# US 2016/0355474 A1 · 3,3'-disubstituted indolines as inhibitors of cholesterol ester transfer protein

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- Number: US 2016/0355474 A1
- Document ID: US20160355474A1
- Status: Published application
- Kind: A1
- Application number: 15/028,306
- Filed: 2014-10-06
- Published: 2016-12-08
- Earliest claimed: 2013-10-10
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: JONATHAN E. WILSON; Petr Vachal; Ravi Kurukulasuriya
- Web page: https://patentgrep.com/patent/US20160355474A1

## CPC

- C07D 209/12: Radicals substituted by oxygen atoms
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D 209/10: with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 209/18: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/24: with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

3,3′-Disubstituted indoline compounds, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis.

## Claims

### Claim 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 R1 is independently —C1-C5 alkyl, —OC1-C5 alkyl, —C2-C5 alkenyl, —OC2-C5 alkenyl, —C2-C5 alkynyl, —OC2-C5 alkynyl, —OH, halogen, —CN, —NR9R10, —CO2R8, —C(O)NR9R10, —SO2NR9R10, HET(1), phenyl, or C3-6 cycloalkyl optionally having 1-2 double bonds, wherein —C1-C5 alkyl, —OC1-C5 alkyl, —C2-C5 alkenyl, —OC2-C5 alkenyl, —C2-C5 alkynyl, and —OC2-C5 alkynyl are each optionally substituted with 1-9 halogens, and wherein HET(1), phenyl, and C3-6 cycloalkyl optionally having 1-2 double bonds are optionally substituted with 1-3 substituent groups which are each independently halogen, —C1-C3 alkyl, —OC1-C3 alkyl, —C2-C3 alkenyl, —OC2-C3 alkenyl, —C2-C3 alkynyl, or —OC2-C3 alkynyl, wherein —C1-C3 alkyl, —OC1-C3 alkyl, —C2-C3 alkenyl, —OC2-C3 alkenyl, —C2-C3alkynyl, and —OC2-C3 alkynyl are each optionally substituted with 1-7 halogens;
R2, R3, R4, R5, R6, and R7 are each independently H, —C1-C5 alkyl, —OC1-C5 alkyl, —C2-C5 alkenyl, —OC2-C5 alkenyl, —C2-C5 alkynyl, —OC2-C5 alkynyl, —OH, halogen, —CN, —NR9R10, —CO2R8, —C(O)NR9R10, —SO2NR9R10, HET(1), phenyl, or C3-6 cycloalkyl optionally having 1-2 double bonds, wherein —C1-C5 alkyl, —OC1-C5 alkyl, —C2-C5 alkenyl, —OC2-C5 alkenyl, —C2-C5 alkynyl, and —OC2-C5 alkynyl are each optionally substituted with 1-9 halogens, and wherein HET(1), phenyl, and C3-6 cycloalkyl optionally having 1-2 double bonds, are optionally substituted with 1-3 substituent groups which are each independently halogen, —C1-C3 alkyl, —OC1-C3 alkyl, —C2-C3 alkenyl, —OC2-C3 alkenyl, —C2-C3 alkynyl, or —OC2-C3 alkynyl, wherein —C1-C3 alkyl, —OC1-C3 alkyl, —C2-C3 alkenyl, —OC2-C3 alkenyl, —C2-C3 alkynyl, and —OC2-C3 alkynyl are each optionally substituted with 1-7 halogens;
R8 is H or —C1-5alkyl optionally substituted with 1-9 halogens;
R9 and R10 are each independently H, —C1-C5 alkyl, —C2-C5 alkenyl, —C2-C5 alkynyl, phenyl, C3-6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein phenyl, C3-6 cycloalkyl optionally having 1-2 double bonds, and HET(1) are optionally substituted with 1-3 substituent groups which are each independently halogen, —C1-C3 alkyl, —OC1-C3 alkyl, —C2-C3 alkenyl, —OC2-C3 alkenyl, —C2-C3 alkynyl, or —OC2-C3 alkynyl, wherein —C1-C3 alkyl, —OC1-C3 alkyl, —C2-C3 alkenyl, —OC2-C3 alkenyl, —C2-C3alkynyl, and —OC2-C3 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;
Ar1 and Ar2 are each independently phenyl, naphthyl, C3-6 cycloalkyl optionally having 1-2 double bonds, or HET(1), wherein Ar1 and Ar2 are each optionally substituted with 1-5 substituents which are independently —C1-C5 alkyl, —OC1-C5 alkyl, —C2-C5 alkenyl, —OC2-C5 alkenyl, —C2-C5 alkynyl, —OC2-C5 alkynyl, —OH, halogen, —CN, —NR9R10, —CO2R8, —SO2C1-C5alkyl, —C(O)C1-C5 alkyl, —C(O)NR9R10, —SO2NR9R10, or —NR9C(O)NR9R10, and optionally 1-2 substituents which are phenyl, C3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), or HET(2), wherein —C1-C5 alkyl, —OC1-C5 alkyl, —C2-C5 alkenyl, —OC2-C5 alkenyl, —C2-C5 alkynyl, —OC2-C5 alkynyl, —SO2C1-C5alkyl, and —C(O)C1-C5 alkyl are optionally substituted with 1-9 halogens, and wherein when phenyl, C3-6 cycloalkyl optionally having 1-2 double bonds, HET(1), and HET(2) are substituents on Ar1 and Ar2, then phenyl, C3-6 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, —NR9R10, —CO2R8, —C1-C3 alkyl, or —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 alkyl are optionally substituted with 1-7 halogens and optionally with 1-2 groups which are —OH, halogen, —CN, —NR9R10, and —CO2R8;
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.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
The phenyl ring in Formula I has no optional heteroatoms;
Each R1 is independently —C1-C5 alkyl, —OC1-C5 alkyl, —OH, halogen, —CN, —NR9R10, —CO2R8, —C(O)NR9R10, —SO2NR9R10, phenyl, or C3-6 cycloalkyl, wherein —C1-C5 alkyl and —OC1-C5 alkyl are each optionally substituted with 1-9 halogens, and wherein phenyl and C3-6 cycloalkyl are each optionally substituted with 1-3 groups which are independently halogen, —C1-C3 alkyl, or —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 are each optionally substituted with 1-7 halogens;
R2, R3, R4, R5, R6, and R7 are each independently H, —C1-C5 alkyl, —OC1-C5 alkyl, —OH, halogen, —CN, —NR9R10, —CO2R8, —C(O)NR9R10, or —SO2NR9R10, wherein —C1-C5 alkyl and —OC1-C5 alkyl are each optionally substituted with 1-9 halogens;
R8 is H or —C1-5alkyl optionally substituted with 1-9 halogens;
R9 and R10 are each independently H, —C1-C5 alkyl, phenyl, C3-6 cycloalkyl, or HET(1), wherein phenyl, C3-6 cycloalkyl, and HET(1) are optionally substituted with 1-3 substituent groups which are each independently halogen, —C1-C3 alkyl, or —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 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;
Ar1 and Ar2 are each independently phenyl, C3-6 cycloalkyl, or HET(1), wherein Ar1 and Ar2 are each optionally substituted with 1-5 substituents which are independently —C1-C3 alkyl, —OC1-C3alkyl, —OH, halogen, —CN, —NR9R10, —CO2R8, —SO2C1-C5alkyl, —C(O)C1-C5 alkyl, —C(O)NR9R10, —SO2NR9R10, or —NR9C(O)NR9R10, and optionally one substituent which is phenyl, C3-6 cycloalkyl, HET(1), or HET(2), wherein —C1-C3alkyl, —OC1-C3 alkyl, —SO2C1-C5alkyl, and —C(O)C1-C5 alkyl are optionally substituted with 1-7 halogens, and wherein when phenyl, C3-6 cycloalkyl, HET(1), and HET(2) are substituents on Ar1 and Ar2, then phenyl, C3-6 cycloalkyl, HET(1), and HET(2) are optionally substituted with 1-3 substituent groups which are each independently halogen, —OH, —CN, —NR9R10, —CO2R8, —C1-C3 alkyl, or —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 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.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein
Each R1 is independently halogen, —C1-C4 alkyl, or —OC1-C4 alkyl, wherein —C1-C4 alkyl and —OC1-C4 alkyl are each optionally substituted with 1-9 halogens;
R2, R3, R4, R5, R6, and R7 are each independently H, halogen, —C1-C4 alkyl or —OC1-C4 alkyl, wherein —C1-C4 alkyl and —OC1-C4 alkyl are optionally substituted with 1-9 halogens;
R8 is H or —C1-4alkyl optionally substituted with 1-9 halogens;
R9 is H or —C1-C4 alkyl;
R10 is H, —C1-C4 alkyl, or HET(1); and
n is 0, 1, 2 or 3.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein
Each R1 is independently halogen, —C1-C3 alkyl, or —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 alkyl are optionally substituted with 1-7 halogens which are F or Cl;
R2, R3, R4, R5, R6, and R7 are each independently H, halogen, —C1-C3 alkyl or —OC1-C3 alkyl, wherein —C1-C3 alkyl and —OC1-C3 alkyl are optionally substituted with 1-7 halogens which are F or Cl;
R8 is H or —C1-3alkyl optionally substituted with 1-7 halogens;
R9 is H or —C1-C3 alkyl; and
R10 is H, —C1-C3 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.

