TRICYCLIC FUSED THIOPHENE DERIVATIVES AS JAK INHIBITORS

• US 20160024109A1
• Filed: 10/01/2015
• Published: 01/28/2016
• Est. Priority Date: 11/01/2012
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Inventors: Li, Yun-Long, Zhu, Wenyu, Mei, Song, Glenn, Joseph
• Granted Patent: US 9,908,895 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 495/12 : in which the condensed system contains three hetero rings
• CPC Class Codes: C07D 495/14 : Ortho-condensed systems

Abstract

The present invention provides tricyclic fused thiophene derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1. A compound of Formula I:

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

the

3. The compound of any one of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is CR⁴.

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

R² is H, methyl, ethyl, propyl, or isopropyl, wherein said methyl, ethyl, propyl, or isopropyl are each optionally optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a, NR^cR^d, NR^cC(═

O)R^b, and NR^cS(═

O)₂R^b;

wherein each R^a, R^c, and R^d are independently selected from H, methyl, and ethyl; and

each R^b is independently selected from methyl and ethyl;

or

alternatively, R² is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R²¹ groups; and

each R²¹ is independently C_1-3 alkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is —

CH₂—

OH, —

CH(CH₃)—

OH, or —

CH₂—

NHSO₂CH₃.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is H.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is Cy⁴.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is -Cy^4A-Cy⁵ or -Cy^4A-Y¹-Cy⁵;

wherein Y is C_1-4 alkylene or Y¹¹—

C_1-4 alkylene; and

Y¹¹ is C(═

O).

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁴ is selected from C_6-10 aryl, C_3-10 cycloalkyl and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups, provided said 3-10 membered heterocycloalkyl is not a saturated heterocycloalkyl group having one or more nitrogen ring members.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁴ is a tetrahydro-2H-pyran ring, which is optionally substituted with 1 or 2 independently selected R³¹ groups.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy^4A is selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁵ is a pyridine ring, a pyrazole ring, or a triazole ring, each of which is optionally substituted with 1 or 2 independently selected R³² groups.

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

R² is H, methyl, ethyl, propyl, or isopropyl, wherein said methyl, ethyl, propyl, or isopropyl are each optionally optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a, NR^cR^d, NR^cC(═

O)R^b, and NR^cS(═

O)₂R^b;

wherein each R^a, R^c, and R^d are independently selected from H, methyl, and ethyl; and

each R^b is independently selected from methyl and ethyl;

or

alternatively, R² is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R²¹ groups;

provided that when X¹X²X³ is —

N═

CR²—

NR³—

, X⁴ is C, and X⁵ is C; and

Cy⁴ is unsubstituted or substituted 3-10 membered saturated heterocycloalkylene having one or more nitrogen atoms or Cy^4A is unsubstituted or substituted 3-10 membered saturated heterocycloalkylene having one or more nitrogen atoms, then R² is selected from H, methyl, ethyl, propyl, or isopropyl, wherein said methyl, ethyl, propyl, or isopropyl are each optionally optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a, NR^cR^d, NR^cC(═

O)R^b, and NR^cS(═

O)₂R^b;

wherein each R^a, R^c, and R^d are independently selected from H, methyl, and ethyl; and

each R^b is independently selected from methyl and ethyl;

each R²¹ is independently C_1-3 alkyl;

R³ is Cy⁴, -Cy^4A-Cy⁵, or -Cy^4A-Y¹-Cy⁵;

Y¹ is C_1-4 alkylene or Y¹¹—

C_1-4 alkylene;

Y¹¹ is C(═

O);

Cy⁴ is selected from C_6-10 aryl, C_3-10 cycloalkyl, and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ group;

Cy^4A is selected from C_3-10 cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups;

Cy⁵ is C_6-10 aryl or 5-10 membered heteroaryl, which are each optionally substituted with 1 or 2, independently selected R³² groups;

each R³¹ or R³² are each independently selected from C_1-6 alkyl, C_1-6 haloalkyl, halo, CN, OR^a2, C(═

