IP Library › Granted Patent US 8,513,232

Granted Patent B2

US 8,513,232 · App. 12/846,100 · Granted Aug 20, 2013

Substituted spirocyclic piperidine derivatives as histamine-3 (H3) receptor ligands

Inventors: Edward R. Bacon (Audobon, PA); Nadine C. Becknell (Coatesville, PA); Reddeppa reddy Dandu (Downingtown, PA); Lisa Guise-Zawacki (Yardley, PA); Tao Guo (Dayton, NJ); Chia-yu Huang (Princeton Junction, NJ); Robert L. Hudkins (Chester Springs, PA); Babu G. Sundar (West Chester, PA); Ming Tao (Maple Glen, PA); Minglang Wu (Monmouth Junction, NJ); Allison L. Zulli (Wayne, PA)

Assignees: Cephalon, Inc.; Pharmacopeia, LLC

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Quick Facts

Patent No.: US 8,513,232
App. No.: 12/846,100
Granted: Aug 20, 2013
Kind: B2

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Abstract

The present invention provides compounds of Formula (I): their use as H 3 antagonists/inverse agonists, processes for their preparation, and pharmaceuticals compositions thereof.

Claims (157)

1. A compound of the Formula (I):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein:

R 1 is cyclobutyl or cyclopentyl;

k is 0, 1, or 2; m is 0, 1, or 2; and the sum of m and k is 1, 2, or 3;

Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from —CH═ and —N═;

provided that when Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from —N═ with the proviso that no more than of Y 1 , Y 2 , Y 3 , and Y 4 may be —N═;

W is —O—, —CH 2 —, —CH 2 —O—, —C(═O)—CH 2 —, —C(OH)—CH 2 —, —CH 2 —CH 2 —, —O—CH 2 —CH 2 — or —CH 2 —CH 2 —O—;

X is R 2 , —OR 2 , —(C 1 -C 3 alkyl)-R 2 ; —(C 2 -C 6 alkenyl)-R 2 ; —O(C 1 -C 3 alkyl)-R 2 , —O(C 2 -C 6 alkenyl)-R 2 ; —NR 29 R 29 , —NR 29 R 2 , —NR 29 (C 1 -C 3 alkyl)-R 2 , —(C 1 -C 3 alkyl)NR 29 R 2 , —NR 29 C(═O)R 2 , —NR 29 C(═O)(C 1 -C 3 alkyl)-R 2 , or —NR 29 C(═O)NHR 2 ; wherein each of said (C 1 -C 3 alkyl) is optionally substituted with —OH or —OC 1 -C 3 alkyl;

R 2 is selected from the group consisting of

C 1 -C 8 alkyl optionally substituted with 1-3 R 20 ;

C 2 -C 6 alkenyl optionally substituted with 1-3 R 20 ;

C 3 -C 10 cycloalkyl optionally substituted with 1-3 R 20 ;

C 6 -C 10 aryl optionally substituted with 1-3 R 20 ;

5 to 10 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1-3 R 20 ;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 , wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R20; and

5 to 10 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 , wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R 20 ;

with the proviso that R 2 is not a substituted or unsubstituted pyridazine or pyridazinone;

R 8 is F, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;

R 9 , at each occurrence, is independently, F, Cl, Br, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;

R 20 at each occurrence is independently selected from the group consisting of

—H, —F, —Cl, —Br, —I, —OR 21 , —NR 23 R 24 , —NHOH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, (═O), —C(═O)R 25 , —C(═O)OR 25 , —OC(═O)R 25 , —OC(═O)NR 23 R 24 , —C(═O)NR 23 R 24 , —NR 27 C(═O)NR 23 R 24 ; —NR 27 C(═O)R 25 ; —NR 27 C(O)OR 25 , —NR 27 C(═S)R 25 , —SR 25 , —S(═O)R 25 , —S(═O) 2 R 25 , —S(═O) 2 NR 23 R 24 , —NR 27 SR 25 , —NR 27 S(═O)R 25 , —NR 27 S(═O) 2 R 25 , methylenedioxy, ethylenedioxy, propylenedioxy, C 1 -C 6 alkyl optionally substituted by 1-3 R 31 ;

C 2 -C 6 alkenyl optionally substituted by 1-3 R 31 ;

C 2 -C 6 alkynyl optionally substituted by 1-3 R 31 ;

C 3 -C 7 cycloalkyl optionally substituted with 1-3 R 30 ;

