3,3′-disubstituted indolines as inhibitors of cholesterol ester transfer protein

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

Wherein 1-2 carbon atoms in the phenyl ring of Formula I are optionally replaced with 1-2 heteroatoms selected from NH, S, and O to create a 5-6 membered heteroaromatic ring, wherein:

Each R 1 is independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , HET(1), phenyl, or C 3-6 cycloalkyl optionally having 1-2 double bonds, wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are each optionally substituted with 1-9 halogens, and wherein HET(1), phenyl, and C 3-6 cycloalkyl optionally having 1-2 double bonds are optionally substituted with 1-3 substituent groups which are each independently halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, or —OC 2 -C 3 alkynyl, wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, and —OC 2 -C 3 alkynyl are each optionally substituted with 1-7 halogens;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , HET(1), phenyl, or C 3-6 cycloalkyl optionally having 1-2 double bonds, wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, and —OC 2 -C 5 alkynyl are each optionally substituted with 1-9 halogens, and wherein HET(1), phenyl, and C 3-6 cycloalkyl optionally having 1-2 double bonds, are optionally substituted with 1-3 substituent groups which are each independently halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, or —OC 2 -C 3 alkynyl, wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, and —OC 2 -C 3 alkynyl are each optionally substituted with 1-7 halogens;

R 8 is H or —C 1-5 alkyl optionally substituted with 1-9 halogens;

R 9 and R 10 are each independently H, —C 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, and HET(1) are optionally substituted with 1-3 substituent groups which are each independently halogen, —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, or —OC 2 -C 3 alkynyl, wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —OC 2 -C 3 alkenyl, —C 2 -C 3 alkynyl, and —OC 2 -C 3 alkynyl are each optionally substituted with 1-7 halogens;

HET(1) is a 3-7 membered heterocyclic or heteroaromatic ring having 1-4 heteroatoms or heteroatom groups which are each independently N, NH, O, S, S(O), or S(O) 2 and optionally having 1-3 double bonds;

Ar 1 and Ar 2 are each independently phenyl, naphthyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein Ar 1 and Ar 2 are each optionally substituted with 1-5 substituents which are independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —SO 2 C 1 -C 5 alkyl, —C(O)C 1 -C 5 alkyl, —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , or —NR 9 C(O)NR 9 R 10 , and optionally 1-2 substituents which are phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), or HET(2), wherein —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 2 -C 5 alkenyl, —C 2 -C 5 alkynyl, —OC 2 -C 5 alkynyl, —SO 2 C 1 -C 5 alkyl, and —C(O)C 1 -C 5 alkyl are optionally substituted with 1-9 halogens, and wherein when phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), and HET(2) are substituents on Ar 1 and Ar 2 , then phenyl, C 3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), and HET(2) are optionally substituted with 1-3 substituent groups which are each independently halogen, —OH, —CN, —NR 9 R 10 , —CO 2 R 8 , —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens and optionally with 1-2 groups which are —OH, halogen, —CN, —NR 9 R 10 , and —CO 2 R 8 ;

HET(2) is a bicyclic or spirocyclic heterocycle having two 3-6 membered heterocyclic rings which are fused or are connected through a single carbon atom to make a spirocyclic connection, wherein HET(2) has 2-4 heteroatoms or heteroatom groups which are O, S, S(O) 2 , N, or NH, and optionally comprises 1-2 double bonds; and

n is 0 or an integer from 1-4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

The phenyl ring in Formula I has no optional heteroatoms;

Each R 1 is independently —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , phenyl, or C 3-6 cycloalkyl, wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are each optionally substituted with 1-9 halogens, and wherein phenyl and C 3-6 cycloalkyl are each optionally substituted with 1-3 groups which are independently halogen, —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 are each optionally substituted with 1-7 halogens;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —C(O)NR 9 R 10 , or —SO 2 NR 9 R 10 , wherein —C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are each optionally substituted with 1-9 halogens;

R 8 is H or —C 1-5 alkyl optionally substituted with 1-9 halogens;

R 9 and R 10 are each independently H, —C 1 -C 5 alkyl, phenyl, C 3-6 cycloalkyl, or HET(1), wherein phenyl, C 3-6 cycloalkyl, and HET(1) are optionally substituted with 1-3 substituent groups which are each independently halogen, —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are each optionally substituted with 1-7 halogens;

HET(1) is a 3-7 membered heterocyclic or heteroaromatic ring having 1-4 heteroatoms or heteroatom groups which are each independently N, NH, O, S, S(O), or S(O) 2 and optionally having 1-3 double bonds;

Ar 1 and Ar 2 are each independently phenyl, C 3-6 cycloalkyl, or HET(1), wherein Ar 1 and Ar 2 are each optionally substituted with 1-5 substituents which are independently —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —OH, halogen, —CN, —NR 9 R 10 , —CO 2 R 8 , —SO 2 C 1 -C 5 alkyl, —C(O)C 1 -C 5 alkyl, —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , or —NR 9 C(O)NR 9 R 10 , and optionally one substituent which is phenyl, C 3-6 cycloalkyl, HET(1), or HET(2), wherein —C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —SO 2 C 1 -C 5 alkyl, and —C(O)C 1 -C 5 alkyl are optionally substituted with 1-7 halogens, and wherein when phenyl, C 3-6 cycloalkyl, HET(1), and HET(2) are substituents on Ar 1 and Ar 2 , then phenyl, C 3-6 cycloalkyl, HET(1), and HET(2) are optionally substituted with 1-3 substituent groups which are each independently halogen, —OH, —CN, —NR 9 R 10 , —CO 2 R 8 , —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens;

