Histamine H3 inverse agonists and antagonists and methods of use thereof
Provided herein are fused imidazolyl compounds, methods of synthesis, and methods of use thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders and metabolic disorders. Compounds provided herein inhibit the activity of histamine H3 receptors and modulate the release of various neurotransmitters, such as histamine, acetylcholine, norepinephrine, and dopamine (e.g. at the synapse). Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.
1. A compound of formula (Ia):
or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, wherein
R N is hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, or (5 to 10 membered)heteroaryl, each of which is optionally substituted with one or more R′;
each occurrence of R′ is independently hydrogen, halogen, cyano, (C 1 -C 10 )alkyl, C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered)heteroaryl, hydroxyl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R 2 ; or two R′ substituents together may form a 3 to 10 membered ring optionally substituted with one or more R 2 ;
R 5 , R 6 , R 7 , and R 8 are each independently (i) hydrogen, halogen, or cyano; (ii) (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered)heteroaryl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R 1 ; (iii) hydroxyl substituted with R 1 ′; or (iv) two adjacent R 5 , R 6 , R 7 , and R 8 together form a 3 to 10 membered ring optionally substituted with one or more R 1 ;
each occurrence of R 1 is independently hydrogen, halogen, cyano, ═O, —OR 3 , —NR 3 R 4 , —N(R 3 )C(O)R 4 , —C(O)NR 3 R 4 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —S(O) 2 NR 3 R 4 , (C 1 -C 10 )alkyl optionally substituted with one or more R 2 , (C 3 -C 10 )cycloalkyl optionally substituted with one or more R 2 , (C 6 -C 12 )aralkyl optionally substituted with one or more R 2 , (6 to 10 membered)aryl optionally substituted with one or more R 2 , (C 1 -C 10 )heteroalkyl optionally substituted with one or more R 2 , (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 , or (5 to 10 membered)heteroaryl optionally substituted with one or more R 2 ;
each occurrence of R 1 ′ is independently —C(O)NR 3 R 4 , —C(O)R 3 , (C 3 -C 10 )cycloalkyl optionally substituted with one or more R 2 , (C 6 -C 12 )aralkyl optionally substituted with one or more R 2 , (6 to 10 membered)aryl optionally substituted with one or more R 2 , (C 1 -C 10 )heteroalkyl optionally substituted with one or more R 2 , (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 , or (5 to 10 membered)heteroaryl optionally substituted with one or more R 2 ;
each occurrence of R 2 is independently hydrogen, (C 1 -C 6 ) alkyl optionally substituted with one or more R 3 , (C 3 -C 6 )cycloalkyl optionally substituted with one or more R 3 , halogen, cyano, ═O, —OR 3 , —NR 3 R 4 , —N(R 3 )C(O)R 4 , —C(O)NR 3 R 4 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —S(O) m R 3 , or —S(O) 2 NR 3 R 4 ;
R 3 and R 4 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 7 -C 10 )aralkyl; (C 1 -C 6 )heteroalkyl, (C 3 -C 6 )heterocycloalkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl; or R 3 and R 4 together may form a 3 to 10 membered ring;
m is 0, 1, or 2;
n is 1, 2, or 3; and
provided that when n is 1, (i) R 5 , R 6 , R 7 , and R 8 cannot all be hydrogen; (ii) when one of R 5 , R 6 , R 7 , and R 8 is halogen, the other three of R 5 , R 6 , R 7 , and R 8 cannot all be hydrogen; and (iii) when R 6 is (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxyl optionally substituted with one or more halogen, R 5 , R 7 , and R 8 cannot all be hydrogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, having formula (IIa):
3. The compound of claim 2 , wherein two adjacent R 5 , R 6 , R 7 , and R 8 together form a 3 to 10 membered ring optionally substituted with one or more R 1 .
4. The compound of claim 3 , wherein the compound is:
5. The compound of claim 2 , or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, having formula (IIIa):
wherein R Ar is (i) cyano; (ii) (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered) heteroaryl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R 1 ; or (iii) hydroxyl substituted with R 1 ′; and provided that R Ar is not (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxyl optionally substituted with one or more halogen.
6. The compound of claim 5 , wherein R N is (C 3 -C 10 )cycloalkyl or (C 1 -C 10 )alkyl, each of which is optionally substituted with one or more R′; and R Ar is (i) cyano; (ii) (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered)heteroaryl, aminoalkyl, amino, amido, or carbonyl, each of which is optionally substituted with one or more R 1 ; (iii) (C 1 -C 10 )alkyl or alkoxyl, each of which is substituted with one or more R 1 ′; or (iv) hydroxyl substituted with R 1 ′.
7. The compound of claim 5 , wherein R N is optionally substituted cyclobutyl.
8. The compound of claim 5 , wherein R Ar is cyano, optionally substituted phenyl, optionally substituted six-membered heteroaryl, optionally substituted five-membered heteroaryl, optionally substituted (8 to 10)membered heteroaryl, optionally substituted six-membered heterocycloalkyl, optionally substituted five-membered heterocycloalkyl, —OR 1 ′, —OCH 2 R 1 ′, —NHR 1 , 13 NHCH 2 R 1 , —N(R 1 ) 2 , —C(O)R 1 , —C(O)N(R 1 ) 2 , —CH 2 R 1 ′, —CH 2 N(R 1 ) 2 , —CH 2 OH, or —CH 2 OR 1 ′.
9. The compound of claim 5 , or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, having formula (IVa):
wherein each X is independently N, CH, or CR 1 .
10. The compound of claim 5 , wherein the compound is:
11. The compound of claim 2 , or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, having formula (IIIb):
wherein R Ar is (i) cyano; (ii) (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered) heteroaryl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R 1 ; or (iii) hydroxyl substituted with R 1 ′.
12. The compound of claim 11 , wherein R N is (C 1 -C 10 )alkyl optionally substituted with one or more R′.
13. The compound of claim 11 , wherein R N is (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R′.
14. The compound of claim 11 , wherein R N is (C 3 -C 10 )cycloalkyl optionally substituted with one or more R′.
15. The compound of claim 14 , wherein R N is cyclobutyl optionally substituted with one or more.
16. The compound of claim 11 , wherein R Ar is phenyl or naphthyl optionally substituted with one or more R 1 .
17. The compound of claim 11 , wherein R Ar is six-membered heteroaryl optionally substituted with one or more R 1 .
18. The compound of claim 11 , wherein R Ar is five-membered heteroaryl optionally substituted with one or more R 1 .
19. The compound of claim 11 , wherein R Ar is 8 to 10 membered heteroaryl optionally substituted with one or more R 1 .
20. The compound of claim 11 , wherein R Ar is (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 1 .
21. The compound of claim 11 , wherein R Ar is (C 1 -C 10 )alkyl or alkoxyl, each of which is optionally substituted with one or more R 1 .
22. The compound of claim 11 , wherein R Ar is hydroxyl substituted with R 1 ′.
23. The compound of claim 11 , wherein R Ar is amino, amido, or carbonyl, each of which is optionally substituted with one or more R 1 .
24. The compound of claim 11 , having formula (IVb):
or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, wherein each X is independently N, CH, or CR 1 .
25. The compound of claim 11 , wherein the compound is:
26. The compound of claim 1 , or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, having formula (V):
wherein R Ar is (i) hydrogen, halogen, or cyano; (ii) (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered)heteroaryl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R 1 ; or (iii) hydroxyl substituted with R 1 ′.
