IP Library › Granted Patent US 7,282,509

Granted Patent B2

US 7,282,509 · App. 11/087,167 · Granted Oct 16, 2007

Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders

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Quick Facts

Patent No.: US 7,282,509
App. No.: 11/087,167
Granted: Oct 16, 2007
Kind: B2

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Abstract

The subject invention provides stereoisomeric compounds of formula (X): wherein the variables are as defined herein, and compositions for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.

Claims (250)

1. A compound of formula:

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3 and 4 are cis relative to each other;

L is —(C 2 -C 6 alkyl)-C(O)— or —(C 3 -C 5 alkyl)— wherein one carbon of the —(C 3 -C 5 alkyl)- group may be replaced by —N(R 9 )—;

R 1 is halogen;

R 2 is amino, NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl);

R 3 is OH or C 1 -C 4 alkoxy;

R 4 is H or methyl; and

R 5 is —O-heterocycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is aza-bicyclo-octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, piperidinyl, piperazinyl, or pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are unsubstituted or substituted at one or two positions with groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, hydroxyl, hydroxy C 1 -C 4 alkyl, amino, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —(C 0 -C 6 alkyl)-C(O)R 11 , or NO 2 , wherein the aza-bicyclo-octyl, aza-bicyclo-nonyl, and aza-bicyclo-decyl nitrogen is optionally substituted with methyl or ethyl;

R 9 at each occurrence is independently H or C 1 -C 4 alkyl;

R 11 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 ; and

R 20 is C 1 -C 6 alkoxy or OH.

2. A compound according to claim 1 , wherein R 1 is chloro.

3. A compound according to claim 1 , wherein R 2 is amino.

4. A compound according to claim 1 , wherein R 3 is methoxy.

5. A compound according to claim 1 , wherein R 4 is H.

6. A compound according to claim 1 , wherein

R 1 is chloro; R 2 is amino; R 3 is methoxy; R 4 is H, and R 1 , R 2 , and R 3 have the following orientation on the phenyl ring:

7. A compound according to claim 1 , wherein

R 5 is heterocycloalkyl wherein the heterocycloalkyl is 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, wherein the 1-aza-bicyclo[2.2.2]oct-3-yl or 8aza-bicyclo[3.2.1]oct-3-yl nitrogen is optionally substituted with methyl or ethyl.

8. A composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

9. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. A method of stimulating the motility of the gastro-intestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. A compound of formula:

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3 and 4 are cis relative to each other;

L is —(C 4 -C 6 alkyl)-C(O)—;

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 is H; and

R 5 is —O-C 3 -C 8 cycloalkyl, —O-heterocycloalkyl, heterocycloalkyl, aryl, —O-aryl, —N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl, or N(R 9 )-C 0 -C 6 alkyl-aryl, —O-heteroaryl, —N(R 9 )-C 1 -C 6 C(O)-heteroaryl, or —N(R 9 )-C 0 -C 6 alkyl-heteroaryl, wherein each of the cyclic groups is unsubstituted or substituted at one or more substitutable positions with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, hydroxy-C 1 -C 4 -alkyl, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)R 11 , —O-(C 0 -C 6 alkyl)-C(O)R 11 , methylsulfone, C 0 -C 6 -sulfonamide, or NO 2 ; wherein

R 9 at each occurrence is independently H or C 1 -C 4 alkyl;

R 11 is C 1 -C 6 alkyl, OH, or

the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF3, or OCF 3 ,

the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 ; or

R 11 is —O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 ; and

R 20 is C 1 -C 6 alkoxy (preferably C 1 -C 4 alkoxy, more preferably methoxy), or OH.

12. The compound of formula

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3 and 4 are cis relative to each other;

R 1 is halogen;

R 2 is amino, NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl);

R 3 is OH or C 1 -C 4 alkoxy;

R 4 is H or methyl; and

R 5 is —O-C 3 -C 5 cycloalkyl, —O-heterocycloalkyl, heterocycloalkyl, aryl, —O-aryl, —N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl, or —N(R 9 )-C 0 -C 6 alkyl-aryl, —O-heteroaryl, —N(R 9 )-C 1 -C 6 C(O)-heteroaryl, or —N(R 9 )-C 0 -C 6 alkyl-heteroaryl, wherein each of the cyclic groups is unsubstituted or substituted at one or more substitutable positions with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, hydroxy-C 1 -C 4 -alkyl, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)R 11 , or —O-(C 0 -C 6 alkyl)-C(O)R 11 , methylsulfone, C 0 -C 6 -sulfonamide, or NO 2 ; wherein

R 9 at each occurrence is independently H or C 1 -C 4 alkyl;

R 11 is C 1 -C 6 alkyl, OH, or

R 20 is C 1 -C 6 alkoxy (preferably C 1 -C 4 alkoxy, more preferably methoxy), or OH.