HET(2) is a bicyclic or spirocyclic heterocycle having two 3-6 membered heterocyclic rings which are fused or are connected through a single carbon atom to make a spirocyclic connection, wherein HET(2) has 2-4 heteroatoms or heteroatom groups which are O, S, S(O) 2 , N, or NH, and optionally comprises 1-2 double bonds; and

n is 0 or an integer from 1-4.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

Each R 1 is independently halogen, —C 1 -C 4 alkyl, or —OC 1 -C 4 alkyl, wherein —C 1 -C 4 alkyl and —OC 1 -C 4 alkyl are each optionally substituted with 1-9 halogens;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, —C 1 -C 4 alkyl or —OC 1 -C 4 alkyl, wherein —C 1 -C 4 alkyl and —OC 1 -C 4 alkyl are optionally substituted with 1-9 halogens;

R 8 is H or —C 1-4 alkyl optionally substituted with 1-9 halogens;

R 9 is H or —C 1 -C 4 alkyl;

R 10 is H, —C 1 -C 4 alkyl, or HET(1); and

n is 0, 1, 2 or 3.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein

Each R 1 is independently halogen, —C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens which are F or Cl;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, —C 1 -C 3 alkyl or —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens which are F or Cl;

R 8 is H or —C 1-3 alkyl optionally substituted with 1-7 halogens;

R 9 is H or —C 1 -C 3 alkyl; and

R 10 is H, —C 1 -C 3 alkyl, or a 5-6-membered heterocycle having 1-2 heteroatoms which are each O or S, and optionally 1-3 double bonds; and

n is 0, 1 or 2.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein

Each R 1 is halogen, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 ;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, —C 1 -C 2 alkyl or —OC 1 -C 2 alkyl, wherein —C 1 -C 2 alkyl and —OC 1 -C 2 alkyl are each optionally substituted with 1-5 halogens which are F;

R 8 is H or —CH 3 ;

R 9 is H or —CH 3 ; and

R 10 is H, —C 1 -C 2 alkyl, or a 5-6-membered heterocycle having one heteroatom which is O or S and optionally one double bond.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is —CH 3 or F;

R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each H;

R 8 is H or —CH 3

R 9 is H or —CH 3 ;

R 10 is H, —CH 3 or a 5-6-membered saturated heterocycle having 1 heteroatom which is S or O; and

n is 0 or 1.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 and Ar 2 are each independently:

(a) Phenyl optionally substituted with 1-2 groups which are independently F, Cl, Br, —CN, —CH 3 optionally substituted with 1-3 F, —OC 1-2 alkyl optionally substituted with 1-5 F, —OCH(CH 3 ) 2 , —CO 2 R 8 , or —SO 2 CH 3 , wherein phenyl is optionally substituted with one group phenyl which is optionally substituted with 1-2 groups which are independently —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , F or —CO 2 R;

(b) Phenyl optionally substituted with 1-2 groups which are independently halogen, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 , wherein phenyl is substituted with —NH-tetrahydrofuryl or with a N-containing heterocycle attached through the N of the heterocycle, wherein the heterocycle is pyrrolidinyl, piperidinyl, azetidinyl, morpholino, or 2-oxa-6-azaspiro[3,3]heptane, wherein the N-containing heterocycle in all cases is optionally substituted with 1-2 groups which are F, —OH, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 ;

(c) Pyridinyl optionally substituted with one group morpholino and optionally 1-2 groups which are independently F, Cl, —CH 3 , —CF 3 , or —OC 1-3 alkyl optionally substituted with 1-7 F; or

(d) 2-Thiazolyl optionally substituted with one group which is —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , or F.

8. A compound, or a pharmaceutically acceptable salt thereof, having the structure below:

9. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.

11. A method of raising HDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.

12. A method of lowering LDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.

13. A method of treating dyslipidemia in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.

14. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:

(i) HMG-CoA reductase inhibitors;

(ii) bile acid sequestrants;

(iii) niacin and related compounds; (iv) PPARα agonists;

(v) cholesterol absorption inhibitors;

(vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors;

(vii) phenolic anti-oxidants;

(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors;

(ix) anti-oxidant vitamins;

(x) thyromimetics;

(xi) LDL (low density lipoprotein) receptor inducers;

(xii) platelet aggregation inhibitors;

(xiii) vitamin B12 (also known as cyanocobalamin);

(xiv) folic acid or a pharmaceutically acceptable salt or ester thereof; (xv) FXR and LXR ligands;

(xvi) agents that enhance ABCA1 gene expression;

(xvii) ileal bile acid transporters; and

(xviii) niacin receptor agonists.

15. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and an HMG-CoA reductase inhibitor.