Macrocyclic orexin receptor agonists and uses thereof
Compounds of formula (I) and their salts serve as more effective and specific orexin agonists, addressing limitations in current treatments by enhancing therapeutic outcomes.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- JAZZ PHARMA IRELAND LTD
- Filing Date
- 2026-06-09
- Publication Date
- 2026-07-17
AI Technical Summary
Current treatments for diseases treatable by orexin agonists are limited in efficacy and specificity, necessitating the development of more effective and targeted compounds.
Development of compounds of formula (I) and their pharmaceutically acceptable salts, which act as orexin agonists, providing enhanced therapeutic effects.
The compounds of formula (I) and their salts demonstrate improved efficacy and specificity in treating diseases targeted by orexin agonists.
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Abstract
Description
This document provides compounds of formula (I), (I), or pharmaceutically acceptable salts thereof, wherein m, n, p, L, R1, R2, R3, R4, R5, R6, formula (AA), (AA), V, X, Y, and Z are defined herein. This document also provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof, and methods of using compounds of formula (I) or pharmaceutically acceptable salts thereof, for example, in the treatment of diseases or conditions treatable by administration of orexin agonists. Abstract
Claims
CLAIMS 1. A compound of Formulaor a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is a linker selected from heteroaryl, –carbocyclyl-(CR7CR7’)r-O–, and –heterocyclyl- (CR7CR7’)r-O–, wherein –carbocyclyl-(CR7CR7’)r-O– and –heterocyclyl-(CR7CR7’)r-O– have the following orientation:;is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently –O–, –CR8R9–, or –NR10–; X is –O–, –CR11R12–, or –NR13–; Y is a bond, –O–, –CR8R9–, or –NR10–; R1 and R2 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R1 and R2 together with the atom to which they are attached form a carbocycle or heterocycle; R3and R4are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R3and R4 together with the atom to which they are attached form a carbocycle or heterocycle;R5is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-SO2-alkyl; R6 is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, alkylene-heterocyclyl, or - CN; R7and R7´are each independently H, halogen, or alkyl; R8 and R9 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R8 and R9together with the atom to which they are attached form a carbocycle or heterocycle; R11and R12are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl; or R11and R12 together with the atom to which they are attached form a carbocycle or heterocycle; R10 and R13 are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, –(C=O)alkyl, –(C=O)cycloalkyl, –(C=O)heterocyclyl,– (C=O)–O–alkyl, –(C=O)–O–cycloalkyl, –(C=O)–O–heterocyclyl, –(C=O)–O–heteroaryl, – S(O)2–alkyl, –S(O)2–cycloalkyl, or –S(O)2–heterocyclyl; m, n, and p are each independently 0, 1, or 2; and r is 0 or 1.
2. The compound of claim 1, wherein R5is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heteroaryl, or alkylene-heteroaryl.
3. The compound of claim 1 or 2, wherein R5is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or alkylene-heterocyclyl.
4. The compound of claim 1 or 2, wherein R5 is heteroaryl or alkylene-heteroaryl.
5. The compound of any one of claims 1-3, wherein R5 is alkyl.
6. The compound of any one of claims 1-5, wherein R5is C1-5alkyl, C1-5haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-(4- to 6-membered heterocyclyl), or C1-3 alkylene-(5- or 6-membered heteroaryl).
7. The compound of any one of claims 1-6, wherein R5is cyclopropyl or cyclobutyl.
8. The compound of any one of claims 1-6, wherein R5is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.
9. The compound of any one of claims 1-8, wherein R5 is optionally substituted with one or more F, CH3, CH2CH3, CH(CH3)2, -CN, CF3, and / or CHF2.
