COMPOUNDS FOR BINDING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity. The compounds of the disclosure include compounds Formula (I).
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof;
wherein:
m is 0, 1, or 2;
X 1 is absent, CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
X 2 , X 3 , and X 4 are each independently CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
ring B is a five- or six-membered ring optionally comprising one or more double bonds;
X 5 and X 6 are either CR 2 or N;
X 7 is C or N; provided that when X 7 is N, then L-R 3 is absent:
ring A is selected from:
where the wavy line in ring A indicates the point of attachment to
L is a bond, C 1-6 -alkylene, —O—, —C(O)—, —SO 2 —, —N(R a )—, —N(R a )SO 2 —, or —SO 2 N(R a )— where R a is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C 1-6 alkyl, or C 1-6 heteroalkyl;
R 1 in each instance is independently halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , or —NR b S(O) 2 R b ;
wherein each R b is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl;
R 2 in each instance is independently hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
wherein each R c is independently, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl;
R 3 is hydrogen, halo, cyano, amino, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R 3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, acyl, C 3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N 3 , —NO 2 , —N(R f ) 2 , —C(O)N(R f ) 2 , —C(NR f )(N(R f ) 2 ), —NR f C(O)OR f , —C(O)N(R f ) 2 , —CO 2 H, —CO 2 R f , —NR f C(NR f )(N(R f ) 2 ), haloalkyl, haloalkoxy, —N(R f )N(R f ) 2 , —C(NR f )R f , —S(O)R f , —SO 2 H, —S(O) 2 R f , —SCN, —SH, or (═S), and where each R f is independently H or C 1-6 alkyl;
R 4 in each instance is independently hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
wherein each R d is independently, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl;
with the following provisos:
1) when m is 0, then both R 4 and L-R 3 cannot be hydrogen;
2) when m is 0, R 4 is hydrogen, X 1 , X 2 , X 3 , X 4 are all CH, then L-R 3 is not CF 3 ;
3) when X 5 and X 6 are both nitrogen, then L-R 3 is not hydrogen, —CH 2 -aryl, or —CH 2 -heteroaryl;
4) when X 1 , X 2 , X 3 , and X 4 are all CH or X 1 is nitrogen and X 2 , X 3 , and X 4 are all CH, then L-R 3 is not —SO 2 -aryl, wherein the aryl is optionally substituted;
5) when A is attached via a carbon atom to the remainder of the molecule and m is other than 0, then R 1 is not appended to the same carbon;
6) the compound is not 3-bromo-8-(4-methylpiperidin-1-yl)quinoline or 4-methyl-1-(naphthalen-1-yl)piperidine; and
7) when A is piperidinyl and L-R 3 is hydrogen, then R 4 is not C(O)NH 2 .
2 . The compound of claim 1 , wherein the moiety
is:
wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with 1 to 7 R 2 .
3 . The compound of claim 1 , wherein the moiety
is:
wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with one or more R 2 .
4 . The compound of claim 1 , wherein the moiety
is:
wherein the wavy line indicates the point of attachment to L and the dashed line represents the point of attachment to ring A, and further wherein the bicyclic ring may be optionally substituted with one or more R 2 .
5 . The compound of claim 1 , wherein ring A is:
6 . The compound of claim 1 , wherein ring A is:
7 . The compound of claim 1 , wherein ring A is:
8 . The compound of claim 1 , wherein m is 0 or 1.
9 . The compound of claim 1 , wherein R 4 is hydrogen, —C(O)NH 2 , or —C(NH)NH 2 .
10 . The compound of claim 1 , wherein R 1 is —NHS(O) 2 CH 3 or —NHC(O)CH 3 .
11 . The compound of claim 1 , wherein R 2 is hydrogen, C 1-6 alkyl, —CO 2 H, or —C(O)NH 2 .
12 . The compound of claim 1 , wherein L is a bond, —CH 2 —, —O—, —C(O)—, —S(O) 2 —, —S(O) 2 NH—, or —NH—.