13. The compound according to claim 12 wherein

R 5 is —O-heterocycloalkyl wherein the heterocycloalkyl is aza-bicyclo-octyl, aza-bicyclo-nonyl, or aza-bicyclo-decyl, wherein the aza-bicyclo-octyl, aza-bicyclo-nonyl, or aza-bicyclo-decyl nitrogen is optionally substituted with methyl or ethyl.

14. The compound according to claim 12 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy; and

15. The compound according to claim 12 that is 8-methyl-8-azabicyclo[3.2.1]oct-3-yl 6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate and pharmaceutically acceptable salts thereof.

16. A composition comprising a therapeutically effective amount of a compound of claim 12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

17. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 12 or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17 wherein the compound is

(3S)-1-azabicyclo[2.2.2]oct-3-yl 6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate;

(3S)-1-azabicyclo[2.2.2]oct-3-yl 6-{(3R,4S)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate;

(3R)-1-azabicyclo [2.2.2]oct-3-yl 6-{(3R,4S)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate; or

(R)-quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoate; or a pharmaceutically acceptable salt thereof.

19. A method of stimulating the motility of the gastro-intestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 12 or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19 wherein the compound is

(3S)-1-azabicyclo[2.2.2]oct-3-yl 6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate;

(3S)-1-azabicyclo[2.2.2]oct-3-yl 6-{(3R,4S)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate;

(3R)-1-azabicyclo[2.2.2oct-3-yl 6-{(3R,4S)-4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}hexanoate; or

(R)-quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoate; or a pharmaceutically acceptable salt thereof.

21. A compound of formula:

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3 and 4 are cis relative to each other;

R 1 is halogen;

R 2 is amino, NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl);

R 3 is OH or C 1 -C 4 alkoxy;

R 4 is H or methyl;

R 9 is H or C 1 -C 4 alkyl;

R 11 is C 1 -C 6 alkyl, OH, or

the heteroaryl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 ; or

R 15 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, hydroxy C 1 -C 4 alkyl, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), methylsulfone, C 0 -C 6 -sulfonamide, or NO 2 ; and

R 16 is H or —O-(C 0 -C 6 alkyl)-C(O)R 11 .

22. The compound according to claim 21 wherein

R 4 and R 9 are independently H or methyl; and

R 11 is OH.

23. The compound according to claim 21 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 and R 9 are independently H or methyl;

R 11 is OH; and

R 15 and R 16 are H.

24. The compound according to claim 21 wherein

R 4 and each R 9 are independently H or methyl; and

R 1 is C 1 -C 6 alkoxy optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl is aza-bicyclo-octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 , wherein the aza-bicyclo-octyl, aza-bicyclo-nonyl, or aza-bicyclo-decyl nitrogen is optionally substituted with methyl or ethyl.

25. The compound according to claim 21 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 and each R 9 are independently H or methyl;

R 11 is C 1 -C 6 alkoxy optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 , wherein the nitrogen of the aza-bicyclo-octyl, aza-bicyclo-nonyl, and aza-bicyclo-decyl is optionally substituted with methyl or ethyl; and

R 15 and R 16 are H.

26. The compound according to claim 21 wherein

R 4 and each R 9 are independently H or methyl; and

R 11 is C 1 -C 6 alkoxy optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), or heteroaryl, wherein the heteroaryl is pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, or indolyl, wherein the heteroaryl is optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 .

27. The compound according to claim 21 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 and each R 9 are independently H or methyl;

R 15 and R 16 are H.

28. The compound according to claim 21 wherein,

R 4 and R 9 are independently H or methyl; and

R 11 is OH, C 1 -C 4 alkoxy, or C 1 -C 2 alkoxy-C 1 -C 3 alkoxy-.

29. The compound according to claim 21 wherein

R 4 and each R 9 are independently H or methyl; and

R 11 is —O-heterocycloalkyl wherein the heterocycloalkyl is aza-bicyclo-octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 , wherein the aza-bicyclo-octyl, aza-bicyclo-nonyl, or aza-bicyclo-decyl nitrogen is optionally substituted with methyl or ethyl.