C 6 -C 10 aryl optionally substituted with 1-3 R 30 ;

5 to 6 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1-3 R 30 ;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 , wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R 30 ; and

5 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 , wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R 30 ;

R 21 at each occurrence is independently H, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl optionally substituted with 1-3 R 22 ; C 2 -C 6 alkenyl optionally substituted with 1-3 R 22 ; C 6 -C 10 aryl optionally substituted with 1-3 R 30 ; 5 to 6 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1-3 R 30 ;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 , wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R 30 ; and

R 22 at each occurrence is independently selected from the group consisting of

—H, —F, —Cl, —Br, —I, —C 1 -C 6 alkoxy, phenyl, —NR 23 R 24 , —NHOH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, (═O), —C(═O)R 28 , —C(═O)OR 28 , —OC(═O)R 28 , —OC(═O)NR 23 R 24 , —C(═O)NR 23 R 24 , —NR 27 C(═O)NR 23 R 24 , —NR 27 C(═O)R 28 , —NR 27 C(═O)OR 28 , —NR 27 C(═S)R 28 , —SR 28 , —S(═O)R 28 , —S(═O) 2 R 28 , —S(═O) 2 NR 23 R 24 , —NR 27 SR 28 , —NR 27 S(═O)R 28 , —NR 27 S(═O) 2 R 28 , and C 3 -C 7 cycloalkyl;

R 23 and R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl optionally substituted with 1-3 R 31 ; C 3 -C 7 cycloalkyl; C 6 -C 10 aryl optionally substituted with 1-3 R 30 ; 5 to 6 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, said heteroaryl optionally substituted with 1-3 R 30 ;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ; and

5 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ;

or R 23 and R 24 , together with the nitrogen atom to which they are attached, may form a 3 to 7 membered heterocycloalkyl ring containing 1 nitrogen atom and optionally a second heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heterocycloalkyl ring is optionally substituted with 1-3 R 30 ;

R 25 at each occurrence is independently H, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, —(C 1 -C 3 alkyl)C 6 -C 10 aryl, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, 5 to 6 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 ; or

5 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 ;

R 27 at each occurrence is independently H or C 1 -C 3 alkyl;

R 28 at each occurrence is independently H or C 1 -C 3 alkyl;

R 29 at each occurrence is independently H, C 1 -C 3 alkyl, or —C(═O)CH 3 ;

R 30 at each occurrence is independently H, —F, —Cl, —Br, —I, —OH, ═O, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl, —C(═O)N(R 32 ) 2 , —NHC(═O)N(R 32 ) 2 , or —S(═O) 2 R 32 ,

R 31 at each occurrence is independently H, —F, —Cl, —Br, —I, —OH, ═O, C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl, —C(═O)N(R 32 ) 2 , —NHC(═O)N(R 32 ) 2 , C 6 -C 10 aryl optionally substituted with 1-3 R 30 ; 3 to 4 membered heterocycloalkyl ring system containing one or two heteroatoms selected from N, O, S, SO, and SO 2 ; or 5 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 ;

R 32 at each occurrence is independently H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;

n is 0, 1, 2, or 3; and

z is 0, 1, 2, 3, 4, 5, or 6.

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

or a stereoisomeric form, mixture of stereoisomeric forms, N-oxide form, or a pharmaceutically acceptable salt thereof, wherein Y 1 is —CH═ or —N═; and Y 2 ═Y 3 is —C(X)═CH— or —CH═C(X)—.

3. The compound of claim 2 wherein W is —CH 2 —O— or —CH 2 —CH 2 —.

4. The compound of claim 1 wherein k is 0.

5. The compound of claim 1 wherein k is 1.

6. The compound of claim 1 wherein m is 0.

7. The compound of claim 1 wherein m is 1.

8. The compound of claim 1 wherein the sum of m and k is 1.

9. The compound of claim 1 wherein the sum of m and k is 2.

10. The compound of claim 1 wherein W is —O—, —CH 2 —, —CH 2 —O—, —C(═O)—CH 2 —, —C(OH)—CH 2 —, —CH 2 —CH 2 — or —CH 2 —CH 2 —O—.

