sequentially at 0 °C. The mixture was stirred at 0 °C for 15 minutes, and then compound 104 (3.65 g, 16.40 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 0 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with EtOAc, washed with water, 1 M HCl, saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:5) to give compound B-2-a as a white solid (5.3 g, 68.4%). LCMS = [M+H] +:474.5.

[0241] A solution of compound B-2-a (3.0 g) in MeOH (30 mL) containing Pd / C (300 mg) was stirred at room temperature under a hydrogen atmosphere for 3 hours. LCMS showed the reaction was complete. After filtering the catalyst, the solvent was removed under reduced pressure to give compound 111 (2.0 g) as an off-white solid. LCMS = [M+H] + :340.3

[0242] To a solution of compound 101 (0.95 g, 5.90 mmol) in anhydrous DMF (20 mL) was added HATU (3.36 g, 8.84 mmol) and DIEA (3 mL, 17.68 mmol) sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes. Compound 111 (2.0 g, 5.90 mmol, 1.0 equiv) was added to the solution, and the reaction mixture was stirred at 0 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc, washed with water, 1 M HCl, saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:5) to give compound A-2-a as a white solid (2.7 g, 94.7%). LCMS = [M+H] + :483.5

[0243] To a stirred solution of compound A-2-a (2.7 g, 5.60 mmol) in THF (40 mL) was added LiBH (2.0 M in THF, 8.4 mL, 16.80 mmol) portionwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h, then warmed and stirred at room temperature for an additional 2 h. The reaction was quenched by the dropwise addition of 1.0 M HCl while cooling in an ice bath. The resulting mixture was diluted with EtOAc and H O. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (5% MeOH in CH Cl as eluent) to give compound A-2-b (2.0 g, 78.7%) as a white solid. LCMS = [M+H] + :455.4.

[0244] To a solution of A-2-b (2.0 g, 4.40 mmol) in DCM (20 mL) was added Dess-Martin periodinane (3.73 g, 8.80 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then warmed to room temperature and stirred for an additional 2 hours. LCMS showed the reaction was complete. The reaction was quenched with saturated NaHCO solution containing 10% NaSO at 0 °C. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography to give compound A-2-c as a white solid (25 mg, 1.2%). LCMS = [M+H] + :453.6. (Example S8) Synthesis of Compounds A-3-a and A-3-b [ka]

[0245] To a flask containing methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound 106) (10 g, 25.03 mmol), ammonia (300 mL) was added. The reaction mixture was placed in an autoclave reactor and stirred at 50° C. overnight. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give crude compound 112 as a white solid (10.5 g, 27.31 mmol, 109.11%), which was used in the next step without further purification. LCMS = [M+H] + :385.0. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 7.03 (s, 1H), 6.98 (d, J = 7.7 Hz, 1H), 4.33 - 4.22 (m, 1H), 3.96 - 3.86 (m, 1H), 3.22 - 2.99 (m, 2H), 2.32 - 2.09 (m, 2H), 2.05 - 1.95 (m, 1H), 1.72 - 1.56 (m, 2H), 1.54 - 1.46 (m, 1H), 1.45 - 1.32 (m, 11H), 0.91 - 0.76 (m, 6H).

[0246] To a solution of tert-butyl ((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound 112) (5 g, 13.00 mmol) in 20 mL of EtOAc was added 50 mL of 4 M HCl in EtOAc. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to a low volume to give compound 113 (3.96 g, 12.34 mmol, 94.96%) as a white solid, which was used in the next step without further purification. LCMS = [M+H] + :285.0.

[0247] To a stirred solution of 4-fluoro-1H-indole-2-carboxylic acid (compound 114) (180 mg, 1.00 mmol) in DMF (4 mL) was added (2S)-2-amino-N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-methylpentanamide hydrochloride (compound 113) (385 mg, 1.21 mmol), HATU (573 mg, 1.51 mmol), and DIEA (0.6 mL, 4.02 mmol). The reaction mixture was stirred at room temperature under N for 1 hour. LCMC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to a low volume, and the resulting residue was purified by reverse-phase column chromatography (0.5% FA / ACN) to give compound 115 (90 mg, 0.20 mmol, 20.11%) as an off-white solid. LCMS = [M+H] + :446.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.16 (s, 1H), 7.04 (s, 1H), 6.81 (s, 1H), 4.57 - 4.44 (m, 1H), 4.33 - 4.22 (m, 1H), 3.17 - 3.02 (m, 2H), 2.37 - 2.19 (m, 1H), 2.20 - 2.08 (m, 1H), 2.07 - 1.96 (m, 1H), 1.78 - 1.45 (m, 5H), 0.93 (d, J = 6.1 Hz, 3H), 0.89 (d, J = 6.2 Hz, 3H).

[0248] To a stirred solution of (2S)-N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-[(4-fluoro-1H-indol-2-yl)formamido]-4-methylpentanamide (Compound 115) (2.45 g, 5.5 mmol) in DCM (30 mL) was added Burgess reagent (2.62 g, 11 mmol). The solution was stirred at room temperature under N for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was diluted with DCM and washed with water. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to a low volume. The resulting residue was then purified by preparative HPLC to give compound A-3-a (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-[(4-fluoro-1H-indol-2-yl)-formamido]-4-methylpentanamide (1.08 g, 45%) as an off-white solid, and the second isomer (A-3-b) (51.6 mg, 2.2%). LCMS = [M+H] + :428.2. A-3-a 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.63 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.39 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.16 (dt, J = 13.4, 6.7 Hz, 1H), 6.82 (dd, J = 10.6, 7.7 Hz, 1H), 5.03 - 4.93 (m, 1H), 4.53 - 4.43 (m, 1H), 3.19 - 3.06 (m, 2H), 2.42 - 2.30 (m, 1H), 2.20 - 2.07 (m, 2H), 1.86 - 1.77 (m, 1H), 1.77 - 1.66 (m, 3H), 1.60 - 1.49 (m, 1H), 0.95 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.3 Hz, 3H).

[0249] Second isomer (A-3-b): LCMS = [M+H]+ :428.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.43 (s, 1H), 8.10 (t, J = 5.6 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.19 - 7.10 (m, 1H), 6.81 (dd, J = 10.6, 7.8 Hz, 1H), 4.64 - 4.54 (m, 1H), 4.53 - 4.43 (m, 1H), 3.28 - 3.04 (m, 2H), 2.78 - 2.60 (m, 1H), 2.36 - 2.19 (m, 1H), 2.02 - 1.79 (m, 2H), 1.76 - 1.59 (m, 2H), 1.59 - 1.38 (m, 2H), 0.90 (dd, J = 15.8, 6.3 Hz, 6H).

[0250] (Example S9) Synthesis of compound A-3-c [ka]

[0251] To a solution of 4-fluoro-1H-indole-2-carboxylic acid (compound 113) (2 g, 11.16 mmol) in DMF (20 mL) was added methyl 2-[(2S)-2-amino-4-methylpentanamido]-3-(2-oxopyrrolidin-3-yl)propanoate (compound 107) (3.34 g, 11.16 mmol), HATU (6.37 g, 16.75 mmol), and DIEA (7.380 mL, 44.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound 116 (3.62 g, 7.86 mmol, 70.41%) as a yellow solid. LCMS=[M+H]+ :461.0.

[0252] To a solution of methyl 2-[(2S)-2-[(4-fluoro-1H-indol-2-yl)formamido]-4-methylpentanamido]-3-(2-oxopyrrolidin-3-yl)propanoate (compound 116) (1.44 g, 3.13 mmol) (16) in THF (10 mL) was added LiBH (0.27 g, 12.51 mmol). The reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction was quenched with water and extracted with EtOAc. The organic phase was concentrated, and the residue was purified by column chromatography (DCM / MeOH = 20:1 to 15:1) to give compound 117 (1.1 g, 2.54 mmol, 81.48%) as a white solid. LCMS = [M+H] + :433.1.

[0253] To a solution of (2S)-2-[(4-fluoro-1H-indol-2-yl)formamide]-N-[1-hydroxy-3-(2-oxopyrrolidin-3-yl)propan-2-yl]-4-methylpentanamide (compound 117) (500 mg, 1.16 mmol) in DMSO (1.5 mL) was added EtOAc (3 mL) and IBX (647.45 mg, 2.31 mmol). The reaction mixture was stirred at 25 °C overnight. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc and then filtered. The filtrate was quenched with saturated aqueous NaSO and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was separated and concentrated under reduced pressure to a reduced volume and then purified by preparative HPLC to give compound A-3-c (14 mg, 0.03 mmol, 2.80%) as a white solid. LCMS = [M+H] + :431.2, HPLC:97.65%. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 9.52 (s, 1H), 8.69 (d, 1H), 7.22 - 7.15 (m, 2H), 7.13 - 7.02 (m, 2H), 6.82 - 6.73 (m, 1H), 6.18 (s, 1H), 4.97 - 4.80 (m, 1H), 4.45 - 4.27 (m, 1H), 3.39 - 3.15 (m, 2H), 2.55 - 2.41 (m, 1H), 2.40 - 2.30 (m, 1H), 2.05 - 1.91 (m, 2H), 1.89 - 1.71 (m, 4H), 0.99 (d, J = 3.8 Hz, 6H). (Example S10) Synthesis of compound A-3-d [ka]

[0254] To a stirred solution of methyl (2S)-2-[(2S)-2-[(4-fluoro-1H-indol-2-yl)formamido]-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (Compound 116) (300 mg, 0.65 mmol) and chloroiodomethane (0.48 mL, 6.51 mmol) in THF (10 mL) was added LDA (4 mL, 30.25 mmol, 2 M in THF) at −78° C. The reaction mixture was stirred at −78° C. under N for 3 hours. LCMS showed the reaction was complete. The reaction mixture was quenched with NH4Cl (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were concentrated under reduced pressure to a low volume. The resulting crude product was purified by preparative HPLC to give compound A-3-d (33.79 mg, 0.07 mmol, 10.83%) as an off-white solid. LCMS = [M+H] + :479.2. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.69 - 8.57 (m, 2H), 7.65 (s, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J = 5.4 Hz, 1H), 6.81 (s, 1H), 4.59 (d, J = 1.3 Hz, 2H), 4.54 - 4.40 (m, 2H), 3.18 - 3.03 (m, 2H), 2.35 - 2.22 (m, 1H), 2.14 - 1.92 (m, 2H), 1.78 - 1.52 (m, 5H), 0.95 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 6.3 Hz, 3H). (Example S11) Synthesis of compound A-3-e [ka]

[0255] To a stirred solution of (2S)-N-[(2S)-4-chloro-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[(4-fluoro-1H-indol-2-yl)formamide]-4-methylpentanamide (Compound A-3-d) (120 mg, 0.25 mmol) in DMF (5 mL) was added 2-oxo-2-phenylacetic acid (0.035 mL, 0.33 mmol) and CsF (87.02 mg, 0.58 mmol). The reaction mixture was stirred at 65 °C under N for 4 hours. LCMS showed the reaction was complete. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to afford Compound 118 (67 mg, 0.11 mmol, 45.12%) as a yellow solid. LCMS=[M+H] + :593.0. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.64 (d, J = 7.4 Hz, 1H), 8.12 - 8.07 (m, 2H), 7.83 (t, J = 7.4 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.41 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.20 - 7.12 (m, 1H), 6.82 (dd, J = 10.5, 7.7 Hz, 1H), 5.28 (s, 2H), 4.58 - 4.48 (m, 2H), 3.18 - 3.07 (m, 2H), 2.38 - 2.30 (m, 1H), 2.15 - 2.03 (m, 2H), 1.80 - 1.60 (m, 5H), 0.97 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.3 Hz, 3H).

[0256] To a stirred solution of (3S)-3-[(2S)-2-[(4-fluoro-1H-indol-2-yl)formamido]-4-methylpentanamido]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl 2-oxo-2-phenylacetate (Compound 118) (100 mg, 0.17 mmol) in MeOH (4 mL) was added NaHCO (2 mg, 0.02 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (ACN / water (0.1% FA)) to give compound A-3-e(2S)-2-[(4-fluoro-1H-indol-2-yl)formamide]-N-[(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-4-methylpentanamide (42.43 mg, 0.09 mmol, 54.60%) as an off-white solid. LCMS=[M+H] + :461.2. 1H NMR (400 MHz, DMSO) δ 11.93 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.19 - 7.11 (m, 1H), 6.85 - 6.77 (m, 1H), 5.06 (s, 1H), 4.57 - 4.40 (m, 2H), 4.30 - 4.09 (m, 2H), 3.16 - 3.05 (m, 2H), 2.34 - 2.29 (m, 1H), 2.13 - 2.05 (m, 1H), 1.99 - 1.88 (m, 1H), 1.78 - 1.58 (m, 5H), 0.95 (d, J = 5.9 Hz, 3H), 0.90 (d, J = 6.3 Hz, 3H). (Example S12) Synthesis of Compound A-4-a [ka] To a stirred mixture of methyl (S)-2-((S)-2-amino-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (compound 107) (3.35 g, 10 mmol) and DIEA (3.87 g, 30 mmol) in DMF (20 mL) was added 4-methyl-1H-indole-2-carboxylic acid (compound 119) (1.75 g, 10 mmol) and HATU (4.57 g, 12 mmol) at room temperature. The reaction mixture was stirred for 3 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc and washed with brine. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (PE / EA=1:1) to give compound 120 as an off-white solid (3 g; 65.6%). LCMS=[M+H] + :457.0.

[0257] To a stirred solution of methyl (S)-2-((S)-4-methyl-2-(4-methyl-1H-indole-2-carboxamido)-pentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate, Compound 120 (1.0 g, 2.18 mmol) in THF (30 mL) was added LiBH (145 mg, 6.6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with saturated aqueous NH Cl until gas generation ceased. The solid was filtered. The filtrate was extracted with EtOAc (100 mL × 3) and washed with water. The organic layer was dried over anhydrous Na SO , and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography (DCM:MeOH=15:1) to give compound 121 (600 mg, 64%) as a white solid. LCMS=[M+H] + :429.5. 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.57 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 4.73 (t, J = 5.5 Hz, 1H), 4.61 - 4.47 (m, 1H), 3.87 (s, 1H), 3.37 - 3.26 (m, 2H), 3.22 - 3.04 (m, 2H), 2.56 (s, 3H), 2.38 - 2.12 (m, 2H), 1.88 - 1.81 (m, 1H), 1.78 - 1.70 (m, 2H), 1.64 - 1.53 (m, 2H), 1.49 - 1.37 (m, 1H), 0.97 (dd, J = 16.0, 6.2 Hz, 6H).

