BENZIMIDAZOLE DERIVATIVES AS ITK INHIBITORS

• US 20150225412A1
• Filed: 08/27/2013
• Published: 08/13/2015
• Est. Priority Date: 08/31/2012
• Status: Active Grant

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: Brameld, Kenneth Albert, Owens, Timothy
• Granted Patent: US 9,573,958 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The present disclosure is directed to certain inhibitors of kinases such as ITK, BLK, BMX, BTK, JAK3, TEC, TXK, HER2 (ERBB2), or HER4 (ERBB4), in particular ITK, pharmaceutical compositions comprising such compounds, and method of treating diseases mediated by such kinases.

Claims

1. A compound of Formula (IA):

2. The compound of claim 1 having the structure (I):

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2 wherein the compound of Formula (I) or a salt thereof has the structure (Ia):

4. The compound or a pharmaceutically acceptable salt thereof of claim 3 wherein Z¹, Z², and Z³ are CH (or C if substituted with R²).

5. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2 wherein the compound of Formula (I) has the structure (lb):

6. The compound or a pharmaceutically acceptable salt thereof of claim 5 wherein Z¹ and Z³ are CH (or C if substituted with R²).

7. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-6 wherein R^b and R^c are hydrogen.

8. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-6 wherein R^b is cyano and R^c is alkyl, substituted alkyl, cycloalkyl, or 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, or S and optionally substituted with one or two substituents independently selected from hydroxy, alkyl or fluoro.

9. The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R^c is alkyl.

10. The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R^c is cycloalkyl.

11. The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R^c is substituted alkyl.

12. The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R^c is alkyl substituted with hydroxy, alkoxy, —

NRR′

(where R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R′

is hydrogen or alkyl) or heterocyclyl which is optionally substituted with one or two groups independently selected from alkyl or hydroxyl.

13. The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R^c is —

C(CH₃)₂NH₂, —

C(CH₃)₂NHCH₃, —

C(CH₃)₂N(CH₃)₂, —

C(CH₃)₂NHCH₂CH₃, —

C(CH₃)₂NHCH(CH₃)₂, —

C(CH₃)₂NH(CH₃)₂OCH₃, —

C(CH₃)₂—

NH—

(3-methyloxetan-3-yl), —

C(CH₃)₂—

N(CH₃)(3-methyloxetan-3-yl), —

C(cH₃)₂OCH₂CH₃, —

C(CH₃)₂OH, —

C(CH₃)₂morpholin-4-yl, —

C(CH₃)₂-(3-methyloxetan-3-yl), —

C(CH₃)₂azetidin-3-yl, —

C(CH₃)₂-(1-methylazetidin-3-yl), —

C(CH₃)₂piperazin-1-yl, —

C(CH₃)₂pyrrolidin-1-yl, or —

C(CH₃)₂-(3-methylpiperazin-1-yl).

14. The compound or a pharmaceutically acceptable salt thereof of claim 8 wherein R^c is 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, or S and optionally substituted with one or two substituents independently selected from hydroxy, alkyl or fluoro.

15. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-14 wherein —

X—

Y—

is

16. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-14 wherein —

X—

Y—

is

17. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-14 wherein —

X—

Y—

is

18. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-14 wherein —

X—

Y—

19. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-14 wherein —

X—

Y—

is

20. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-19 wherein R¹ is hydrogen, —

NR³COR^d, or -(alkylene)-NR³R⁵ where R³ is hydrogen or alkyl, R⁴ is optionally substituted aryl or heteroaryl, and R⁵ is hydrogen, alkyl, haloalkyl, or acyl or R³ and R⁵ together with the nitrogen atom to which they are attached form heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxyalkyl, or alkoxy alkyl.

21. The compound or a pharmaceutically acceptable salt thereof of claim 20 wherein R³ is hydrogen.

22. The compound or a pharmaceutically acceptable salt thereof of claim 20 wherein R¹ is —

NR³COR⁴.

23. The compound or a pharmaceutically acceptable salt thereof of claim 20 wherein R¹ is -(alkylene)-NR³R⁵ where R³ is hydrogen or alkyl and R⁵ is hydrogen, alkyl, haloalkyl, or acyl.

24. The compound or a pharmaceutically acceptable salt thereof of claim 20 wherein R¹ is (S)—

CH₂N(COCF₃)CH(CH₃)C(CH₃)₃, (S)—

CH₂NHCH(CH₃)C(CH₃)₃, or (S)—

CH₂N(CH₃)CH(CH₃)C(CH₃)₃, preferably (S)—

CH₂NHCH(CH₃)C(CH₃)₃.

25. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24 wherein R² is hydrogen.

26. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-24 wherein Ar is phenyl optionally substituted with one, two, or three substituents selected from, alkyl, alkoxy, hydroxy, cyano, alkylthio, halo, haloalkyl, haloalkoxy, cycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl.

