IP Library › Granted Patent US 8,188,137

Granted Patent B2

US 8,188,137 · App. 12/541,347 · Granted May 29, 2012

HCV protease inhibitors and uses thereof

Assignee: Avila Therapeutics, Inc.

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,188,137
App. No.: 12/541,347
Granted: May 29, 2012
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims (139)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

one of R a and R b is hydrogen and the other is —OH or —OC(O)R′, or R a and R b are taken together to form an oxo group;

R′ is an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R x and R y are taken together to form an optionally substituted C 3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 1 is an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl(C 1-3 alkyl);

R 2 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl;

R 3 is a warhead group —(CH 2 ) n -L-Y, wherein n is an integer from 0 to 5, inclusive, and -L-Y is selected from the following (a), (b), (c), (h), (i), (k), (l), (m), (n), (o), and (p) combinations of -L- and —Y:

(a) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or

(b) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or

(c) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or

(h) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or

(i) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or

(k) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—; and Y is C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN; or

(l) L is a covalent bond and Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN;

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 R e groups;

(m) L is —C(O)—and Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 R e groups;

(n) L is —N(R)C(O)—and Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 R e groups;

(o) L is a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and

Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN;

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 R e groups;

(p) L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—; and Y is selected from:

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 R e groups;

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:

Q is a covalent bond or a bivalent C 1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and

each Z is independently hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN;

R 4 is —NHC(O)NHR 5 , —NHC(O)OR 6 , or

R 5 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 6 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 7 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2. The compound according to claim 1 , wherein the compound is of formula II-a or II-b:

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 , wherein the compound is of formula III-a or III-b:

or a pharmaceutically acceptable salt thereof, wherein:

R 2 is an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl.

4. The compound according to claim 2 , wherein the compound is of formula IV-a or IV-b:

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2 , wherein the compound is of formula V-a or V-b:

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4 , wherein the compound is of formula IV-a-1 or IV-a-2:

7. The compound according to claim 4 , wherein the compound is of formula IV-b-1 or IV-b-2:

8. The compound according to claim 5 , wherein the compound is of formula V-a-1 or V-a-2:

9. The compound according to claim 5 , wherein the compound is of formula V-b-1 or V-b-2:

10. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

one of R a and R b is hydrogen and the other is —OH or —OC(O)R′, or R a and R b are taken together to form an oxo group;

R x and R y are taken together to form an optionally substituted C 3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 1 is an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl(C 1-3 alkyl);

R 2 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl;

R 3 is a warhead —(CH 2 ) n -L-Y, wherein:

n is an integer from 0 to 5, inclusive;

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;

Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; and

Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN;

R 4 is —NHC(O)NHR 5 , —NHC(O)OR 6 , or

R 5 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

11. The compound according to claim 10 , wherein n is an integer from 1 to 5, inclusive.

12. The compound according to claim 10 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and

Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

13. The compound according to claim 12 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

14. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

one of R a and R b is hydrogen and the other is —OH or —OC(O)R′, or R a and R b are taken together to form an oxo group;

R x and R y are taken together to form an optionally substituted C 3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 1 is an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl(C 1-3 alkyl);

R 2 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl;

R 3 is a warhead —(CH 2 ) n -L-Y, wherein:

n is an integer from 0 to 5 , inclusive;

L is a covalent bond, —C(O)—, —N(R)C(O)—, —NH—, —CH 2 NH—, —NHCH 2 —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and

Y is selected from the following (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), or (xvii):

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN;

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(x)

(xvii) an 8-10 membered bicyclic, saturated or partially unsaturated ring, wherein said ring is substituted with 1-4 R e groups;

wherein:

each R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN;

R 4 is —NHC(O)NHR 5 , —NHC(O)OR 6 , or

R 5 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

15. The compound according to claim 1 , wherein R 3 is selected from:

16. The compound according to claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

17. A method for inhibiting HCV protease, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound according to claim 1 or a composition thereof.

18. A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

19. The composition according to claim 18 , in combination with an additional therapeutic agent.

20. The composition according to claim 19 , wherein the additional therapeutic agent is an antiviral agent.

21. A composition comprising a compound according to claim 10 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

22. The composition according to claim 21 , in combination with an additional therapeutic agent.

23. The composition according to claim 22 , wherein the additional therapeutic agent is an antiviral agent.

24. A composition comprising a compound according to claim 14 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

25. The composition according to claim 24 , in combination with an additional therapeutic agent.

26. The composition according to claim 25 , wherein the additional therapeutic agent is an antiviral agent.

27. A composition comprising a compound according to claim 16 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

28. The composition according to claim 27 , in combination with an additional therapeutic agent.

29. The composition according to claim 28 , wherein the additional therapeutic agent is an antiviral agent.

Assignments (3)

MERGER AND CHANGE OF NAME Recorded Feb 16, 2017

From: CELGENE AVILOMICS RESEARCH, INC.; CELGENE CAR LLC

To: CELGENE CAR LLC

Reel/Frame 041738/0041 →

CHANGE OF NAME Recorded Sep 28, 2012

From: AVILA THERAPEUTICS, INC.

To: CELGENE AVILOMICS RESEARCH, INC.

Reel/Frame 029058/0058 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 29, 2009

From: NIU, DEQIANG; PETTER, RUSSELL C.; QIAO, LIXIN; SINGH, JUSWINDER

To: AVILA THERAPEUTICS, INC.

Reel/Frame 023296/0616 →

Continuity (3)

Provisional Application 61089269 · Aug 15, 2008

Provisional Application 61098662 · Sep 19, 2008

Related Publication 20100041674A1 · Feb 18, 2010