O)R^b2, C(═

O)OR^a2, and NR^c2R^d2;

wherein said C_1-6 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a2, C(═

O)NR^c2R^d2, C(═

O)OR^a2, NR^c2R^d2, NR^c2C(═

O)R^b2, NR^c2C(═

O)OR^a2, NR^c2C(═

O)NR^c2R^d2, NR^c2S(═

O)₂R^b2, NR^c2S(═

O)₂NR^c2R^d2, S(═

O)₂R^b2, and S(═

O)₂NR^c2R^d2;

each R^a2, R^c2, and R^d2 are independently selected from H, C_1-6 alkyl, and C_1-6 haloalkyl, wherein said C_1-6 alkyl, and C_1-6 haloalkyl are each optionally substituted by 1, 2, or 3 CN;

each R^b2 is independently selected from C_1-6 alkyl and C_1-6 haloalkyl, which are each optionally substituted by 1, 2, or 3 CN;

R⁴ is H; and

R⁵ is H.

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

R² is H, methyl, ethyl, propyl, or isopropyl, wherein said methyl, ethyl, propyl, or isopropyl are each optionally optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a, NR^cR^d, NR^cC(═

O)R^b, and NR^cS(═

O)₂R^b;

wherein each R^a, R^c, and R^d are independently selected from H, methyl, and ethyl; and

each R^b is independently selected from methyl and ethyl;

or

alternatively, R² is cyclopropyl or an azetidine ring, each of which is optionally substituted with 1, 2, or 3 independently selected R²¹ groups;

provided that when X¹X²X³ is —

N═

CR²—

NR³—

, X⁴ is C, and X⁵ is C; and

Cy⁴ is unsubstituted or substituted 3-10 membered saturated heterocycloalkylene having one or more nitrogen atoms or Cy^4A is unsubstituted or substituted 3-10 membered saturated heterocycloalkylene having one or more nitrogen atoms, then R² is selected from H, methyl, ethyl, propyl, or isopropyl, wherein said methyl, ethyl, propyl, or isopropyl are each optionally optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR^a, NR^cR^d, NR^cC(═

O)R^b, and NR^cS(═

O)₂R^b;

wherein each R^a, R^c, and R^d are independently selected from H, methyl, and ethyl; and

each R^b is independently selected from methyl and ethyl;

each R²¹ is independently C_1-3 alkyl;

R³ is Cy⁴, -Cy^4A-Cy⁵, or -Cy^4A-Y¹-Cy⁵;

Y¹ is C_1-4 alkylene, Y¹¹—

C_1-4 alkylene, or C_1-6 alkylene-Y¹¹;

Y¹¹ is C(═

O) or NHC(═

O)O;

Cy⁴ is selected from phenyl, C_3-7 cycloalkyl, and 4-6 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ group;

Cy^4A is selected from C_3-7 cycloalkylene and 4-6 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups;

Cy⁵ is phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, which are each optionally substituted with 1 or 2 independently selected R³² groups;

each R³¹ or R³² are each independently selected from C_1-6 alkyl, C_1-6 haloalkyl, halo, CN, OR^a2, C(═

O)R^b2, C(═

O)OR^a2, and NR^c2R^d2;

wherein said C_1-6 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OR², C(═

O)NR^c2R^d2, C(═

O)OR^a2, NR^c2R^d2, NR^c2C(═

O)R^b2, NR^c2C(═

O)OR^a2, NR^c2C(═

O)NR^c2R^d2, NR²S(═

O)₂R^b2, NR^c2S(═

O)₂NR^c2R^d2, S(═

O)₂R^b2, and S(═

O)₂NR^c2R^d2;

each R^a2, R^c2, and R^d2 are independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, and wherein said C_1-6 alkyl, and C_1-6 haloalkyl are each optionally substituted by 1, 2, or 3 CN;

each R^b2 is independently selected from C_1-6 alkyl and C_1-6 haloalkyl, which are each optionally substituted by 1, 2, or 3 CN;

R⁴ is H; and

R⁵ is H.