13 . The compound of claim 1 , wherein R 3 is hydrogen, amino, halo, C 1-6 alkyl, aryl, or C 3-10 heterocyclyl, wherein C 1-6 alkyl, aryl, or C 3-10 heterocyclyl is optionally substituted with 1 to 3 halo.
14 . The compound of claim 1 , wherein L is a bond and R 3 is hydrogen.
15 . The compound of claim 1 , wherein L is a bond, and R 3 is CF 3 .
16 . The compound of claim 1 , wherein R 3 is:
wherein:
Y is —O—, —N(R e )—, —CH(CH 2 ) f OH, or —N(CH 2 ) f OH;
each R e is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl; and
f is 0, 1, 2, 3, or 4.
17 . The compound of claim 16 , wherein Y is —N(R e )—.
18 . A compound selected from
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
19 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
20 . A method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound of Formula (I):
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof;
wherein:
m is 0, 1, or 2;
X 1 is absent, CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
X 2 , X 3 , and X 4 are each independently CR 2 , CR 2 R 2 , C(O), N, NR 2 , S, SO 2 , or O;
ring B is a five- or six-membered ring optionally comprising one or more double bonds;
X 5 and X 6 are either CR 2 or N;
X 7 is C or N; provided that when X 7 is N, then L-R 3 is absent:
ring A is selected from:
where the wavy line in ring A indicates the point of attachment to
L is a bond, C 1-6 -alkylene, —O—, —C(O)—, —SO 2 —, —N(R a )—, —N(R a )SO 2 —, or —SO 2 N(R a )— where R a is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl are optionally substituted with 1 to 3 substituents independently selected from halo, oxo, hydroxy, C 1-6 alkyl, or C 1-6 heteroalkyl;
R 1 in each instance is independently halo, cyano, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, —NR b C(O)NR b R b , or —NR b S(O) 2 R b ;
wherein each R b is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl;
R 2 in each instance is independently hydrogen, halo, C 1-6 alkyl optionally substituted with halo or hydroxy, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, cyano, —C(O)OR c , or —C(O)NR c R c ;
wherein each R c is independently, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl;
R 3 is hydrogen, halo, cyano, amino, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl, or heteroaryl;
wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, aryl, heteroalkyl, heterocyclyl and heteroaryl of R 3 is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, acyl, C 3-10 cycloalkyl, heteroalkyl, heteroaryl, heterocyclyl, aryl, oxo, —N 3 , —NO 2 , —N(R f ) 2 , —C(O)N(R f ) 2 , —C(NR f )(N(R f ) 2 ), —NR f C(O)OR f , —C(O)N(R f ) 2 , —CO 2 H, —CO 2 R f , —NR f C(NR f )(N(R f ) 2 ), haloalkyl, haloalkoxy, —N(R f )N(R f ) 2 , —C(NR f )R f , —S(O)R f , —SO 2 H, —S(O) 2 R f , —SCN, —SH, or (═S), and where each R f is independently H or C 1-6 alkyl;
R 4 in each instance is independently hydrogen, C 1-6 alkyl, —C(O)NR d R d , —C(NR d )NR d R d , —C(O)R d , or —S(O) 2 NR d R d ;
wherein each R d is independently, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 2-6 hydroxyalkyl.
21 . A method of treating a disease or condition mediated, at least in part, by PCSK9, the method comprising administering to a patient in need thereof a compound selected from
or a pharmaceutically acceptable salt, ester, prodrug, isomer, or mixture of isomers thereof.
22 . The method of claim 20 , wherein the disease or condition is a cardiovascular disease, a metabolic disease, or hypocholesterolemia.
23 . The method of claim 21 , wherein the cardiovascular disease is coronary disease, hypertension, hypercholesterolemia, or atherosclerosis.
24 . The method of claim 21 , the metabolic disease is diabetes.
25 . The method of claim 20 , wherein the patient has elevated plasma levels of low density lipoprotein cholesterol.
26 . The method of claim 20 , wherein the patient has depleted plasma levels of low density lipoprotein cholesterol.
27 . A method of inhibiting the activity of PCSK9, the method comprising binding a compound of claim 1 to PCSK9, thereby inhibiting the activity of PCSK9.