IP Library › Granted Patent US 11,154,563

Granted Patent B2

US 11,154,563 · App. 16/478,788 · Granted Oct 26, 2021

Immunoproteasome inhibitors

Inventors: Yan Lou (Pleasanton, CA); Timothy Duncan Owens (Redwood City, CA); Kenneth Albert Brameld (Menlo Park, CA); David Michael Goldstein (Redwood City, CA)

Assignee: Principia Biopharma Inc.

A61K31/69 A61K47/00

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Quick Facts

Patent No.: US 11,154,563
App. No.: 16/478,788
Granted: Oct 26, 2021
Kind: B2

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Abstract

Provided herein are compounds, such as a compound of Formula (I), as described herein, or a pharmaceutically acceptable salt thereof, that are immunoproteasome (such as LMP2 and LMP7) inhibitors. The compounds described herein can be useful for the treatment of diseases treatable by inhibition of immunoproteasomes. Also provided herein are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Claims (396)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W is —O—P—Q—C(R 8a )═C(R 8b )(R 8c ) or a group of formula

A l is hydrogen, hydroxy, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or —S(═O) 2 -alkyl, wherein said alkyl of said —S(═O) 2 -alkyl is unsubstituted;

P is -alkyl-N(R)—, -alkyl-(C 3 -C 6 )cycloalkyl-N(R)—, -alkyl-O-alkyl-N(R)—,

Z and Z 1 are independently a covalent bond, -alkyl-, -alkyl-O—, -alkyl-N(R)—, or -alkyl-O-alkyl-, with the proviso that Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom;

ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;

ring J with the ring nitrogen atom and ring Y 1 atom shown is a saturated 4 to 10 membered heterocyclyl;

Y 1 is C or N;

Z 2 is a covalent bond or N(R), with the proviso that when Y 1 in ring J is nitrogen, then Z 2 is a covalent bond;

each R is independently hydrogen, or alkyl;

Q is —C(═O)— or —S(═O) 2 —;

R 8a is hydrogen, halogen, or cyano;

R 8b is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein when R 8b is alkyl, the alkyl is optionally substituted with 1-2 substituents chosen from a —N(alkyl)(haloalkyl), —N(alkyl)2, and heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-3 substituents chosen from halo, alkyl, and —C(═O)-alkyl; and the heterocyclyl is optionally substituted with 1-2 substituents chosen from halo, alkyl, alkoxy, haloalkyl, cyano and —S(═O) 2 -alkyl; or

R 8a and R 8b are taken together to form a bond; and

R 8c is hydrogen or alkyl;

R b1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein when R b1 is alkyl, the alkyl is optionally substituted with 1-2 substituents chosen from aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently chosen from halo, alkyl, alkoxy, haloalkyl, cyano and —S(═O) 2 -alkyl; and

R b2 and R b3 are independently hydrogen or optionally substituted alkyl; or

R b2 and R b3 together with the boron atom to which they are shown attached form a cyclic boronic ester;

wherein when the optionally substituted aryl, the optionally substituted heteroaryl, the optionally substituted heterocyclyl and the optionally substituted cycloalkyl is substituted, the optionally substituted aryl, the optionally substituted heteroaryl, the optionally substituted heterocyclyl and the optionally substituted cycloalkyl are substituted with one or more ring system substituents each independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, acyl, aroyl, halo, haloalkyl, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —SH, —SF 5 , —OSF 5 (for aryl), —O-alkyl-O-alkyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH 2 , —C(═NH)—NH 2 , —C(═NH)—NH(alkyl), oxime (e.g., ═N—OH), —NY 1 Y 2 , -alkyl-NY 1 Y 2 , —C(O)NY 1 Y 2 , —SO 2 NY 1 Y 2 and —SO 2 NY 1 Y 2 , wherein Y 1 and Y 2 are the same or different and are independently chosen from hydrogen, alkyl, -alkyl-O-alkyl, aryl, cycloalkyl, heterocyclyl and aralkyl; or two available hydrogens on two adjacent carbon atoms of the optionally substituted aryl, the optionally substituted heteroaryl, the optionally substituted heterocyclyl and the optionally substituted cycloalkyl are taken together to form methylenedioxy, ethylenedioxy and —C(CH 3 ) 2 —.