10. The compound of claim 1 or 2, wherein R5is: , , ,11. The compound of claim 1 or 2, wherein R5 is, , .
12. The compound of any one of claims 1-11, wherein R6 is H or -CN.
13. The compound of any one of claims 1-11, wherein R6is H.
14. The compound of any one of claims 1-12, wherein R1 and R2 are each independently H, halogen, or alkyl.
15. The compound of any one of claims 1-12, wherein R1and R2are each independently H or halogen.
16. The compound of any one of claims 1-12, wherein R1 and R2 are H.
17. The compound of any one of claims 1-12, wherein R1and R2together with the carbon atom to which they are attached form a carbocycle or heterocycle.
18. The compound of any one of claims 1-12, wherein R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
19. The compound of any one of claims 1-12, wherein R1and R2together with the carbon atom to which they are attached form a 3- or 6-membered heterocycle.
20. The compound of any one of claims 1-12, wherein R1 and R2 together with the carbon atom to which they are attached form a heterocycle, comprising 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
21. The compound of any one of claims 1-20, wherein R3 and R4 are each independently H, halogen, or alkyl.
22. The compound of any one of claims 1-21, wherein R3and R4are each independently H or C1-5 alkyl.
23. The compound of any one of claims 1-22, wherein R3 and R4 are each independently methyl or ethyl.
24. The compound of any one of claims 1-22, wherein R3and R4are H.
25. The compound of any one of claims 1-21, wherein R3 and R4 are halogen.
26. The compound of any one of claims 1-21, wherein R3 and R4 are fluorine.
27. The compound of any one of claims 1-21, wherein R3and R4together with the carbon atom to which they are attached form a carbocycle or heterocycle.
28. The compound of any one of claims 1-21, wherein R3and R4together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
29. The compound of any one of claims 1-21, wherein R3 and R4 together with the carbon atom to which they are attached form a 3- or 6-membered heterocycle.
30. The compound of any one of claims 1-21, wherein R3and R4together with the carbon atom to which they are attached form a heterocycle, comprising 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
31. The compound of any one of claims 1-30, wherein V is –O– or –CR8R9–.
32. The compound of any one of claims 1-30, wherein V is –O– or –NR10–.
33. The compound of any one of claims 1-30, wherein V is –O–.
34. The compound of any one of claims 1-33, wherein Y is a bond or –CR8R9–.
35. The compound of any one of claims 1-34, wherein Y is a bond.
36. The compound of any one of claims 1-35, wherein Z is a –NR10– or –CR8R9–.
37. The compound of any one of claims 1-35, wherein Z is –CR8R9–.
38. The compound of any one of claims 1-37, wherein R8and R9are each independently H or C1-5 alkyl.
39. The compound of any one of claims 1-37, wherein R8 and R9 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
40. The compound of any one of claims 1-39, wherein R10 is H or C1-5 alkyl.
41. The compound of any one of claims 1-39, wherein R10 is methyl, ethyl, or isopropyl.
42. The compound of any one of claims 1-41, wherein X is –CR11R12–.
43. The compound of any one of claims 1-42, wherein R11and R12are each independently H or C1-5 alkyl.
44. The compound of any one of claims 1-42, wherein R11 and R12 are each independently methyl or ethyl.
45. The compound of any one of claims 1-42, wherein R11and R12together with the carbon atom to which they are attached form a C3-6 cycloalkyl., wherein Ra is halogen, C1-5 alkyl, or C1-5 alkoxy; and q is 0, 1, or 2.
47. The compound of any one of claims 1-46, whereinis:, wherein Ra is halogen, C1-5alkyl, or C1-5alkoxy; and q is 0, 1, or 2.
48. The compound of any one of claims 1-47, wherein, , , , , , ., 1, or 2.
50. The compound of any one of claims 1-46 and 49, wherein,, wherein Ra is halogen, C1-5 alkyl, or C1-5 alkoxy; and q is 0, 1, or 2. ,52. The compound of any one of claims 46, 47, and 49, wherein q is 0 or 1.
