# US 8,569,345 B2 · Compounds and compositions as LXR modulators

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- Number: US 8,569,345 B2
- Document ID: US8569345B2
- Status: Granted
- Kind: B2
- Application number: 13/414,385
- Filed: 2012-03-07
- Published: 2012-08-23
- Granted: 2013-10-29
- Earliest claimed: 2004-02-11
- Applicants: Valentina Molteni; Xiaolin Li; Juliet Nabakka; David Archer Ellis; Beth Anaclerio; Enrique Saez; John Wityak
- Inventors: Valentina Molteni; Xiaolin Li; Juliet Nabakka; David Archer Ellis; Beth Anaclerio; Enrique Saez; John Wityak
- Web page: https://patentgrep.com/patent/US8569345B2

## CPC

- C07D 285/12: 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- A61K 31/433: Thidiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- 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

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of liver X receptors (LXRs).

## Claims

### Claim 1

A compound of Formula I:
in which
n is selected from 0, 1, 2 and 3;
Z is selected from C and S(O);
each Y is CR4;
or one Y is CR4 and the other is N, thereby forming a pyridine-3-yl;
or one Y is CR4 and the other is N, thereby forming a pyridine-2-yl;
wherein R4 is selected from hydrogen, cyano, hydroxyl, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
R1 is selected from halo, cyano, hydroxyl, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy and —C(O)OR4; wherein is selected from hydrogen, cyano, hydroxyl, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
R2 is selected from C6-10aryl, and C3-12cycloalkyl;
wherein any aryl, or cycloalkyl of R2 is optionally substituted with 1 to 5 radicals independently selected from halo, hydroxy, cyano, nitro, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —C(O)NR5R5, —OR5, —OC(O)R5, —NR5R6, —C(O)R5 and —NR5C(O)R5;
wherein R5 and R6 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, C6-10aryl-C0-4alkyl, and C3-12cycloalkyl-C0-4alkyl;
wherein any aryl, or cycloalkyl of R5 is optionally substituted with 1 to 4 radicals independently selected from halo, hydroxy, cyano, nitro, C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkyl and halo-substituted-C1-6alkoxy;
R3 is C5-10heteroaryl;
wherein any heteroaryl of R3 is substituted with 1 to 5 radicals independently selected from halo, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —OXR7, —OXC(O)NR7R8, —OXC(O)NR7XC(O)OR8, —OXC(O)NR7XOR8, —OXC(O)NR7XNR7R8, —OXC(O)NR7XS(O)0-2R8, —OXC(O)NR7XNR7C(O)R8, —OXC(O)NR7XC(O)XC(O)OR8, —OXC(O)NR7R9, —OXC(O)OR7, —OXOR7, —OXR9, —XR9, —OXC(O)R9, —OXS(O)0-2R9 and —OXC(O)NR7CR7[C(O)R8]2;
wherein:
X is a selected from a bond and C1-6alkylene wherein any methylene of X can optionally be replaced with a divalent radical selected from C(O), NR7, S(O)2 and O;
R7 and R8 are independently selected from hydrogen, cyano, C1-6alkyl, halo-substituted-C1-6alkyl, C2-6alkenyl and C3-12cycloalkyl-C0-4-alkyl;
and wherein:
when R3 is C5-10heteroaryl,
then R9 is selected from C6-10aryl-C0-4-alkyl, and C3-12cycloalkyl-C0-4alkyl;
wherein any alkyl of R9 can have a hydrogen replaced with —C(O)OR10; and any aryl, or cycloalkyl of R9 is optionally substituted with 1 to 4 radicals independently selected from halo, C1-6alkyl, C3-12cycloalkyl, halo-substituted-C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkoxy, —XC(O)OR10, —XC(O)R10, —XC(O)NR10R10, —XS(O)0-2NR10R10 and —XS(O)0-2R10;
wherein R10 is independently selected from hydrogen and C1-6alkyl;
and a pharmaceutically acceptable salt or isomer thereof.

