Methods of inhibiting pcsk9

A method for reducing the PCSK9 level in a subject, the method comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable stereoisomer, isotope, solvate or salt thereof:

• wherein
• dashed bonds, independently, are present or absent;
• X is O, S, CR2 or NR1;
• Y is, for each occurrence, independently N or C(R6);
• Z1 is CH2, CH(R5), C(R5)2 or is absent;
• Z2 is CH2, CH(R5), C(R5)2, NR2 or is absent;
• Ra and Rb are absent, or independently selected from hydrogen, alkyl, hydroxyl, and amino;
• wherein Ra and Rb may combine to form a 5- or 6-membered ring;
• R1 is hydrogen, alkyl, alkenyl, alkynyl or aryl;
• R2 is, for each occurrence, independently selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R7-cycloalkyl, aryl, —NHR7, Het, —NHHet, —NHR7Het, —OR8, —O-aryl, —OHet, —R7OR8, —NR8R9, —NR8-aryl, —R7NR8R9, —R7NR8-aryl, —R7C(O)R8, —C(O)R8, —CO2R8, —R7CO2R8, —C(O)NR8R9, —C(O)aryl, —C(O)NR8aryl, —C(O)Het, —C(O)NHR7Het, —R7C(O)NR8R9, —C(S)NR8R9, —R7C(S)NR8R9, —R7(NH)NR8R9, —C(NH)NR8R9, —R7C(NH)NR8R9, —S(O)2NR8R9, —S(O)2NR8aryl, —R7SO2NHCOR8, —R7SO2NR8R9, —R7SO2R8, —S(O)mR8, cyano, nitro, and azido;
• R3 is selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Het, aryl, —NHR7, —NHHet, —NHR7Het, —OR8, —O-aryl, —OHet, —R7OR8, —NR8R9, —NR8-aryl, —R7NR8R9, —R7NR8-aryl, —R7C(O)R8, —C(O)R8, —CO2R8, —R7CO2R8, —C(O)NR8R9, —C(O)aryl, —C(O)NR8aryl, —C(O)Het, —C(O)NHR7Het, —R7C(O)NR8R9, —C(S)NR8R9, —R7C(S)NR8R9, —R7(NH)NR8R9, —C(NH)NR8R9, —R7C(NH)NR8R9, —S(O)2NR8R9, —S(O)2NR8aryl, —R7SO2NHCOR8, —R7SO2NR8R9, —R7SO2R8, —S(O)mR8, cyano, nitro, and azido;
• R4 is selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Het, aryl, —NHR7, —NHHet, —NHR7Het, —OR8, —O-aryl, —OHet, —R7OR8, —NR8R9, —NR8-aryl, —R7NR8R9, —R7NR8-aryl, —CO(O)R8, —C(O)R8, —CO2R8, —R7CO2R8, —C(O)NR8R9, —C(O)aryl, —C(O)NR8aryl, —C(O)Het, —C(O)NHR7Het, —R7C(O)NR8R9, —C(S)NR8R9, —R7C(S)NR8R9, —R7(NH)NR8R9, —C(NH)NR8R9, —R7C(NH)NR8R9, —S(O)2NR8R9, —S(O)2NR8aryl, —R7SO2NHCOR8, —R7SO2NR8R9, —R7SO2R8, —S(O)mR8, cyano, nitro, and azido;
• R5 is, for each occurrence, independently selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Het, aryl, —NHR7, —NHHet, —NHR7Het, oxo, —OR8, —O-aryl, —OHet, —R7OR8, —NR8R9, —NR8-aryl, —R7NR8R9, —R7R8-aryl, —R7C(O)R8, —C(O)R8, —CO2R8, —R7CO2R8, —C(O)NR8R9, —C(O)aryl, —C(O)NR8aryl, —C(O)Het, —C(O)NHR7Het, —R7C(O)NR8R9, —C(S)NR8R9, —R7C(S)NR8R9, —R7(NH)NR8R9, —C(NH)NR8R9, —R7C(NH)NR8R9, —S(O)2NR8R9, —S(O)2NR8aryl, —R7SO2NHCOR8, —R7SO2NR8R9, —R7SO2R8, —S(O)mR7R8, cyano, nitro, and azido;
• R6 is, for each occurrence, independently selected from hydrogen, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R7-cycloalkyl, aryl, —NHR7, Het, —NHHet, —NHR7Het, —OR8, —O-aryl, —OHet, —R7OR8, —NR8R9, —NR8-aryl, —R7NR8R9, —R7NR8-aryl, —R7C(O)R8, —C(O)R8, —CO2R8, —R7CO2R8, —C(O)NR8R9, —C(O)aryl, —C(O)NR8aryl, —C(O)Het, —C(O)NHR7Het, —R7C(O)NR8R9, —C(S)NR8R9, —R7C(S)NR8R9, —R7(NH)NR8R9, —C(NH)NR8R9, —R7C(NH)NR8R9, —S(O)2NR8R9, —S(O)2NR8, —R7SO2NHCOR8, —R7SO2NR8R9, —R7SO2R8, —S(O)mR8, cyano, nitro, and azido;
• R7 is independently selected from an alkyl, cycloalkyl alkenyl, cycloalkenyl and alkynyl
• R8 is independently selected from the group of hydrogen, an alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R7cycloalkyl, —R7OH, —R7(OR7)w, and —R7NR10R11 group;
• R9 is independently selected from the group of hydrogen, an alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R7cycloalkyl, —R7OH, —R7(OR7)w, and —R7NR10R11 group;
• R13 and R11 are the same or different and are independently selected from the group of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl;
• m, for each occurrence, independently is 0, 1 or 2;
• n is 0, 1, 2, 3, 4, 5 or 6;
• w is an integer selected from 1-10;
• and
• wherein any two of R2, R3, R4 and R5, or two R5, may combine to form a 5- or 6-membered ring.