Cysteine protease inhibitors and methods of use thereof

1. A compound having Formula V:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

R 1 is selected from the group consisting of:

R 2a is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, and —C 1-6 alkyl-C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, or —C 1-6 alkyl-C 3-6 cycloalkyl is independently optionally substituted with one, two, three, or four groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR 5 , and —N(R 5 )(R 6 );

R 3 is selected from the group consisting of:

R 3a , R 3b , R 3c , and R 3d are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 ); or

R 3a and R 3b taken together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is independently optionally substituted with one or two C 1-6 alkyl groups; and

R 3c and R 3d are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 ); or

R 3b and R 3c taken together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is independently optionally substituted with one or two C 1-6 alkyl groups; and

R 3a and R 3d are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 ); or

R 3c and R 3d taken together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is independently optionally substituted with one or two C 1-6 alkyl groups; and

R 3a and R 3b are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 );

R 3e is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 3f , R 3g , R 3h , and R 3i are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 ); or

R 3f and R 3g taken together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is independently optionally substituted with one or two C 1-6 alkyl groups; and

R 3h and R 3i are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 ); or

R 3g and R 3h taken together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is independently optionally substituted with one or two C 1-6 alkyl groups; and

R 3f and R 3i are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 ); or

R 3h and R 3i taken together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl, wherein the 5- or 6-membered heterocycloalkyl is independently optionally substituted with one or two C 1-6 alkyl groups; and

R 3f and R 3g are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —OR 5 , and —N(R 5 )(R 6 );

R 3j is selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl;

R 3k is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl;

R 3m is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 4a is C 1-3 alkyl;

R 4b is selected from the group consisting of hydrogen and C 1-3 alkyl; or

R 4a and R 4b taken together with the nitrogen to which they are attached form a 3- to 8-membered heterocycloalkyl;

each R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1 -heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl are independently optionally substituted with one, two, or three groups independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl;

each R 6 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;

R 7 is selected from the group consisting of —OR 7a and —NR 7b R 7c ;

R 7a is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

R 7b and R 7c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

R 8a , R 8b , and R 8c are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and —N(R 5 )(R 6 ); and

R 9a , R 9b , R 9c , and R 9d are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR 5 , and —N(R 5 )(R 6 ).

2. The compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , wherein R 1 is R 1 -1 and R 8a , R 8b , and R 8c are hydrogen.

3. The compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , wherein R 1 is R 1 -2 and R 9a , R 9b , R 9c , and Rod are hydrogen.

4. The compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , wherein R 3 is R 3 -1 and R 3 -1 is selected from the group consisting of:

5. The compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , wherein R 3 is R 3 -2 and R 3 -2 is selected from the group consisting of:

6. The compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , wherein R 3 is R 3 -3;

R 3 -3 is:

 and

R 3j is C 1-3 haloalkyl.

7. The compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , wherein R 3 is R 3 -4 and R 3 -4 is:

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof of claim 1 , and a pharmaceutically acceptable excipient.

9. A compound selected from the group consisting of:

N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide;

4-methoxy-N-((S)-4-methyl-1-(((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)amino)-1-oxopentan-2-yl)-1H-indole-2-carboxamide;

(S)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-4-methyl-N-((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)pentanamide;

6-fluoro-N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-(2-methoxyethoxy)-1H-indole-2-carboxamide;

(2R,4S)-4-hydroxy-N-((S)-4-methyl-1-(((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)amino)-1-oxopentan-2-yl)pyrrolidine-2-carboxamide;

5-cyano-N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide;

N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-5-methoxy-1H-benzo[d]imidazole-2-carboxamide;

(S)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-N-((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)-4-methylpentanamide;

4-methoxy-N-((S)-4-methyl-1-(((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)amino)-1-oxopentan-2-yl)-1H-benzo[d]imidazole-2-carboxamide;

(S)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-4-methyl-N-((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)pentanamide;

N-((S)-1-(((S)-4-(aziridin-1-yl)-1-(2-hydroxypyridin-3-yl)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide;

N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-5H-[1,3]dioxolo[4,5-f]indole-6-carboxamide;

4-methoxy-N-((S)-1-(((S)-1-(2-methoxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide;

N-((S)-1-(((S)-1-(2-aminopyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide;

N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-5-methoxy-1H-indole-2-carboxamide;

(1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-N-((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and

(1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-N-((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide,

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

10. A method of treating coronavirus disease 2019 (COVID-19) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of:

N-((S)-1-(((S)-1-(2-hydroxypyridin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof; or

4-methoxy-N-((S)-4-methyl-1-(((S)-4-(methylamino)-3,4-dioxo-1-(2-oxoimidazolidin-1-yl)butan-2-yl)amino)-1-oxopentan-2-yl)-1H-indole-2-carboxamide, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.