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

R² is —

CH₂—

OH, —

CH(CH₃)—

OH, or —

CH₂—

NHSO₂CH₃;

R³ is Cy⁴;

Cy⁴ is selected from C_3-10 cycloalkyl and 3-10 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups, provided said 3-10 membered heterocycloalkyl is not a saturated heterocycloalkyl group having one or more nitrogen ring members;

each R³¹ is independently selected from CN, OH, F, Cl, C_1-3 alkyl, C_1-3 haloalkyl, cyano-C_1-3 alkyl, HO—

C_1-3 alkyl, amino, C_1-3 alkylamino, and di(C_1-3 alkyl)amino, wherein said C_1-3 alkyl and di(C_1-3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, C_1-3 alkylaminosulfonyl, and C_1-3 alkylsulfonyl;

R⁴ is H; and

R⁵ is H.

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

R² is —

CH₂—

OH, —

CH(CH₃)—

OH, or —

CH₂—

NHSO₂CH₃;

R³ is -Cy^4A-Cy⁵;

Cy^4A is selected from C_3-10 cycloalkylene and 3-10 membered heterocycloalkylene, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups, provided said 3-10 membered heterocycloalkylene is not a saturated heterocycloalkylene group having one or more nitrogen ring members;

Cy⁵ is selected from 5-10 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R³² groups;

each R³¹ is independently selected from CN, OH, F, Cl, C_1-3 alkyl, C_1-3 haloalkyl, cyano-C_1-3 alkyl, HO—

C_1-3 alkyl, amino, C_1-3 alkylamino, and di(C_1-3 alkyl)amino, wherein said C_1-3 alkyl and di(C_1-3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, C_1-3 alkylaminosulfonyl, and C_1-3 alkylsulfonyl;

each R³² is independently selected from CN, OH, F, Cl, C_1-3 alkyl, C_1-3 haloalkyl, cyano-C_1-3 alkyl, HO—

C_1-3 alkyl, amino, C_1-3 alkylamino, and di(C_1-3 alkyl)amino, wherein said C_1-3 alkyl and di(C_1-3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, C_1-3 alkylaminosulfonyl, and C_1-3 alkylsulfonyl;

R⁴ is H; and

R⁵ is H.

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

R² is —

CH₂—

OH, —

CH(CH₃)—

OH, or —

CH₂—

NHSO₂CH₃;

R³ is Cy⁴ or -Cy^4A-Cy⁵,

Cy⁴ is selected from cyclohexylene and a 2H-tetrahydrofuran ring, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups;

Cy^4A is selected from cyclohexylene and a 2H-tetrahydrofuran ring, each of which are optionally substituted with 1, 2, 3, or 4 independently selected R³¹ groups;

Cy⁵ is selected from 5-10 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R³² groups;

each R³¹ is independently selected from CN, OH, F, Cl, C_1-3 alkyl, C_1-3 haloalkyl, cyano-C_1-3 alkyl, HO—

C_1-3 alkyl, amino, C_1-3 alkylamino, and di(C_1-3 alkyl)amino, wherein said C_1-3 alkyl and di(C_1-3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, C_1-3 alkylaminosulfonyl, and C_1-3 alkylsulfonyl;

each R³² is independently selected from CN, OH, F, Cl, C_1-3 alkyl, C_1-3 haloalkyl, cyano-C_1-3 alkyl, HO—

C_1-3 alkyl, amino, C_1-3 alkylamino, and di(C_1-3 alkyl)amino, wherein said C_1-3 alkyl and di(C_1-3 alkyl)amino is optionally substituted with 1, 2, or 3 substituents independently selected from F, C1, C_1-3 alkylaminosulfonyl, and C_1-3 alkylsulfonyl;

R⁴ is H; and

R⁵ is H.

