Piperazine derivatives useful as CCR5 antagonists

1. A method of treating arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis, comprising administering to a human in need of such treatment a therapeutically effective amount of a CCR5 antagonist of the structural formula I:

or a pharmaceutically acceptable salt thereof, wherein

R is R 8 -phenyl, R 8 -pyridyl, R 8 -thiophenyl or R 8 -naphthyl;

R 1 is hydrogen or C 1 -C 6 alkyl;

R 2 is R 9 , R 10 , R 11 -phenyl; R 9 , R 10 , R 11 -substituted 6-membered heteroaryl;

R 9 , R 10 , R 11 -substituted 6-membered heteroaryl N-oxide;

R 12 , R 13 -substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl

R 3 is hydrogen, C 1 -C 6 alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl(C 1 -C 6 )alkyl, R 8 -phenyl, R 8 -phenyl(C 1 -C 6 )alkyl, R 8 -naphthyl, R 8 -naphthyl(C 1 -C 6 )alkyl, R 8 -heteroaryl or R 8 -heteroaryl(C 1 -C 6 )alkyl;

R 4 , R 5 , R 7 and R 13 are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl;

R 6 is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkenyl;

R 8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CF 3 , CF 3 O—, CH 3 C(O)—, —CN, CH 3 SO 2 —, CF 3 SO 2 —, R 14 -phenyl, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCH 2 CH 3 ),

 —NH 2 , —NHCOCF 3 , —NHCONH(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl), 5-membered heteroaryl and

 wherein X is —O—, —NH— or —N(CH 3 )—;

R 9 and R 10 are independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —NR 17 R 18 , —OH, —CF 3 , —OCH 3 , —O-acyl, —OCF 3 and —Si(CH 3 ) 3 ;

R 11 is R 9 , hydrogen, phenyl, —NO 2 , —CN, —CH 2 F, —CHF 2 , —CHO, —CH═NOR 17 , pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R 17 )CONR 18 R 19 , —NHCONH(chloro-(C 1 -C 6 )alkyl), —NHCONH((C 3 -C 1 )cycloalkyl(C 1 -C 6 )alkyl), —NHCO(C 1 -C 6 )alkyl, —NHCOCF 3 , —NHSO 2 N((C 1 -C 6 )alkyl) 2 , —NHSO 2 (C 1 -C 6 )alkyl, —N(SO 2 CF 3 ) 2 , —NHCO 2 (C 1 -C 6 )alkyl, C 3 -C 10 cycloalkyl, —SR 20 , —SOR 20 , —SO 2 R 20 , —SO 2 NH(C 1 -C 6 alkyl), —OSO 2 (C 1 -C 6 )alkyl, —OSO 2 CF 3 , hydroxy(C 1 -C 6 )alkyl, —CON R 17 R 18 , —CON(CH 2 CH 2 —O—CH 3 ) 2 , —OCONH(C 1 -C 6 )alkyl, —CO 2 R 17 , —Si(CH 3 ) 3 or —B(OC(CH 3 ) 2 ) 2 ;

R 12 is (C 1 -C 6 )alkyl, —NH 2 or R 14 -phenyl;

R 14 is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, —CF 3 , —CO 2 R 17 , —CN, (C 1 -C 6 )alkoxy and halogen;

R 15 and R 16 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R 15 and R 16 together are a C 2 -C 5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;

R 17 , R 18 and R 19 are independently selected from the group consisting of H and C 1 -C 6 alkyl; and

R 20 is C 1 -C 6 alkyl or phenyl.

2. The method of claim 1 wherein R is R 8 -phenyl or R 8 -naphthyl.

3. The method of claim 2 wherein R is

4. The method of claim 1 wherein R 3 is hydrogen, (C 1 -C 6 ) alkyl, R 8 -phenyl, R 8 -benzyl or R 8 -pyridyl.

5. The method of claim 1 wherein R 1 is hydrogen and R 6 is hydrogen or methyl.

6. The method of claim 1 wherein R 2 is R 9 , R 10 , R 11 -phenyl; R 9 , R 10 , R 11 -pyridyl or an N-oxide thereof, or R 9 , R 10 , R 11 -pyrimidyl.

7. The method of claim 6 wherein R 2 is selected from the group consisting of

wherein R 9 and R 10 are selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —OH and —NH 2 .

8. The method of claim 7 wherein R 2 is phenyl or pyridyl and R 11 is hydrogen, or wherein R 2 is pyrimidyl and R 11 is hydrogen, methyl or phenyl.

9. The method of claim 1 further comprising one or more other agents useful in the treatment of said diseases.

10. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis which comprises in one container a pharmaceutical composition comprising an effective amount of a CCR5 antagonist of claim 1 in a pharmaceutically acceptable carrier, and in separate containers, one or more pharmaceutical compositions comprising an effective amount of an agent useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis in a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising an effective amount of the compound of formula

or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

12. A method treating arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis, comprising administering to a human in need of such treatment a therapeutically effective amount of a CCR5 antagonist of the structural formula

or a pharmaceutically acceptable salt thereof.

13. A compound which is a maleic acid addition salt of

14. A pharmaceutical composition comprising an effective amount of the compound of claim 13 in combination with a pharmaceutically acceptable carrier.