Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use

1. A method of inhibiting PCSK9 in a subject with a metabolic disease, wherein the method comprises administering to the subject a compound of formula I:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

A is —SO 2 — and B is —NH—; or

A is —O— or —CH 2 — and B is —CH 2 — or absent;

ring C is a 5 or 6 membered heteroaryl or heterocyclic ring, or a 6 membered aryl ring;

E 1 , E 2 , and E 3 are independently selected from C, CH, and N, wherein one of E 1 , E 2 , and E 3 may be absent;

R 1 and R 2 are independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH 2 , —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo; or

R 1 and R 2 with the atoms attached thereto form a 5-6 membered fused aryl, heteroaryl, carbocyclic or heterocyclic ring D containing 0-3 heteroatoms, where ring D may further be substituted at a position two atoms away from the juncture with ring C;

R 3 is independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH 2 , —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo;

R 4 is selected from the group consisting of H, OH, halogen, and lower alkyl;

each R 5 is hydrogen or taken together are oxo;

Y is selected from the group consisting of N and CH; and

X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of CH, C-R 4 , and N.

2. The method of claim 1 , wherein an uptake of LDL by hepatocytes in the subject is modulated.

3. The method of claim 1 , wherein said metabolic disease is diabetes.

4. The method of claim 1 , wherein the compound of formula I is formulated as a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

5. The method of claim 4 , wherein said pharmaceutical composition further comprises a second pharmaceutical drug compound.

6. The method of claim 5 , wherein said second pharmaceutical drug compound is selected from the group consisting of a statin, a cardiovascular drug, a metabolic drug, and an antihypertensive drug.

7. The method of claim 1 , wherein the compound is selected from the group

consisting of:

N-phenyl-4-(piperazin-1-yl)benzenesulfonamide;

N-isopropyl-4-((4-(piperazin-1-yl)phenyl)sulfonamido)benzamide;

N-methyl-4-((4-(piperazin-1-yl)phenyl)sulfonamido)benzamide;

N-(3,4-dimethylphenyl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(3,5-dimethylphenyl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(3,5-dichlorophenyl)-4-(piperazin-1-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzenesulfonamide;

N-(naphthalen-2-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(cinnolin-7-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(isoquinolin-7-yl)-4-(piperazin-1-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(quinolin-6-yl)benzenesulfonamide;

N-(cinnolin-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(quinoxalin-6-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyrido[2,3-b]pyrazin-7-yl)benzenesulfonamide;

N-(1H-benzo[d][1,2,3]triazol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2-methylbenzo[b]thiophen-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(1H-indol-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(1H-indol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(benzo[d]isoxazol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2-aminoimidazo[1,2-a]pyrimidin-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2,3-dihydrobenzofuran-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2,3-dihydrobenzofuran-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

2-hydroxy-N-phenyl-4-(piperazin-1-yl)benzenesulfonamide;

4-(2-oxopiperazin-1-yl)-N-phenylbenzenesulfonamide;

2-fluoro-4-(2-oxopiperazin-1-yl)-N-phenylbenzenesulfonamide;

N-phenyl-4-(piperazin-1-yl-2,2,6,6-d 4 )benzenesulfonamide;

N-phenyl-4-(piperidin-4-yl)benzenesulfonamide;

4-(piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyridin-4-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyridin-3-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyridin-2-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(thiazol-2-yl)benzene sulfonamide;

4-(piperazin-1-yl)-N-(quinolin-7-yl)benzene sulfonamide;

N-phenyl-6-(piperazin-1-yl)pyridine-3-sulfonamide;

N-phenyl-5-(piperazin-1-yl)pyridine-2-sulfonamide;

N-(3,5-difluorophenyl)-4-(piperazin-1-yl)benzenesulfonamide;

3-fluoro-4-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzenesulfonamide;

6-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-3-sulfonamide;

5-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-2-sulfonamide;

N-phenyl-4-(piperidin-4-yl)benzenesulfonamide; and

4-(piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzene sulfonamide;

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is selected from the group

consisting of:

1-(4-benzylphenyl)piperazine;

1-(4-(benzyloxy)phenyl)piperazine;

1-(4-phenoxyphenyl)piperazine;

1-(4-(4-(methylthio)phenoxy)phenyl)piperazine;

4-(4-(piperazin-1-yl)phenoxy)benzoic acid;

4-(4-(piperazin-1-yl)phenoxy)benzamide;

5-(4-(piperazin-1-yl)phenoxy)picolinamide;

1-(4-(3,4-dimethylphenoxy)phenyl)piperazine;

4-(4-phenoxyphenyl)piperidine;

4-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidine;

4-(4-(piperidin-4-yl)phenoxy)piperidine;

1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperazine;

1-(4-(piperidin-4-yloxy)phenyl)piperazine; and

1-(4-phenoxyphenyl)piperazin-2-one;

or a pharmaceutically acceptable salt thereof.

9. A kit comprising:

(i) a compound of formula I:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

A is —SO 2 — and B is —NH—; or

A is —O— or —CH 2 — and B is —CH 2 — or absent;

ring C is a 5 or 6 membered heteroaryl or heterocyclic ring, or a 6 membered aryl ring;

E 1 , E 2 , and E 3 are independently selected from C, CH, and N, wherein one of E 1 , E 2 , and E 3 may be absent;

R 1 and R 2 are independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH 2 , —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo; or

R 1 and R 2 with the atoms attached thereto form a 5-6 membered fused aryl, heteroaryl, carbocyclic or heterocyclic ring D containing 0-3 heteroatoms, where ring D may further be substituted at a position two atoms away from the juncture with ring C;

R 3 is independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH 2 , —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo;

R 4 is selected from the group consisting of H, OH, halogen, and lower alkyl;

each R 5 is hydrogen or taken together are oxo;

Y is selected from the group consisting of N and CH; and

X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of CH, C-R 4 , and N; and

(ii) instructions for use of said compound for inhibiting PCSK9 in a subject with a metabolic disease.

