Compounds comprising a naphthyridine or pyridopyrimidine core as PTC read-through agents
Compounds of formula (I) or their tautomer forms or pharmaceutically acceptable salts or N-oxides provide an effective treatment for diseases associated with PTC mutations, addressing the inadequacies of existing treatments.
Patent Information
- Application Number
- HK62026125033
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-12-21
- Filing Date
- 2026-06-18
- Publication Date
- 2026-07-31
AI Technical Summary
Current treatments for diseases associated with PTC mutations are inadequate, and there is a need for effective pharmaceutical compounds to target these conditions.
Development of compounds of formula (I) or their tautomer forms or pharmaceutically acceptable salts or N-oxides, which are suitable for treating diseases/conditions associated with PTC mutations.
The compounds effectively treat conditions associated with PTC mutations, providing a targeted therapeutic approach.
Smart Images
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Abstract
Description
This application discloses compounds of formula (I) or their tautomer forms or pharmaceutically acceptable salts or N-oxides thereof, wherein R1, R2a, R2b, R3, R4, R5, and X are as defined herein. The compounds of this invention are suitable for treating diseases / conditions associated with PTC mutations. This application also discloses pharmaceutical compositions comprising said compounds; and compounds for treating conditions or symptoms associated with PTC mutations in subjects. Abstract
Claims
CLAIMS 1. A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof: I) whereinX is N or CR6; R1is independently selected from C0-C6-alkylene-R1a, and C2-C6-alkylene-R1b; R1ais independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein R1ais optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; wherein where R1ais heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; R1bis independently selected from NR7aR8aand OR7; wherein R1comprises at least one nitrogen atom; R2ais independently at each occurrence selected from H and C1-C4alkyl; R2bis independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C0-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl, and S(O)2-C1-C4-alkyl; R2cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 8- membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis phenyl, or heteroaryl, R2cis optionally substituted with from 1 to 5 R10groups; R2dis independently selected from NR7R8and OR7;R3is independently selected from H, cyano, C1-C4-alkylene-NR7R8, NR7R8, C1-C4-alkylene- OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2- C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R3c, O-C0-C4-alkylene-R3c, and C0-C4-alkylene-R3c; R3cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R3cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R3cis optionally substituted with from 1 to 4 R9groups; and where R3cis phenyl or heteroaryl, R3cis optionally substituted with from 1 to 5 R10groups; R4is independently selected from H, halo, cyano, NR7bR8, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- haloalkyl, O-C0-C4-alkylene-R4c, and C0-C4-alkylene-R4c; R4cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups; R5is independently selected from H, halo, cyano, C1-C4-alkylene-NR7R8, NR7bR8, C1-C4- alkylene-OR7, OR7b, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R5c, O-C0-C4- alkylene-R5c, and C0-C4-alkylene-R5c; R5cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R5cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R5cis optionally substituted with from 1 to 4 R9groups; and where R5cis phenyl or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R3and R4together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; or R4and R5together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionallysubstituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; R6is independently selected from H, halo, C1-C6-alkyl, and C1-C6-haloalkyl; R7and R7aare each independently at each occurrence selected from H and C1-C4alkyl; R7bis independently at each occurrence selected from C1-C4alkyl; R8is independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl R8ais independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C(O)- C1-C4-alkyl and phenyl optionally substituted with from 1 to 5 R10groups; or R7aand R8a, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups; R9is independently at each occurrence selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8; R9ais independently at each occurrence selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R9ais cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups; R10is independently at each occurrence selected from halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR7R8, and C1-C3-alkylene-OR7; and wherein any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: C1-C4-alkyl, oxo, halo, nitro, cyano, NRaRb, ORa, SRa, CO2Ra, C(O)Ra, CONRaRa, S(O)Ra, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and C1-C4-alkyl; and Rbis independently at each occurrence selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.
2. A compound according to claim 1, wherein X is N.
3. A compound according to claim 1 or claim 2, wherein R2aand R2bare each H.
4. A compound according to any one of claims 1 to 3, wherein R1comprises at least one amine nitrogen.
5. A compound according to any one of claims 1 to 4, wherein R1is C0-C6-alkylene-R1a.
6. A compound according to claim 5, wherein R1is R1a.
7. A compound according to claim 5 or claim 6, wherein R1ais a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, wherein R1ais optionally substituted with from 1 to 6 R9groups.
8. A compound according to any one of claims 1 to 7, wherein R3is H.
9. A compound according to any one of claims 1 to 7, wherein R3is C1-C4-alkyl.
10. A compound according to any one of claims 1 to 9, wherein R4is H.
11. A compound according to any one of claims 1 to 9, wherein R4is C1-C4-alkyl.
12. A compound according to any one of claims 1 to 11, wherein R5is R5c.
13. A compound according to any one of claims 1 to 12, wherein R5cis phenyl optionally substituted with from 1 to 5 R10groups.
14. A compound according to any one of claims 1 to 12, wherein R5cis 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups.
15. A compound according to any one of claims 1 to 11, wherein R5is H.
16. A compound according to any one of claims 1 to 11, wherein R5is C1-C4-alkyl.
17. A compound according to any one of claims 1 to 9, wherein R4and R5together with the carbon atoms to which they are attached form a C5-C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups.
18. A compound according to claim 1, wherein the compound of formula (I) is selected from:, , ,,19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, and one or more pharmaceutically acceptable excipients.
20. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use as a medicament.
21. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in the treatment of: a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.
22. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in the treatment of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI,Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome and Retinitis Pigmentosa.
23. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in a method of treating conditions or disorders which are associated with a PTC mutation in a subject.