[0258] To a stirred mixture of N-((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methyl-1H-indole-2-carboxamide (compound 121) (150 mg, 0.35 mmol) in DMSO (5 mL) was added IBX (196.03 mg, 0.70 mmol). The reaction mixture was stirred at 30° C. overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to a low volume, and the resulting residue was purified by preparative HPLC (ACN / water (0.1% FA)) to give compound A-4-a. LCMS=[M+H] + :427.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.43 (s, 1H), 8.63 - 8.32 (m, 1H), 7.66 - 7.53 (m, 1H), 7.48 (s, 1H), 7.33 (d, J = 10.7 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 5.78 - 5.63 (m, 1H), 4.74 - 4.66 (m, 0.5H), 4.61 - 4.48 (m, 1H), 3.79 - 3.64 (m, 0.5H), 3.18 - 2.98 (m, 2H), 2.50 (s, 3H), 2.36 - 2.08 (m, 2H), 1.96 - 1.34 (m, 6H), 1.03 - 0.85 (m, 6H). (Example S13) Synthesis of compound A-4-b [ka] [ka]

[0259] To a flask containing tert-butyl N-[(1S)-1-{[(1S)-1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]-carbamoyl}-3-methylbutyl]carbamate (compound 112) (500 mg, 1.30 mmol), DCM (5 mL) was added, followed by TFA (1.5 mL, 20.19 mmol). The reaction mixture was stirred at room temperature overnight. DCM was removed under reduced pressure to give crude compound 122 (510 mg, 99%) as a yellow oil, which was used in the next step without further purification. LCMS = [M+H] + :285.2.

[0260] To a solution of 4-methyl-1H-indole-2-carboxylic acid (compound 119) (175 mg, 1.00 mmol) in DMF (5 mL) was added HATU (570 mg, 1.50 mmol), DIEA (0.660 mL, 3.99 mmol), and (2S)-2-amino-N-[(1S)-1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]-4-methylpentanamide TFA salt (compound 122) (crude, 510 mg, 1.30 mmol). The reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound 123 (356 mg, 0.81 mmol, 67.43%) as a white solid. LCMS=[M+H] + :442.1.

[0261] To a solution of (2S)-N-[(1S)-1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]-4-methyl-2-[(4-methyl-1H-indol-2-yl)formamido]pentanamide (compound 123) (356 mg, 0.81 mmol) in DCM (6 mL) was added Burgess reagent (0.373 mL, 2.04 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to a low volume. The residue was purified by preparative HPLC to give compound A-4-b (30 mg, 0.07 mmol, 8.79%) as a white solid. LCMS = [M+H] + :424.2; HPLC:99.71%. 1 H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.74 (s, 1H), 7.25 - 7.24 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.96 - 6.83 (m, 3H), 6.25 (s, 1H), 4.91 - 4.74 (m, 2H), 3.37 - 3.17 (m, 2H), 2.48 (s, 3H), 2.41 - 2.29 (m, 2H), 2.03 - 1.90 (m, 1H), 1.86 - 1.76 (m, 5H), 1.09 - 0.92 (m, 6H). (Example S14) Synthesis of compound A-4-c [ka]

[0262] To a stirred mixture of methyl (2R)-2-[(2S)-4-methyl-2-[(4-methyl-1H-indol-2-yl)formamido]pentanamido]-3-[(3R)-2-oxopyrrolidin-3-yl]propanoate (compound 120) (300 mg, 0.66 mmol) and chloroiodomethane (1.16 g, 6.6 mmol) in THF (5 mL) was added LDA (21 mL, 7 mmol, 2 M in THF) at −78° C. The reaction mixture was stirred at −78° C. for 2 hours, then quenched with saturated NH4Cl and extracted with EtOAc (15 mL × 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give compound A-4-c (28.1 mg, 0.06 mmol, 9.00%). LCMS=[M+H] + :475.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.63 (d, J = 7.7 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 4.59 (s, 2H), 4.51 - 4.40 (m, 2H), 3.21 - 3.03 (m, 2H), 2,54 (s, 3H), 2.35 - 2.20 (m, 1H), 2.10 (m, 1H), 2.01 - 1.93 (m, 1H), 1.78 - 1.52 (m, 5H), 0.96 - 0.88 (m, 6H). (Example S15) Synthesis of compound A-4-d [ka]

[0263] To a stirred solution of (2S)-N-[(2S)-4-chloro-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-4-methyl-2-[(4-methyl-1H-indol-2-yl)formamido]pentanamide (Compound A-4-c) (200 mg, 0.42 mmol) in DMF (3 mL) was added 2-oxo-2-phenylacetic acid (0.060 mL, 0.55 mmol) and CsF (146.23 mg, 0.97 mmol). The reaction mixture was stirred at 65 °C under N for 4 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to a low volume, and the resulting residue was purified by preparative HPLC to give Compound 124 (85 mg, 0.14 mmol, 34.29%) as a brown solid. LCMS=[M+H] + :589.2. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 8.93 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 7.3 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.27 - 7.25 (m, 1H), 7.21 - 7.16 (m, 1H), 6.99 (s, 1H), 6.91 (d, J = 7.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 16.9 Hz, 1H), 5.00 (d, J = 16.9 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.54 - 4.47 (m, 1H), 3.36 - 3.23 (m, 2H), 2.51 (s, 3H), 2.48 - 2.40 (m, 1H), 2.39 - 2.31 (m, 1H), 2.13 - 2.03 (m, 1H), 2.01 - 1.93 (m, 1H), 1.89 - 1.66 (m, 4H), 1.03 (d, J = 4.9 Hz, 6H).

[0264] To a stirred solution of (3S)-3-[(2S)-4-methyl-2-[(4-methyl-1H-indol-2-yl)formamido]-pentanamido]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl 2-oxo-2-phenylacetate (compound 124) (80 mg, 0.14 mmol) in MeOH (3 mL) was added NaHCO (1.14 mg, 0.01 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (ACN / water (0.084% NHHCO)) to give compound A-4-d (22.97 mg, 0.05 mmol, 37.02%) as an off-white solid. LCMS = [M+H] + :457.3. 1 H NMR (400 MHz, CDCl3) δ 9.73 - 9.48 (m, 1H), 8.79 - 8.55 (m, 1H), 7.29 - 7.26 (m, 1H), 7.20 - 7.16 (m, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 6.9 Hz, 1H), 6.25 (br s, 1H), 4.81 - 4.73 (m, 1H), 4.59 - 4.42 (m, 2H), 4.41 - 4.31 (m, 1H), 3.38 - 3.17 (m, 2H), 2.52 (s, 3H), 2.37 - 2.27 (m, 1H), 2.17 - 1.99 (m, 6H), 1.93 - 1.91 (m, 1H), 1.01 (d, J = 4.7 Hz, 6H). (Example S16) Synthesis of compound A-4-e [ka]

[0265] To a stirred solution of 4-methyl-N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-4-a) (2.0 g, 4.69 mmol) in ethyl acetate (13 mL) and EtOH (8 mL) was added a solution of NaHSO (0.46 mg, 4.42 mmol) in water (4.6 mL) at room temperature. The reaction mixture was stirred at 50 °C for 3 hours. After the reaction was completed (monitored by LCMS), the organic layer was removed. The aqueous layer was washed with ethyl acetate (100 mL × 5) and concentrated to a reduced volume to remove the remaining solvent. The residue was lyophilized to give compound A-4-e as an off-white solid (2.0 g, 80.4%). LCMS = [M-Na+2H] + :509.4. 1 H NMR (500 MHz, DMSO) δ 11.57 (d, J = 5.3 Hz, 1H), 8.46 (dd, J = 24.4, 8.0 Hz, 1H), 7.71 (dd, J = 58.5, 9.0 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J = 9.6 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 6.7 Hz, 1H), 5.42 (d, J = 40.7 Hz, 1H), 4.48 (d, J = 32.9 Hz, 1H), 4.26 (t, J = 9.8 Hz, 0.5H), 4.03 (dd, J = 12.3, 5.5 Hz, 0.5H), 3.95 (s, 0.5H), 3.84 (s, 0.5H), 3.35 (s, 3H), 3.14 - 2.99 (m, 2H), 2.22 - 2.09 (m, 2H), 1.95 (dd, J = 25.4, 11.7 Hz, 2H), 1.82 - 1.52 (m, 6H), 0.90 (d, J = 18.6 Hz, 6H). (Example S17) Synthesis of Compound A-5-a [ka]

[0266] To a stirred solution of methyl (2S)-2-[(2S)-2-amino-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound 107) (500 mg, 1.67 mmol) in DMF (10 mL) was added 4-methoxy-1H-indole-2-carboxylic acid (compound 125) (320 mg, 1.67 mmol), HATU (952 mg, 2.51 mmol), and DIEA (1.104 mL, 6.68 mmol). The reaction mixture was stirred at room temperature under N for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound 126 (560 mg, 1.19 mmol, 70.96%) as an off-white solid. LCMS=[M+H] + :473.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.44 (dd, J = 64.4, 7.9 Hz, 2H), 7.64 (s, 1H), 7.35 (s, 1H), 7.13 - 6.97 (m, 2H), 6.51 (d, J = 7.6 Hz, 1H), 4.59 - 4.30 (m, 2H), 3.88 (s, 3H), 3.62 (s, 3H), 3.20 - 3.02 (m, 2H), 2.41 - 2.27 (m, 1H), 2.18 - 2.02 (m, 2H), 1.77 - 1.49 (m, 5H), 0.96 - 0.86 (m, 6H).

[0267] To a stirred solution of methyl (2S)-2-[(2S)-2-[(4-methoxy-1H-indol-2-yl)-formamido]-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound 126) (290 mg, 0.61 mmol) in THF (5 mL) was added LiBH (53 mg, 2.45 mmol) under N at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was quenched with water, and the solid was filtered off. The filtrate was extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume to give crude compound 127 (230 mg, 0.52 mmol, 84.31%) as an off-white solid, which was used in the next step without further purification. LCMS=[M+H] + :445.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 7.09 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 7.5 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 4.47 (dd, J = 8.7, 3.9 Hz, 1H), 3.89 (s, 3H), 3.83 - 3.77 (m, 1H), 3.39 - 3.34 (m, 1H), 3.28 - 3.20 (m, 1H), 3.16 - 2.99 (m, 2H), 2.33 - 2.07 (m, 2H), 1.87 - 1.75 (m, 1H), 1.74 - 1.62 (m, 2H), 1.62 - 1.47 (m, 2H), 1.46 - 1.32 (m, 1H), 0.96 - 0.84 (m, 6H).

[0268] To a stirred solution of (2S)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-[(4-methoxy-1H-indol-2-yl)formamide]-4-methylpentanamide (compound 127) (400 mg, 1.80 mmol) in DMSO (2 mL) and EtOAc (6 mL) was added IBX (503 mg, 1.80 mmol). The reaction mixture was stirred at 30 °C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was diluted with EtOAc and washed with a mixture of NaCl and NaSO (10:1), aqueous NaHCO, and brine. The organic layer was separated and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (ACN / water (0.084% NH4HCO3)) to give compound A-5-a (20.81 mg, 0.05 mmol, 2.61%) as an off-white solid. LCMS = [M+H] + :443.2. 1 H NMR (400 MHz, CDCl3) δ 9.55 - 9.39 (m, 2H), 8.57 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.50 (d, J = 7.8 Hz, 1H), 6.12 - 5.94 (m, 1H), 4.89 - 4.81 (m, 1H), 4.38 - 4.30 (m, 1H), 3.94 (s, 3H), 3.39 - 3.19 (m, 2H), 2.57 - 2.42 (m, 1H), 2.40 - 2.25 (m, 1H), 1.99 - 1.91 (m, 2H), 1.85 - 1.77 (m, 4H), 1.00 (d, J = 6.0 Hz, 6H). (Example S18) Synthesis of compound A-5-b [ka]

[0269] To a stirred solution of 4-methoxy-1H-indole-2-carboxylic acid (Compound 125) (191 mg, 1.00 mmol) in DMF (5 mL) was added (2S)-2-amino-N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-methylpentan-amide (Compound 113) (341 mg, 1.20 mmol), HATU (570 mg, 1.50 mmol), and DIEA (0.660 mL, 4.00 mmol). The reaction mixture was stirred at room temperature under N for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was diluted with EtOAc, and the organic layer was separated, washed with brine, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (ACN / water (0.5% FA)) to give compound 128 (200 mg, 0.44 mmol, 43.76%) as a yellow solid. LCMS = [M+H] + :458.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J = 1.7 Hz, 1H), 7.29 (s, 1H), 7.09 - 7.04 (m, J = 19.6, 8.2 Hz, 3H), 6.51 (d, J = 7.7 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.31 - 4.24 (m, 1H), 3.88 (s, 3H), 3.16 - 2.99 (m, 2H), 2.35 - 2.19 (m, 1H), 2.19 - 2.06 (m, 1H), 2.05 - 1.95 (m, 1H), 1.74 - 1.61 (m, 3H), 1.60 - 1.46 (m, 2H), 0.93 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H).