11. The compound of claim 1 wherein W is —O—, —CH 2 —O—, —CH 2 —CH 2 —, or —CH 2 —CH 2 —O—.

12. The compound of claim 1 wherein W is —CH 2 —O— or —CH 2 —CH 2 —.

13. The compound of claim 1 wherein z is 0.

14. The compound of claim 1 having the structure of Formula (II):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 having the structure of Formula (III):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein Y 2 ═Y 3 is —C(X)═CH— or —CH═C(X)—.

16. The compound of claim 15 wherein W is —CH 2 —O— or —CH 2 —CH 2 —.

17. The compound of claim 1 having the structure of Formula (III):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 having the structure of Formula (IV):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein:

W is —O—, —CH 2 —O—, —C(═O)—CH 2 —, —C(OH)—CH 2 —, —CH 2 —CH 2 —, or —CH 2 —CH 2 —O—;

R 23 at each occurrence are each independently selected from H, methyl, ethyl, and propyl; and

R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl optionally substituted with 1-3 R 31 ; C 3 -C 7 cycloalkyl; C 6 -C 10 aryl optionally substituted with 1-3 R 30 ; 5 to 6 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, said heteroaryl optionally substituted with 1-3 R 30 ;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ; and

5 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ;

20. The compound of claim 19 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein W is —CH 2 —O— or —CH 2 —CH 2 —.

21. The compound of claim 19 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein X is R 2 , —OR 2 , —OCH 2 —R 2 , —OCH(OH)—R 2 , —OCH(OCH 3 )—R 2 , —(CH 2 —CH═CH—CH 2 )—R 2 , —O—(CH 2 —CH═CH—CH 2 )—R 2 , —NR 29 R 2 , —N(R 29 )CH 2 —R 2 , —CH 2 NR 29 R 2 , —NR 29 C(═O)R 2 , —NR 29 C(═O)CH 2 —R 2 , or —NR 29 C(═O)NHR 2 .

22. The compound of claim 18 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein:

W is —CH 2 —O— or —CH 2 —CH 2 —;

X is R 2 , —OR 2 , —OCH 2 —R 2 , —NR 29 R 2 , —N(R 29 )CH 2 —R 2 , —CH 2 NR 29 R 2 , —NR 29 C(═O)R 2 , —NR 29 C(═O)CH 2 —R 2 , or —NR 29 C(═O)NHR 2 ;

R 2 is selected from the group consisting of:

phenyl optionally substituted with 1-3 R 20 ;

5 to 10 membered heteroaryl ring system selected from benzofuranyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, cinnolinyl, furanyl, imidazolyl, imidazopyridinyl, 1H-indazolyl, indolyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, and thienyl, wherein said heteroaryl ring system is optionally substituted with 1-3 R 20 ; and

5 to 10 membered heterocycloalkyl ring system selected from azetidinyl, 1,1-dioxo-thiomorpholinyl, 1,4-diazapinyl, 2,3-dihydrobenzofuranyl, 3H-benzooxazolyl, imidazolidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyrazolopyridinyl, tetrahydro-1,3a,7-triaza-azulenyl, and tetrahydrofuran, wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R 20 ;

R 9 , at each occurrence, is independently, F or Cl;

R 20 at each occurrence is independently selected from the group consisting of

—H, —F, —Cl, —OR 21 , —NR 23 R 24 , —CN, —CF 3 , (═O), —C(═O)R 25 , —C(═O)OR 25 , —OC(═O)R 25 , —OC(═O)NR 23 R 24 , —C(═O)NR 23 R 24 , —NR 27 C(═O)NR 23 R 24 , —NR 27 C(═O)R 25 , —NR 27 C(═O)OR 25 , —NR 27 C(═S)R 25 , —SR 25 , —S(═O)R 25 , —S(═O) 2 R 25 , —S(═O) 2 NR 23 R 24 , —NR 27 SR 25 , —NR 27 S(═O)R 25 , —NR 27 S(═O) 2 R 25 , methyl, ethyl, propyl, butyl, ethylenedioxy, methyl substituted with R 31 ; phenyl optionally substituted with 1-3 R 30 ; and 5 to 6 membered heteroaryl ring system selected from oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein said heteroaryl ring system is optionally substituted with 1-3 R 30 ;

3 to 7 membered heterocycloalkyl ring system selected from dihydro-oxazolyl, morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl, wherein said heterocycloalkyl ring system is optionally substituted with 1-3 R 30 ;

R 21 at each occurrence is independently H, —CF 3 , methyl, ethyl, propyl, butyl, methoxyethyl, cyclopropylmethyl, phenyl, or pyridyl;

