IP Library › Granted Patent US 8,486,967
Granted Patent B2
US 8,486,967 · App. 13/023,563 · Granted Jul 16, 2013

Heteroaryl substituted piperidines

Inventors: Karlheinz Baumann (Efringen-Kirchen, DE); Alexander Flohr (Loerrach, DE); Erwin Goetschi (Reinach BL, CH); Luke Green (Basel, CH); Synese Jolidon (Blauen, CH); Henner Knust (Rheinfelden, DE); Anja Limberg (Basel, CH); Thomas Luebbers (Loerrach, DE); Andrew Thomas (Binningen, CH)
Assignee: Hoffmann-La Roche Inc.
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Quick Facts
Patent No.
US 8,486,967
App. No.
13/023,563
Granted
Jul 16, 2013
Kind
B2
Abstract

The invention relates to compounds of formula where hetaryl I, hetaryl II, R 1 , R 2 , R 3 , R 4 , m, n, and o are as defined in the specification or to pharmaceutically active acid addition salts thereof. The compounds of formula I are modulators for amyloid beta and thus may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

Claims (96)

1. A compound of formula I

wherein

hetaryl I is 1,2,4-thiadiazole;

hetaryl II is a [1,2,4]triazolo1,5-a]pyridine ring or a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine ring;

R 1 is lower alkyl, lower alkoxy, lower alkyl substituted by halogen, or halogen;

R 2 is halogen, lower alkyl, lower alkoxy, hydroxy, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or benzo[1,3]dioxolyl, or is —(CHR) p -phenyl, optionally substituted by halogen, lower alkyl, lower alkoxy, S(O) 2 -lower alkyl, cyano, nitro, lower alkoxy substituted by halogen, dimethylamino, —(CH 2 )p-NHC(O)O-lower alkyl, or lower alkyl substituted by halogen,

R is hydrogen, halogen, hydroxy or lower alkoxy, or is cycloalkenyl or cycloalkyl, each of which is optionally substituted by hydroxy or lower alkyl substituted by halogen, or

 is a five or six membered heteroaryl group, containing 1 to 3 heteroatoms, selected from O, S and N, which is optionally substituted by halogen, lower alkyl, lower alkoxy or dimethylamino, or

 is O-phenyl, optionally substituted by halogen, or

 is heterocycloalkyl, optionally substituted by halogen, hydroxy, lower alkyl substituted by halogen or C(O)O-lower alkyl;

R 3 is hydrogen, lower alkyl, cyano or phenyl;

R 4 is lower alkoxy, lower alkyl or halogen;

p is 0 or 1;

n is 0, 1 or 2; when n is 2 then each R 4 is the same or different;

m is 0, 1 or 2; when m is 2 then each R 1 is the same or different;

o is 0, 1, 2 or 3, when o is 2 or 3 then each R 2 is the same or different;

or a pharmaceutically active acid addition salt thereof.

2. The compound of claim 1 , selected from the group consisting of

[8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[5-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-chloro-4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2,4-difluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3-chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-chloro-4-fluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine; and

[8-(3,4-difluoro-phenyl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine.

3. The compound of claim 1 , selected from the group consisting of

[8-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(4-fluoro-2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2,4-difluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-fluoro-4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3,4-difluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2,4-dichloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-fluoro-4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine; and

[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-[8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine.

4. The compound of claim 1 , selected from the group consisting of

[8-(3,4-difluoro-phenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3,4-difluoro-phenyl)-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3-chloro-4-fluoro-phenyl)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(6-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-[8-(3,4,5-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine;

[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-[8-(2,3,4-trifluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine;

[8-(3,4-difluoro-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine; and

[8-(3,4-difluoro-phenyl)-5-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine.

5. The compound of claim 1 , selected from the group consisting of

[8-(3,4-difluoro-phenyl)-6-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-(8-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;

N-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-8-(3-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

8-(2,3-dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

8-(3,4-dichlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

8-(3-chlorophenyl)-N-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

[8-(5-dimethylamino-2-nitro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3,5-bis-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine; and

N-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-8-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

6. The compound of claim 1 , selected from the group consisting of

[8-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3-chloro-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(5-chloro-2-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

(8-benzo[1,3]dioxol-5-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine;

[8-(3,5-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine; and

[8-(4-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine.

7. The compound of claim 1 , selected from the group consisting of

(cis, rac)-N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(3S,4R)— and (3R,4S)—N-(3-fluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

(cis, rac)-[3-fluoro-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine;

(cis, rac)-[3,4-difluoro-1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-[8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine;

N-(3,3-difluoro-1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine;

4-chloro-3-(2-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile;

(4-fluorophenyl)(2-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol; and

N-((3S,5S)-3,5-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

8. A pharmaceutical composition comprising a compound of formula I

wherein

hetaryl I is 1,2,4-thiadiazole;

hetaryl II is a [1,2,4]triazolo1,5-a]pyridine ring or a 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine ring;

R 1 is lower alkyl, lower alkoxy, lower alkyl substituted by halogen, or halogen;

R 2 is halogen, lower alkyl, lower alkoxy, hydroxy, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or benzo[1,3]dioxolyl, or is —(CHR) p -phenyl, optionally substituted by halogen, lower alkyl, lower alkoxy, S(O) 2 -lower alkyl, cyano, nitro, lower alkoxy substituted by halogen, dimethylamino, —(CH 2 )p-NHC(O)O-lower alkyl, or lower alkyl substituted by halogen,

R is hydrogen, halogen, hydroxy or lower alkoxy, or is cycloalkenyl or cycloalkyl, each of which is optionally substituted by hydroxy or lower alkyl substituted by halogen, or

 is a five or six membered heteroaryl group, containing 1 to 3 heteroatoms, selected from O, S and N, which is optionally substituted by halogen, lower alkyl, lower alkoxy or dimethylamino, or

 is O-phenyl, optionally substituted by halogen, or

 is heterocycloalkyl, optionally substituted by halogen, hydroxy, lower alkyl substituted by halogen or C(O)O-lower alkyl;

R 3 is hydrogen, lower alkyl, cyano or phenyl;

R 4 is lower alkoxy, lower alkyl or halogen;

p is 0 or 1;

n is 0, 1 or 2; when n is 2 then each R 4 is the same or different;

m is 0, 1 or 2; when m is 2 then each R 1 is the same or different;

o is 0, 1, 2 or 3, when o is 2 or 3 then each R 2 is the same or different;

or a pharmaceutically active acid addition salt thereof and a pharmaceutically acceptable carrier.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 21, 2011
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE, INC.
Reel/Frame 026004/0280 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 21, 2011
From: BAUMANN, KARLHEINZ; FLOHR, ALEXANDER; GOETSCHI, ERWIN; GREEN, LUKE; JOLIDON, SYNESE; KNUST, HENNER; LIMBERG, ANJA; LUEBBERS, THOMAS; THOMAS, ANDREW
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 026009/0307 →
Priority Claims (1)
EP 10153843 · Feb 17, 2010 · regional
Continuity (1)
Related Publication 20110201605A1 · Aug 18, 2011