[0270] To a stirred solution of (2S)-N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-[(4-methoxy-1H-indol-2-yl)formamido]-4-methylpentanamide (compound 128) (100 mg, 0.22 mmol) in DCM (6 mL) was added Burgess reagent (260 mg, 0.55 mmol). The reaction mixture was stirred at room temperature under N for 3 hours. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound A-5-b (26.35 mg, 0.06 mmol, 27.43%) as an off-white solid. LCMS = [M+H] + :440.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.90 (d, J = 8.1 Hz, 1H), 8.47 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.48 - 4.41 (m, 1H), 3.89 (s, 3H), 3.18 - 3.07 (m, 2H), 2.40 - 2.30 (m, 1H), 2.19 - 2.07 (m, 2H), 1.84 - 1.77 (m, 1H), 1.77 - 1.65 (m, 3H), 1.57 - 1.48 (m, 1H), 0.96 - 0.87 (m, 6H). (Example S19) Synthesis of compound A-5-c [ka]

[0271] To a stirred solution of methyl (2S)-2-[(2S)-2-[(4-methoxy-1H-indol-2-yl)formamido]-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (Compound 126) (300 mg, 0.63 mmol) in THF (10 mL) at −78° C. under N was added chloroiodomethane (0.5 mL, 6.35 mmol) and LDA (2 M in THF, 2.1 mL, 15.87 mmol). The reaction mixture was stirred at −78° C. for 2 hours until LCMS showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give compound A-5-c (44 mg, 0.09 mmol, 14.12%) as an off-white solid. LCMS = [M+H] + :491.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.60 (d, J = 7.7 Hz, 1H), 8.43 (d, J = 7.5 Hz, 1H), 7.63 (s, 1H), 7.36 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 4.58 (d, J = 2.3 Hz, 2H), 4.49 - 4.42 (m, 2H), 3.88 (s, 3H), 3.18 - 3.04 (m, 2H), 2.34 - 2.22 (m, 1H), 2.17 - 2.04 (m, 1H), 2.03 - 1.92 (m, 1H), 1.77 - 1.65 (m, 3H), 1.64 - 1.52 (m, 2H), 0.94 (d, J = 6.2 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H). (Example S20) Synthesis of compound A-5-d [ka]

[0272] To a stirred solution of (2S)-N-[(2S)-4-chloro-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[(4-methoxy-1H-indol-2-yl)formamide]-4-methylpentanamide (Compound A-5-c) (200 mg, 0.41 mmol) in DMF (3 mL) was added 2-oxo-2-phenylacetic acid (0.1 mL, 0.53 mmol) and CsF (142 mg, 0.94 mmol). The reaction mixture was heated at 65 °C under N for 4 hours. LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Compound 129 (45 mg, 0.07 mmol, 18.27%) as a yellow solid. LCMS = [M+H] + :605.1.

[0273] To a stirred solution of (3S)-3-[(2S)-2-[(4-methoxy-1H-indol-2-yl)formamido]-4-methylpentan-amido]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl 2-oxo-2-phenylacetate (compound 129) (50 mg, 0.08 mmol) in MeOH (1 mL) was added NaHCO (0.69 mg, 0.01 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. The mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (ACN / water (0.084% NHHCO)) to give compound A-5-d (12.79 mg, 0.03 mmol, 32.73%) as an off-white solid. LCMS = [M+H] + :473.3. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.43 (dd, J = 14.8, 8.1 Hz, 2H), 7.62 (s, 1H), 7.36 (s, 1H), 7.12 - 7.06 (m, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 7.5 Hz, 1H), 5.08 (br s, 1H), 4.53 - 4.40 (m, 2H), 4.31 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 3.88 (s, 3H), 3.17 - 3.03 (m, 2H), 2.35 - 2.24 (m, 1H), 2.20 - 2.04 (m, 1H), 1.98 - 1.88 (m, 1H), 1.76 - 1.47 (m, 5H), 0.97 - 0.86 (m, 6H). (Example S21) Synthesis of compounds B-1-a and B-1-b [ka]

[0274] To a solution of compound 130 (5 g, 19.2 mmol) in anhydrous DMF (50 mL) was added compound 104 (5.0 g, 19.2 mmol, 1.0 equiv), HATU (11.0 g, 28.8 mmol, 1.5 equiv), and DIEA (5.0 g, 38.4 mmol, 2.0 equiv) sequentially at 0°C. The reaction mixture was stirred at 0-5°C for 30 min. The mixture was diluted with EtOAc and washed with water, 1 M HCl, and saturated NaCl. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:5) to give compound B-1-a as a white solid (5.2 g, 44.8%). LCMS = [M+H] + :434.5.

[0275] To a stirred solution of compound B-1-a (2.2 g, 5.1 mmol) in THF (50 mL) was added LiBH (2.0 M in THF, 12.8 mL, 25.5 mmol) portionwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for an additional 2 h. The reaction was cooled in an ice bath and quenched by the dropwise addition of 1.0 M HCl. The solution was diluted with H O and extracted with EtOAc. The organic layers were combined, dried over Na SO , and concentrated under reduced pressure to give a yellow oily residue, which was further purified by column chromatography (5% MeOH in DCM as eluent) to give compound 131 (1.3 g, 61.9%) as a white solid. LCMS = [M+H] + :406.5.

[0276] To a solution of compound 131 (1.3 g, 3.2 mmol) in DCM (10 mL) was added Dess-Martin periodinane (4.1 g, 9.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction was quenched with saturated NaHCO3 solution containing 10% Na2S2O3 and extracted with DCM. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by flash column chromatography to give compound B-1-b as a white solid (700 mg, 53.8%). LCMS = [M+H] + :404.6. (Example S22) Synthesis of compound B-1-c [ka]

[0277] To a stirred solution of methyl (S)-2-((S)-2-(((benzyloxy)carbonyl)-amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound B-1-a) (300 mg, 0.69 mmol) and chloroiodomethane (732 mg, 4.15 mmol) in dry THF (5 mL) was added dropwise LDA (2 M in THF, 3.5 mL, 7 mmol) under a N atmosphere at −70° C. The reaction mixture was continuously stirred at −70° C. for 3 hours until LCMS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography (SNAP silica column 20 g, 5% MeOH in DCM) and further purified by preparative HPLC to give compound B-1-c as a white solid (8 mg, 3%). LCMS = [M+H] + :452.2. Purity=85%. 1 H NMR (400 MHz, CDCl3) δ 7.42 - 7.24 (m, 5H), 5.16 - 5.01 (m, 2H), 4.70 - 4.54 (m, 1H), 4.41 (s, 1H), 4.30 (s, 1H), 4.14 (t, J = 7.6 Hz, 1H), 3.62 - 3.46 (m, 1H), 3.28 - 3.15 (m, 2H), 2.54 - 2.42 (m, 1H), 2.32 (s, 1H), 2.30 - 2.13 (m, 1H), 2.11 - 1.93 (m, 1H), 1.89 - 1.63 (m, 3H), 1.56 (t, J = 7.3 Hz, 2H), 1.01 - 0.88 (m, 6H). (Example S23) Synthesis of compound B-1-d [ka]

[0278] To a stirred solution of benzyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (compound B-1-b) (200 mg, 0.50 mmol) in dry THF (5 mL) under a N atmosphere at 0° C. was added vinylmagnesium bromide (1 M in THF, 1.8 mL, 1.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 hours. After LCMS showed the reaction was complete, the reaction mixture was warmed to room temperature, diluted with saturated NH4Cl (aq), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (C18, 40 g 20-35 μm, 100 Å; mobile phase 60% ACN in water (0.1% FA in water)) to give compound 132 as a white solid (50 mg, 23% yield). LCMS = [M+H] + :432.1. 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 5H), 7.21 (d, J = 8.3 Hz, 1H), 5.96 (s, 1H), 5.88 - 5.72 (m, 1H), 5.47 - 5.39 (m, 1H), 5.31 (t, J = 14.4 Hz, 1H), 5.23 - 5.14 (m, 1H), 5.14 - 5.03 (m, 2H), 4.28 - 4.16 (m, 1H), 4.16 - 4.09 (m, 1H), 4.00 (dd, J = 11.6, 7.5 Hz, 1H), 3.56 (s, 1H), 3.36 - 3.20 (m, 2H), 2.46 - 2.29 (m, 2H), 2.13 - 2.00 (m, 1H), 1.98 - 1.86 (m, 1H), 1.83 - 1.80 (m, 1H), 1.67 - 1.59 (m, 2H), 1.52 - 1.44 (m, 1H), 0.93 (d, J = 6.2 Hz, 6H).

[0279] A mixture of benzyl ((2S)-1-(((2S)-3-hydroxy-1-((S)-2-oxopyrrolidin-3-yl)pent-4-en-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate Compound 132 (45 mg, 0.095 mmol) and Dess-Martin periodinane (243 mg, 0.573 mmol) in DCM (10 mL) was stirred at room temperature for 1 hour. After the completion of the reaction was indicated by LCMS, the reaction mixture was diluted with DCM and washed with saturated NaSO (aq), saturated NaHCO (aq), and brine. The organic layer was collected, dried over NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by preparative TLC plate (DCM:MeOH=30:1) to give Compound B-1-d as a white solid (12 mg, 27% yield). LCMS=[M+H] + :430.1. Purity=95% 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 6.7 Hz, 1H), 7.26 (s, 5H), 6.51 - 6.40 (m, 1H), 6.33 (d, J = 17.2 Hz, 1H), 6.25 (s, 1H), 5.77 (d, J = 10.1 Hz, 1H), 5.42 (d, J = 8.1 Hz, 1H), 5.03 (s, 2H), 4.72 - 4.54 (m, 1H), 4.30 - 4.07 (m, 1H), 3.22 (d, J = 7.8 Hz, 2H), 2.41 - 2.24 (m, 2H), 2.07 - 1.94 (m, 1H), 1.79 - 1.68 (m, 2H), 1.60 - 1.58 (m, 2H), 1.49 - 1.38 (m, 1H), 0.88 (d, J = 5.1 Hz, 6H). (Example S24) Synthesis of compound B-1-e [ka]

[0280] To a stirred solution of methyl (2S)-2-[(2S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentan-amido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound B-1-a) (400 mg, 0.92 mmol) in THF (10 mL) at 0 °C under N was slowly added LiOH (44 mg, 1.85 mmol) in HO (12 mL). The reaction mixture was stirred at room temperature for 40 min. The aqueous phase was separated, and the pH was adjusted to approximately 3–4 with citric acid, then extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to a low volume to give crude compound 133 (320 mg, 0.76 mmol, 82.67%) as a yellow oil, which was used directly in the next step without further purification. LCMS=[M+H] + :419.9. 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 6.6 Hz, 1H), 7.31 - 7.26 (m, 5H), 6.44 (br s, 1H), 5.54 (d, J = 8.2 Hz, 1H), 5.13 - 5.03 (m, 2H), 4.55 (br s, 1H), 4.29 (d, J = 4.7 Hz, 1H), 3.40 - 3.28 (m, 2H), 2.55 - 2.46 (m, 1H), 2.35 (s, 1H), 2.24 - 2.11 (m, 1H), 2.06 - 2.03 (m, 1H), 1.99 - 1.78 (m, 2H), 1.57 - 1.47 (m, 1H), 0.94 (d, J = 6.3 Hz, 6H).

[0281] To a stirred solution of (2S)-2-[(2S)-2-{[(benzyloxy)carbonyl]amino}-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoic acid (Compound 133) (320 mg, 0.76 mmol) in DMF (4 mL) was added NH4Cl (204 mg, 3.81 mmol), HATU (377 mg, 0.99 mmol), and DIEA (0.60 mL, 3.81 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The resulting crude product was purified by reverse phase HPLC (ACN / water (0.1% FA)) to give compound 134 (240 mg, 0.57 mmol, 75.18%) as a yellow solid. LCMS = [M+H] + :419.0.

[0282] To a stirred solution of benzyl N-[(1S)-1-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-3-methylbutyl]carbamate (compound 134) (60 mg, 0.14 mmol) in THF (2 mL) was added TEA (0.04 mL, 0.29 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and then TFAA (0.20 mL, 1.51 mmol) was added. The resulting mixture was continuously stirred at 0 °C for an additional hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to a reduced volume, and the resulting crude material was purified by preparative HPLC to give compound B-1-e (8.72 mg, 0.02 mmol, 15.19%) as an off-white solid. LCMS = [M+H] + :401.3. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.33 - 7.30 (m, 5H), 6.21 (br s, 1H), 5.36 (br s, 1H), 5.10 (s, 2H), 4.80 (br s, 1H), 4.31 (br s, 1H), 3.35 - 3.33 (m, 2H), 2.38 - 2.33 (m, 3H), 1.94 - 1.90 (m, 4H), 1.53 - 1.50 (m, 1H), 0.95 (d, J = 5.0 Hz, 6H). (Example S25) Synthesis of compound B-1-f [ka]

[0283] To a stirred solution of benzyl N-[(1S)-1-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-carbamoyl}-3-methylbutyl]carbamate (compound 134) (90 mg, 0.22 mmol) in ACN (1 mL) and HO (1 mL) was added [bis(trifluoroacetoxy)iodo]benzene (93 mg, 0.22 mmol). The solution was stirred at room temperature under N2 and protected from light for 15 hours. The mixture was purified by preparative HPLC (ACN / water (0.1% FA)) to give compound 135 (45 mg, 0.12 mmol, 53.59%) as an off-white solid. LCMS = [M-NH2] + :374.2.

[0284] To a stirred solution of benzyl N-[(1S)-1-{[(1S)-1-amino-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-carbamoyl}-3-methylbutyl]carbamate (compound 135) (45 mg, 0.12 mmol) and DIEA (0.07 mL, 0.46 mmol) in DCM (1 mL) at 0 °C, prop-2-enoyl chloride (0.01 mL, 0.15 mmol) was slowly added. The reaction mixture was stirred at room temperature under N for 15 minutes. The mixture was concentrated, and the resulting crude was purified by preparative HPLC to give compound B-1-f (12.78 mg, 24.95%) as an off-white solid. LCMS = [M+H] + :445.3. 1 H NMR (400 MHz, CDCl3) δ 7.90 (br s, 1H), 7.52 (br s, 1H), 7.33 (br s, 5H), 7.22 (br s, 1H), 6.28 (d, J = 17.0 Hz, 1H), 5.75 - 5.70 (m, 3H), 5.64 (d, J = 9.1 Hz, 1H), 5.09 (s, 2H), 4.18 (br s, 1H), 3.30 - 3.26 (m, 2H), 2.51 - 2.48 (m, 1H), 2.23 - 2.20 (m, 2H), 2.03 -1.83 (m, 4H), 1.51 - 1.49 (m, 1H), 0.92 (d, J = 5.7 Hz, 6H). (Example S26) Synthesis of compounds B-2-a and B-2-b [ka]

[0285] To a solution of compound 110 (5 g, 16.40 mmol) in anhydrous DMF (40 mL) was added HATU (5.7 g, 15.03 mmol) and DIEA (8.3 mL, 50.15 mmol) sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes. Compound 104 (3.65 g, 16.40 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional hour. The mixture was directly purified by medium pressure reverse phase column chromatography to give compound B-2-a as a white solid (5.3 g, 68.4%). LCMS = [M+H] + :474.5.

[0286] To a stirred solution of compound B-2-a (1.85 g, 3.91 mmol) in THF (10 mL) was added LiBH (2.0 M in THF, 5.9 mL, 11.73 mmol) portionwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and continued stirring for an additional 2 h. While cooling on an ice bath, the reaction was quenched by the dropwise addition of saturated NH Cl. The reaction mixture was diluted with H O and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to a low volume. The resulting yellow solid was further purified by medium-pressure reverse-phase column chromatography to give compound 136 as a white solid (1.6 g, 92.0%). LCMS = [M+H] + :446.3.

