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

A compound of Formula (I):

• wherein:
• X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form ═(O);
• X3 is —CH2— when X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form ═(O), or X3 is —O—, —NH— or —N(C1-C6)alkyl-, when X1 and X2 together with the carbon atom to which they are attached form ═(O);
• R1 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 substituted with —OR10 or —NR21R10 and optionally substituted with one or more 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;
• R3 is H, D, (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 R14;
• R4 is H or (C1-C6)alkyl;
• or
• R3 and R4 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;
• 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;
• each R14 is independently at each occurrence D, NR15R15′, (C3-C7)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, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and (C1-C6)haloalkoxy;
• R15 and R15′ 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 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.