Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders

Patent metadata

Field	Value
Publication number	US-11026993-B2
Application number	US-201916695843-A
Country	US
Kind code	B2
Filing date	Nov 26, 2019
Priority date	Nov 27, 2018
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , R 1 , X 1 , X 2 , and X 3 are described herein.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
X 1 and X 2 are each independently H or (C 1 -C 6 )alkyl, or X 1 and X 2 together with the carbon atom to which they are attached form ═(O);
X 3 is —CH 2 — when X 1 and X 2 are each independently H or (C 1 -C 6 )alkyl, or X 1 and X 2 together with the carbon atom to which they are attached form ═(O), or X 3 is —O—, —NH— or —N(C 1 -C 6 )alkyl-, when X 1 and X 2 together with the carbon atom to which they are attached form ═(O);
R 1 is (C 6 -C 10 )aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are substituted with —OR 10 or —NR 21 R 10 and optionally substituted with one or more R 11 ;
R 2 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )haloalkyl, —NR 12 R 13 , (C 3 -C 7 )carbocyclyl, (C 3 -C 7 )cycloalkenyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more R 18 , and the carbocyclyl, (C 3 -C 7 )cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 19 ;
R 3 is H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, or (C 1 -C 6 )hydroxyalkyl, wherein the alkyl is optionally substituted with one or more R 14 ;
R 4 is H or (C 1 -C 6 )alkyl; or
R 3 and R 4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O, and S;
R 5 and R 7 are each independently H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, or (C 1 -C 6 )hydroxyalkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more D;
R 6 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, or (C 1 -C 6 )hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)(C 1 -C 6 )alkyl, —C(O)OH, and —C(O)O(C 1 -C 6 )alkyl;
R 8 is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )haloalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, —NR 16 R 17 , and —C(O)NR 16 R 17 ;
R 9 is halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, or CN;
R 10 is (C 6 -C 10 )aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 22 ;
each R 11 is independently at each occurrence halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, or CN;
R 12 and R 13 are each independently H or (C 1 -C 6 )alkyl;
each R 14 is independently at each occurrence D, NR 15 R 15′ , (C 3 -C 7 )carbocyclyl, or 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more substituents each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )haloalkoxy;
R 15 and R 15′ are each independently H or (C 1 -C 6 )alkyl;
R 16 and R 17 are each independently H or (C 1 -C 6 )alkyl, or
R 16 and R 17 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S;
each R 18 is independently at each occurrence (C 3 -C 7 )carbocyclyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R 20 ;
each R 19 is independently at each occurrence halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, or CN; or
two R 19 together, when on adjacent atoms, form a (C 6 -C 10 )aryl or 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, and CN;
each R 20 is independently at each occurrence halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, oxo, —OH, or CN; or
when R 18 a carbocyclyl or a heterocyclyl, two R 20 , when attached to the same carbon atom, together form ═(O);
R 21 is H or (C 1 -C 6 )alkyl;
each R 22 is independently at each occurrence halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, CN, (C 6 -C 10 )aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 23 ;
each R 23 is independently at each occurrence halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —CH 2 (OCH 2 CH 2 ) 1-3 OCH 2 CH 3 , —OH, CN, or 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, —C(O)R 24 R 25 , —NR 24 C(O)R 25 , —NH 2 , —NH(C 1 -C 6 )alkyl, and —N((C 1 -C 6 )alkyl) 2 , and the alkyl is optionally substituted with —NR 24 R 25 or a 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S optionally substituted with one or more substituents each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —OH, —NH 2 , —NH(C 1 -C 6 )alkyl, and —N((C 1 -C 6 )alkyl) 2 ; and
R 24 and R 25 are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C 7 )carbocyclyl optionally substituted with one to two (C 1 -C 6 )alkyl;
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof.

2. The compound according to claim 1 , wherein R 4 is H or (C 1 -C 6 )alkyl.

3. The compound according to claim 1 , wherein R 4 is H.

4. The compound according to claim 1 , wherein R 3 and R 4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O, and S.

5. The compound according to claim 4 , wherein R 3 and R 4 together with the atoms to which they are attached form a 6-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O, and S.

6. The compound according to claim 1 , wherein R 5 is H or (C 1 -C 6 )alkyl.

7. The compound according to claim 1 , wherein R 5 is (C 1 -C 6 )alkyl.

8. The compound according to claim 1 , wherein R 7 is H or (C 1 -C 6 )alkyl.

9. The compound according to claim 1 , wherein R 7 is (C 1 -C 6 )alkyl.

10. The compound according to claim 1 , wherein R

Assignees

• Novartis Ag

Inventors

• Briner Karin
• Dechristopher Brian Addison
• Flyer Alec Nathanson
• Golosov Andrei Alexandrovich
• Grosche Philipp
• Liu Eugene Yuejin
• Mao Justin Yik Ching
• Monovich Lauren Gilchrist
• Patel Tajesh Jayprakash
• Sanchez Carina Cristina
• Su Liansheng
• Yang Lihua
• Zheng Rui

Classifications

• C07D471/08 Primary

  Bridged systems · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• C07K5/126

  Tetrapeptides · CPC title

• C07D211/56

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title