30. The compound according to claim 21 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 and each R 9 are independently H or methyl;

R 15 and R 16 are H.

31. The compound according to claim 21 that is

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoic acid;

methyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

ethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

isopropyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

2-methoxyethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

2-pyrrolidin-1-ylethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

2-pyridin-2-ylethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

2-(dimethylamino)ethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

2-morpholin-4-ylethyl 4-[({(3S,4R)-4-1(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin 1-yl}acetyl)amino]benzoate;

2-oxo-2-(piperidin-4-ylamino)ethyl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

1-methylpiperidin-4-yl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

1-methylpiperidin-3-yl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

1,4-dimethylpiperidin-4-yl 4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

and pharmaceutically acceptable salts thereof.

32. A composition comprising a therapeutically effective amount of a compound of claim 21 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

33. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 21 or a pharmaceutically acceptable salt thereof.

34. A method of stimulating the motility of the gastro-intestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 21 or a pharmaceutically acceptable salt thereof.

35. A compound of formula

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3 and 4 are cis relative to each other;

R 1 is halogen;

R 2 is amino, NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl);

R 3 is OH or C 1 -C 4 alkoxy;

R 4 is H or methyl;

R 9 is H or C 1 -C 4 alkyl;

R 11 is C 1 -C 6 alkyl, OH, or

R 1 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, —O-heterocycloalkyl, —C 1 -C 6 (O)N(R 9 )-heteroaryl, or heteroaryl, wherein

the heteroaryl group are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 ; or

is —O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, —CO 2 H, CF 3 , or OCF 3 ;

R 16 is H or —O-(C 0 -C 6 alkyl)-C(O)R 11 .

36. The compound according to claim 35 wherein

R 4 and R 9 are independently H or methyl; and

R 11 is OH, C 1 -C 4 alkoxy, or C 1 -C 2 alkoxy-C 1 -C 3 alkoxy-.

37. The compound according to claim 35 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 and each R 9 are independently H or methyl;

R 11 is OH, C 1 -C 4 alkoxy, or C 1 -C 2 alkoxy-C 1 -C 3 alkoxy-; and

R 15 and R 16 are H.

38. The compound according to claim 35 that is

4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}ethyl)(methyl)amino]methyl}benzoic acid;

methyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}ethyl)(methyl)amino]methyl}benzoate;

methyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]3-methoxypiperidin-1-yl}ethyl)amino]methyl}benzoate;

isopropyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}ethyl)amino]methyl}benzoate;

ethyl 4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}ethyl)amino]methyl}benzoate Dihydrochloride;

and pharmaceutically acceptable salts thereof.

39. A composition comprising a therapeutically effective amount of a compound of claim 35 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

40. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 35 or a pharmaceutically acceptable salt thereof.

41. A method of stimulating the motility of the gastro-intestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 35 or a pharmaceutically acceptable salt thereof.

42. The compound of formula

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3and 4 are cis relative to each other;

n is 1 or 2;

R 1 is halogen;

R 2 is amino, NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl);

R 3 is OH or C 1 -C 4 alkoxy;

R 4 is H or methyl;

R 9 is H or C 1 -C 4 alkyl; and

R 11 is C 1 -C 6 alkyl, OH, or

R 11 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 - 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, —O-heterocycloalkyl, —( 1 -C 6 (O)N(R 9 )-heteroaryl, or heteroaryl, wherein

43. The compound according to claim 42 wherein

R 4 is H or methyl; and

R 11 is OH, C 1 -C 4 alkoxy, or C 1 -C 2 alkoxy-C 1 -C 3 alkoxy-.

44. The compound according to claim 42 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 4 is H or methyl; and

R 11 is OH, C 1 -C 4 alkoxy, or C 1 -C 2 alkoxy-C 1 -C 3 alkoxy-.

45. The compound according to claim 42 that is

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piperidine-4-carboxylic acid;

methyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piperidine-4-carboxylate;

ethyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piperidine-4-carboxylate;

2-methoxyethyl 1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piperidine-4-carboxylate;

and pharmaceutically acceptable salts thereof.

46. A composition comprising a therapeutically effective amount of a compound of claim 42 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

47. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 42 or a pharmaceutically acceptable salt thereof.

48. A method of stimulating the motility of the gastrointestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 42 or a pharmaceutically acceptable salt thereof.

