9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid derivatives
The present invention relates to 9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid derivatives, their manufacture, pharmaceutical compositions containing them and their use as a medicament.
1. A compound of formula (I)
or a pharmaceutically acceptable salt, a racemic mixture, a corresponding enantiomer or, if applicable, a corresponding diastereomer thereof,
wherein
R 1 is selected from the group consisting of hydrogen, a linear or branched C 1 to C 6 alkyl, a C 3 to C 5 cycloalkyl, a C 1 -C 3 -alkyl-C 3 -C 5 -cycloalkyl, and a cyclic ether comprising 4 to 5 ring atoms,
wherein said C 1 to C 6 linear or branched alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxy and C 1 to C 3 alkoxy,
wherein said C 3 to C 5 cycloalkyl and said C 1 -C 3 -alkyl-C 3 -C 5 -cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, C 1 to C 3 alkyl, hydroxy and C 1 to C 3 alkoxy, and
wherein said cyclic ether comprising 4 to 5 ring atoms is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, C 1 to C 3 alkyl, hydroxy and C 1 to C 3 alkoxy;
R 2 is selected from the group consisting of hydrogen and methyl;
R 3 is selected from the group consisting of hydrogen, a linear or branched C 1 to C 6 alkyl, a C 3 to C 6 cycloalkyl, a 4-6-membered heterocycloalkyl, C 1 -C 3 -alkyl-C 3 -C 6 -cycloalkyl and a C 1 -C 3 -alkyl-4-6-membered heterocycloalkyl,
wherein said linear or branched C 1 to C 6 alkyl may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, cyano, hydroxy and C 1 to C 3 alkoxy, and
wherein said C 3 to C 6 cycloalkyl, said 4-6-membered heterocycloalkyl, said C 1 -C 3 -alkyl-C 3 -C 6 -cycloalkyl and said C 1 -C 3 -alkyl-4-6-membered heterocycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, cyano, C 1 to C 3 alkyl, hydroxy and C 1 to C 3 alkoxy; or
R 2 and R 3 may form together a 4 to 6 membered cycloalkyl or heterocycloalkyl, which may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, cyano, C 1 to C 3 alkyl, hydroxy and C 1 to C 3 alkoxy;
R 4 is selected from the group consisting of a linear or branched C 1 to C 6 alkoxy, an alkoxyalkoxyl group having up to 6 carbon atoms, a C 1 -C 3 alkoxy C 3 -C 8 cycloalkyl, a 4-7-membered heterocycloalkyl, a C 1 -C 6 alkyl 4-7 membered monocyclic heterocycloalkyl, a C 2 to C 8 alkenyl and a C 2 to C 8 alkynyl,
wherein said C 1 to C 6 alkoxy, said alkenyl and said alkynyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, chloro and fluoro, a 3 to 6 membered monocyclic cycloalkyl group, a 4 to 6 membered monocyclic heterocycloalkyl group, a spirocyclic 3 to 7 membered monocyclic cycloalkyl group and a spirocyclic 3 to 7 membered monocyclic heterocycloalkyl group, and
wherein said C 1 -C 3 alkoxy C 3 -C 8 cycloalkyl, said 4-7-membered heterocycloalkyl, and said C 1 -C 6 alkyl 4-7 membered monocyclic heterocycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of hydroxy, chloro, fluoro, and C 1 to C 3 alkyl and C 1 to C 3 alkoxy; and
R 5 is selected from the group consisting of fluoro, chloro, bromo, cyano, C 1 to C 5 alkoxy, C 1 to C 5 alkyl, alkoxyalkyl having up to 6 carbon atoms, 4 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkyl, 5-membered heteroaryl, and NR 6 R 7 ,
wherein said C 1 to C 5 alkoxy and said alkoxyalkyl having up to 6 carbon atoms may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxy, C 1 to C 3 alkoxy,
wherein said C 1 to C 5 alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, C 1 to C 3 alkoxy, 3 to 6 membered cycloalkyl and 4 to 6 membered heterocycloalkyl,
wherein said 4 to 6 membered heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxy, C 1 to C 3 alkoxy, and C 1 to C 3 alkyl,
wherein said 3 to 6 membered cycloalkyl is optionally substituted one or more substituents selected from the group consisting of with fluoro, chloro, hydroxy, C 1 to C 3 alkoxy, and C 1 to C 3 alkyl,
wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, methyl and ethyl, and
wherein said 5-membered heteroaryl is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxy, C 1 to C 3 alkoxy, and C 1 to C 3 alkyl.
2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, 2,2-difluoroethyl and cyclopropyl.
3. The compound according to claim 1 , wherein R 2 is hydrogen.
4. The compound according to claim 1 , wherein R 3 is selected from the group consisting of isopropyl, sec-butyl, (1-methyl)cyclopropyl and tert-butyl.
5. The compound according to claim 4 , wherein R 3 is isopropyl or tert-butyl.
6. The compound according to claim 1 , wherein R 2 and R 3 form together a 4 to 6 membered cycloalkyl or a 4 to 6 membered heterocycloalkyl.