2. A compound or a pharmaceutically acceptable salt of claim 1 , wherein:

W is —O—P—Q—C(R 8a )═C(R 8b )(R 8c ) or a group of formula

A l is hydrogen;

P is

Z is -alkyl- or -alkyl-O-alkyl-, with the proviso that Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom;

ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;

Q is —C(═O)—;

R 8a is hydrogen, halogen, or cyano;

R 8b is hydrogen; alkyl which is optionally substituted with 1-2 substituents chosen from a —N(alkyl)(haloalkyl), —N(alkyl) 2 , and optionally substituted heterocyclyl; and heterocyclyl which is optionally substituted with 1-2 substituents chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and —S(═O) 2 -alkyl; or

R 8a and R 8b are taken together to form a bond; and

R 8c is hydrogen or alkyl;

R b1 is alkyl which is optionally substituted with 1-2 substituents chosen from aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and —S(═O) 2 -alkyl; and

R b2 and R b3 are each hydrogen.

3. The compound or a pharmaceutically acceptable salt of claim 1 , wherein W is

4. The compound or a pharmaceutically acceptable salt of claim 3 , wherein A l is H.

5. The compound or a pharmaceutically acceptable salt of claim 1 , wherein W is —O—P—Q—C(R 8a )═C(R 8b )(R 8c ).

6. The compound or a pharmaceutically acceptable salt of claim 1 , wherein:

said -alkyl-N(R)— of P is:

said -alkyl-O-alkyl-N(R)— of P is:

said of P is:

and

said of P is:

7. The compound or a pharmaceutically acceptable salt of claim 1 , wherein P is

8. The compound or a pharmaceutically acceptable salt of claim 7 , wherein ring A of P with the ring nitrogen atom shown is:

9. The compound or a pharmaceutically acceptable salt of claim 3 , wherein Z of P is -alkyl-O-alkyl- or -alkyl-.

10. The compound or a pharmaceutically acceptable salt of claim 9 , wherein:

said -alkyl-O-alkyl- of Z is —(CH 2 ) 1-4 —O—(CH 2 ) 1-4 —; and

said -alkyl- of Z is —(CH 2 ) 1-4 —.

11. The compound or a pharmaceutically acceptable salt of claim 5 , wherein Z of P is -alkyl-; and said -alkyl- of Z is —(CH 2 )—.

12. The compound or a pharmaceutically acceptable salt of claim 1 , wherein Q is —C(═O)—.

13. The compound or a pharmaceutically acceptable salt of claim 1 , wherein R 8a is hydrogen or cyano; and

said optionally substituted alkyl of R ab is chosen from:

and

said optionally substituted heterocyclyl of R ab is chosen from:

14. The compound or a pharmaceutically acceptable salt of claim 1 , wherein:

R 8b is H, or an alkyl which is optionally substituted with 1-2 substituents chosen from —N(alkyl)(haloalkyl), —N(alkyl) 2 , and optionally substituted heterocyclyl; and

R 8c is H.

15. The compound or a pharmaceutically acceptable salt of claim 14 , wherein R 8b is an unsubstituted or substituted alkyl chosen from isopropyl, t-butyl, —C(CH 3 ) 2 —N(CH 3 )—CH 2 CF 3 , —CH 2 —N(CH 3 ) 2 , —C(CH 3 ) 2 —N(CH 3 )—CH 2 —CHF 2 ,

16. The compound or a pharmaceutically acceptable salt of claim 14 ,

wherein R 8b is an optionally substituted heterocyclyl chosen from

17. The compound or a pharmaceutically acceptable salt of claim 1 , wherein R b1 is an unsubstituted alkyl or a substituted alkyl, wherein the substituents are 1-2 substituents chosen from aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and —S(═O) 2 -alkyl.