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

X¹X²X³ is —

N═

CR²—

NR³—

, X⁴ is C, X¹ is C, and Y is CR⁴;

or

X¹X²X³ is —

CR¹═

CR²—

NR³—

, X⁴ is C, X⁵ is C, and Y is CR⁴;

or

X¹X²X³ is —

CR¹R^1a—

C(═

O)—

NR³—

, X⁴ is C, X⁵ is C, and Y is CR⁴;

or

X¹X²X³ is —

O—

C(═

O)—

NR³—

, X⁴ is C, X⁵ is C, and Y is CR⁴;

or

X¹X²X³ is ═

N—

CR²═

CR³—

, X⁴ is N, X⁵ is C, and Y is CR⁴.

42. The compound of claim 1, having Formula IIb:

44. The compound of claim 1, having Formula IId:

45. The compound of claim 1, having Formula IIIa:

46. The compound of claim 1, having Formula IIIb:

47. The compound of claim 1, selected from:

(1R)-1-{1-[(3S)-Tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexanol;

(1R)-1-(1-{trans-4-[(2,2,2-Trifluoroethyl)amino]cyclohexyl}-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl) ethanol;

(1R)-1-(1-{trans-4-[2-(Methylsulfonyl)ethyl]cyclohexyl}-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol;

(1R)-1-{1-[cis-4-(1H-1,2,4-Triazol-1-yl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

cis-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexanecarbonitrile;

3-(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)propanenitrile;

(1R)-1-[1-(3-Fluoropiperidin-4-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl]ethanol;

(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

(1R)-1-{1-[trans-4-(Hydroxymethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

(1R)-1-{1-[trans-4-(Fluoromethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

(1R)-1-(1-Cyclohexyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol;

1-(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)-N-methylmethanesulfonamide;

(1R)-1-{1-[1-(2,2,2-Trifluoroethyl)piperidin-4-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

3-(4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)propanenitrile;

{trans-4-[2-(Hydroxymethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile;

N-({1-[trans-4-(Cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)methanesulfonamide;

(1R)-1-{1-[(3S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

((2R,5S)-5-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile;

((2S,5S)-5-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile;

N-((1-((2S)-Bicyclo[2.2.1]heptan-2-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)methanesulfonamide; and

(trans-4-{7-[(1R)-1-Hydroxyethyl]-8H-pyrrolo[2,3-d]thieno[3,2-b]pyridin-8-yl}cyclohexyl)acetonitrile;

or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, selected from:

(1-Hydroxy-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

{(2E)-1-[trans-4-(Cyanomethyl)cyclohexyl]-1,3-dihydro-2H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-ylidene}cyanamide;

[trans-4-(2-Cyclopropyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

[trans-4-(2-Isopropyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

[trans-4-(2-Azetidin-3-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

2 {trans-4-[2-(1-Methylazetidin-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile;

3-[(cis-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)amino]propanenitrile;

N-Ethyl-2-(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetamide;

3-(3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)propanenitrile

[4-(7-Methylimidazo[1,2-a]thieno[3,2-e]pyrazin-8-yl)phenyl]acetonitrile;

[(1R,2R,4S)-2-hydroxy-4-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

[(1S,2S,4R)-2-hydroxy-4-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

[(1R,2R,4S)-4-(2-ethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-2-methoxycyclohexyl]acetonitrile;

[(1 S,2S,4R)-4-(2-ethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-2-methoxycyclohexyl]acetonitrile;

((1R,2R,4S)-2-Hydroxy-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

((1 S,2S,4R)-2-hydroxy-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

((1R,2S,4S)-2-Hydroxy-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

((1 S,2R,4R)-2-hydroxy-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

[(2R,5S)-5-(2-Methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]acetonitrile;

[(2R,5S)-5-(2-Ethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]acetonitrile;

[(1R,2S,4S)-4-(2-Ethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-2-hydroxycyclohexyl]acetonitrile;