[0287] To a solution of compound 136 (1.6 g, 3.60 mmol) in DCM (6 mL) was added Dess-Martin periodinane (3.05 g, 7.18 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then warmed to room temperature and continued stirring for an additional 2 hours. The reaction was quenched with saturated NaHCO containing 10% NaSO at 0 °C. The reaction mixture was diluted with DCM and H2O, and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to give compound B-2-b as a pale yellow solid (285 mg, HPLC 98%). LCMS = [M+H] + :444.6. (Example S27) Synthesis of compound B-2-c [ka]

[0288] To a stirred solution of methyl (S)-2-((S)-2-(((benzyloxy)carbonyl)amino)-3-cyclohexylpropan-amido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (B-2-a) (270 mg, 0.57 mmol) and chloroiodomethane (402 mg, 2.28 mmol) in dry THF (5 mL) was added dropwise LDA (2 M in THF, 1.7 mL, 3.4 mmol) at −70° C. under N. The reaction mixture was stirred at −70° C. for 3 h. The reaction mixture was quenched with saturated NH4Cl(aq) (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume. The resulting crude material was purified by reverse-phase HPLC (C18, 120 g 20-35 μm, 100 Å; 65% ACN in water (0.1% aqueous FA)) to give compound B-2-c as a white solid (15 mg, 5%). LCMS = [M+H] + :492.3, purity 93%. 1 H NMR (400 MHz, CDCl3) δ 8.47 (br s, 1H), 7.44 - 7.28 (m, 5H), 5.85 (br s, 1H), 5.25 (d, J = 7.3 Hz, 1H), 5.12 (s, 2H), 4.79 - 4.50 (m, 1H), 4.28 (s, 2H), 4.25 - 4.10 (m, 1H), 3.42 - 3.28 (m, 2H), 2.48 - 2.40 (m, 2H), 2.06 - 1.93 (m, 3H), 1.90 - 1.76 (m, 2H), 1.71 - 1.63 (m, 4H), 1.53 - 1.44 (m, 1H), 1.43 - 1.30 (m, 1H), 1.29 - 1.09 (m, 3H), 1.03 - 0.84 (m, 2H). (Example S28) Synthesis of compound B-2-d [ka]

[0289] To a stirred solution of methyl (S)-2-((S)-2-(((benzyloxy)carbonyl)amino)-3-cyclohexylpropan-amido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound B-2-a) (600 mg, 1.27 mmol) in THF / water (20 mL, 1:1) at 0 °C was added LiOH hydrate (133 mg, 3.17 mmol). The reaction mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to a low volume. The residue was diluted with water, the pH adjusted to approximately 3-4 with 1 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume to give compound 137 (540 mg, 92.4%) as an off-white solid. LCMS = [M+H] + :460.5. 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 18.0 Hz, 1H), 7.37 - 7.28 (m, 5H), 6.64 (s, 1H), 5.59 (d, J = 7.5 Hz, 1H), 5.19 - 5.00 (m, 2H), 4.60 - 4.52 (m, 1H), 4.37 - 4.29 (m, 1H), 3.39 - 3.25 (m, 2H), 2.57 - 2.44 (m, 1H), 2.39 - 2.30 (m, 1H), 2.22 - 2.12 (m, 1H), 2.09 - 2.05 (m, 1H), 1.97 - 1.88 (m, 1H), 1.86 - 1.75 (m, 2H), 1.72 - 1.68 (m, 1H), 1.67 - 1.61 (m, 3H), 1.55 - 1.46 (m, 1H), 1.41 - 1.31 (m, 1H), 1.22 - 1.07 (m, 3H), 0.98 - 0.82 (m, 2H).

[0290] To a solution of (S)-2-((S)-2-(((benzyloxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid (compound 137) (300 mg, 0.65 mol) in THF (5 mL) was added 4-methylmorpholine (200 mg, 0.95 mmol) and isobutyl carbonochloridate (136 mg, 0.98 mmol) at 0° C. The reaction mixture was stirred for 15 minutes, and NH3 in dioxane (5 mL, 0.4 M) was added. The resulting mixture was stirred at 0° C. for 1.5 hours under a nitrogen atmosphere. LCMS showed the reaction was complete. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to a low volume. The resulting residue was purified by reverse phase HPLC to give compound 138 (250 mg, 83%) as a yellow semi-solid. LCMS=[M+H] + :459.2.

[0291] To a stirred solution of benzyl ((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound 138) (100 mg, 0.22 mmol) in DCM (5 mL) was added TEA (66 mg, 0.66 mmol) and TFAA (92 mg, 0.44 mmol). The reaction mixture was stirred at room temperature under N for 1.5 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give compound B-2-d (12 mg, 47.7%) as a white solid. LCMS = [M+H] + :441.3. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.41 - 7.30 (m, 5H), 6.24 - 5.72 (m, 1H), 5.38 - 5.16 (m, 1H), 5.16 - 5.06 (m, 2H), 5.00 - 4.75 (m, 1H), 4.37 - 4.19 (m, 1H), 3.53 - 3.24 (m, 2H), 2.97 - 2.76 (m, 1H), 2.56 - 2.23 (m, 2H), 2.06 - 1.97 (m, 1H), 1.92 - 1.85 (m, 1H), 1.83 - 1.74 (m, 2H), 1.74 - 1.67 (m, 3H), 1.64 - 1.58 (m, 1H), 1.55 - 1.44 (m, 1H), 1.37 - 1.29 (m, 1H), 1.25 - 1.08 (m, 3H), 1.02 - 0.80 (m, 2H). (Example S29) Synthesis of compound B-2-e [ka]

[0292] To a stirred solution of benzyl N-[(1S)-1-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-carbamoyl}-2-cyclohexylethyl]carbamate (compound 138) (140 mg, 0.31 mmol) in ACN (1 mL) and HO (1 mL) was added bis(trifluoroacetoxy)iodobenzene (132 mg, 0.31 mmol). The reaction mixture was stirred at room temperature under N2 and protected from light for 16 hours. The mixture was directly purified by reverse-phase HPLC (C18, ACN / water (0.1% FA)) to give compound 139 (90 mg, 0.21 mmol, 68.47%) as an off-white solid. LCMS = [M+H] + :431.1.

[0293] To a stirred solution of benzyl N-[(1S)-1-{[(1S)-1-amino-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-carbamoyl}-2-cyclohexylethyl]carbamate (compound 139) (85 mg, 0.20 mmol) and TEA (0.110 mL, 0.79 mmol) in DCM (1.5 mL) at 0 °C, prop-2-enoyl chloride (0.02 mL, 0.26 mmol) was slowly added. The reaction mixture was stirred at room temperature under N for 15 minutes. The reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to afford compound B-2-e (12.75 mg, 13.33%) as an off-white solid. LCMS = [M+H] + :485.3. 1 H NMR (400 MHz, CDCl3) δ 8.08 - 7.63 (m, 1H), 7.62 - 7.47 (m, 1H), 7.33 (s, 5H), 6.33 - 6.21 (m, 1H), 6.16 - 6.03 (m, 2H), 5.81 - 5.67 (m, 1H), 5.66 - 5.57 (m, 1H), 5.55 - 5.30 (m, 1H), 5.15 - 5.00 (m, 2H), 4.29 - 4.11 (m, 1H), 3.56 - 3.21 (m, 2H), 2.54 - 2.26 (m, 2H), 2.23 - 1.97 (m, 2H), 1.96 - 1.66 (m, 7H), 1.54 - 1.40 (m, 1H), 1.40 - 1.28 (m, 1H), 1.23 - 1.03 (m, 3H), 1.01 - 0.75 (m, 2H). (Example S30) Synthesis of compounds C-1-a and C-1-b [ka]

[0294] To a solution of compound 107 (3 g, 10.02 mmol) in anhydrous DMF (10 mL) was added compound 140 (3.1 g, 10.02 mmol), HATU (5.7 g, 15.03 mmol), and DIEA (8.3 mL, 50.15 mmol) sequentially at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. LCMS showed the reaction was complete. The mixture was diluted with EtOAc, washed with water, 1 M HCl, saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:2) to give compound C-1-a as a white solid (3.7 g, 62.5%). LCMS = [M+H] + :591.6.

[0295] To a stirred solution of compound C-1-a (3.0 g, 5.08 mmol) in THF (30 mL) at 0 °C under a nitrogen atmosphere, LiBH (2.0 M in THF, 7.62 mL, 15.24 mmol, 3.0 equiv.) was added portionwise. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for an additional 2 h. LCMS indicated the reaction was complete. The reaction was cooled in an ice bath and quenched by the dropwise addition of 1.0 M HCl. The solution was diluted with ethyl acetate and H O. The organic phase was separated, and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure to a reduced volume to give a yellow oily residue, which was further purified by column chromatography (6% MeOH in DCM) to give compound 141 as a white solid (2.7 g, 94.4%). LCMS = [M+H] + :563.4.

[0296] To a solution of compound 141 (2.7 g, 4.80 mmol) in DCM (20 mL) was added Dess-Martin periodinane (7.38 g, 14.40 mmol). The resulting mixture was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction was quenched with saturated NaHCO3 containing 10% Na2S2O3. The organic layer was washed with saturated brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash chromatography to give compound C-1-b as a white solid (890 mg, 33.0%). LCMS = [M+H] + :561.7. (Example S31) Synthesis of compounds C-2-a and C-2-b [ka]

[0297] To a solution of compound 111 (3 g, 8.84 mmol, 1.0 equiv.) in anhydrous DMF (10 mL) was added compound 140 (2.73 g, 8.84 mmol, 1.0 equiv.), HATU (5.04 g, 13.26 mmol, 1.5 equiv.), and DIEA (7.3 mL, 44.2 mmol, 5.0 equiv.) sequentially at 0 °C. The reaction mixture was stirred at room temperature for 6 h. LCMS showed the reaction was complete. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, 1 M HCl, saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (MeOH:DCM = 1:15) to give compound C-2-a as a white solid (4.3 g, 77.1%). LCMS = [M+H] + :631.6.

[0298] To a stirred solution of compound C-2-a (3.6 g, 5.71 mmol) in THF (36 mL) was added LiBH (2 M in THF, 8.57 mL, 17.13 mmol) portionwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for an additional 2 h. LCMS showed the reaction was complete. The reaction mixture was quenched by the dropwise addition of 1.0 M HCl in an ice bath and diluted with ethyl acetate and H O. The phases were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were combined, dried over anhydrous Na SO , and concentrated under reduced pressure to a reduced volume to give a yellow oily residue, which was further purified by column chromatography (MeOH:DCM=1:15) to give compound 142 as a white solid (3.0 g, 87.2%). LCMS=[M+H] + :603.7.

[0299] To a solution of compound 142 (5.0 g, 8.30 mmol) in DCM (50 mL) was added Dess-Martin periodinane (10.56 g, 24.90 mmol) slowly at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction was quenched with saturated NaHCO containing 10% NaSO. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash chromatography to give compound C-2-b as a white solid (2.3 g, 46.2%). LCMS = [M+H] + :601.7. (Example S32) Synthesis of compound D-1-a [ka]

[0300] To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid (compound 143) (3.8 g, 14.3 mmol) in anhydrous DMF (50 mL) was added compound 144 (3.0 g, 14.3 mmol), HATU (8.3 g, 21.4 mmol), and DIEA (4.7 g, 35.8 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was diluted with EtOAc, washed with water, saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:5) to give compound 145 as a white solid (5.0 g, 83.8%). LCMS = [M+H] + :417.4.

[0301] To a solution of compound 145 (5 g, 12.0 mmol) in THF / HO (1:1) cooled to 0 °C, LiOH·HO (1.0 g, 24.0 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was neutralized with 1 M HCl solution and then extracted with EtOAc. The combined organic layers were washed with saturated NaCl, dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume to give crude compound 146 (1.2 g, 25%), which was used directly in the next reaction without further purification. LCMS = [M+H] + :403.3.

[0302] To a solution of compound 146 (1.2 g, 2.98 mmol) in anhydrous DMF (15 mL) was added compound 104 (555.2 mg, 2.98 mmol), HATU (1.7 g, 4.47 mmol), and DIEA (964.1 mg, 7.45 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by TLC), the mixture was diluted with EtOAc, washed with water, saturated NaCl, dried over Na2SO4, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:5) to give compound 147 (1.7 g, 99%). LCMS = [M+H] + :571.5.

[0303] To a stirred solution of compound 147 (1.7 g, 2.98 mmol) in MeOH (20 mL) was added Pd / C (10 wt%, 170 mg) portionwise at room temperature. The reaction mixture was stirred under an H atmosphere for 3 hours. After the reaction was complete (monitored by TLC), the mixture was filtered, and the filtrate was concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (5% MeOH in CH2Cl2) to give compound 148 as a white solid (300 mg; 23%). LCMS = [M+H] + :527.6.

[0304] To a solution of compound 148 (300 mg, 0.69 mmol) in anhydrous DCM (15 mL) was added TFAA (289 mg, 1.38 mmol) and TEA (208 mg, 2.07 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, saturated NaCl, and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (EtOAc:hexane = 1:5) to give compound D-1-a (260 mg, 71%). LCMS = [M+H] + :533.3. (Example S33) Synthesis of compound D-1-b [ka]

[0305] To a stirred solution of methyl (2S)-2-{[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(trifluoroacetamido)-butanoyl]-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamido}-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (Compound D-1-a) (300 mg, 0.56 mmol) in anhydrous THF (7 mL) was added LDA (1.86 mL, 14.08 mmol) and chloroiodomethane (0.40 mL, 5.63 mmol) at −78° C. under a nitrogen atmosphere. The reaction mixture was continuously stirred at −78° C. under N for 1.5 hours. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated under reduced pressure to reduce the volume. The resulting residue was purified by preparative HPLC (ACN / water (0.1% FA)) to give compound D-1-b (27.76 mg, 0.05 mmol, 8.94%) as an off-white solid. LCMS = [M+H] + :551.3. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 8.6 Hz, 1H), 8.74 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 4.63 (s, 2H), 4.49 - 4.39 (m, 2H), 4.23 (s, 1H), 3.94 - 3.86 (m, 1H), 3.69 (d, J = 10.3 Hz, 1H), 3.19 - 3.11 (m, 1H), 3.10 - 3.01 (m, 1H), 2.42 - 2.31 (m, 1H), 2.18 - 2.07 (m, 1H), 2.01 - 1.90 (m, 1H), 1.69 - 1.57 (m, 2H), 1.57 - 1.51 (m, 1H), 1.38 (d, J = 7.7 Hz, 1H), 1.03 (s, 3H), 0.98 (s, 9H), 0.87 (s, 3H). (Example S34) Synthesis of compound D-1-c [ka]

[0306] To a solution of (1R,2S,5S)—N-((S)-4-chloro-3-oxo-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 (Compound D-1-b) (290 mg, 0.53 mmol) in DMF (5 mL) was added 2-oxo-2-phenylacetic acid (0.074 mL, 0.68 mmol) and CsF (0.045 mL, 1.22 mmol). The reaction mixture was heated at 65° C. under N for 2 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to a low volume. The resulting residue was purified by flash chromatography (C18, ACN / water (0.1% FA)) to give compound 149 (260 mg, 0.47 mmol, 31.33%) as a brown solid. LCMS = [M+H] + :665.3.