R 22 at each occurrence is independently selected from the group consisting of

—H, —F, —Cl, methoxy, ethoxy, propoxy, butoxy, —NR 23 R 24 , —NHOH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, (═O), —C(═O)R 28 , —C(═O)OR 28 , —OC(═O)R 28 , —OC(═O)NR 23 R 24 , —C(═O)NR 23 R 24 , —NR 27 C(═O)NR 23 R 24 , —NR 27 C(═O)R 28 , —NR 27 C(═O)OR 28 , —NR 27 C(═S)R 28 , —SR 28 , —S(═O)R 28 , —S(═O) 2 R 28 , —S(═O) 2 NR 23 R 24 , —NR 27 SR 28 , —NR 27 S(═O)R 28 , and —NR 27 S(═O) 2 R 28 ;

R 23 at each occurrence are each independently selected from H, methyl, ethyl, and propyl;

R 24 at each occurrence are each independently selected from H, methyl, ethyl, propyl, butyl, hydroxyethyl, methoxyethyl, ethoxyethyl, cyclopropyl, cyclobutyl, phenyl optionally substituted with 1-3 R 30 ; 3 to 7 membered heterocycloalkyl ring system selected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl, said heterocycloalkyl optionally substituted with 1-3 R 30 ; or R 23 and R 24 , together with the nitrogen atom to which they are attached, may form a 3 to 7 membered heterocycloalkyl ring selected from azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, wherein said heterocycloalkyl ring is optionally substituted with 1-3 R 30 ;

R 25 at each occurrence is independently H, methyl, ethyl, propyl, butyl, CF 3 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl and furanyl;

R 27 at each occurrence is independently H or methyl;

R 28 at each occurrence is independently H or methyl;

R 29 at each occurrence is independently H, methyl, ethyl, or —C(═O)CH 3 ;

R 30 at each occurrence is independently H, —F, —Cl, —OH, ═O, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, CF 3 , —C(═O)N(R 32 ) 2 , —NHC(═O)N(R 32 ) 2 , or —S(═O) 2 CH 3 ;

R 31 at each occurrence is independently H, —F, —Cl, —OH, ═O, methoxy, ethoxy, propoxy, butoxy, CF 3 , —C(═O)N(R 32 ) 2 , —NHC(═O)N(R 32 ) 2 , phenyl optionally substituted with 1-3 R 30 ; or tetrahydrofuranyl;

R 32 at each occurrence is independently H or methyl;

n is 0, 1, or 2; and

z is 0 or 1.

23. The compound of claim 1 having the structure of Formula (IV):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein:

W is —O—, —CH 2 —O—, —C(═O)—CH 2 —, —C(OH)—CH 2 —, —CH 2 —CH 2 —, or —CH 2 —CH 2 —O—;

R 2 is selected from the group consisting of

C 1 -C 8 alkyl optionally substituted with 1-3 R 20 ;

C 2 -C 6 alkenyl optionally substituted with 1-3 R 20 ;

C 3 -C 10 cycloalkyl optionally substituted with 1-3 R 20 ;

C 6 -C 10 aryl optionally substituted with 1-3 R 20 ;

5 to 10 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1-3 R 20 ; and

with the proviso that R 2 is not a substituted or unsubstituted pyridazinone ring or a substituted or unsubstituted pyridazine ring;

R 23 at each occurrence are each independently selected from H, methyl, ethyl, and propyl;

4 membered heterocycloalkyl ring system containing one heteroatom selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ; and

5 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ; or R 23 and R 24 , together with the nitrogen atom to which they are attached, may form a 3 to 7 membered heterocycloalkyl ring containing 1 nitrogen atom and optionally a second heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heterocycloalkyl ring is optionally substituted with 1-3 R 30 .

