Telomerase inhibitor compounds
Telomerase inhibitor compounds, featuring lactone, sulfonamide, or isothiazolidine-1,1-dioxide groups, address the need for effective inhibitors to treat telomerase-related diseases by inhibiting telomerase activity.
Patent Information
- Application Number
- HK62026124959
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-02-09
- Filing Date
- 2026-06-17
- Publication Date
- 2026-07-31
AI Technical Summary
Current treatments for telomerase-related diseases lack effective inhibitors that can target and inhibit telomerase activity.
Development of telomerase inhibitor compounds, including those with a lactone or sulfonamide group linked to a benzene ring, a pyrazole group, or an isothiazolidine-1,1-dioxide core, for use in pharmaceutical compositions to treat such diseases.
The compounds effectively inhibit telomerase activity, providing potential therapeutic benefits for telomerase-related conditions.
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Abstract
Description
Abstract This invention provides telomerase inhibitor compounds. Some compounds contain a lactone or lactone group covalently bonded to a benzene ring, which in turn is linked to a pyrazole group. In other cases, a sulfonamide group is covalently bonded to a benzene ring, which in turn is linked to a pyrazole group. In some embodiments, the telomerase inhibitor compound has a vinylsulfonamide group linked to both a lactone group and an aromatic group. In other cases, the inhibitor compound has an isothiazolidine-1,1-dioxide core linked to a phenyl group. The invention also extends to pharmaceutical compositions comprising said telomerase inhibitor compounds, and methods for treating telomerase-related diseases or conditions.
Claims
CLAIMS What Is Claimed Is:
1. A compound of formula (I):wherein: X is O or NRX; RXis selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; each R1and R2is independently selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, thiol, thioether, and substituted versions thereof; R9is H, D, or alkyl; and A is a 5- or 6-membered aromatic ring that is optionally substituted or a heterocyclic ring that is optionally substituted.
2. The compound of claim 1, wherein X is O.
3. The compound of claim 1, wherein X is NRX.
4. The compound of any one of claims 1-3, wherein the compound has formula (Ia-A):wherein: m is 0 or an integer from 1 to 5; and each R3is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof, provided that two adjacent R3groups along with the atoms to which they are attached can form a cyclic ring.
5. The compound of any one of claims 1-3, wherein the compound has formula (Ib-A)wherein: n is 0 or an integer from 1 to 4; and E is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
6. The compound of claim 5, wherein E is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.
7. The compound of claim 6, wherein E is a 5-membered heteroaryl or substituted heteroaryl group.
8. The compound of claim 7, wherein E is pyrazole or substituted pyrazole.
9. The compound of claim 8, wherein the compound has formula (Ib-1-A):wherein: R4is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; z is 0, 1, or 2; and each R5is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
10. The compound of claim 7, wherein E is selected from the group consisting of triazole, substituted triazole, 6-membered aryl, 6-membered substituted aryl, 6-membered heteroaryl, and 6-membered substituted heteroaryl.
11. The compound of any one of claims 1-3, wherein the compound has formula (Ic-A):wherein: p is 0 or an integer ranging from 1 to 4; and G is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
12. The compound of claim 11, wherein G is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.
13. The compound of any one of claims 1-3, wherein the compound has formula (Id-A):wherein: q is 0 or an integer from 1 to 3; and ring B is a 5- or 6-membered aryl or heteroaryl ring.
14. The compound of claim 13, wherein ring B is heteroaryl.
15. The compound of claim 14, wherein ring B is pyridine, pyrrole, imidazole, or pyrrolidine.
16. The compound of claim 1, wherein the compound has a structure selected from the group consisting of:17. A compound of formula (II):wherein: n is 0, 1, 2, or 3; each R1, R2, R6, R7, and R9is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; and each R3, R4, R5, and R8is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.
18. The compound of claim 17, wherein R1is H.
19. The compound of any one of claims 17-18, wherein each R2is H.
20. The compound of any one of claims 17-19, wherein R3is H.
21. The compound of any one of claims 17-20, wherein R4is H or alkyl.
22. The compound of any one of claims 17-21, wherein R5is H or alkyl.
23. The compound of any one of claims 17-22, wherein n ranges from 1 to 3 and at least one R6is halo.
24. The compound of any one of claims 17-23, wherein R7is H.
25. The compound of any one of claims 17-24, wherein R8is H or alkyl.
26. The compound of any one of claims 17-25, wherein R9is H.
27. The compound of claim 17, wherein the compound has a structure selected from the group consisting of:
28. A compound of formula (III):wherein: n is 0 or an integer ranging from 1 to 4; each R1, R4, and R5is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R2is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and R3is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.