### Claim 2 (depends on 1)

The compound of claim 1 of Formula Ia:
in which
n is selected from 1, 2 and 3;
Y is CH or N;
R1 is selected from halo, C1-6alkyl, and —C(O)OR4; wherein R4 is selected from hydrogen and C1-6alkyl;
R2 is selected from C6-10aryl and C3-12cycloalkyl;
wherein any aryl or cycloalkyl of R2 is optionally substituted with 1 to 4 radicals independently selected from halo, hydroxy, C1-6alkyl, halo-substituted-C1-6 alkyl and —OC(O)R5;
wherein R5 is selected from hydrogen and C1-6alkyl; and
R3 is C5-10heteroaryl;
wherein any heteroaryl of R3 is substituted with 1 to 5 radicals independently selected from halo, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —OXR7, —OXC(O)NR7R8, —OXC(O)NR7C(O)OR8, —OXC(O)NR7XOR8, —OXC(O)NR7XNR7R8, —OXC(O)NR7XS(O)0-2R8, —OXC(O)NR7XNR7C(O)R8, —OXC(O)NR7C(O)XC(O)OR8, —OXC(O)NR7R9, —OXC(O)OR7, —OXOR7, —OXR9, —XR9, —OXC(O)R9 and —OXC(O)NR7CR7[C(O)R8]2;
wherein X is a selected from a bond and C1-6alkylene;
R7 and R8 are independently selected from hydrogen, cyano, C1-6alkyl, halo-substituted-C1-6alkyl, C2-6alkenyl and C3-12cycloalkyl-C0-4alkyl;
and wherein:
when R3 is C5-10heteroaryl,
then R9 is selected from C6-10aryl-C0-4alkyl, and C3-12cycloalkyl-C0-4alkyl;
wherein any alkyl of R9 can have a hydrogen replaced with —C(O)OR10; and any aryl, or cycloalkyl of R9 is optionally substituted with 1 to 4 radicals independently selected from halo, C1-6alkyl, C3-12cycloalkyl, halo-substituted-C1-6alkyl, C1-6alkoxy, halo-substituted-C1-6alkoxy, —XC(O)OR10, —XC(O)R10, —XC(O)NR10R10, —XS(O)0-2NR10R10 and —XS(O)0-2R10;
wherein R10 is independently selected from hydrogen and C1-6alkyl.

### Claim 3 (depends on 2)

The compound of claim 2 in which
R1 is selected from fluoro, chloro, methyl and —C(O)OCH3; and
R2 is selected from phenyl, cyclohexyl, cyclopentyl, and naphthyl,;
wherein any aryl or cycloalkyl of R2 is optionally substituted with 1 to 4 radicals independently selected from fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, t-butyl, amino, dimethyl-amino, methoxy, trifluoromethyl, trifluoromethoxy and —OC(O)CH3.

### Claim 4 (depends on 3)

The compound of claim 3 in which
R3 is selected from pyridinyl substituted with 1 to 5 radicals independently selected from fluoro, chloro, bromo, methoxy, hydroxyl, difluoromethoxy, —OCH2C(O)NH2, —OCH2C(O)OCH3, —OCH2C(O)NHCH3, —OCH2C(O)N(CH3)2, —R9, —OR9, —OCH2R9, —OCH2C(O)R9, —OCH2C(O)NHR9, —OCH2C(O)N(CH3)R9, —OCH2C(O)NHCH2R9, —OCH2CN, —OCH2C2H3, —OCH2C2H4, —O—(CH2)2OH, —OCH2C(O)NH(CH2)2C(O)OC2H5, —OCH2C(O)NH(CH2)2CH2F, —OCH2C(O)NHCH2CH2F, —OCH2C(O)NH(CH2)2C(O)OH, —OCH2C(O)NHC(O)(CH2)2C(O)OCH3, —OCH2C(O)NH(CH2)2NHC(O)CH3, —OCH2C(O)NH(CH2)2C(O)OC4H9, —OCH2C(O)NHCH2C(O)OC2H5, —S(O)2CH3, —OCH2C(O)NHCH2CF3, —OCH2C(O)NHCH2C(O)(CH2)2C(O)OCH3, —OCH2C(O)N(CH3)CH2C(O)OCH3, —OCH2C(O)NH(CH2)3OC2H5, —OCH2C(O)NH(CH2)3OCH(CH3)2, —OCH2C(O)NH(CH2)2SCH3, —OCH2C(O)NHCH2CH(CH3)2, —OCH2C(O)NHCH(CH3)CH2OH, —OCH2C(O)NHCH2CH(CH3)C2H5, —OCH2C(O)NHCH(CH3)C(O)OC2H5, —OCH2C(O)NHCH2CH(CH3)2 and —OCH2C(O)(CH2)3OCH(CH3)2;
wherein R9 is phenyl, cyclopropyl-methyl, and phenethyl; wherein any alkyl of R9 can have a hydrogen replaced with —C(O)OC2H5; and wherein any aryl, of R9 is optionally substituted with 1 to 4 radicals independently selected from methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, —OC(O)CH3, —COOH, —S(O)2NH2, —C(O)OC2H5, —CH2C(O)OH, —CH2C(O)OC2H5, —CH2C(O)OCH3, —C(O)OCH3, —C(O)NH2, —C(O)NHCH3 and —C(O)CH3.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

### Claim 6 (depends on 1)

The compound of claim 1 selected from: