Piperidinylpyridinylcarbonitrile derivatives as inhibitors of glutaminyl-peptide cyclotransferase and glutaminyl-peptide cyclotransferase like protein

Abstract

The present disclosure provides certain piperidinyIpyridinylcarbonitrile derivatives, and pharmaceutically acceptable salts thereof, that are inhibitors of Glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), and are therefore useful for the treatment of diseases treatable by inhibition of QPCT / L. Also provided are pharmaceutical compositions containing the same, and processes for preparing said compounds.

Description

This invention provides certain piperidinylpyridinyl carboxylate derivatives and their pharmaceutically acceptable salts, which are inhibitors of glutamine acyltransferase (QPCT) and glutamine acyltransferase-like protein (QPCTL), and therefore can be used to treat diseases that can be treated by inhibiting QPCT / L. This invention also provides pharmaceutical compositions containing them and methods for preparing said compounds. Abstract

Claims

WHAT IS CLAIMEDwhereinA is Ala which is a 5- or 6-membered mono-heteroaryl ring containing one or two heteroatom members selected from the group consisting of nitrogen and oxygen; wherein at least one of the heteroatom members is nitrogen; or A is Alb which is a 9- or 10-membered fused bicyclic-heteroaryl ring containing one to four heteroatom members selected from the group consisting of nitrogen and oxygen, wherein at least one of the heteroatom members is nitrogen; and wherein A is independently optionally substituted with one or two R2;R1is selected from the group Ria, consisting of H, Ci-4-alkyl, Ci-4-alkyloxy, hydroxy-Ci-4- alkyl, Fi-9-fluoro-Ci-4-alkyl and Fi-s-fluoro-Cs-s-cycloalkyl;R2is selected from the group R2a, consisting of halo, NH2, Ci-6-alkyl, Fi-9-fluoro-Ci-6- alkyl, Ci-4-alkyl-O-H2CH2C-O-, Fi-9-fluoro-Ci-4-alkyloxy and CHsS(O); orR2is selected from the group R2b, consisting of phenyl, pyridinyl, isoxazolyl, oxazolyl, pyrazolyl and thiophenyl; wherein R2b is optionally substituted independently by one or two R3; orR2is selected from the group R2c, consisting ofR3is R3a, selected from halo, Ci-4-alkyl, Ci-4-alkyloxy, HO-Ci-4-alkyl or CN; or a salt thereof, particularly a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, wherein A is the group A3 consisting of pyridinyl, pyrimidinyl, pyrazolo[l,5-b]pyridazinyl, 2H-[l,2,3]triazolo[4,5- b]pyridinyl, pyrazolo[3,4-b]pyridinyl, l,2-dihydropyridin-2-onyl, imidazo[l,2- a]pyrimidinyl, [l,3]oxazolo[4,5-b]pyridinyl and furo[2,3-b]pyridinyl; and wherein A is independently optionally substituted with one or two R2; or a salt thereof.

3. The compound of formula (I) according to claim 1, wherein A is selected from the groupor a salt thereof.

4. The compound of formula (I) according to any of claims 1 to 3, wherein R1is selected from the group Rib, consisting of H, Ci-4-alkyl, Ci-4-alkyloxy, hydroxy-Ci-4-alkyl, F1-3- fluoro-Ci-4-alkyl and Fi-3-fluoro-C3-5-cycloalkyl; or a salt thereof.

5. The compound of formula (I) according to any of claims 1 to 4 having formula (1-a)(I-a) or a salt thereof.

6. The compound of formula (I) according to claim 1 or claim 4 having formula (1-c)or a salt thereof.

7. The compound of formula (I) according to claim 1 or claim 4 having formula (1-d)(I d) or a salt thereof.

8. The compound of formula (I) according to claim 1 or claim 4 having formula (1-e)or a salt thereof.

9. The compound of formula (I) according to claim 1, selected from the group consisting ofor a salt thereof.

10. A pharmaceutically acceptable salt of a compound according to one or more of claims 1 to 9.

11. A pharmaceutical composition comprising one or more compounds according to one or more of claims 1 to 9, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

12. A pharmaceutical composition comprising one or more compounds according to one or more of the claims 1 to 9, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

13. The pharmaceutical composition according to claim 12 wherein the one or more additional therapeutic agents are selected from the group consisting of anticancer agents and antifibrotic agents.

14. The compound according to one or more of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use as a medicament.

15. A method for the treatment of diseases, such as cancer or fibrotic diseases, and conditions associated with these diseases, in a patient in need thereof, the method being characterized in that one or more compounds according to one or more of claims 1 to 9 or pharmaceutically acceptable salts thereof are administered to the patient.

16. A compound according to one or more of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in a method for the treatment of cancer, fibrotic diseases, neuro- degenerative diseases, atherosclerosis, infectious diseases, or chronic kidney diseases.