Pcsk9 inhibitors and methods of use thereof

Abstract

This invention relates to novel heteroaryl compounds and their pharmaceutical preparations. Further, this invention relates to methods for treating or preventing cardiovascular diseases using the novel heterocyclic compounds disclosed herein, and methods for treating sepsis or septic shock.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein: A is selected from H, halogen, hydroxyl, C1-10 alkyl, C1-10 thioalkyl, C2-10 alkenyl, C1-10 alkoxy, C1-10 acetoxy, cyano, C3-10 cycloalkyl, -C(O)OR6 and -C(O)NR6R7; B is selected from H, C1-10 alkyl and halogen, or A and B together with the carbon atom to which they are attached form a 5- or 6-membered heteroaryl group; X is NR5; n is 0, and R1 and R1' together with the atom to which they are attached form an unsubstituted or cyclopentyl ring substituted with one or more hydroxyl groups; R2 is selected from H, halogen, C1-10 alkyl, C1-10 alkoxy, C1-10 acetylalkyl, C1-10 aminoalkyl, C1-10 hydroxyalkyl, C1-10 alkylamino, cyano and hydroxyl; R2' is selected from H, halogen, C1-10 alkyl, C1-10 alkoxy, C1-10 aminoalkyl, C1-10 aminoalkyl, and cyano; each of R3 and R4 is independently H or C1-10 alkyl; R5 is H or C1-10 alkyl; each of R6 and R7 is independently H or C1-10 alkyl; and Y is selected from C5-7 aryl, 5- to 7-membered monocyclic heteroaryl, polycyclic heteroaryl containing two rings each containing 5 to 7 atoms, and 3- to 10-membered heterocyclic groups, wherein each heteroaryl and heterocyclic group has 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein A is selected from H, hydroxyl, C1-10 thioalkyl, C1-10 alkyl, C1-10 alkoxy, C1-10 acetoxy, cyano, C3-10 cycloalkyl, -C(O)OR6 and -C(O)NR6R7.

3. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein A is selected from -SCH3, -SCHF2 and -OCHF2.

4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein B is H.

5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein R2 is selected from H, halogen, C1-10 alkyl, C1-10 alkoxy, C1-10 amide alkyl, C1-10 amino alkyl, C1-10 alkylamino, cyano and hydroxy.

6. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein R2' is H.

7. A compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein Y is a 5- to 7-membered monocyclic heteroaryl group.

8. The compound of claim 7 or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein Y is selected from pyridyl, pyridinyl, pyrazinyl, pyrimidinyl and thiazolyl.

9. The compound of claim 7 or its pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer, wherein the 5- to 7-membered monocyclic heteroaryl group is unsubstituted or substituted with one or more substituents selected from: C1-10 alkyl, C1-10 thioalkyl, C1-10 alkoxy, C1-10 alkoxycarbonyl, acetylamino, carboxyl, cyano, haloyl, C5-7 aryl, 5- to 7-membered monocyclic heteroaryl, polycyclic heteroaryl containing two rings each comprising 5 to 7 atoms, 3- to 10-membered heterocyclic group, nitro, sulfonamide and C1-10 thioalkyl, wherein the heteroaryl group and the heterocyclic group each have 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.

10. A compound or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, wherein the compound is selected from the group consisting of , ...

11. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, and one or more pharmaceutically acceptable excipients.

12. Use of a compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, enantiomer or diastereomer thereof, for the preparation of a medicament for the treatment of cardiovascular diseases in an individual in need.

13. As claimed in claim 12, wherein the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease.

14. As claimed in claim 12, wherein the cardiovascular disease is selected from a) familial hypercholesterolemia; b) overt hypercholesterolemia; or c) atherosclerosis.

15. For the purposes of claim 12, wherein a) the individual’s circulating serum LDL-cholesterol level is reduced; b) the individual’s circulating serum VLDL-cholesterol level is reduced; c) the individual’s circulating serum triglyceride level is reduced; or d) the individual’s circulating serum lipoprotein A level is reduced.

16. The use of any of claims 12 to 15, wherein the drug further comprises one or more other therapeutic agents or the drug is used in combination with one or more other therapeutic agents.

17. As claimed in claim 16, wherein the one or more additional therapeutic agents are selected from alirocumab, evolocumab, bococizumab, RG7652, LY3015014, mAb316P, berberine, quercetin, ezetimbe, policosanol, BMS-962476, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

18. As claimed in claim 16, wherein the one or more additional therapeutic agents are selected from HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, HMG-CoA synthase gene expression inhibitors, MTP / Apo B secretion inhibitors, CETP inhibitors, bile acid absorption inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, squalene synthase inhibitors, squalene cyclooxygenase inhibitors, squalene cyclase inhibitors, combinations of squalene cyclooxygenase / squalene cyclase inhibitors, cellulose esters, niacin, combinations of niacin and lovastatin, ion exchange resins, antioxidants, ACAT inhibitors, bile acid separators, and PCSK9 translation inhibitors.

19. As claimed in claim 16, wherein the one or more additional therapeutic agents are statins.

20. As claimed in claim 16, wherein the one or more other therapeutic agents are selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.