10. A method of treating a patient with diabetes, wherein the method comprises administering to the patient a compound of formula I:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

A is —SO 2 — and B is —NH—; or

A is —O— or —CH 2 — and B is —CH 2 — or absent;

Ring C is a 5 or 6 membered heteroaryl or heterocyclic ring, or a 6 membered aryl ring;

E 1 , E 2 , and E 3 are independently selected from C, CH, and N, wherein one of E 1 , E 2 , and E 3 may be absent;

R 1 and R 2 are independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH 2 , —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo; or

R 1 and R 2 with the atoms attached thereto form a 5-6 membered fused aryl, heteroaryl, carbocyclic or heterocyclic ring D containing 0-3 heteroatoms, where ring D may further be substituted at a position two atoms away from the juncture with ring C;

R 3 is independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH 2 , —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo;

R 4 is selected from the group consisting of H, OH, halogen, and lower alkyl;

each R 5 is hydrogen or taken together are oxo;

Y is selected from the group consisting of N and CH; and

X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of CH, C-R 4 , and N.

11. The method of claim 10 , wherein PCSK9 in the patient is inhibited.

12. The method of claim 11 , wherein an uptake of LDL by hepatocytes in the patient is modulated.

13. The method of claim 10 , wherein the compound of formula I is formulated as a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

14. The method of claim 13 , wherein said pharmaceutical composition further comprises a second pharmaceutical drug compound.

15. The method of claim 14 , wherein said second pharmaceutical drug compound is selected from the group consisting of a statin, a cardiovascular drug, a metabolic drug, and an antihypertensive drug.

16. The method of claim 10 , wherein the compound is selected from the group

consisting of:

N-phenyl-4-(piperazin-1-yl)benzenesulfonamide;

N-isopropyl-4-((4-(piperazin-1-yl)phenyl)sulfonamido)benzamide;

N-methyl-4-((4-(piperazin-1-yl)phenyl)sulfonamido)benzamide;

N-(3,4-dimethylphenyl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(3,5-dimethylphenyl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(3,5-dichlorophenyl)-4-(piperazin-1-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzenesulfonamide;

N-(naphthalen-2-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(cinnolin-7-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(isoquinolin-7-yl)-4-(piperazin-1-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(quinolin-6-yl)benzenesulfonamide;

N-(cinnolin-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(quinoxalin-6-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyrido[2,3-b]pyrazin-7-yl)benzenesulfonamide;

N-(1H-benzo[d][1,2,3]triazol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2-methylbenzo[b]thiophen-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(1H-indol-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(1H-indol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(benzo[d]isoxazol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2-aminoimidazo[1,2-a]pyrimidin-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2,3-dihydrobenzofuran-6-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2,3-dihydrobenzofuran-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-(piperazin-1-yl)benzenesulfonamide;

2-hydroxy-N-phenyl-4-(piperazin-1-yl)benzenesulfonamide;

4-(2-oxopiperazin-1-yl)-N-phenylbenzenesulfonamide;

2-fluoro-4-(2-oxopiperazin-1-yl)-N-phenylbenzenesulfonamide;

N-phenyl-4-(piperazin-1-yl-2,2,6,6-d 4 )benzenesulfonamide;

N-phenyl-4-(piperidin-4-yl)benzenesulfonamide;

4-(piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyridin-4-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyridin-3-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(pyridin-2-yl)benzenesulfonamide;

4-(piperazin-1-yl)-N-(thiazol-2-yl)benzene sulfonamide;

4-(piperazin-1-yl)-N-(quinolin-7-yl)benzenesulfonamide;

N-phenyl-6-(piperazin-1-yl)pyridine-3-sulfonamide;

N-phenyl-5-(piperazin-1-yl)pyridine-2-sulfonamide;

N-(3,5-difluorophenyl)-4-(piperazin-1-yl)benzenesulfonamide;

3-fluoro-4-(piperazin-1-yl)-N-(5,6,7, 8-tetrahydronaphthalen-2-yl)benzenesulfonamide;

6-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-3-sulfonamide;

5-(piperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-2-sulfonamide;

N-phenyl-4-(piperidin-4-yl)benzenesulfonamide; and

4-(piperidin-4-yl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)benzene sulfonamide;

or a pharmaceutically acceptable salt thereof.

17. The method of claim 10 , wherein the compound is selected from the group

consisting of:

1-(4-benzylphenyl)piperazine;

1-(4-(benzyloxy)phenyl)piperazine;

1-(4-phenoxyphenyl)piperazine;

1-(4-(4-(methylthio)phenoxy)phenyl)piperazine;

4-(4-(piperazin-1-yl)phenoxy)benzoic acid;

4-(4-(piperazin-1-yl)phenoxy)benzamide;

5-(4-(piperazin-1-yl)phenoxy)picolinamide;

1-(4-(3,4-dimethylphenoxy)phenyl)piperazine;

4-(4-phenoxyphenyl)piperidine;

4-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperidine;

4-(4-(piperidin-4-yl)phenoxy)piperidine;

1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)piperazine;

1-(4-(piperidin-4-yloxy)phenyl)piperazine; and

1-(4-phenoxyphenyl)piperazin-2-one;

or a pharmaceutically acceptable salt thereof.