27. The compound or a pharmaceutically acceptable salt thereof of claim 26 wherein Ar is phenyl substituted with one, two, or three substituents independently selected from chloro, fluoro, methyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, or difluromethyl.

28. The compound or a pharmaceutically acceptable salt thereof of any of claims 1-25 wherein Ar is heteroaryl optionally substituted with one, two, or three substituents selected from, alkyl, alkoxy, hydroxy, cyano, alkylthio, halo, haloalkyl, haloalkoxy, cycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl.

29. The compound or a pharmaceutically acceptable salt thereof of claim 25 wherein Ar is thien-2-yl, 5-chlorothien-2-yl, 5-cyanothien-2-yl, 2-oxazol-4-ylthien-5-yl, 5-CF₃-thien-2-yl, 1-methyl-pyrazol-3-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl, 2-methyl, 1,2,3-triazol-4-yl, oxazol-5-yl, 2-methyl-oxazol-4-yl, 2-methyl-thiazol-5-yl, 5-CHF₂thien-2-yl, or isoxazol-5-yl.

31. A pharmaceutical composition comprising a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable excipient.

32. A method of treating a disease treatable by inhibition of ITK in a patient which method comprises administering to the patient in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. The method of any one of claims 32-34, wherein the pharmaceutical composition is administered in combination with one or more anti-inflammatory, anti-autoimmune, or anti-lymphoproliferative agent.

36. A compound or a salt of any of claims 1-30 for use as a medicament.

37. A compound or a salt of any of claims 1-30 for use in the treatment of inflammatory disorders, autoimmune disorders, and proliferative disorders.

30. A compound or a pharmaceutically acceptable salt thereof chosen from:

N-(1-(1-acryloylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3-H)-ylidene)-4-chlorobenzamide;

N-(1-(1-acryloylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide;

N-(1-(1-actyloylpiperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-chlorobenzamide;

4-chloro-N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide;

N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide;

N-(1-(1-acryloyl piperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide;

4-chloro-N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide;

N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-chlorobenzamide;

N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide;

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide;

N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)nicotinamide;

(S)—

N-(1-(1-acryloylpiperidin-4-yl)-5-(((3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-chlorobenzamide;

4-chloro-N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-((N—

((S)-3,3-dimethylbutan-2-yl)-2,2,2-trifluoroacetamido)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide;

N-(1-(1-acryloylpiperidin-3-yl)-5-((N—

((S)-3,3-dimethylbutan-2-3H)-2,2,2-trifluoroacetamido)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-chlorobenzamide;

4-chloro-N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((N—

((S)-3,3-dimethylbutan-2-yl)-2,2,2-trifluoroacetamido)methyl)-111-benzo[d]imidazol-2(3H)-ylidene)benzamide;

N-(1((1-acryloylpyrrolidin-2-yl)methy

     1)-5-((N—

((S)-3,3-dimethylbutan-2H)-2,2,2-trifluoroacetamido)methyl)-111-benzo[d]imidazol-2(3H)-ylidene)-4-chlorobenzamide;

4-chloro-N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(0)-3,3-dimethylbutan-2-yl)(methyl)amino)methyl)-1H-benzo[1]imidazol-2(1H)-yl idene)benzamide;

4-chloro-N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)(methyl)amino)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide;

N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide

N-(1-(1-acryloylpiperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(1-(2-cyano-4-(dimethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(1-(4-(dim ethylamino)but-2-enoyl)piperidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

4-chloro-N-(1-(1-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzoimidazol-2(3H)-ylidene)benzamide;

N-(1-(1-(4-amino-2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-chlorobenzamide;

4-chloro-N-(1-(1-(2-cyano-4-methyl-4-(methylamino)pent-2-enoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

4-chloro-N-(1-(1-(2-cyano-4-(dimethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

N-(1-(1-acryloylpiperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

4-chloro-N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(R(S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

N-(1-((1-(4-amino-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((s)-3,3-dimethylbutan-2-yl)amino)methyl)-4H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

4-chloro-N-(1-((1-(2-cyano-4-methyl-4-(methylamino)pent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((1)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

4-chloro-N-(1-((1-(2-cyano-4-(dimethylamino)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

4-chloro-N-(1-((1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

4-chloro-N-(1-(1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)benzamide;

4-chloro-N-(14(1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidi n-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-114-benzo[d]imidazol-2-yl)benzamide;

N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-(difluoromethyl)benzamide;

N-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-(difluoromethyl)benzamide;

N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)azetidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(4-amino-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

(S)—

N-(1-((1-(2-cyano-4-m ethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-((1-(4-amino-2-cyano-4-methylpent-2-enoyl)azetidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