53. The compound of any one of claims 46, 47, 49, and 52, wherein q is 0.
54. The compound of any one of claims 1-53, wherein m is 0 or 1.
55. The compound of any one of claims 1-54, wherein m is 1.
56. The compound of any one of claims 1-55, wherein n is 0 or 1.
57. The compound of any one of claims 1-56, wherein n is 1.
58. The compound of any one of claims 1-57, wherein p is 0 or 1.
59. The compound of any one of claims 1-58, wherein p is 0.
60. The compound of any one of claims 1-58, wherein p is 1.
61. The compound of any one of claims 1-60, wherein L is –carbocyclyl-(CH2)r-O– or – heterocyclyl-(CH2)r-O–.
62. The compound of any one of claims 1-60, wherein L is –carbocyclyl-(CH2)r-O–.
63. The compound of any one of claims 1-62, wherein L isor.
64. The compound of any one of claims 1-62, wherein L is.
65. The compound of any one of claims 1-64, wherein r is 0.
66. The compound of any one of claims 1-64, wherein r is 1.
67. The compound of any one of claims 1-61, wherein when r is 0, L is a –carbocyclyl-O– orindependently –O– or –CH2–, and * represents the point of attachment to .
68. The compound of claim 67, wherein A5 is –O–.
69. The compound of claim 67, wherein A5is –CH2–.
70. The compound of any one of claims 67-69, wherein A6 is –O–.
71. The compound of any one of claims 67-69, wherein A6 is –CH2–.
72. The compound of any one of claims 1-61, wherein, wherein Rbis halogen, alkyl, or alkoxy; and u is 0, 1, or 2.
73. The compound of claim 72, wherein Rb is halogen.
74. The compound of claim 73, wherein Rb is fluoride.
75. The compound of any one of claims 72-74, wherein u is 1.
76. The compound of any one of claims 72-74, wherein u is 0.
77. The compound of any one of claims 1-75, wherein.
78. The compound of any one of claims 1-61, wherein L is a 5- or 6-membered heteroaryl linker having 1-2 nitrogen atoms.
79. The compound of any one of claims 1-61 and 78, wherein,, wherein Rbis halogen, alkyl, or alkoxy; and u is 0 or 1.
80. The compound of any one of claims 1-71, having the structure:pharmaceutically acceptable salt thereof, wherein: r is 0 or 1; s is 1 or 2; and t is 1 or 2.
81. The compound of claim 80, wherein r is 0.
82. The compound of claim 80 or 81, wherein s is 2.
83. The compound of any one of claims 80-82, wherein t is 2.
84. The compound of any one of claims 1-11, having the structure:pharmaceutically acceptable salt thereof, wherein Rais halogen, C1-5alkyl, or C1-5alkoxy; and q is 0, 1, or 2.
85. The compound of any one of claims 46, 47, 49, and 84, wherein each Ra is independently F or Me.
86. The compound of any one of claims 46, 47, 49, 84, and 85, wherein each Ra is F.
87. The compound of any one of claims 46, 47, 49, and 84-86, wherein q is 1 or 2.
88. The compound of claim 1, wherein the compound is: , (rel), , , (rel), , , , , (rel), , ,(rel), , (rel), (rel), (rel), , (rel), , (rel), , , (rel),, (rel), , (rel), (rel), (rel), , (rel), (rel), (rel), (rel),(rel), , (rel), , , (rel), (rel), (rel), (rel), (rel),(rel), (rel), (rel), , (rel), , (rel), (rel), , ,, , , (rel), , , (rel), , (rel), (rel), (rel), (rel),or a pharmaceutically acceptable salt thereof.
89. A pharmaceutical composition comprising a compound of any one of claims 1-88 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
90. A method of treating a disease or disorder that is treatable by administration of an orexin agonist, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-88 or the pharmaceutical composition of claim 89.
91. A method of treating a disease or disorder by modulating one or more orexin receptors, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-88 or the pharmaceutical composition of claim 89.
92. A method of treating, preventing, ameliorating, controlling, or reducing the risk of a disease or disorder associated with one or more orexin receptors, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-88 or the pharmaceutical composition of claim 89.