[(1 S,2R,4R)-4-(2-ethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-2-hydroxycyclohexyl]acetonitrile;

[(1R,2S,4S)-4-(2-Methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-2-hydroxycyclohexyl]acetonitrile;

[(1 S,2R,4R)-4-(2-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)-2-hydroxycyclohexyl]acetonitrile;

[(2R,5S)-5-(2-Isopropyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]acetonitrile;

[(2R,5S)-5-(2-Cyclopropyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl]acetonitrile;

((2S,5R)-5-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile;

((2R,5S)-5-{2-[(1S)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile;

[4-(8-Methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidin-9-yl)phenyl]acetonitrile;

[trans-4-(2-Ethyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

[trans-4-(2-Methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

((1R,3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclopentyl)acetonitrile;

Ethyl(3S)-3-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate;

3-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)-3-oxopropanenitrile;

(1R)-1-{1-[(3S)-1-(4,4,4-Trifluorobutanoyl)piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

(1R)-1-(1-{(3S)-1-[3-(1H-Pyrazol-4-yl)propanoyl]piperidin-3-yl}-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl) ethanol;

(1R)-1-{1-[(3S)-1-(3-Pyridin-3-ylpropanoyl)piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

(1R)-1-{1-[(3S)-1-(3-Phenylbutanoyl)piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

3-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)propanenitrile;

(1R)-1-{1-[(3S)-1-(3-Phenylpropanoyl)piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

4-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)-4-oxobutanenitrile;

5-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)-5-oxopentanenitrile;

(1R)-1-{1-[1-(4,4,4-Trifluorobutyl)piperidin-4-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

(4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)acetonitrile;

3-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}pyrrolidin-1-yl)propanenitrile;

3-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}pyrrolidin-1-yl)-3-oxopropanenitrile;

(1R)-1-{1-[(3S)-1-(4,4,4-Trifluorobutyl)pyrrolidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol;

4-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}pyrrolidin-1-yl)butanenitrile;

5-((3S)-3-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}pyrrolidin-1-yl)pentanenitrile;

((1R,2R,4S)-2-Amino-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetonitrile;

{(2R,5S)-5-[2-(1-Aminoethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile;

N-(1-{1-[(3S,6R)-6-(Cyanomethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethyl)acetamide;

((2R,5S)-5-{2-[1-(Methylamino)ethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile;

{(2R,5S)-5-[2-(1-Fluoroethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile; and

[4-(Hydroxymethyl)-4-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile;

or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1, selected from:

{(2R,5S)-5-[2-(Cyanomethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile;

{(2S,5S)-5-[2-(Cyanomethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile;

N-[((2R,5S)-5-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)methyl]methanesulfonamide;

Isopropyl [((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)methyl]carbamate;

[trans-4-(8-Methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidin-9-yl)cyclohexyl]acetonitrile;

Methyl [(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate;

N-[(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]acetamide;

N-[(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]methanesulfonamide;

N′

-[(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]-N,N-dimethylurea;

Ethyl [(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate;

Propyl [(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate;

Isopropyl [(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate;

Tetrahydrofuran-3-yl [(trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate;

Methyl({trans-4-[2-(cyanomethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}methyl)carbamate;

Ethyl({trans-4-[2-(cyanomethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}methyl)carbamate;

Isopropyl({trans-4-[2-(cyanomethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}methyl)carbamate;

N-({trans-4-[2-(Cyanomethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}methyl)propanamide;

{1-[trans-4-(Cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile; and

{(2R,5S)-5-[2-(Hydroxymethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile;

or a pharmaceutically acceptable salt thereof.

50. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. (canceled)

10. (canceled)

13-15. -15. (canceled)

17-21. -21. (canceled)

23-24. -24. (canceled)

26-33. -33. (canceled)

40-41. -41. (canceled)

43. (canceled)

51-67. -67. (canceled)