(S)—

N-(1-((1-(4-amino-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

(S)—

N-(1-((1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-4-methylpent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-((1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)azetidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(2-(4-amino-2-cyano-4-methylpent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-4-methyl-4-morpholinopent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(S)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-N,4-dimethylpent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-N,4-dimethyl-4-morpholinopent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide;

N-(1-(((S)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-3-cyclopropylacryloyl)pyrrolidin-2-yl)methyl)-5-(((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((R)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-(dimethylamino)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-1H-benzo[d](difluoromethyl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-N,4,4-trimethylpent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)benzamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-methylbenzamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3,4-difluorobenzamide;

(R)—

N-(1-((1-(2-cyano-5-hydroxy-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(4-amino-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(S)—

N-(1-(1-(4-amino-2-cyano-4-methylpent-2-enoyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((1-(4-amino-2-cyano-4-methy 3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(S)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidi n-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-N,4-dimethyl-4-morpholinopent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(2-(2-cyano-4-(dimethylamino)-N,4-dimethylpent-2-enamido)ethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((1-(2-cyano-4-(dimethylamino)-4-methylpent-2-enoyl)azetidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((1-(2-cyano-4-methyl-4-morpholinopent-2-enoyl)azetidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((1-((2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((2,6-dimethylmorpholino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((neopentylamino)methyl)-1H-benzo[4]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-0(R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((2,6-dimethylmorpholino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((a)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(5-amino-2-cyano-4,4-dim ethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-di methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

97

N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((2,6-dimethylmorpholino)methyl)-1 I-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

100

N-(1-(((R)-1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-((2,6-dimethylmorpholino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide,

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((isobutylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((isobutylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-((isobutylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((3-methyloxetan-3-yl)methyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((3-methyloxetan-3-yl)methyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-((((3-methyloxetan-3-yl)methyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(but-2-ynoyl)pyrrolidin-2-yl)methy

     1)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methy

     1)-1-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(but-2-ynoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

N-(1-(1-(but-2-ynoyl)piperidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(1-(but-2-ynoyl)piperidin-3-yl)-5-(((S)-3,3-dimethylbutan-2-yl)amino)methyl)-benzo[d]imidazol-2-yl)-4-chlorobenzamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrol din-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(5-amino-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-m ethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((neopentylamino)-methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methy

     1)-6-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)-1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-2-(5-(difluoromethyl)thiophene-2-carboxamido)-N-neopentyl-1H-benzo[d]imidazole-5-carboxamide;

(R)-1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-2-(5-(difluoromethyl)thiophene-2-carboxamido)-N-neopentyl-1H-benzo[d]imidazole-5-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)-N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((3-hydroxyazetidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-(1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(S)—

N-(1-(1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-dimethyl-5-morpholinopent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)-1-((1-acryloylpyrrolidin-2-yl)methyl)-2-(5-(difluoromethyl)thiophene-2-carboxamido)-N-neopentyl-1H-benzo[d]imidazole-5-carboxamide;

N-(3-(((R)-1-(2-cyano-4-(2-methoxyethoxy)-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-2-(5-(difluoromethyl)thiophene-2-carboxamido)-N—

((S)-3,3-dimethylbutan-2-yl)-1H-benzo[d]imidazole-5-carboxamide;

(S)—

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)azetidin-3-yl)methyl)-5-(((3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-2-(5-(difluoromethyl)thiophene-2-carboxamido)-N-((S)-3,3-dimethylbutan-2-yl)-1H-benzo[d]imidazole-5-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(3-hydroxypentan-3-yl)-1H-benzo[d]imidazol-2H)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-(((S)-3,3-di methylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-114-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

(R)—

N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

(R)—

N-(1-((1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)nicotinamide;

(R)—

N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)benzamide;

N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

N-(1-(((R)-1-(2-cyano-4-ethoxy-4-methyl pent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

N-(1-(((R)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzoimidazol-2-yl)isoxazole-5-carboxamide;

N-(1-(((S)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-(((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

N-(1-4(S)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-(WS)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)isoxazole-5-carboxamide;

N-(1-(((S)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-((((S)-3,3-methylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((S)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-3-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)benzamide;

N-(1-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)benzamide;

N-(1-(((R)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)benzamide;

(R)—

N-(1-(1-(2-cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((R)-1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(1-((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-3-yl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methy

     1)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

N-(3-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

or

N-(3-(((R)-1-(2-cyano-4-ethoxy-4-methyl pent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

(R)—

N-(3-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yi)methyl)-6-((neopentylamino)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

or

(R)—

N-(3-((1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-6-((neopentylamino)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide;

or

an individual E or Z isomers thereof.

33. The method of claim 30, wherein the disease is chosen from inflammatory disorders, autoimmune disorders, and proliferative disorders.

34. The method of claim 33 wherein the disease is asthma, allergic dermatitis, atopic dermatitis, and psoriasis.