[0307] To a stirred solution of (S)-3-((1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)-butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-2-oxo-4-((S)-2-oxopyrrolidin-3-yl)butyl 2-oxo-2-phenylacetate (compound 149) (287 mg, 0.43 mmol) in MeOH (4 mL) was added NaHCO (3.63 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (ACN / water (0.1% FA)) to give compound D-1-c (81 mg, 0.15 mmol, 35.22%) as a white solid. LCMS = [M+H] + :533.3. HPLC:93.33%. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 5.8 Hz, 1H), 7.06 - 6.87 (m, 1H), 5.82 - 5.78 (m, 1H), 4.69 - 4.27 (m, 5H), 4.09 - 3.94 (m, 1H), 3.89 - 3.74 (m, 1H), 3.55 - 3.30 (m, 2H), 2.60 - 2.47 (m, 1H), 2.47 - 2.30 (m, 1H), 2.13 - 2.01 (m, 1H), 1.97 - 1.86 (m, 2H), 1.61 - 1.42 (m, 2H), 1.11 - 0.85 (m, 15H). (Example S35) Synthesis of compound D-1-d [ka] [ka]

[0308] To a flask containing compound 103 (10 g, 34.93 mmol), 7.0 M ammonia in MeOH (300 mL) was added. The reaction mixture was stirred overnight at 50 °C in an autoclave reactor. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give crude compound 150 as a white solid (9.50 g, 35.01 mmol, 100.26%), which was used directly in the next step without further purification. LCMS = [M+H] + :272.4.

[0309] To a solution of compound 150 (9.0 g, 33.17 mmol) in ethyl acetate (60 mL) was added 4.0 M HCl in ethyl acetate (50 mL). The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to a low volume to give compound 151 (7.20 g, 34.67 mmol, 104.52%) as a white solid, which was used directly in the next reaction without further purification. LCMS = [M+H] + :208.3.

[0310] To a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (Compound 152) (10.16 g, 43.93 mmol) and methyl (1R,2S,5S)-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]-hexane-2-carboxylate (Compound 144) (8.14 g, 48.22 mmol) in DMF (10 mL) and ACN (90 mL) was added DIEA (19.8 mL, 119.80 mmol) and HATU (15.18 g, 39.93 mmol) sequentially at 0 °C. The reaction mixture was stirred overnight at room temperature under N2. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume to give compound 153 (13.7 g, 35.82 mmol, 89.69%) as a yellow oil. LCMS = [M+H] + :383.1.

[0311] To a stirred solution of methyl (1R,2S,5S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoyl]-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 153) (13.7 g, 35.82 mmol) in MeOH (60 mL) was added dropwise LiOH (1.7 g, 71.63 mmol) in HO (60 mL) at 0 °C. The reaction mixture was stirred at room temperature under N for 3 h. After the reaction was complete (monitored by LCMS), the resulting mixture was diluted with water (150 mL) and extracted with DCM (300 mL). The aqueous phase was adjusted to pH 3–4 with 1 M HCl and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound 154 (7.48 g, 20.30 mmol, 56.68%) as a yellow solid. LCMS = [M+H] + :369.0. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 5.18 (d, J = 9.9 Hz, 1H), 4.48 (s, 1H), 4.24 (d, J = 10.2 Hz, 1H), 4.06 (d, J = 10.4 Hz, 1H), 3.84 (dd, J = 10.4, 5.4 Hz, 1H), 1.73 - 1.68 (m, 1H), 1.52 - 1.47 (m, 1H), 1.40 (s, 9H), 1.06 (s, 3H), 1.01 (s, 9H), 0.90 (s, 3H).

[0312] To a stirred solution of (1R,2S,5S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethyl-butanoyl]-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 154) (2 g, 5.43 mmol) in DCM (20 mL) was added 4.0 M HCl / dioxane (6.77 mL) at 0 °C. The solution was stirred at room temperature for 3 h. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give compound 155 (1.9 g, crude) as a yellow solid. LCMS = [M+H] + :269.1.

[0313] To a stirred solution of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethylbutanoyl]-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 155) (2 g, 7.45 mmol) in MeOH (20 mL) at 0 °C, methyl 2,2,2-trifluoroacetate (3 mL, 29.81 mmol) and TEA (5.2 mL, 37.26 mmol) were added. The reaction mixture was stirred overnight at 50 °C under N2. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3–4 with 1 M HCl, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume to give crude compound 156 (2.2 g, 6.04 mmol, 81.02%) as an off-white solid. LCMS = [M+H] + :365.2. 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.27 (m, 1H), 4.57 - 4.51 (m, 1H), 4.40 (s, 1H), 3.89 - 3.84 (m, 1H), 3.79 (d, J = 10.4 Hz, 1H), 1.58 - 1.51 (m, 1H), 1.48 - 1.40 (m, 1H), 1.02 - 0.97 (m, 12H), 0.82 (s, 3H).

[0314] To a stirred solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(trifluoroacetamido)butanoyl]-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Compound 156) (600 mg, 1.65 mmol) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (Compound 151) (338 mg, 1.98 mmol) in butan-2-one (10 mL) was added DIEA (0.80 mL, 4.94 mmol), EDCI (410 mg, 2.14 mmol), and 2-pyridinol-1-oxide (0.20 mL, 2.14 mmol) at 0° C. The reaction mixture was stirred at room temperature under N2 overnight. After the reaction was completed (monitored by LCMS), the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 157 (380 mg, 0.73 mmol, 44.59%) as an off-white solid. LCMS = [M+H] + :518.5.

[0315] To a stirred solution of (2S)-2-{[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(trifluoroacetamido)butanoyl]-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (compound 157) (330 mg, 0.64 mmol) in DCM (6 mL) was added Burgess reagent (152 mg, 0.64 mmol). The solution was stirred at room temperature under N for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume, and the resulting residue was purified by preparative HPLC to give compound D-1-d (111.19 mg, 0.22 mmol, 34.91%) as an off-white solid. LCMS=[M+H] + :500.3. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 8.4 Hz, 1H), 9.01 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 5.01 - 4.93 (m, 1H), 4.41 (d, J = 8.5 Hz, 1H), 4.16 (s, 1H), 3.94 - 3.88 (m, 1H), 3.69 (d, J = 10.5 Hz, 1H), 3.18 - 3.00 (m, 2H), 2.44 - 2.35 (m, 1H), 2.20 - 2.04 (m, 2H), 1.77 - 1.66 (m, 2H), 1.59 - 1.54 (m, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.01 (d, J = 19.1 Hz, 12H), 0.87 (s, 3H). (Example S36) Synthesis of compound D-1-e [ka]

[0316] A solution of (1R,2S,5S)—N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound 157) (150 mg, 0.29 mmol) and bis(trifluoroacetoxy)iodobenzene (125 mg, 0.29 mmol) in ACN (5 mL) and water (5 mL) was stirred at room temperature overnight. After the reaction was complete (monitored by LCMS), the reaction mixture was purified by flash column chromatography (C18, 40 g, 20-35 um, 100 Å) using 50% ACN in water (0.1% FA) as eluent to give compound 158 as a white solid (65 mg, 46%). LCMS = [M+H] + :490.2.

[0317] To a solution of (1R,2S,5S)—N-((S)-1-amino-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 158) (60 mg, 0.12 mmol) and DIEA (63 mg, 0.49 mmol) in DCM (3 mL) was added acryloyl chloride (15 mg, 0.16 mmol) at 0° C. under N. The reaction mixture was stirred at room temperature for 15 minutes. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume and purified by preparative HPLC to give compound D-1-e as a white solid (2.96 mg, 5%). LCMS = [M+H] + :544.4, purity=94%. 1 H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.23 ​​(s, 1H), 7.67 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.30 (t, J = 7.5 Hz, 1H), 6.15 (s, 1H), 5.98 (s, 1H), 5.79 (s, 1H), 5.72 - 5.51 (m, 2H), 4.56 (d, J = 9.3 Hz, 1H), 4.32 (t, J = 15.1 Hz, 1H), 3.93 (s, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.58 (d, J = 12.6 Hz, 1H), 3.48 - 3.34 (m, 2H), 2.89 (s, 1H), 2.65 (s, 1H), 2.56 - 2.47 (m, 1H), 2.41 (s, 1H), 2.23 (s, 1H), 2.09 (s, 1H), 1.60 - 1.46 (m, 2H), 1.07 - 1.00 (m, 9H), 0.85 (s, 3H). (Example S37) Synthesis of compound D-1-f [ka]

[0318] To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound 103) (500 mg, 1.75 mmol) in THF (10 mL) under N was added LiBH (154 mg, 6.98 mmol) portionwise. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was cooled to 0 °C in an ice bath, quenched with water (20 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume to give crude compound 159 (340 mg, 75%) as a white solid, which was used in the next reaction without further purification. LCMS = [M+H] + :259.1. 1 H NMR (400 MHz, CDCl3) δ 5.88 (s, 1H), 5.44 (d, J = 7.1 Hz, 1H), 3.74 (d, J = 5.3 Hz, 1H), 3.66 - 3.55 (m, 2H), 3.40 - 3.30 (m, 2H), 3.16 (s, 1H), 2.56 - 2.37 (m, 2H), 2.00 - 1.90 (m, 1H), 1.88 - 1.79 (m, 1H), 1.68 - 1.59 (m, 1H), 1.44 (s, 9H).

[0319] A solution of tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (compound 159) (340 mg, 12.18 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature for 1 hour. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give compound 160 as a yellow oil (350 mg, crude), which was used in the next reaction without further purification. LCMS = [M+H] + :159.1.

[0320] To a stirred solution of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 156) (100 mg, 0.27 mmol) in DMF (3 mL) was added HATU (156 mg, 0.41 mmol) and DIEA (142 mg, 1.108 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then (S)-3-((S)-2-amino-3-hydroxypropyl)pyrrolidin-2-one TFA salt (compound 160) (84 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with EtOAc, washed with water, 1 M HCl, saturated NaCl, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by flash column chromatography (C18, 40 g, 20-35 μm, 100 Å, 60% ACN in water (0.1% FA)) to give compound 161 as a brown solid (40 mg, 29%). LCMS = [M+H] + :505.2.

[0321] A solution of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 161) (63 mg, 0.13 mmol) and Dess-Martin periodinane (265 mg, 0.62 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. After the reaction was complete (monitored by LCMS), the reaction mixture was diluted with DCM. The organic layer was washed with saturated NaSO (aq), saturated NaHCO (aq), brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-1-f as a white solid (10 mg, 17%). LCMS = [M+H] + :503.3. Purity=86%. 1H NMR (400 MHz, CDCl3) δ 9.47 (d, J = 6.0 Hz, 1H), 8.03 (s, 1H), 6.91 (d, J = 12.7 Hz, 1H), 5.67 (s, 1H), 4.50 (d, J = 9.2 Hz, 1H), 4.37 (s, 1H), 4.30 (s, 1H), 4.15 (d, J = 9.0 Hz, 1H), 3.95 (dd, J = 10.1, 4.9 Hz, 1H), 3.74 (d, J = 10.2 Hz, 1H), 3.33 (s, 2H), 2.50 (s, 1H), 2.37 (s, 1H), 1.93 (s, 1H), 1.82 (s, 1H), 1.52 - 1.46 (m, 2H), 1.01 (d, J = 2.8 Hz, 3H), 0.96 (d, J = 6.1 Hz, 9H), 0.83 (s, 3H). (Example S38) Synthesis of compound D-2-a

change

[0322] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (Compound 162) (1.18 g, 5.5 mmol) and methyl (1R,2S,5S)-1,5-dihydrogenio-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Compound 144) (1.12 g, 6.6 mmol) in DMF (4 mL) and ACN (36 mL) was added DIEA (1.42 g, 11 mmol) and HATU (2.51 g, 6.6 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature under N. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to reduce the volume to remove ACN, then diluted with water (80 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (C18, (ACN / water (0.1% FA)) to give compound 163 (1.6 g, 79%) as a colorless oil. LCMS = [M+Na] + :388.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.15 (d, J = 7.6 Hz, 1H), 4.18 (s, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.75 - 3.69 (m, 1H), 3.67 (d, J = 2.2 Hz, 1H), 3.65 (s, 3H), 1.56 - 1.49 (m, 1H), 1.40 (d, J = 7.5 Hz, 1H), 1.35 (d, J = 2.4 Hz, 9H), 1.09 - 1.03 (m, 1H), 1.01 (d, J = 3.7 Hz, 3H), 0.91 (s, 3H), 0.41 (d, J = 8.0 Hz, 2H), 0.33 (d, J = 3.2 Hz, 2H).

[0323] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropyl-acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 163) (350 mg, 0.96 mmol) in THF / water (10 mL, 1:1) was added LiOH (91 mg, 3.82 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3–4 with 1 M HCl, and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (C18, (ACN / water (0.1% FA)) to give compound 164 (320 mg, 95%) as an off-white solid. LCMS = [M+H] + :353.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.06 (d, J = 6.8 Hz, 1H), 4.09 (s, 1H), 3.80 (d, J = 10.4 Hz, 1H), 3.76 - 3.66 (m, 2H), 3.45 (d, J = 5.8 Hz, 1H), 1.56 - 1.45 (m, 1H), 1.43 - 1.27 (m, 10H), 1.11 - 0.98 (m, 4H), 0.90 (d, J = 17.6 Hz, 3H), 0.51 - 0.23 (m, 4H).

