Compounds for binding proprotein convertase subtilisin/kexin type 9
The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity, for treatment of a disease or condition mediated, at least in part, by PCSK9. The compounds of the disclosure include compounds Formula (I).
1. A method of treating a disease or condition, wherein the disease or condition is selected from hypocholesterolemia, coronary disease, hypertension, hypercholesterolemia, atherosclerosis, and diabetes, the method comprising administering to a patient in need thereof a compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
m is 0, 1, or 2;
X 1 is N;
X 2 , X 3 , and X 4 are each independently CR 2 or CR 2 R 2 ;
ring B is a six-membered ring comprising one or more double bonds;
X 5 and X 6 are CR 2 ;
X 7 is C;
ring A is:
where the wavy line in ring A indicates the point of attachment to
L is a bond;
R 1 in each instance is independently halo or C 1-6 alkyl optionally substituted with halo or hydroxy;
R 2 in each instance is independently hydrogen, halo, or C 1-6 alkyl optionally substituted with halo or hydroxy
R 3 is halo, C 1-6 alkyl, C 3-6 cycloalkyl, or aryl;
wherein each C 1-6 alkyl, C 3-6 cycloalkyl, or aryl of R 3 is optionally substituted with 1 to 3 substituents independently selected from halo and hydroxy; and
R 4 is hydrogen or C 1-6 alkyl;
provided that 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 atom.
2. The method of claim 1 , wherein the disease or condition is hypocholesterolemia.
3. The method of claim 1 , wherein the disease or condition is coronary disease, hypertension, hypercholesterolemia, or atherosclerosis.
4. The method of claim 1 , wherein the disease or condition is diabetes.
5. The method of claim 4 , wherein the patient has elevated plasma levels of low density lipoprotein cholesterol.