Compounds and methods for modulating serotonin receptors in the periphery

1. A compound that is a 5-HT receptor modulator having the structure of Formula (I):

or pharmaceutically acceptable salt thereof, wherein:

each of R 1 , R 2 , and R 3 is independently a substituent,

each of R 5 , R 6 , and R 7 is independently hydrogen or a substituent, and

R 4 is an optionally substituted carbocyclic or heterocyclic ring system.

2. The compound of claim 1 , wherein the compound does not substantially accumulate in the human brain.

3. The compound of claim 1 , wherein the compound is a modulator of one or more of 5-HT 1 receptors (e.g. one or more of 5-HT 1A , 5-HT 1B , 5-HT 1C , 5-HT 1D , 5-HT 1E , 5-HT 1F ), 5-HT 2 receptors (e.g. one or more of 5-HT 2A , 5-HT 2B , 5-HT 2C ); 5-HT 3 receptors; 5-HT 4 receptors; 5-HT 5 receptors (e.g. 5-HT 5A ); 5-HT 6 receptors; and HT 7 receptors.

4. The compound of claim 1 , wherein the modulation is selected from full agonism, partial agonism, antagonism, inverse agonism and inhibition.

5. The compound of claim 1 , wherein the compound is a dual partial agonist at the serotonin 5-HT 7 and 5-HT 1A receptors.

6. The compound of claim 1 , wherein the compound is a modulator of one or more of the serotonin 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors.

7. The compound of claim 6 , wherein the compound selectively inhibits the serotonin 5-HT 2C receptor relative to 5-HT 2A or 5-HT 2B .

8. The compound of claim 1 , wherein the compound is enantiomerically pure.

9. The compound of claim 1 , wherein each of R 1 , R 2 , and R 3 are methyl.

10. The compound of claim 1 , wherein R 5 , R 6 , and R 7 are each independently hydrogen, alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy.

11. The compound of claim 1 , wherein R 4 is an optionally substituted phenyl, naphthyl, or furan ring.

12. The compound of claim 11 , wherein R 4 is substituted with one or more alkyl, alkoxy, or halo substituents.

13. The compound of claim 11 , wherein R 4 is phenyl substituted with one fluoro or chloro.

14. The compound of claim 13 , wherein R 4 is ortho-fluoro or ortho-chloro substituted phenyl.

15. The compound of claim 11 , wherein R 4 has a methyl or methoxy substituent.

16. The compound of claim 15 , wherein R 4 is meta-methyl or meta-methoxy substituted phenyl.

17. The compound of claim 11 , wherein R 4 is unsubstituted naphthyl.

18. The compound of claim 1 , wherein the compound is not a physiologically-relevant substrate for one or more forms of P450, selected from CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4.

19. A pharmaceutical composition comprising a therapeutic amount of the compound of claim 1 , and a pharmaceutically acceptable excipient or carrier.

20. The pharmaceutical composition of claim 19 , wherein the compound is substantially enantiomerically pure.

21. A method for treating a gastrointestinal disorder or condition, comprising administering the compound of claim 1 to a patient in need thereof.

22. The method of claim 21 , wherein the gastrointestinal disorder or condition is selected from inflammatory bowel disease, irritable bowel syndrome, celiac disease, and an enteric infection.

23. The method of claim 21 , wherein the patient has Crohn's Disease or ulcerative colitis.

24. A method for treating a cardiopulmonary disorder, comprising administering the composition of claim 1 to a patient in need thereof.

25. The method of claim 24 , wherein the cardiopulmonary disorder is one or more of cardiac valvulopathy and pulmonary hypertension.

26. The compound of claim 14 , wherein the compound is (2S)-5-(2′-fluorophenyl)-N,N,N-trimethyl-tetrahydronaphthalen-2-amine.

27. The pharmaceutical composition of claim 19 , wherein the compound is (2S)-5-(2′-fluorophenyl)-N,N,N-trimethyl-tetrahydronaphthalen-2-amine.

28. The method of claim 21 , wherein the compound is (2S)-5-(2′-fluorophenyl)-N,N,N-trimethyl-tetrahydronaphthalen-2-amine.