24. The compound of claim 1 having the structure of Formula (V):

or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein:

W is —O—, —CH 2 —O—, —C(═O)—CH 2 —, —C(OH)—CH 2 —, —CH 2 —CH 2 —, or —CH 2 —CH 2 —O—;

R 23 at each occurrence are each independently selected from H, methyl, ethyl, and propyl; and

R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl optionally substituted with 1-3 R 31 ; C 3 -C 2 cycloalkyl; C 6 -C 10 aryl optionally substituted with 1-3 R 30 ; 5 to 6 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, said heteroaryl optionally substituted with 1-3 R 30 ; and 3 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 said heterocycloalkyl optionally substituted with 1-3 R 30 ;

26. The compound of claim 25 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein W is —CH 2 —O— or —CH 2 —CH 2 —.

27. The compound of claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein X is R 2 , —OR 2 , —OCH 2 —R 2 , —OCH(OH)—R 2 , —OCH(OCH 3 )—R 2 , —(CH 2 —CH═CH—CH 2 )—R 2 , —O—(CH 2 —CH═CH—CH 2 )—R 2 , —NR 29 R 2 , —N(R 29 )CH 2 —R 2 , —CH 2 NR 29 R 2 , —NR 29 C(═O)R 2 , —NR 29 C(═O)CH 2 —R 2 , or —NR 29 C(═O)NHR 2 .

28. The compound of claim 27 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein R 8 is H.

29. The compound of claim 24 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, wherein:

W is —CH 2 —O— or —CH 2 —CH 2 —;

X is R 2 , —OR 2 , —OCH 2 —R 2 , —NR 29 R 2 , —N(R 29 )CH 2 —R 2 , —CH 2 NR 29 R 2 , —NR 29 C(═O)R 2 , —NR 29 C(═O)CH 2 —R 2 , or —NR 29 C(═O)NHR 2 ;

R 2 is selected from the group consisting of

phenyl optionally substituted with 1-3 R 20 ;

R 9 , at each occurrence, is independently, F or Cl;

R 20 at each occurrence is independently selected from the group consisting of

—H, —F, —Cl, —OR 21 , —NR 23 R 24 , —CN, —CF 3 , (═O), —C(═O)R 25 , —C(═O)OR 25 , —OC(═O)R 25 , —OC(═O)NR 23 R 24 , C(═O)NR 23 R 24 , —NR 27 C(═O)NR 23 R 24 , —NR 27 C(═O)R 25 , —NR 27 C(═O)OR 25 , —NR 27 C(═S)R 25 , —SR 25 , —S(═O)R 25 , —S(═O) 2 R 25 , —S(═O) 2 NR 23 R 24 , —NR 27 SR 25 , —NR 27 S(═O)R 25 , —NR 27 S(═O) 2 R 25 , methyl, ethyl, propyl, butyl, ethylenedioxy, methyl substituted with R 31 ;

phenyl optionally substituted with 1-3 R 30 ; and 5 to 6 membered heteroaryl ring system selected from oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein said heteroaryl ring system is optionally substituted with 1-3 R 30 ;

R 21 at each occurrence is independently H, —CF 3 , methyl, ethyl, propyl, butyl, methoxyethyl, cyclopropylmethyl, phenyl, or pyridyl;

R 22 at each occurrence is independently selected from the group consisting of

R 23 at each occurrence are each independently selected from H, methyl, ethyl, and propyl;

R 24 at each occurrence are each independently selected from H, methyl, ethyl, propyl, butyl, hydroxyethyl, methoxyethyl, ethoxyethyl, cyclopropyl, cyclobutyl,

phenyl optionally substituted with 1-3 R 30 ;

3 to 7 membered heterocycloalkyl ring system selected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl, said heterocycloalkyl optionally substituted with 1-3 R 30 ; or R 23 and R 24 , together with the nitrogen atom to which they are attached, may form a 3 to 7 membered heterocycloalkyl ring selected from azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, wherein said heterocycloalkyl ring is optionally substituted with 1-3 R 30 ;

R 25 at each occurrence is independently H, methyl, ethyl, propyl, butyl, CF 3 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl and furanyl;

R 27 at each occurrence is independently H or methyl;

R 28 at each occurrence is independently H or methyl;

R 29 at each occurrence is independently H, methyl, ethyl, or —C(═O)CH 3 ;

R 32 at each occurrence is independently H or methyl; and

n is 0 or 1.

30. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomeric form, mixture of stereoisomeric forms, an N-oxide form, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Assignments (4)

CHANGE OF NAME Recorded Jan 10, 2011

From: PHARMACOPEIA, INC.

To: PHARMACOPEIA, LLC

Reel/Frame 025611/0417 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2010

From: GUO, TAO; WU, MINGLANG

To: PHARMACOPEIA, INC.

Reel/Frame 025473/0939 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 16, 2010

From: BECKNELL, NADINE C.; SUNDAR, BABU G.; ZULLI, ALLISON L.

To: CEPHALON, INC.