US 11,813,306 B2
Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders
Karin Briner, Cambridge, MA (US); Brian Addison Dechristopher, Belmont, MA (US); Alec Nathanson Flyer, Cambridge, MA (US); Andrei Alexandrovich Golosov, Cambridge, MA (US); Philipp Grosche, Inzlingen (DE); Eugene Yuejin Liu, Lexington, MA (US); Justin Yik Ching Mao, North Reading, MA (US); Lauren Gilchrist Monovich, Belmont, MA (US); Tajesh Jayprakash Patel, Westford, MA (US); Liansheng Su, Winchester, MA (US); Lihua Yang, Westford, MA (US); and Rui Zheng, Needham, MA (US)
Assigned to Novartis AG, Basel (CH)
Filed by NOVARTIS AG, Basel (CH)
Filed on Mar. 12, 2021, as Appl. No. 17/200,471.
Application 17/200,471 is a continuation of application No. 16/695,843, filed on Nov. 26, 2019, granted, now 11,026,993.
Claims priority of provisional application 62/924,828, filed on Oct. 23, 2019.
Claims priority of provisional application 62/772,030, filed on Nov. 27, 2018.
Prior Publication US 2021/0252103 A1, Aug. 19, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 38/12 (2006.01); A61K 45/06 (2006.01); C07K 5/12 (2006.01)
CPC A61K 38/12 (2013.01) [A61K 45/06 (2013.01); C07K 5/126 (2013.01)] 20 Claims
 
1. A compound of Formula (Ig):

OG Complex Work Unit Chemistry
wherein:
R1 is (C6-C10)aryl substituted with —OR10 and substituted with one to three R11;
R2 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, —NR12R13, (C3-C7)carbocyclyl, (C3-C7)cycloalkenyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, (C6-C10)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 R18, and the carbocyclyl, (C3-C7)cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R19;
R5 and R7 are each independently H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more D;
R6 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)(C1-C6)alkyl, —C(O)OH, and —C(O)O(C1-C6)alkyl;
R8 is H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, —NR16R17, and —C(O)NR16R17;
R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, or CN;
R10 is (C6-C10)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 R22;
each R11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, or CN;
R12 and R13 are each independently H or (C1-C6)alkyl;
R16 and R17 are each independently H or (C1-C6)alkyl, or
R16 and R17 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 R18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, (C6-C10)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 R20;
each R19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, or CN; or
two R19 together, when on adjacent atoms, form a (C6-C10)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, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, and CN;
each R20 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, —OH, or CN; or
when R18 is a carbocyclyl or a heterocyclyl, two R20, when attached to the same carbon atom, together form ═(O);
R21 is H or (C1-C6)alkyl;
each R22 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, CN, (C6-C10)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 R23;
each R23 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —CH2(OCH2CH2)1-3OCH2CH3, —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, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, —C(O)R24R25, —NR24C(O)R25, —NH2, —NH(C1-C6)alkyl, and —N((C1-C6)alkyl)2, and the alkyl is optionally substituted with —NR24R25 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, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, —NH2, —NH(C1-C6)alkyl, and —N((C1-C6)alkyl)2; and
R24 and R25 are each independently H, (C1-C6)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C6)alkyl;
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof.