Substituted 1-methyl-1,2,3,4-tetrahydroisoquinoline molecules as PCSK9 allosteric binders

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein:

R A is —C 1 -C 6 alkyl, —[OCH 2 CH 2 ] m NR a C(O)R C , —(CH 2 ) n -AryA1, —(CH 2 ) n -HetA1 or —C 1 -C 3 alkylN 3 ; wherein the —C 1 -C 6 alkyl or —C 1 -C 3 alkylN 3 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —C(O)OR a , —NR a R b and —OH;

AryA1 is a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N and O, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —CN, —CH 2 OH, —C(O)NR a R b , —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , —C(O)OR a , —CH(OH)C(NH 2 )C(O)OR a , —CH 2 OCH 2 CH 2 CH, AryA2, —(CH 2 ) n -HetA1, —NR a and —OH; wherein the —C 1 -C 6 alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —OR a , —NR a R b , —COOR a , —C 3 -C 6 cycloalkyl, —C 1 -C 4 alkylCOOR a , —NR a C(O)R b , —NR a S(O) 2 R b , —(CH 2 ) n -AryA2, —OAryA2 and —NR a C(O)-AryA2,

each occurrence of AryA2 is individually a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N and O, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl-C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —COOR a , —CN, —CH 2 OH, —C(O)NR a R b , —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , —OR a , —NR a R b , AryA3 and oxo;

HetA1 is a 5-6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from the group consisting of N and O, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C 1 -C 6 alkyl, —CH 2 OH, —C(O)NR a R b , —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , —OR a , —NR a R b , —CN and oxo;

X 1 and X 2 are independently selected from the group consisting of N and CH;

wherein if X 1 is CH, X 1 is optionally linked to R B through an —OC 6 -C 7 alkylene or an —OC 6 -C 7 alkenylene, wherein the O of the —OC 6 -C 7 alkylene or —OC 6 -C 7 alkenylene is bound at the X 1 position;

or alternatively X 1 and X 2 together with the ring atoms to which they are attached form a 5-6 membered aromatic monocyclic ring with 0, 1 or 2 heteroatom ring atoms independently selected from the group consisting of N and O, wherein said monocyclic ring is fused to the ring having X 1 and X 2 , further wherein said monocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl and —C 1 -C 6 haloalkyl;

Y is O or a bond;

R 1 is:

1) hydrogen,

2) halogen,

3) —C 1 -C 6 alkyl,

4) —C 1 -C 6 haloalkyl,

5) —C 1 -C 6 alkoxy,

6) —C 1 -C 6 haloalkoxy,

7) —C(O)OR a ,

8) —C(O)NR a R b ,

9) —CN,

10) —CH 2 OH,

11) —SC 1 -C 6 alkyl,

12) —SO 2 R a ,

13) —SO 2 NR a R b ,

14) —OR a ,

15) —NR a R b ,

16) —C(O)NR a AryA3, or

17) -AryA3;

AryA3 is an aromatic 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N and O, wherein the 5-6 membered monocyclic ring or the 8-10 membered bicyclic ring are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl, —C 1 -C 6 alkenyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —CN, —CH 2 OH, —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , —OR a , —C(O)OR a , —C(O)NR a R b , —C(O)NR a AryA4, —NR a C(O)AryA4, AryA4, —NR a R b , oxo and —OH wherein the —C 1 -C 6 alkyl or the —C 1 -C 6 alkenyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C 1 -C 6 cycloalkyl, —C(O)OR a and —C(O)NR a R b ;

AryA4 is a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N and O, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —CN, —CH 2 OH, —C(O)NR a R b , —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , —OR a and —NR a R b ;

each R 2 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —CN, —CH 2 OH, —C(O)NR a R b , —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , —OR a or —NR a R b ;