[0324] To a mixture of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 164) (320 mg, 0.9 mmol) in DCM (5 mL) was added a solution of 4.0 M HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give crude compound 165 (250 mg) as a yellow semi-solid. LCMS = [M+H]+ :253.1.

[0325] To a stirred solution of (1R,2S,5S)-3-((S)-2-amino-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (compound 165) (250 mg, 0.87 mmol) in MeOH (10 mL) at 0 °C, TEA (0.264 g, 2.61 mmol) and methyl 2,2,2-trifluoroacetate (0.335 g, 2.61 mmol) were added. The reaction mixture was stirred overnight at 50 °C under N. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3–4 with 1 M HCl, and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 166 (200 mg, 65%) as an off-white solid. LCMS = [M+H] + :349.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 9.93 (d, J = 6.0 Hz, 1H), 4.11 (s, 1H), 4.03 - 3.94 (m, 1H), 3.80 - 3.72 (m, 1H), 3.69 (d, J = 10.5 Hz, 1H), 1.56 - 1.49 (m, 1H), 1.41 (d, J = 7.6 Hz, 1H), 1.19 - 1.09 (m, 1H), 1.02 (d, J = 3.4 Hz, 3H), 0.88 (s, 3H), 0.55 - 0.37 (m, 4H).

[0326] To a stirred solution of (1R,2S,5S)-3-((S)-2-cyclopropyl-2-(2,2,2-trifluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Compound 166) (200 mg, 0.57 mmol) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (Compound 151) (142 mg, 0.68 mmol) in DMF (8 mL) was added DIEA (220 mg, 1.71 mmol) and HATU (259 mg, 0.68 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting crude product was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 167 (80 mg, 28%) as an off-white solid. LCMS = [M+H] + :502.3. 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 7.03 (s, 1H), 4.30 - 4.20 (m, 2H), 4.08 (d, J = 8.3 Hz, 1H), 3.85 - 3.78 (m, 1H), 3.65 (d, J = 10.5 Hz, 1H), 3.19 - 3.02 (m, 2H), 2.40 - 2.29 (m, 1H), 2.20 - 2.09 (m, 1H), 2.02 - 1.85 (m, 1H), 1.72- 1.60 (m, 1H), 1.59 - 1.45 (m, 2H), 1.38 (d, J = 7.6 Hz, 1H), 1.20 - 1.10 (m, 1H), 1.07 - 0.99 (m, 3H), 0.95 - 0.83 (m, 3H), 0.57 - 0.38 (m, 4H).

[0327] To a stirred solution of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-cyclopropyl-2-(2,2,2-trifluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 167) (80 mg, 0.16 mmol) in DCM (5 mL) was added Burgess reagent (76 mg, 0.32 mmol). The reaction mixture was stirred at room temperature under N for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-2-a (37 mg, 47.7%) as a white solid. LCMS = [M+H] + :484.3. HPLC:95.14%. 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (d, J = 6.5 Hz, 1H), 8.95 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 5.02 - 4.90 (m, 1H), 4.14 (d, J = 8.2 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.86 - 3.77 (m, 1H), 3.67 (d, J = 10.5 Hz, 1H), 3.18 - 3.04 (m, 2H), 2.41 - 2.35 (m, 1H), 2.17 - 2.07 (m, 2H), 1.79 - 1.64 (m, 2H), 1.60 - 1.54 (m, 1H), 1.30 (d, J = 7.5 Hz, 1H), 1.18 - 1.12 (m, 1H), 1.08 - 0.99 (m, 3H), 0.98 - 0.86 (m, 3H), 0.55 - 0.38 (m, 4H). (Example S39) Synthesis of compound D-2-b [ka] [ka]

[0328] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropyl-acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 163) (1.2 g, 3.28 mmol) in DCM (10 mL) was added HCl in dioxane (4.0 M, 15 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give crude compound 168 (1.1 g) as a yellow semi-solid. LCMS = [M+H] + :267.0.

[0329] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-amino-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (compound 168) (293 mg, 0.97 mmol) in DCM (10 mL) was added DIEA (0.387 g, 3 mmol) and isobutyryl chloride (compound 169) (123 mg, 1.16 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 170 (200 mg, 61%) as a white solid. LCMS = [M+H] + :337.3. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.5 Hz, 1H), 4.16 (s, 1H), 4.05 - 3.91 (m, 1H), 3.74 (d, J = 2.6 Hz, 2H), 3.64 (d, J = 9.1 Hz, 3H), 2.48 - 2.39 (m, 1H), 1.57 - 1.50 (m, 1H), 1.40 (d, J = 7.5 Hz, 1H), 1.14 - 1.04 (m, 1H), 1.01 (d, J = 6.3 Hz, 3H), 0.99 - 0.91 (m, 6H), 0.87 (s, 3H), 0.47 - 0.36 (m, 2H), 0.35 - 0.23 (m, 2H).

[0330] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-cyclopropyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 170) (200 mg, 0.59 mmol) in THF / water (10 mL, 2:1) was added LiOH (29 mg, 1.18 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3-4 with 1 M HCl, and extracted with DCM (40 mL x 3). The combined organic layers were concentrated under reduced pressure to a low volume, and the resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 171 (170 mg, 89%) as an off-white solid. LCMS = [M+H] + :323.2. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 4.07 (s, 1H), 4.05 - 3.98 (m, 1H), 3.72 (d, J = 2.8 Hz, 2H), 2.48 - 2.39 (m, 1H), 1.55 - 1.44 (m, 1H), 1.38 (d, J = 7.6 Hz, 1H), 1.16 - 1.03 (m, 1H), 1.00 (s, 3H), 0.98 - 0.91 (m, 6H), 0.86 (s, 3H), 0.43 - 0.29 (m, 4H).

[0331] To a stirred solution of (1R,2S,5S)-3-((S)-2-cyclopropyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Compound 171) (170 mg, 0.53 mmol) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (Compound 151) (124 mg, 0.6 mmol) in DMF (5 mL) was added DIEA (0.205 g, 1.59 mmol) and HATU (0.229 g, 0.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 172 (150 mg, 59.5%) as an off-white solid. LCMS = [M+H] + :476.4. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.61 (s, 1H), 7.16 (s, 1H), 7.05 (s, 1H), 4.27 - 4.19 (m, 1H), 4.17 (s, 1H), 4.12 - 4.06 (m, 1H), 3.84 - 3.76 (m, 1H), 3.66 (d, J = 10.4 Hz, 1H), 3.18 - 3.05 (m, 2H), 2.47 - 2.41 (m, 1H), 2.40 - 2.28 (m, 1H), 2.25 - 2.10 (m, 1H), 2.01 - 1.85 (m, 1H), 1.73 - 1.51 (m, 2H), 1.51 - 1.42 (m, 1H), 1.39 - 1.32 (m, 1H), 1.13 - 1.04 (m, 1H), 1.04 - 0.99 (m, 4H), 0.98 - 0.90 (m, 6H), 0.87 (s, 2H), 0.47 - 0.22 (m, 4H).

[0332] To a stirred solution of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-cyclopropyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 172) (150 mg, 0.31 mmol) in DCM (10 mL) was added Burgess reagent (0.147 g, 0.62 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-2-b (50 mg, 35.2%) as a white solid. LCMS = [M+H] + :458.3, HPLC:99.55%. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.69 (s, 1H), 5.01 - 4.85 (m, 1H), 4.15 - 3.98 (m, 2H), 3.85 - 3.74 (m, 1H), 3.69 (d, J = 10.3 Hz, 1H), 3.21 - 3.03 (m, 2H), 2.49 - 2.35 (m, 2H), 2.19 - 2.07 (m, 2H), 1.81 - 1.63 (m, 2H), 1.57 - 1.48 (m, 1H), 1.28 (d, J = 7.5 Hz, 1H), 1.10 - 0.99 (m, 4H), 0.99 - 0.85 (m, 9H), 0.44 - 0.27 (m, 4H). (Example S40) Synthesis of compound D-2-c [ka]

[0333] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-amino-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (compound 168) (220 mg, 0.73 mmol) in DCM (10 mL) was added DIEA (0.387 g, 3 mmol) and cyclopropanecarbonyl chloride (compound 173) (91 mg, 0.87 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 174 (170 mg, 69.5%) as a white solid. LCMS = [M+H] + :335.2. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 7.3 Hz, 1H), 4.16 (s, 1H), 4.03 - 3.94 (m, 1H), 3.81 - 3.69 (m, 2H), 3.66 (s, 3H), 1.74 - 1.62 (m, 1H), 1.56 - 1.48 (m, 1H), 1.40 (d, J = 7.5 Hz, 1H), 1.17 - 1.03 (m, 1H), 1.01 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 33.8 Hz, 3H), 0.70 - 0.53 (m, 4H), 0.45 (d, J = 8.1 Hz, 2H), 0.38 - 0.24 (m, 2H).

[0334] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-(cyclopropanecarboxamido)-2-cyclopropyl-acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 174) (170 mg, 0.51 mmol) in THF / water (10 mL, 2:1) was added LiOH (27 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3–4 with 1 M HCl, and extracted with DCM (50 mL × 3). The combined organic layers were concentrated under reduced pressure to a low volume, and the resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 175 (150 mg, 92%) as an off-white solid. LCMS=[M+H] + :321.2. 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.76 - 3.67 (m, 2H), 1.74 - 1.63 (m, 1H), 1.55 - 1.44 (m, 1H), 1.37 (d, J = 7.5 Hz, 1H), 1.15 - 1.05 (m, 1H), 1.01 (d, J = 7.8 Hz, 3H), 0.84 (s, 3H), 0.70 - 0.54 (m, 4H), 0.48 - 0.17 (m, 4H).

[0335] To a stirred solution of (1R,2S,5S)-3-((S)-2-(cyclopropanecarboxamido)-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Compound 175) (150 mg, 0.47 mmol) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (Compound 151) (124 mg, 0.6 mmol) in DMF (5 mL) was added DIEA (0.205 g, 1.59 mmol) and HATU (0.229 g, 0.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting crude product was purified by reverse-phase column chromatography to give compound 176 (140 mg, 62.8%) as an off-white solid. LCMS = [M+H] + :474.4. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 4.29 - 4.20 (m, 1H), 4.20 - 4.07 (m, 2H), 3.82 - 3.74 (m, 1H), 3.67 (d, J = 10.3 Hz, 1H), 3.19 - 3.03 (m, 2H), 2.42 - 2.30 (m, 1H), 2.21 - 2.09 (m, 1H), 2.00 - 1.86 (m, 1H), 1.73 - 1.42 (m, 4H), 1.39 - 1.33 (m, 1H), 1.13 - 1.04 (m, 1H), 1.03 - 0.97 (m, 3H), 0.85 (d, J = 12.2 Hz, 3H), 0.68 - 0.54 (m, 4H), 0.49 - 0.32 (m, 4H).

[0336] To a stirred solution of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-(cyclopropanecarboxamide)-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]-hexane-2-carboxamide (compound 176) (140 mg, 0.29 mmol) in DCM (10 mL) was added Burgess reagent (0.143 g, 0.6 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. After the reaction was complete (monitored by LCMS), the mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-2-c (74 mg, 55.9%) as a white solid. LCMS = [M+H] + :456.3, HPLC:95.06%. 1H NMR (400 MHz, DMSO-d6) δ 8.94 - 8.85 (m, 1H), 8.41 (d, J = 7.4 Hz, 1H), 7.67 (s, 1H), 5.01 - 4.81 (m, 1H), 4.15 - 3.97 (m, 2H), 3.80 - 3.73 (m, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.21 - 3.04 (m, 2H), 2.45 - 2.35 (m, 1H), 2.21 - 2.08 (m, 2H), 1.80 - 1.63 (m, 3H), 1.56 - 1.49 (m, 1H), 1.27 (d, J = 7.6 Hz, 1H), 1.11 - 0.98 (m, 4H), 0.97 - 0.84 (m, 3H), 0.69 - 0.51 (m, 4H), 0.46 - 0.27 (m, 4H). (Example S41) Synthesis of compound D-2-d [ka]

[0337] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-amino-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (compound 168) (1.0 g, 3.31 mmol) in DCM (10 mL) at 0 °C, DIEA (1.28 g, 9.93 mmol) and 2,2-difluoroacetic anhydride (0.63 g, 3.6 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed (monitored by LCMS), the reaction mixture was diluted with DCM, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 177 (1.0 g, 87.5%) as a white solid. LCMS = [M+H] + :345.2. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 6.5 Hz, 1H), 6.39 - 6.04 (m, 1H), 4.20 (d, J = 5.4 Hz, 1H), 4.10 - 4.02 (m, 1H), 3.83 - 3.72 (m, 2H), 3.70 - 3.62 (m, 3H), 1.62 - 1.53 (m, 1H), 1.48 - 1.39 (m, 1H), 1.19 - 1.11 (m, 1H), 1.03 (d, J = 5.2 Hz, 3H), 0.95 - 0.87 (m, 3H), 0.58 - 0.23 (m, 4H).

[0338] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-cyclopropyl-2-(2,2-difluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 177) (1.0 g, 2.9 mmol) in THF / water (10 mL, 2:1) was added LiOH (0.139 g, 5.8 mmol). The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3–4 with 1 M HCl, and extracted with ethyl acetate (100 mL × 2). The combined organic layers were concentrated under reduced pressure to a low volume, and the resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 178 (550 mg, 57%) as an off-white solid. LCMS=[M+H] + :331.2. 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.96 (d, J = 7.0 Hz, 1H), 6.16 - 5.81 (m, 1H), 3.94 - 3.78 (m, 2H), 3.58 - 3.41 (m, 2H), 1.36 - 1.24 (m, 1H), 1.16 (d, J = 7.5 Hz, 1H), 0.95 - 0.86 (m, 1H), 0.78 (d, J = 5.3 Hz, 3H), 0.64 (s, 3H), 0.28 - 0.03 (m, 4H).

[0339] To a stirred solution of (1R,2S,5S)-3-((S)-2-cyclopropyl-2-(2,2-difluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Compound 178) (250 mg, 0.75 mmol) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (Compound 151) (187 mg, 0.91 mmol) in DMF (5 mL) was added DIEA (0.29 g, 2.25 mmol) and HATU (0.342 g, 0.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by reverse-phase column chromatography to give compound 179 (180 mg, 49.5%) as an off-white solid. LCMS = [M+H] + :483.8.