29. The compound of claim 28, wherein the compound has formula (IIIa):wherein: m is 0 or an integer ranging from 1 to 5; and each R22is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
30. The compound of claim 28, wherein the compound has formula (IIIb):
31. The compound of any one of claims 29-30, wherein m ranges from 1 to 5 and at least one R22is halo.
32. The compound of any one of claims 29-31, wherein n is 0.
33. The compound of any one of claims 29-32, wherein R3is H.
34. The compound of any one of claims 29-33, wherein R4is H.
35. The compound of any one of claims 29-34, wherein each R5is H.
36. The compound of claim 28, wherein the compound has a structure selected from the group consisting of:
37. A compound of formula (IV):wherein: R1and R2are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof, provided that at least one of R1and R2is aryl, heteroaryl, or a substituted version thereof; L1and L2are each independently absent or an alkylene group;R3is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof; and R4is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
38. The compound of claim 37, wherein R1is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
39. The compound of claim 38, wherein the compound has formula (IVa): wherein:x is 0 or an integer ranging from 1 to 5; and each R11is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
40. The compound of claim 39, wherein x is an integer ranging from 1 to 5 and at least one R11is halo.
41. The compound of any one of claims 39-40, wherein R2is H or alkyl.
42. The compound of any one of claims 39-41, wherein L1is absent.
43. The compound of any one of claims 39-41, wherein L1has the formula –CH2–.
44. The compound of any one of claims 39-43, wherein each R4is H.
45. The compound of any one of claims 39-40 or 42-44, wherein R2is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
46. The compound of claim 37, wherein the compound has formula (IVb):wherein: y is 0 or an integer ranging from 1 to 5; and each R22is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.
47. The compound of claim 46, wherein y is an integer ranging from 1 to 5 and at least one R22is halo.
48. The compound of any one of claims 46-47, wherein R1is H or alkyl.
49. The compound of any one of claims 46-48, wherein L2is absent.
50. The compound of any one of claims 46-48, wherein L2has the formula –CH2–.
51. The compound of any one of claims 46-50, wherein R3is H or alkyl.
52. The compound of any one of claims 46-51, wherein each R4is H.
53. The compound claim 37, wherein the compound has a structure selected from the group consisting of:
54. A compound of formula (V):wherein: R1is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; each R2and R3is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; and n is 0 or an integer from 1 to 4.
55. The compound of claim 54, wherein the compound has formula (Va)56. The compound of any one of claims 54-55, wherein R1is alkyl.
57. The compound of claim 56, wherein R1is methyl.
58. The compound of any one of claims 54-57, wherein n is 0.
59. The compound of claim 54, wherein the compound has a structure selected from the group consisting of:
60. A compound of formula (VI):wherein: n is 0, 1, 2, or 3;each R1, R2, R3, R5, R6, and R8is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; and R4and R7are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.
61. The compound of claim 60, wherein R1is cyano or carboxy.
62. The compound of any one of claims 60-61, wherein each R2is H and R3is H.
63. The compound of any one of claims 60-62, wherein R4is H.
64. The compound of any one of claims 60-63, wherein n is 1, 2, or 3 and at least one R5is halo.
65. The compound of any one of claims 60-64, wherein R6is H and R8is H.
66. The compound of any one of claims 60-65, wherein R7is alkyl or substituted alkyl.
67. The compound of claim 60, wherein the compound has a structure selected from the group consisting of:
68. A pharmaceutical composition comprising a compound of any one of claims 1-67.
69. The pharmaceutical composition of claim 68, further comprising a second compound.
70. The pharmaceutical composition of claim 69, wherein the second compound is imetelstat or imetelstat sodium.
71. A method of treating a patient for a telomerase-related condition, the method comprising: administering a pharmaceutical composition of any one of claims 68-70.
72. The method of claim 71, wherein the compound is a telomerase inhibitor.
73. The method of claim 72, wherein the telomerase-related condition is a cancer.
74. The method of claim 73, wherein the cancer is a hematological malignancy.
75. The method of claim 73, wherein the cancer is selected from the group consisting of acute and chronic leukemias, lymphomas, multiple myeloma and myelodysplastic syndromes, myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), Chronic Myelogenous Leukemia (CML), myelofibrosis (MF), acute myelogenous leukemia (AML), and myelodysplastic syndromes (MDS).
76. A method of treating a patient for a telomerase-related condition, the method comprising: administering a compound of any one of claims 1-67.
77. The method of claim 76, wherein the compound is a telomerase inhibitor.
78. The method of claim 77, wherein the telomerase-related condition is a cancer.
79. The method of claim 78, wherein the cancer is a hematological malignancy.
80. The method of claim 79, wherein the cancer is selected from the group consisting of acute and chronic leukemias, lymphomas, multiple myeloma and myelodysplastic syndromes, myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), Chronic Myelogenous Leukemia (CML), myelofibrosis (MF), acute myelogenous leukemia (AML), and myelodysplastic syndromes (MDS).