7. The compound according to claim 6 , wherein R 2 and R 3 form together a cyclopentyl ring.
8. The compound according to claim 1 , wherein R 4 is selected from the group consisting of cyclopropylmethoxy, 2-cyclopropylethoxy and —O(CH 2 ) 3 OCH 3 .
9. The compound according to claim 8 , wherein R 4 is —O(CH 2 ) 3 OCH 3 .
10. The compound according to claim 1 , wherein R 5 is selected from the group consisting of methoxy, ethoxy, methyl, ethyl, methoxymethyl and cyclopropyl.
11. The compound according to claim 1 , wherein said compound is selected from the group of compounds 501 to 511
No.
Structure
501
502
503
504
505
506
507
508
509
510
511
12. The compound according to claim 11 , wherein said compound is (RS)-6-(tert-butyl)-10-cyclopropyl-2-methoxy-3-(3-methoxypropoxy)-9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid or (RS)-10-cyclopropyl-6-isopropyl-2-methoxy-3-(3-methoxypropoxy)-9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid.
13. A pharmaceutical composition comprising:
at least one compound according to claim 1 as a therapeutically active substance; and
a pharmaceutically acceptable carrier and/or adjuvant.
14. The pharmaceutical composition according to claim 13 , wherein said at least one compound is selected from the group of compounds 501 to 511
No.
Structure
501
502
503
504
505
506
507
508
509
510
511
15. The pharmaceutical composition according to claim 14 , wherein said at least one compound comprises (RS)-6-(tert-butyl)-10-cyclopropyl-2-methoxy-3-(3-methoxypropoxy)-9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid and (RS)-10-cyclopropyl-6-isopropyl-2-methoxy-3-(3-methoxypropoxy)-9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid.
16. The pharmaceutical composition according to claim 15 , wherein said at least one compound comprises (S)-6-(tert-butyl)-10-cyclopropyl-2-methoxy-3-(3-methoxypropoxy)-9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid and (S)-10-cyclopropyl-6-isopropyl-2-methoxy-3-(3-methoxypropoxy)-9-oxo-9,10-dihydro-6H-pyrano[3,2-b:4,5-b′]dipyridine-8-carboxylic acid.
17. The pharmaceutical composition according to claim 13 for use as a medicament.
18. The pharmaceutical composition according to claim 13 for use in the treatment of a disease which benefits from PAPD5 inhibition, the disease being selected from the group consisting of a telomere biology disorder, poikiloderma with neutropenia and hepatitis B.
19. The pharmaceutical composition according to claim 18 ,
wherein the telomere biology disorder is selected from the group consisting of dyskeratosis congenita, idiopathic pulmonary fibrosis (IPF), liver cirrhosis, aplastic anemia, bone marrow failure syndrome, immunodeficiencies, neurodevelopmental disorders, growth retardation linked to telomere biology diseases, and age-related diseases and premature aging caused by telomere shortening.
20. The pharmaceutical composition according to claim 19 , wherein the telomere biology disorder is selected from the group consisting of dyskeratosis congenita, idiopathic pulmonary fibrosis (IPF), and liver cirrhosis.
21. The pharmaceutical composition according to claim 20 , wherein the dyskeratosis congenita is selected from the group consisting of Høyeraal-Hreidarsson syndrome (HHS), Revesz syndrome (RS) and Coats plus syndrome (CPS).
22. The pharmaceutical composition according to claim 18 for use in the treatment of hepatitis B.
23. The pharmaceutical composition according to claim 18 for use in the treatment of poikiloderma with neutropenia.
24. A method for preparing the compound of claim 1 , the method comprising;
reacting a compound of formula II-a
in the presence of
i. a base and R 1 -LG or
ii. R 1 —B(OH) 2 or R 1 —BF 3 M, a copper-salt, and an amine,
to obtain a compound of formula II-b
wherein
R 1 is selected from the group consisting of a linear or branched C 1 to C 6 alkyl, a C 3 to C 5 cycloalkyl, a C 1 -C 3 -alkyl-C 3 -C 5 -cycloalkyl, and a cyclic ether comprising 4 to 5 ring atoms,
wherein said C 1 to C 6 linear or branched alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxy and C 1 to C 3 alkoxy,
wherein said C 3 to C 5 cycloalkyl and said C 1 -C 3 -alkyl-C 3 -C 5 -cycloalkyl may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, C 1 to C 3 alkyl, hydroxy and C 1 to C 3 alkoxy, and
wherein said cyclic ether comprising 4 to 5 ring atoms is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, C 1 to C 3 alkyl, hydroxy and C 1 to C 3 alkoxy;
R 2 , R 3 , R 4 and R 5 in the formulae II-a and II-b have the same definition as in claim 1 ;
LG is a leaving group; and
M is an alkali metal.
25. The method according to claim 24 , further comprising hydrolyzing the compound of formula II-a or II-b
in the presence of an acid or a base
to obtain the compound of formula (I)
wherein R 1 , R 2 , R 3 , R 4 and R 5 have the same definition as in claim 1 .