18. The compound or a pharmaceutically acceptable salt of claim 17 , wherein R b1 is chosen from —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 -phenyl, —CH 2 CH 2 -phenyl, —CH 2 -tolyl, —CH 2 -methoxyphenyl, —CH 2 -chlorophenyl, —CH 2 -fluorophenyl, —CH 2 -trifluoromethylphenyl, —CH 2 -benzofuranyl, —CH 2 -naphthyl, —CH 2 -cyanophenyl, —CH 2 -difluorophenyl, and —CH 2 -phenyl-S(═O) 2 —CH 3 .

19. The compound or a pharmaceutically acceptable salt of claim 1 , wherein R b2 and R b3 are each H.

20. The compound or a pharmaceutically acceptable salt of claim 3 , wherein the compound is chosen from:

((R)-1-(3-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)propanamido)-2-phenylethyl)boronic acid;

((1R)-1-(3-(1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)propanamido)-2-phenylethyl)boronic acid; and

((1R)-1-(3-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)propanamido)-2-phenylethyl)boronic acid;

an individual E or Z isomer thereof; and/or

a pharmaceutically acceptable salt of any of the foregoing compounds.

21. The compound or a pharmaceutically acceptable salt of claim 5 , wherein the compound is chosen from:

((R)-1-(((((R)-1-(2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-acryloylpiperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((S)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((S)-1-acryloylpiperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((S)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((S)-1-(2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-acryloylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-acryloylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(piperidin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(4,4-difluoropiperidin-1-yl)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid

((R)-1-(((((1R,2S,5S)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((1S,2R,5R)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(pyrrolidin- 1-yl)pent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(piperidin- 1-yl)pent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(4,4-difluoropiperidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((S)-1-(2-cyano-4,4-dimethylpent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(pyrrolidin- 1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-acryloylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)- 1-(((((1R,2R,5S)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((1 S,2S,5R)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-4-(2-cyano-4,4-dimethylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((1S,2R,5R)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)- 1-((E)-4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-3-phenylpropyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((1s,2R,5R)-3-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((1s,2R,5R)-3-acryloyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)-1-(((((R)- 1-(4-(4-acetylpiperazin-1-yl)-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((1s,2R,5R)-3-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-4,4-difluoropyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((2R,5S)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-5-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-4-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-3-(4-methyltetrahydro-2H-pyran-4-yl)acryloyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)- 1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)-4,4-difluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropiperidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((S)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-4-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-(4,4-difluoropiperidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((1S,2R,5R)-3-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-4-(2-cyano-4,4-dimethylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-methoxyphenyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-4-(2-cyano-4,4-dimethylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((1S,2R,5R)-3-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)- 1-(((((1S,2R,5R)-3-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((1 S,2R,5R)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(3-methoxyphenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-methoxyphenyl)ethyl)boronic acid;

((R)-2-(4-chlorophenyl)- 1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((2,2-difluoroethyl)(methyl)amino)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)- 1-(((((S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-(trifluoromethyl)phenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)azepan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-4-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((1S ,2R,5R)-3-((E)-4-(dimethylamino)but-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((1S,2R,5R)-3-(but-2-ynoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((2R,4R)-1-acryloyl-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4R)- 1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-acryloyl-4,4-difluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)-1-(((((1s,2R,5R)-3-(2-cyano-3-(4-methyltetrahydro-2H-pyran-4-yl)acryloyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-4-acryloylmorpholin-3-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)-1-(((((R)-4-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((1 S,2R,5R)-3-acryloyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(3-methoxyphenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(methyl(2,2,2-trifluoroethyl)amino)pent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-4-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)morpholin-3-yl)methoxy)carbonyl)amino)-3-phenylpropyl)boronic acid;

((R)-1-(((((1 S,2R,5R)-3-acryloyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-acryloyl-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-3-phenylpropyl)boronic acid;