### Claim 5 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein
Each R1 is halogen, —CH3, —CF3, —OCH3, or —OCF3;
R2, R3, R4, R5, R6, and R7 are each independently H, halogen, —C1-C2 alkyl or —OC1-C2 alkyl, wherein —C1-C2 alkyl and —OC1-C2 alkyl are each optionally substituted with 1-5 halogens which are F;
R8 is H or —CH3;
R9 is H or —CH3; and
R10 is H, —C1-C2alkyl, or a 5-6-membered heterocycle having one heteroatom which is O or S and optionally one double bond.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein
R1 is —CH3 or F;
R2, R3, R4, R5, R6, and R7 are each H;
R8 is H or —CH3
R9 is H or —CH3;
R10 is H, —CH3 or a 5-6-membered saturated heterocycle having 1 heteroatom which is S or O; and
n is 0 or 1.

### Claim 7 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Ar1 and Ar2 are each independently:
(a) Phenyl optionally substituted with 1-2 groups which are independently F, Cl, Br, —CN, —CH3 optionally substituted with 1-3 F, —OC1-2 alkyl optionally substituted with 1-5 F, —OCH(CH3)2, —CO2R8, or —SO2CH3, wherein phenyl is optionally substituted with one group phenyl which is optionally substituted with 1-2 groups which are independently —CH3, —CF3, —OCH3, —OCF3, F or —CO2R;
(b) Phenyl optionally substituted with 1-2 groups which are independently halogen, —CH3, —CF3, —OCH3, or —OCF3, 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, —CH3, —CF3, —OCH3, or —OCF3;
(c) Pyridinyl optionally substituted with one group morpholino and optionally 1-2 groups which are independently F, Cl, —CH3, —CF3, or —OC1-3alkyl optionally substituted with 1-7 F; or
(d) 2-Thiazolyl optionally substituted with one group which is —CH3, —CF3, —OCH3, —OCF3, or F.

### Claim 8

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

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 1)

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.

### Claim at position 14

14-16. (canceled)

### Claim 17 (depends on 1)

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.

### Claim 18 (depends on 1)

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.