27. The compound of claim 26 , wherein the compound is:
28. A compound of formula (IIb):
or a pharmaceutically acceptable salt, non-stoichiometric hydrate, or stereoisomer thereof, wherein
R N is hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, or (5 to 10 membered)heteroaryl, each of which is optionally substituted with one or more R′;
each occurrence of R′ is independently hydrogen, halogen, cyano, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )heterocycloalkyl, (5 to 10 membered)heteroaryl, hydroxyl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R 2 ; or two R′ substituents together may form a 3 to 10 membered ring optionally substituted with one or more R 2 ;
R 6 , R 7 , and R 8 are independently hydrogen, halogen, cyano, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkenyl, (C 3 -C 10 )cycloalkyl, (6 to 10 membered)aryl, (C 1 -C 10 )heteroalkyl, (C 3 -C 10 )-heterocycloalkyl, (5 to 10 membered)heteroaryl, hydroxyl, alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which may be optionally substituted with one or more R 1 ; or two adjacent R 6 , R 7 , and R 8 may together form a 3 to 10 membered ring;
each occurrence of R 1 ′ is independently —C(O)NR 3 R 4 , —C(O)R 3 , (C 3 -C 10 )cycloalkyl optionally substituted with one or more R 2 , (C 6 -C 12 )aralkyl optionally substituted with one or more R 2 , (6 to 10 membered)aryl optionally substituted with one or more R 2 , (C 1 -C 10 )heteroalkyl optionally substituted with one or more R 2 , (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 , or (5 to 10 membered)heteroaryl optionally substituted with one or more R 2 ;
each occurrence of R 2 is independently hydrogen, (C 1 -C 6 ) alkyl optionally substituted with one or more R 3 , (C 3 -C 6 )cycloalkyl optionally substituted with one or more R 3 , halogen, cyano, ═O, —OR 3 , —NR 3 R 4 , —N(R 3 )C(O)R 4 , —C(O)NR 3 R 4 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —S(O) m R 3 , or —S(O) 2 NR 3 R 4 ;
R 3 and R 4 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 7 -C 10 )aralkyl; (C 1 -C 6 )heteroalkyl, (C 3 -C 6 )heterocycloalkyl, (6 to 10 membered)aryl, or (5 to 10 membered)heteroaryl; or R 3 and R 4 together may form a 3 to 10 membered ring;
m is 0, 1, or 2.
29. The compound of claim 28 , wherein R 6 and R 8 are hydrogen, and R N is (C 3 -C 10 )cycloalkyl optionally substituted with one or more R′.
30. The compound of claim 28 , wherein R 7 is halogen, (6 to 10 membered) aryl optionally substituted with one or more R 1 , or (5 to 10 membered)heteroaryl optionally substituted with one or more R 1 .
31. The compound of claim 28 , wherein the compound is:
32. A pharmaceutical composition comprising a compound of claim 1 , and one or more excipients.
33. The pharmaceutical composition of claim 32 , which further comprises one or more additional active agents.
34. The compound of claim 11 , wherein R N is cyclobutyl optionally substituted with one or more R; and R Ar is (C 1 -C 10 )alkyl or alkoxyl, each of which is optionally substituted with one or more R 1 .
35. The compound of claim 34 , wherein R 1 is (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 .
36. The compound of claim 34 , wherein R Ar is —CH 2 R 1 .
37. The compound of claim 36 , wherein R 1 is (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 .
38. The compound of claim 11 , wherein the compound is:
39. The compound of claim 26 , wherein R N is cyclobutyl optionally substituted with one or more R′.
40. The compound of claim 26 , wherein R Ar is (C 1 -C 10 )alkyl or alkoxyl, each of which is optionally substituted with one or more R 1 .
41. The compound of claim 26 , wherein R N is cyclobutyl optionally substituted with one or more R′; and R Ar is (C 1 -C 10 )alkyl or alkoxyl, each of which is optionally substituted with one or more R 1 .
42. The compound of claim 41 , wherein R 1 is (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 .
43. The compound of claim 41 , wherein R Ar is —CH 2 R 1 .
44. The compound of claim 43 , wherein R 1 is (C 3 -C 10 )heterocycloalkyl optionally substituted with one or more R 2 .
45. The compound of claim 26 , wherein the compound is:
46. The compound of claim 26 , wherein the compound is:
47. The compound of claim 11 , wherein the compound is:
48. The compound of claim 11 , wherein the compound is:
49. A compound having the following structure, or a pharmaceutically acceptable salt thereof:
50. A pharmaceutical composition comprising a compound of claim 49 , and one or more excipients.
51. A compound having the following structure, or a pharmaceutically acceptable salt thereof:
52. A pharmaceutical composition comprising a compound of claim 51 , and one or more excipients.
53. A compound having the following structure, or a pharmaceutically acceptable salt thereof:
54. A pharmaceutical composition comprising a compound of claim 53 , and one or more excipients.
55. A compound having the following structure, or a pharmaceutically acceptable salt thereof:
56. A pharmaceutical composition comprising a compound of claim 55 , and one or more excipients.
57. A compound having the following structure, or a pharmaceutically acceptable salt thereof:
58. A pharmaceutical composition comprising a compound of claim 57 , and one or more excipients.