((R)-1-(((((2R,4S)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)- 1-((Z)-2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((1S,2R,5R)-3-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-3-phenylpropyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-3-methylbutyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(2-cyanophenyl)ethyl)boronic acid;

((R)- 1-(((((1S,2R,5R)-3-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((1 S,2R,5R)-3-acryloyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(2-(trifluoromethyl)phenyl)ethyl)boronic acid;

((R)-1-(((((S)-4-acryloyl- 1,1-dioxidothiomorpholin-3-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)-1-(((((R)-1-acryloyl-4,4-difluoropiperidin-2-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)- 1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(2,4-difluorophenyl)ethyl)boronic acid;

((R)-1-(((((1S,2R,5R)-3-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(4-(trifluoromethyl)phenyl)ethyl)boronic acid;

((R)-1-(((((1 S,2R,5R)-3-acryloyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(4-(trifluoromethyl)phenyl)ethyl)boronic acid;

((R)-1-(((((1S,2R,5R)-3-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)- 1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-3,3-dimethylbutyl)boronic acid;

((R)- 1-(((((1S,2R,5R)-3-(2-cyano-3-(4-methyltetrahydro-2H-pyran-4-yl)acryloyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)- 1-(2-fluoroacryloyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-cyanophenyl)ethyl)boronic acid;

((R)- 1-(((((1S,2R,5R)-3-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-(methylsulfonyl)phenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(4-(methoxycarbonyl)piperazin- 1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)- 1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)piperazin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)- 1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpiperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-2-methylpiperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-acryloyl-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(benzofuran-3-yl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((2R,4S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((2R,4S)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-acryloyl-4-fluoropyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((R)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((S)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((3S,4R)-3,4-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((R)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((S)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((3S,4R)-3,4-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((R)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((S)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((3S,4R)-3,4-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((R)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((S)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-((3S,4R)-3,4-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-((S)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-((R)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-acryloyl-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-((S)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-(2-cyano-4-((R)-3-fluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((2R,4S)-1-acryloyl-4-fluoro-2-methylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)-2-methylpiperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid; and

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)-2-methylpiperidin-2-yl)methoxy)carbonyl)amino)-2-(4-fluorophenyl)ethyl)boronic acid;

an individual E or Z isomer thereof; and/or

a pharmaceutically acceptable salt of any of the foregoing compounds.

22. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. A method of inhibiting Large Multifunctional Protease 2 (LMP2) and/or Large Multifunctional Protease 7 (LMP7) in a subject comprising administering to said subject in need of said inhibition a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and thereby inhibiting Large Multifunctional Protease 2 (LMP2) and/or Large Multifunctional Protease 7 (LMP7).

24. A method of treating a disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is chosen from lupus, rheumatoid arthritis, scleroderma, ankylosing spondylitis, Duchene muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathies (IIMs), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathies (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's Syndrome, bronchitis, conjunctivitis, pancreatitis, cholecstitis, bronchiectasis, aortic valve stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, chronic liver inflammation, Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrilar myopathy, GVHD, and multiple myeloma.

25. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is chosen from:

((R)-1-(3-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)propanamido)-2-phenylethyl)boronic acid;

((1R)-1-(3-(1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)propanamido)-2-phenylethyl)boronic acid;

((1R)-1-(3-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)propanamido)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-acryloylpiperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((S)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((S)-1-acryloylpiperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)- 1-(((((S)- 1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)- 1-(((((S)- 1-(2-cyano-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)- 1-(((((R)- 1-acryloylpyrrolidin-2-yl)methoxy)carbonyl) amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-acryloylpyrrolidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-(piperidin- 1-yl)pent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-(4,4-difluoropiperidin-1-yl)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid

((R)-1-(((((1R,2S,5S)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo [3 0.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;

((R)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-(p-tolyl)ethyl)boronic acid;

((R)-2-(benzofuran-3-yl)-1-(((((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)ethyl)boronic acid;

((R)- 1-(((((1S,2R,5R)-3-(2-cyano-4,4-dimethylpent-2-enoyl)-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid;