Chemokine receptor binding heterocyclic compounds with enhanced efficacy

1. A compound of the formula

or the pharmaceutically acceptable salts thereof;

wherein each of rings A and B is independently a pyridinyl optionally substituted with one or more substituents selected from the group consisting of alkyl (C 1-10 ), alkenyl (C 2-10 ), and alkynyl (C 2-10 );

ring C is an unsubstituted piperidine or is piperidine substituted only at position 4 with OH, OMe, CN, OBz, ═NOEt, or ═NOBz;

wherein Y is phenyl, benzimidazole or imidazole; or

is selected from the group consisting of,

—(CH 2 ) m NH 2 ,

—(CH 2 ) m NHCH 3 ,

—(CH 2 ) m NH(CH 2 ) m NH 2 ,

—(CH 2 ) m NH(CH 2 ) m NH(CH 2 )mNH 2 ,

—(CH 2 ) m OH,

—(CH 2 ) m CO(CH 2 ) m OH,

—(CH 2 ) m CO(CH 2 ) m NH 2 ,

—(CH 2 ) m CO(CH 2 ) m NH(CH 2 ) m NH 2 ,

—(CH 2 ) m NHCO(CH 2 ) m NH 2 ,

—(CH 2 ) m NH (CH 2 ) m CO 2 H,

—(CH 2 ) m NH (CH 2 ) m SO 2 H,

—(CH 2 ) m NHCO(CH 2 ) m NH(CH 2 ) m NH 2 ,

—(CH 2 ) m NHCO(CH 2 ) m NH(CH 2 ) m NH(CH 2 ) m NH(CH 2 ) m NH 2 ,

—(CH 2 ) m NH(CH 2 ) m OH,

—(CH 2 ) m CH═NOH,

—(CH 2 ) m CONH(CH 2 ) m OH,

—(CH 2 ) m N[(CH 2 ) m CO 2 H] 2 ,

—(CH 2 ) m NHCOZ and

—(CH 2 ) m NH—(CH 2 ) m Z,

wherein each m is independently 0-4; and Z is an optionally substituted aromatic or heteroaromatic moiety containing 5-12 ring members;

L is (CR 3 2 ) 1 where each R 3 is H or alkyl wherein a single bond in alkyl may be replaced with a double or triple bond and wherein 1 is 1-6.

2. The compound of claim 1 , wherein Y is (CH 2 ) m NH 2 wherein m is 1-4.

3. The compound of claim 1 , wherein each of rings A and B contain a single substituent at the position adjacent to the bond linking the rings to ring C.

4. The compound of claim 3 , wherein said substituents are identical on rings A and B.

5. A pharmaceutical composition which comprises as active ingredient the compound of claim 1 or a pharmaceutically acceptable salt thereof along with at least one excipient.

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

4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[cis-2,2′;6′,2″]terpyridin-1′-yl) -butylamine;

4-(3,3″-diisopropyl-3′,4′,5′,6′-tetrahydro-2′H-[cis-2,2′;6′,2″]terpyridin-1′-yl)-butylamine;

(2′R,6′S)-1′-[3-(1H-Imidazol-4-yl)-propyl ]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis- [2,2′;6′,2″]terpyridine;

[4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2 ′H-cis-[2,2′;6′,2″]terpyridin-1′-yl) -butyl]-urea;

N-[4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2 ′H-cis-[2,2′;6′,2″]terpyridin-1′-yl) -butyl]-6-hydroxy-nicotinamide;

meso-2′β,6′β-[3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-propylamine];

3,5-dichloro-N-[4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′:6′,2″]terpyridin-1′-yl)-butyl]-isonicotinamide;

4-meso-[2,7-Bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydroazepin-1-yl]butylamine;

meso-cis-2′,5′-[4-(2,5-di-pyridin-2-yl-pyrrolidin-1-yl)-butylamine];

(2′R,6′S)-1′-(1H-benzoimidazol-4-ylmethyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

meso-2′,6′-[3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-propyl]-urea;

meso-2′,6′-N-[3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-propyl]-6-hydroxy-nicotinamide;

meso-2′,6′-[4-(3,5,3″,5″-tetramethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butylamine];

meso-2′β,4′α,6′β-[1′-(4-amino-butyl)-3,3′-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2′]terpyridin-4′-ol];

meso-2′,6′-[4-(3,3′-dichloro-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin -1′-yl)-butylamine];

a 1:1 mixture of meso-2′13,4′α,6′β-[1′-(4-amino-butyl)-3,4′,3″-trimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol] and meso-2′β,4′β,6′β-[1′-(4-amino-butyl)-3,4′,3″-trimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol];

meso-2′β,4′α,6′β-[1′-(4-amino-butyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol];

meso-2′β,4′α,6β-[4-(4′-fluoro-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-butylamine];

meso-2′β,4′β,6′β-[4′-benzyloxy-1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl -1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

5-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-pentanoic acid hydroxyamide;

6-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-hexanoic acid hydroxyamide;

Methyl-[4-(3,5,3″,5″-tetramethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-butyl]-amine;

4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butyramide;

[4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butyl]-pyridin-2-ylmethyl-amine;

4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl) -N-hydroxy-butyramide;

4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butyric acid hydrazide;

4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butan-1 -ol;

4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl) -N-(2-hydroxy-ethyl)-butyramide;

(2′S,6′R)- 1′-[3-(1H-benzoimidazol-2-yl)-propyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-]2,2′;6′,2″]terpyridine;

[4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butyl]-(1H-imidazol-2-yl)-amine;

1′-(3-imidazol-1-yl-propyl)-3,3″-dimethyl-1,′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

1′-(4-imidazol-1-yl-butyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

[4-meso-(3,5,3″,5″-tetramethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-butyl]-urea;

4-meso-[3,5-bis-(3-methyl-pyridin-2-yl)-morpholin-4-yl]-butylamine;

meso-2-[4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′2″]terpyridin-2′-yl) -butylamino]-ethanol;

1′-(2-imidazol-1-yl-ethyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-ethylamine;

1′-(1H-imidazol-4-ylmethyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

1′(1H-imidazol-2-ylmethyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine;

meso-2′β,4′α,6′β-[1′-(4-amino-butyl)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine-4′-carbonitrile];

meso-2′β,4′α,6β-[4-(4′-methoxy-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-butylamine;

meso-2′β,6′β-[1′-(4-amino-butyl)-3,3″-dimethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,2′;6′,2″]terpyridin-4′-one O-ethyl-oxime];

meso-2′β,6′β-[1′-(4-amino-butyl)-3,3″-dimethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,2′;6′,2″]terpyridin-4′-one O-benzyl-oxime];

meso-2′β,4′β,6′β-{1′-[2-(3H-imidazol-4-yl)-ethyl]-4′-methoxy-3,3″-dimethyl -1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine; and

meso-2′β,6′β-{1′-[2(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-2′,3′,5′,6′-tetrahydro -1′H-[2,2′;6′,2″]terpyridin-4′-one O-benzyl-oxime}; and the pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising as active ingredient the compound of claim 6 or a pharmaceutically acceptable salt thereof along with at least one excipient.

8. The compound of claim 6 which is 4-(3,3″,-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-cis-[2,2′;6′,2″]terpyridin-1′-yl)-butylamine or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising as active ingredient the compound of claim 8 or a pharmaceutically acceptable salt thereof along with at least one excipient.

10. The compound of claim 6 which is N-[4-meso-(3,5,3″,5″-tetramethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridine-1′-yl)-butyl]-N′-hydroxyurea or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising as active ingredient the compound of claim 10 or a pharmaceutically acceptable salt thereof along with at least one excipient.