[0340] To a stirred solution of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-cyclopropyl-2-(2,2-difluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 179) (180 mg, 0.37 mmol) in DCM (10 mL) was added Burgess reagent (0.176 g, 0.74 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-2-d (63 mg, 36.5%) as a white solid. LCMS = [M+H] + :466.4, HPLC:99.55%. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 6.9 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 6.37 - 6.03 (m, 1H), 5.04 - 4.90 (m, 1H), 4.21 - 4.14 (m, 1H), 4.12 (s, 1H), 3.87 - 3.78 (m, 1H), 3.69 (d, J = 10.3 Hz, 1H), 3.18 - 3.04 (m, 2H), 2.44 - 2.34 (m, 1H), 2.18 - 2.07 (m, 2H), 1.81 - 1.63 (m, 2H), 1.59 - 1.53 (m, 1H), 1.30 (d, J = 7.6 Hz, 1H), 1.17 - 1.08 (m, 1H), 1.03 (s, 3H), 0.90 (s, 3H), 0.51 - 0.37 (m, 4H). (Example S42) Synthesis of compounds D-2-e and D-2-f [ka]

[0341] To a solution of dimethyl(tert-butoxycarbonyl)-L-glutamate (compound 180-1) (20 g, 72.7 mmol) in anhydrous THF (300 mL) was added lithium bis(trimethylsilyl)amide (145 mL, 1.0 M in THF, 145 mmol) dropwise under nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and bromopropionitrile (6.8 mL, 82 mmol) was added dropwise with stirring. The reaction mixture was continuously stirred at −78° C. for 2 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched dropwise with glacial acetic acid (10 mL). The reaction mixture was warmed to room temperature, and the organic solvent was removed under reduced pressure. The residue was diluted with water (200 mL) and extracted with DCM (200 mL × 2). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash column chromatography (PE:ethyl acetate=2:1) ​​to give compound 180-2 as a pale yellow oil (4.0 g, 16.7%). LCMS=[M+H] + :329.1. 1 H NMR (400 MHz, CDCl3) δ 5.05 (d, J = 8.2 Hz, 1H), 4.42 - 4.29 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.68 - 2.58 (m, 1H), 2.43 - 2.34 (m, 2H), 2.08 - 1.94 (m, 4H), 1.45 (s, 9H).

[0342] To a solution of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2-cyanoethyl)pentanedioate (compound 180-2) (4 g, 12.2 mmol) and cobalt chloride hexahydrate (3.2 g, 11.6 mmol) in methanol (50 mL) was added sodium borohydride (4.8 g, 126 mmol) portionwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with saturated ammonium chloride (30 mL) and stirred for 10 min. The reaction mixture was filtered, and the filtrate was concentrated to a low volume to remove the organic solvent. The resulting residue was extracted with DCM (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to a low volume. The resulting residue was purified by column chromatography to give compound 180-3 (1.78 g, 48.7%) as a white semi-solid. LCMS=[M+H] + :301.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.31 (m, 2H), 4.12 - 4.02 (m, 1H), 3.61 (s, 4H), 3.14 - 3.06 (m, 2H), 2.21 - 2.07 (m, 2H), 1.92 - 1.83 (m, 1H), 1.82 - 1.71 (m, 1H), 1.67 - 1.53 (m, 2H), 1.43 - 1.35 (m, 10H).

[0343] A sealed pressure tube was charged with methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoate (compound 180-3) (1.78 g, 5.93 mmol) and 4 M ammonia in MeOH (2.8 mL). The reaction mixture was stirred at 65° C. for 16 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give crude compound 180-4 (1.7 g), which was used directly in the next reaction without further purification. LCMS=[M+H] + :285.9.

[0344] A mixture of crude tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate (compound 180-4) (1.7 g, crude) in HCl (4.0 M in isopropanol) (20 mL) was stirred at room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by reverse-phase column chromatography to give compound 180 (870 mg, 66% for two steps) as a white solid. LCMS = [M+H] + :186.1.

[0345] To a stirred solution of (1R,2S,5S)-3-((S)-2-cyclopropyl-2-(2,2-difluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 178) (300 mg, 0.91 mmol) and (R)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanamide hydrochloride (compound 180) (231 mg, 1.0 mmol) in DMF (5 mL) at 0 °C, DIEA (0.352 g, 2.73 mmol) and HATU (0.81 g, 1.0 mmol) were added. The reaction mixture was stirred at room temperature under N for 1 h. After completion of the reaction (monitored by LCMS), the mixture was diluted with EtOAc, washed with water, 1 M HCl, saturated NaCl, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by reverse phase column chromatography to give compound 181 (230 mg, 50.7%) as an off-white solid. LCMS = [M+H] + :498.3. 1H NMR (400 MHz, DMSO) δ 9.38 - 9.02 (m, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.51 - 7.30 (m, 1H), 7.25 - 6.90 (m, 2H), 6.38 - 6.05 (m, 1H), 4.40 - 3.97 (m, 3H), 3.92 - 3.78 (m, 1H), 3.69 - 3.60 (m, 1H), 3.11 (s, 2H), 2.26 - 2.10 (m, 1H), 2.01 - 1.88 (m, 1H), 1.77 - 1.64 (m, 1H), 1.65 - 1.11 (m, 7H), 1.05 - 0.85 (m, 6H), 0.59 - 0.34 (m, 4H).

[0346] To a stirred solution of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-((S)-2-cyclopropyl-2-(2,2-difluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 181) (230 mg, 0.46 mmol) in DCM (10 mL) was added Burgess reagent (0.22 g, 0.92 mmol). The reaction mixture was stirred at room temperature under N for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give two isomers: Compound D-2-e (56 mg, 25.9%) and Compound D-2-f (6 mg, 2.8%) as a white solid. LCMS = [M+H] + :480.4. HPLC:99.10%.

[0347] D-2-e: HPLC: 99.10%. 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 7.1 Hz, 1H), 8.92 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 6.38 - 6.06 (m, 1H), 5.06 - 4.94 (m, 1H), 4.18 - 4.06 (m, 2H), 3.85 - 3.76 (m, 1H), 3.68 (d, J = 10.5 Hz, 1H), 3.09 (s, 2H), 2.34 - 2.24 (m, 2H), 1.88 (s, 1H), 1.79 - 1.66 (m, 2H), 1.65 - 1.51 (m, 2H), 1.44 - 1.35 (m, 1H), 1.30 - 1.26 (m, 1H), 1.16 - 1.09 (m, 1H), 1.07 - 1.01 (m, 3H), 0.97 - 0.87 (m, 3H), 0.51 - 0.37 (m, 4H).

[0348] D-2-f:HPLC: 86.15%; 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 7.3 Hz, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 6.37 - 6.04 (m, 1H), 4.60 - 4.54 (m, 1H), 4.13 (s, 1H), 4.11 - 4.04 (m, 1H), 3.84 - 3.77 (m, 1H), 3.65 (d, J = 10.5 Hz, 1H), 3.17 - 3.10 (m, 1H), 3.05 - 2.97 (m, 1H), 2.36 - 2.22 (m, 2H), 1.94 - 1.84 (m, 1H), 1.74 - 1.63 (m, 1H), 1.52 - 1.41 (m, 3H), 1.40 - 1.30 (m, 1H), 1.28 (d, J = 7.6 Hz, 1H), 1.19 - 1.11 (m, 1H), 1.07 - 0.99 (m, 3H), 0.96 - 0.82 (m, 3H), 0.57 - 0.36 (m, 4H). (Example S43) Synthesis of compound D-3-a [ka]

[0349] To a stirred solution of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 156) (400 mg, 1.1 mmol) and (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanamide hydrochloride (compound 180) (0.265 g, 1.2 mmol) in DMF (5 mL) was added DIEA (0.387 g, 3 mmol) and HATU (0.457 g, 1.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 4 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 182 (270 mg, 46%) as an off-white solid. LCMS = [M+H] + :532.6. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 4.42 (d, J = 8.6 Hz, 1H), 4.33 - 4.21 (m, 2H), 3.91 - 3.84 (m, 1H), 3.74 - 3.61 (m, 1H), 3.15 - 3.05 (m, 2H), 2.29 - 2.12 (m, 2H), 1.97 - 1.87 (m, 1H), 1.72 - 1.63 (m, 1H), 1.60 - 1.46 (m, 3H), 1.36 (d, J = 7.7 Hz, 1H), 1.33 - 1.24 (m, 1H), 1.01 (s, 3H), 0.99 (s, 9H), 0.84 (s, 3H).

[0350] To a stirred solution of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 182) (300 mg, 0.56 mmol) in DCM (10 mL) was added Burgess reagent (266 mg, 1.12 mmol). The solution was stirred at room temperature under N for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by preparative HPLC to afford compound D-3-a (206 mg, 71%) as a white solid. LCMS=[M+H] + :514.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 8.3 Hz, 1H), 8.99 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 5.09 - 4.92 (m, 1H), 4.41 (d, J = 8.3 Hz, 1H), 4.17 (s, 1H), 3.97 - 3.83 (m, 1H), 3.68 (d, J = 10.4 Hz, 1H), 3.09 (s, 2H), 2.34 - 2.19 (m, 2H), 1.92 - 1.80 (m, 1H), 1.79 - 1.64 (m, 2H), 1.60 - 1.50 (m, 2H), 1.42 - 1.22 (m, 2H), 1.03 (s, 3H), 0.99 (s, 9H), 0.85 (s, 3H). (Example S44) Synthesis of compound D-3-b [ka] [ka]

[0351] A solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 153) (10 g, 26.2 mmol) in HCl in dioxane (4 M, 100 mL) was stirred at room temperature for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give crude compound 183 (9.1 g) as a yellow semi-solid. LCMS = [M+H] + :283.3.

[0352] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (compound 183) (9.1 g, 28.6 mmol) in DCM (100 mL) was added DIEA (11.1 g, 85.8 mmol) and 2,2-difluoroacetic anhydride (4.98 g, 28.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed (monitored by LCMS), the reaction mixture was diluted with water (40 mL) and extracted with DCM (200 mL × 3). The combined organic layers were washed with 0.5 M HCl (60 mL x 3) and saturated NaHCO (50 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume to give compound 184 (9.4 g, 91%) as a yellow oil. LCMS = [M+H] + :361.4. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 8.7 Hz, 1H), 6.28 (t, J = 53.7 Hz, 1H), 4.41 (d, J = 8.7 Hz, 1H), 4.22 (s, 1H), 3.90 - 3.82 (m, 1H), 3.79 (d, J = 10.5 Hz, 1H), 3.67 (s, 3H), 1.59 - 1.53 (m, 1H), 1.45 (d, J = 7.5 Hz, 1H), 1.01 (s, 3H), 0.98 (s, 9H), 0.84 (s, 3H).

[0353] To a stirred solution of methyl (1R,2S,5S)-3-((S)-2-(2,2-difluoroacetamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (compound 184) (9.4 g, 26 mmol) in THF / water (100 mL, 2:1) was added LiOH (1.56 g, 65 mmol). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water, the pH was adjusted to approximately 3-4 with 1 M HCl, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume to give compound 185 (8.6 g, 95%) as a white solid. LCMS = [M+H] + :347.1. 1 H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 8.85 (d, J = 8.8 Hz, 1H), 6.28 (t, J = 53.7 Hz, 1H), 4.42 (d, J = 8.9 Hz, 1H), 4.14 (s, 1H), 3.91 - 3.70 (m, 2H), 1.58 - 1.47 (m, 1H), 1.43 (d, J = 7.5 Hz, 1H), 1.06 - 0.94 (m, 12H), 0.84 (s, 3H).

[0354] To a stirred solution of (1R,2S,5S)-3-((S)-2-(2,2-difluoroacetamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 185) (6.6 g, 19.0 mmol) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (compound 151) (5.14 g, 24.7 mmol) in DMF (50 mL) was added HATU (8.67 g, 22.8 mmol) and DIEA (9.81 g, 76 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 186 (7.0 g, 73%) as an off-white solid. LCMS = [M+H] + :500.7. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.31 (s, 1H), 7.03 (s, 1H), 6.27 (t, J = 53.8 Hz, 1H), 4.40 (d, J = 8.9 Hz, 1H), 4.34 - 4.24 (m, 2H), 3.92 - 3.84 (m, 1H), 3.70 (d, J = 10.4 Hz, 1H), 3.16 - 3.09 (m, 1H), 3.07 - 2.97 (m, 1H), 2.46 - 2.36 (m, 1H), 2.17 - 2.06 (m, 1H), 2.00 - 1.89 (m, 1H), 1.71 - 1.58 (m, 1H), 1.54 - 1.45 (m, 2H), 1.38 (d, J = 7.7 Hz, 1H), 1.02 (s, 3H), 0.96 (s, 9H), 0.82 (s, 3H).

[0355] To a stirred solution of (1R,2S,5S)—N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-(2,2-difluoroacetamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 186) (5.0 g, 10 mmol) in DCM (50 mL) was added Burgess reagent (4.76 g, 20 mmol). The reaction mixture was stirred at room temperature under N for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was washed with brine, and the organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by flash column chromatography (DCM / MeOH=30:1) to give compound D-3-b (3.12 g, 64.7%) as a white solid. LCMS=[M+H] + :482.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 8.5 Hz, 1H), 8.84 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 6.27 (t, J = 53.7 Hz, 1H), 5.03 - 4.91 (m, 1H), 4.38 (d, J = 8.7 Hz, 1H), 4.14 (s, 1H), 3.95 - 3.85 (m, 1H), 3.73 (d, J = 10.5 Hz, 1H), 3.18 - 3.10 (m, 1H), 3.07 - 2.99 (m, 1H), 2.44 - 2.35 (m, 1H), 2.20 - 2.01 (m, 2H), 1.78 - 1.64 (m, 2H), 1.61 - 1.51 (m, 1H), 1.31 (d, J = 7.6 Hz, 1H), 1.03 (s, 3H), 0.96 (s, 9H), 0.86 (s, 3H).