R B is -AryA5; wherein if X 1 is CH, R B is optionally linked to X 1 through an —OC 6 -C 7 alkylene or an —OC 6 -C 7 alkenylene, wherein the O of the —OC 6 -C 7 alkylene or —OC 6 -C 7 alkenylene is bound at the X 1 position;

AryA5 is an aromatic 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from the group consisting of N, O and S, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —NR a R b , —CN, —CH 2 OH, —C(O)NR a R b , —SC 1 -C 6 alkyl, —SO 2 R a , —SO 2 NR a R b , and —OR a ;

R C is —(CH 2 ) p -adamantane, —(CH 2 ) m -5,5-difluoro-1,3-dimethyl-5H-5λ 4 ,6λ 4 -dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinine, —(CH 2 ) m -(3aR,6aS)-tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, —C 1 -C 6 alkyl and —C 1 -C 2 alkylene[OC 1 -C 2 alkylene] o C(O)NR a C 1 -C 6 alkyl;

wherein the —C 1 -C 6 alkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —NR a C(O)C 1 -C 6 alkyl, —NR a C(O)OC 1 -C 6 alkyl, —NR a C(═NC(O)OR b )(NR a C(O)OR b ), —[OC 1 -C 2 alkylene] o C(O)NR a C 1 -C 6 alkyl and AryB1;

wherein the —NR a C(O)C 1 -C 6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of —OR a , —NR a R b and AryB1;

wherein the —C 1 -C 2 alkylene[OC 1 -C 2 alkylene] o C(O)NR a C 1 -C 6 alkyl is optionally substituted with a substituent selected from the group consisting of -HetB1 and —C(O)HetB1;

HetB1 is a 5-membered saturated monocyclic ring with 1 N atom, optionally substituted with 1 or 2 substituents independently selected from the group consisting of —C(O)NR a (CH 2 ) n -AryB1 and —OR a ;

AryB1 is a 5-6 membered aromatic monocyclic ring with 0 or 1 N ring atoms, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of AryB2, halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —C(O)OR a , —NR a R b and —OH;

AryB2 is a 5-6 membered aromatic monocyclic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from the group consisting of N, O and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, and —OR a ;

R a and R b are independently H or C 1 -C 6 alkyl;

or alternatively R a and R b , if bound to the same atom, can together with the atom to which they are both attached form a —C 1 -C 6 cycloalkyl;

each n is independently 0, 1 or 2;

each m is independently 1, 2, 3 or 4;

each o is independently 1, 2 or 3; and

each p is independently 1, 2, 3 or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are CH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CH.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R B is -AryA5 linked to X 1 through an —OC 6 -C 7 alkylene or an —OC 6 -C 7 alkenylene, wherein the O of the —OC 6 -C 7 alkylene or —OC 6 -C 7 alkenylene is bound at the X 1 position.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is O.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B is thiazolyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is —[OCH 2 CH 2 ] m NR a C(O)R C ; each m is 2, 3 or 4, and R C is selected from the group consisting of:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is —[OCH 2 CH 2 ] m NR a C(O)R C ; each m is 2, 3 or 4, and R C is a BODIPY group which is:

9. A pharmaceutical composition which comprises a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method for the in vitro labeling, detection and/or quantification of PCSK9 in a biological sample, which comprises the steps of: (i) incubating the sample with a compound or pharmaceutically acceptable salt of claim 8 for a time sufficient for the compound or salt to bind to PCSK9 present in the sample, (ii) activating or irradiating the detectable marker of step (i), and (iii) visualizing a fluorescent signal conferred by the BODIPY group of the compound or pharmaceutically acceptable salt of step (i).

11. A method for inducing PCSK9 protein degradation in a subject which comprises administering to the subject (i) an effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof or (ii) a pharmaceutical composition comprising a compound according to claim 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. The method of claim 11 wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. A method for treating atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound according to claim 7 , or a pharmaceutically acceptable salt thereof or (ii) a pharmaceutical composition comprising a compound according to claim 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The method of claim 13 wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.