49. A compound of formula:

and pharmaceutically acceptable salts thereof, wherein

the bonds at positions 3 and 4 are cis relative to each other;

L is —(C 1 -C 6 alkyl)-;

R 1 is halogen;

R 2 is amino, NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl);

R 3 is OH or C 1 -C 4 alkoxy;

R 4 is H or methyl;

R 5 is —N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl wherein the aryl is optionally substituted with 1 or 2 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, hydroxy-C 1 -C 4 -alkyl, amino, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)R 11 , or —O-(C 0 -C 6 alkyl)-C(O)R 11 , methylsulfone, C 0 -C 6 -sulfonamide, or NO 2 ;

R 9 at each occurrence is independently H or C 1 -C 4 alkyl;

R 11 is C 1 -C 6 alkyl, OH, or

R 11 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, amino, —NH(C 1 -C 6 alkyl), —N(C 6 alkyl)(C 1 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, —O-heterocycloalkyl, -C 1 -C 6 (O)N(R 9 )-heteroaryl, or heteroaryl, wherein

R 20 is C 1 -C 6 alkoxy (preferably C 1 -C 4 alkoxy, more preferably methoxy), or OH.

50. The compound according to claim 49 wherein

R 5 is —N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl wherein the aryl is substituted with —(C 0 -C 6 alkyl)-C(O)R 11 ; and

51. The compound according to claim 49 wherein

R 1 is chloro;

R 2 is amino;

R 3 is methoxy;

R 5 is —N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl wherein the aryl is substituted with —(C 0 -C 6 alkyl)-C(O)R 11 ; and

52. The compound according to claim 49 that is (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-{[(2-{(3S,4R)-4[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}ethyl)amino]carbonyl}benzoate.

53. A composition comprising a therapeutically effective amount of a compound of claim 49 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

54. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 49 or a pharmaceutically acceptable salt thereof.

55. A method of stimulating the motility of the gastro-intestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 49 or a pharmaceutically acceptable salt thereof.

56. A composition comprising a therapeutically effective amount of 6((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoic acid or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, solvent, adjuvant, or excipient.

57. A method of treating gastroesophageal reflux disease comprising administering to a patient in need of such treatment a therapeutically effective amount of 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoic acid or a pharmaceutically acceptable salt thereof.

58. A method of stimulating the motility of the gastro-intestinal system comprising administering to a patient in need of such treatment a therapeutically effective amount of 6-((3S ,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoic acid or a pharmaceutically acceptable salt thereof.

Assignments (7)

CHANGE OF NAME Recorded Dec 9, 2016

From: NARONAPRIDE, LLC

To: RENEXXION, LLC

Reel/Frame 040876/0342 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 9, 2016

From: ARMETHEON, INC.

To: NARONAPRIDE, LLC

Reel/Frame 040699/0559 →

RELEASE OF SECURITY INTEREST Recorded Feb 6, 2013

From: AYER CAPITAL PARTNERS MASTER FUND, L.P.; MPM BIOVENTURES III, L.P.; MPM BIOVENTURES III-QP, L.P.; MPM BIOVENTURES III GMBH & CO. BETEILIGUNGS KG; MPM BIOVENTURES III PARALLEL FUND, L.P.; AYER CAPITAL PARTNERS KESTREL FUND, L.P.; MPM ASSET MANAGEMENT INVESTORS 2002 BVIII LLC

To: ARYX THERAPEUTICS, INC.

Reel/Frame 029767/0524 →

CORRECTIVE ASSIGNMENT TO CORRECT THE THE NAME OF THE ASSIGNEE WHICH SHOULD BE ARYX THERAPEUTICS PREVIOUSLY RECORDED ON REEL 016757 FRAME 0545. ASSIGNOR(S) HEREBY CONFIRMS THE NAME OF THE ASSIGNEE SHOULD HAVE BEEN ARYX THERAPEUTICS. THE ASSIGNEE NAME SHOULD NOT HAVE HAD INC.. Recorded Oct 10, 2012

From: IRWIN, IAN; PALME, MONICA; BECKER, CYRUS

To: ARYX THERAPEUTICS

Reel/Frame 029109/0542 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 10, 2012

From: ARYX THERAPEUTICS

To: ARYX THERAPEUTICS, INC.

Reel/Frame 029106/0435 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 4, 2012

From: ARYX THERAPEUTICS, INC.

To: ARMETHEON, INC.

Reel/Frame 029080/0290 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 4, 2012

From: IRWIN, IAN; PALME, MONICA; BECKER, CYRUS

To: ARYX THERAPEUTICS

Reel/Frame 028894/0453 →