[0356] (Example S45) Synthesis of compound D-3-c [ka]

[0357] To a stirred solution of (1R,2S,5S)-3-((S)-2-(2,2-difluoroacetamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (compound 185) (346 mg, 1.0 mmol) and (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanamide hydrochloride (compound 180) (0.265 g, 1.2 mmol) in DMF (5 mL) was added DIEA (0.387 g, 3 mmol) and HATU (0.457 g, 1.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by column chromatography (C18, ACN / water (0.1% FA)) to give compound 187 (300 mg, 58%) as an off-white solid. LCMS = [M+H] + :514.5. 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 7.00 (s, 1H), 6.28 (t, J = 53.8 Hz, 1H), 4.40 (d, J = 8.9 Hz, 1H), 4.33 - 4.22 (m, 2H), 3.94 - 3.83 (m, 1H), 3.70 (d, J = 10.3 Hz, 1H), 3.08 (s, 2H), 2.31 - 2.12 (m, 2H), 1.98 - 1.86 (m, 1H), 1.74 - 1.63 (m, 1H), 1.61 - 1.44 (m, 3H), 1.39 - 1.33 (m, 1H), 1.32 - 1.23 (m, 1H), 1.02 (s, 3H), 0.96 (s, 9H), 0.84 (s, 3H).

[0358] To a stirred solution of (1R,2S,5S)—N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-((S)-2-(2,2-difluoroacetamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 187) (300 mg, 0.58 mmol) in DCM (10 mL) was added Burgess reagent (276 mg, 1.16 mmol). The reaction mixture was stirred at room temperature under N for 4 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was washed with brine, and the organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-3-c (86 mg, 29.9%) as a white solid. LCMS = [M+H] + :496.4. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 8.3 Hz, 1H), 8.83 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 6.27 (t, J = 53.7 Hz, 1H), 5.05 - 4.94 (m, 1H), 4.38 (d, J = 8.8 Hz, 1H), 4.16 (s, 1H), 3.93 - 3.87 (m, 1H), 3.73 (d, J = 10.4 Hz, 1H), 3.08 (s, 2H), 2.37 - 2.29 (m, 1H), 2.28 - 2.18 (m, 1H), 1.89 - 1.81 (m, 1H), 1.79 - 1.64 (m, 2H), 1.60 - 1.48 (m, 2H), 1.38 (t, J = 10.2 Hz, 1H), 1.30 - 1.21 (m, 1H), 1.02 (s, 3H), 0.96 (s, 9H), 0.83 (s, 3H). (Example S46) Synthesis of compound D-4-a [ka]

[0359] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (compound 188) (1.35 g, 5 mmol) and (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (compound 151) (1.2 g, 5.5 mmol) in DMF (20 mL) was added HATU (1.9 g, 5 mmol) and DIEA (2.58 g, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was diluted with water and extracted with ethyl acetate (200 mL x 3). The combined organic layers were concentrated under reduced pressure to a low volume. The resulting residue was purified by reverse-phase column chromatography to give compound 189 (1.8 g, 4.24 mmol, 84.80%) as a red solid. LCMS = [M+H] + :425.1. 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.21 (s, 1H), 5.75 (s, 1H), 5.38 (s, 1H), 5.04 (d, J = 6.4 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.12 - 4.02 (m, 1H), 3.43 - 3.32 (m, 2H), 2.49 - 2.34 (m, 2H), 2.15 - 1.97 (m, 2H), 1.96 - 1.84 (m, 1H), 1.78 (d, J = 13.0 Hz, 1H), 1.73 - 1.66 (m, 3H), 1.49 - 1.32 (m, 12H), 1.31 - 1.08 (m, 4H), 1.01 - 0.85 (m, 2H).

[0360] To a solution of tert-butyl N-[(1S)-1-{[1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]carbamoyl}-2-cyclohexylethyl]carbamate (compound 189) (400 mg, 0.94 mmol) in ethyl acetate (8 mL) was added HCl (4.0 M in EtOAc, 2 mL). The reaction mixture was stirred at 25° C. for 2 hours. After the reaction was complete (monitored by LCMS), the mixture was concentrated under reduced pressure to a low volume to give crude compound 190 (397 mg, 1.22 mmol, 100%) as a white solid, which was used in the next reaction without further purification. LCMS = [M+H] + :325.2.

[0361] To a solution of 2-[(2S)-2-amino-3-cyclohexylpropanamido]-3-(2-oxopyrrolidin-3-yl)propenamide (Compound 190) (397 mg, 1.22 mmol) in ACN (40 mL) and DMF (4 mL) was added 2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (Compound 152) (311.33 mg, 1.35 mmol), DIEA (0.807 mL, 4.88 mmol), and HATU (695.82 mg, 1.83 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layer was washed with brine (40 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (C18, ACN / water (0.1% FA)) to give compound 191 (420 mg, 0.78 mmol, 63.83%) as a white solid. LCMS = [M+H] + :538.1.

[0362] To a stirred solution of tert-butyl N-(1-{[(1S)-1-{[1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]carbamoyl}-2-cyclohexylethyl]carbamoyl}-2,2-dimethylpropyl)carbamate (compound 191) (420 mg, 0.78 mmol) in ethyl acetate (5 mL) was added HCl (4.0 M in ethyl acetate, 10 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume to give compound 192 (330 mg, 0.70 mmol, 89.12%) as a white solid, which was used in the next reaction without further purification. LCMS = [M+H] + :438.3.

[0363] To a solution of 2-amino-N-[(1S)-1-{[1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]carbamoyl}-2-cyclohexylethyl]-3,3-dimethylbutanamide (compound 192) (330 mg, 0.75 mmol) in DCM (5 mL) was added dropwise DIEA (0.137 mL, 0.83 mmol) and TFAA (0.420 mL, 3.02 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC (C18, ACN / water (0.1% FA)) to give compound 193 (90 mg, 0.17 mmol, 22.37%) as a white solid. LCMS = [M+H] + :534.1.

[0364] To a solution of N-[(1S)-1-{[1-carbamoyl-2-(2-oxopyrrolidin-3-yl)ethyl]carbamoyl}-2-cyclohexylethyl]-3,3-dimethyl-2-(trifluoroacetamido)butanamide (compound 193) (90 mg, 0.17 mmol) in DCM (5 mL) was added Burgess reagent (81 mg, 0.34 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was purified by preparative HPLC to give compound D-4-a (10 mg, 0.02 mmol, 11.50%) as a white solid. LCMS = [M+H] + :516.3. HPLC:89.75%. 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 9.3 Hz, 1H), 8.91 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.67 (s, 1H), 4.98 - 4.87 (m, 1H), 4.41 (d, J = 9.3 Hz, 1H), 4.27 - 4.18 (m, 1H), 3.19 - 3.11 (m, 1H), 3.10 - 3.00 (m, 1H), 2.39 - 2.29 (m, 1H), 2.21 - 2.02 (m, 2H), 1.79 - 1.55 (m, 7H), 1.53 - 1.39 (m, 2H), 1.33 - 1.20 (m, 1H), 1.20 - 1.03 (m, 3H), 0.99 - 0.80 (m, 11H). (Example S47) Synthesis of compounds E-1-a and E-1-b [ka]

[0365] To a solution of methyl (S)-2-amino-3-cyclohexylpropanoate (compound 194) (15 g, 67.65 mmol) in MeOH / THF (75 mL / 75 mL) was added compound 195 (23.59 g, 135.30 mmol), AcOH (8.13 g, 135.30 mmol), and NaBHCN (4.26 g, 67.65 mmol). The reaction mixture was stirred at 60 °C for 6 h. After the reaction was completed (monitored by LCMS), the reaction mixture was cooled to room temperature, concentrated to a reduced volume to remove the organic solvent, basified with saturated NaHCO, and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine solution (100 mL) and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash column chromatography (PE / ethyl acetate = 50:1) to give compound 196 (5.34 g) as a colorless oil. LCMS=[M+H] + :226.4.

[0366] To a stirred solution of compound 196 (5.34 g, 23.71 mmol) in THF / HO (50 mL, 1:1) was added dropwise NaCO (5.03 g, 47.42 mmol) and Cbz-Cl (4.86 g, 28.46 mmol) at 5 °C. The reaction mixture was stirred at 5 °C for 30 min, warmed to room temperature, and stirred for 2 h. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash column chromatography (PE / ethyl acetate = 30:1) to give compound 197 (6.17 g) as a colorless oil. LCMS = [M+H] + :360.3.

[0367] To a stirred solution of compound 197 (5.17 g, 14.39 mmol) in MeOH (150 mL) was added 1 M LiOH (aq) (72 mL). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure to a low volume. The resulting residue was diluted with water (25 mL), acidified with saturated citric acid, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to a low volume to give crude compound 198 (5.17 g) as a colorless oil. LCMS = [M+H] + :346.2.

[0368] To a solution of compound 198 (5.17 g, 14.97 mmol) in anhydrous DMF (25 mL) was added HATU (8.54 g, 22.46 mmol) and DIEA (9.67 g, 74.88 mmol) at 5 °C. The reaction mixture was stirred at 5 °C for 10 minutes, followed by the addition of compound 199 (3.14 g, 22.46 mmol). The reaction mixture was stirred at 5 °C for 30 minutes and at room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the mixture was diluted with water (30 mL) and extracted with ethyl acetate (90 mL × 2). The combined organic layers were washed with brine (30 mL) and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash column chromatography (PE / ethyl acetate = 10:1) to give compound E-1-a (5.1 g) as a colorless oil. LCMS = [M+H] + :431.4.

[0369] To a stirred solution of compound E-1-a (2.77 g, 6.44 mmol) in anhydrous THF (27 mL) was added lithium borohydride (16.1 mL, 32.2 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. After the reaction was completed (monitored by LCMS), the reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash column chromatography (PE / ethyl acetate = 20:1) to give compound 200 (1.69 g) as a colorless oil. LCMS = [M+H] + :403.2.

[0370] To a stirred solution of compound 200 (1.69 g, 4.20 mmol) in anhydrous DCM (16 mL) was added Dess-Martin periodinane (5.34 g, 12.60 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 10 minutes and warmed to room temperature for 2 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with 10% aqueous sodium thiosulfate solution (20 mL). The organic layer was washed with 10% aqueous sodium thiosulfate solution (20 mL), saturated sodium bicarbonate (20 mL × 2), water (20 mL × 2), and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to a reduced volume. The resulting residue was purified by flash column chromatography (DCM / MeOH = 20:1) to give compound E-1-b (320 mg) as a colorless oil. LCMS = [M+H] + :401.44. (Example S48) Synthesis of compound F-1-a [ka]

[0371] To a solution of compound 146 (1.2 g, 3.0 mmol) in anhydrous DMF (15 mL) was added compound 199 (400 mg, 3.0 mmol), HATU (1.7 g, 4.5 mmol), and DIEA (1.2 g, 9.0 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and saturated NaCl, and the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to a low volume. The resulting residue was purified by flash column chromatography (EtOAc:hexane = 1:5) to give compound 201 (1.4 g, 95.9%). LCMS = [M+H] + :488.4.

[0372] ...

Claims

1. A compound of formula (I): 【Chemical 225】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof [wherein, Z is -CH ２ CN, -C(=O)-CH=CH ２ , -NH-C(=O)-CH=CH ２ , -CH ２ -C(=O)-CH=CH ２ , -CH(OH)SO ３ － (and associated cations such as Na ＋ ), -C(=O)OH, -CH(OCH ３ )2, and is selected from L is -NH C(=O)-, -C(=O)-NH-, -NH C(=O)-CHR2-NH C(=O)-, or -C(=O)NH-CHR2-C(=O)NH-; R １ is indril, R ２ is each independently selected from C １～６ alkyl, 3- to 7-membered cycloalkyl, C １～３ alkyl-(3- to 7-membered cycloalkyl) and (3- to 7-membered cycloalkyl)-C １～３ alkyl, and each of these is optionally substituted by up to three groups independently selected from halo, CN, C １～３ alkyl, C １～６ alkoxy, C １～３ haloalkyl and C １～３ haloalkoxy, R ３ is H or C １～４ and is alkyl, R ＊ each represents C １～３ alkyl, C １～３ alkoxy, C １～３ haloalkyl, CN, halo and -OH, independently selected m is an integer from 0 to 2; n is an integer from 0 to 4].

2. The compound according to claim 1, wherein the compound is 【Chemical 301】 and an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, selected from

3. A compound of formula (IE) 【Chemical 234】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof [wherein, p is 0], which is the compound according to claim 1.

4. A compound of formula (IF) 【Chemical 235】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof [wherein, R ５ is hydrogen], the compound according to claim 1.

5. A compound of formula (IG) 【Chemical 236】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof [wherein, R5 is hydrogen], which is the compound according to claim 1.

6. A compound of formula (IG2) 【Chemical 238】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the compound according to claim 1.

7. R ２ is, independently of one another, C １～６ alkyl optionally substituted by alkoxy, C １～４ alkyl, 3- to 7-membered cycloalkyl, C １～２ alkyl-(C ３～６ cycloalkyl) or (C ３～６ cycloalkyl)C １～２ alkyl, preferably, each R 2 is independently methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, isopropylmethyl, 1-methyl-t-butoxyethyl, cyclopropyl, cyclohexyl, cyclopropylmethyl or cyclohexylmethyl, preferably, each R 2 is independently t-butyl, isopropylmethyl, cyclohexylmethyl or 1-methyl-t-butoxyethyl, the compound according to any one of claims 1 and 3 to 6.

8. The compound according to any one of claims 1, 3, or 4, wherein n is 1, 2, or 3, preferably n is 1.

9. The compound according to claim 1 or 3, wherein m is 0.

10. Z is -C(=O)OH, -NH-C(=O)CH=CH ２ , -C(=O)CH=CH ２ , -CH(OCH ３ ), or -CH(OH)SO ２ , or -CH(OH)SO ３ － (and associated cations such as Na ＋ ), and preferably Z is -CH(OH)SO 3 - (and associated cations such as Na +), a compound according to any one of claims 1 to 6.

11. The compound is: 【Chemical 239】 【Chemical 240】 【Chemical Formula 241】 【Chemical 242】 and tautomers, a mixture of two or more tautomers, and isotopic variants thereof; and a pharmaceutically acceptable salt, solvate, and hydrate thereof, the compound according to claim 1.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and at least one pharmaceutically acceptable excipient, and optionally comprising a second therapeutic agent.

13. A composition comprising the compound according to any one of claims 1 to 6 for use in therapy.

14. The composition according to claim 13, wherein the therapy is for the treatment of a viral infection.

15. The composition according to claim 14, wherein the viral infection is a coronavirus infection, and optionally, the coronavirus infection is a SARS-CoV-2 infection.

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