Octahydro-pyrrolo[3,4-c]pyrrole CCR5 receptor antagonists

1. A compound according to formula I

wherein

R 1 is selected from the group consisting of (a) phenyl, (b) pyridinyl, (c) pyrimidinyl, each optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy, cyano, NHSO 2 C 1-6 alkyl, SO 2 NR 9a R 10a , —NR 9b R 10b , and halogen, and (d) B1

 wherein R 8 is C 3-7 cycloalkyl, phenyl or heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine and pyridazine said heteroaryl or said phenyl optionally substituted with C 1-3 alkyl or C 1-3 haloalkyl;

One of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is A1, A2 or A3, or R 2 and R 3 together are (CH 2 ) m NR 4 (CH 2 ) n wherein m and n are independently one or two;

R 4 is C 1-6 alkyl, C 1-6 haloalkyl, CH 2 C≡N, —C(═O)R 5 or —SO 2 R 5 ;

R 5 is (a) C 1-6 alkyl, (b) C 3-6 cycloalkyl optionally independently substituted with one or two C 1-6 alkyl, halogen, hydroxy, cyano, oxo or C 1-6 haloalkyl, (c) C 1-6 haloalkyl, (d) C 1-6 hydroxyalkyl, (e) C 1-3 alkoxy-C 1-3 alkyl, (f) C 3-6 cycloalkyl-C 1-6 alkyl, (g) C 1-6 alkoxy, (h) amino, (i) C 1-6 alkylamino, (j) di-C 1-6 alkylamino (k) C 3-6 cycloalkylamino, (l) phenyl-C 1-3 alkyl (m) phenyl, wherein said phenyl is optionally substituted with one to three groups independently selected in each occurrence from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, —SO 2 NR 6a R 6b and —NHSO 2 C 1-6 alkyl, (n) tetrahydropyranyl, (o) tetrahydrofuranyl, (p) cycloalkoxy optionally independently substituted with one or two halogen, hydroxy or oxo, (q) C 4-6 cycloalkyl-amino, (r) tetrahydropyranyl-methyl, (s) pyridinyl or (t) cyanomethyl;

R 6a and R 6b are independently hydrogen, C 1-6 alkyl or C 1-6 acyl;

R 7 is hydrogen or C 1-3 alkyl;

R 9a and R 10a (i) taken independently, one of R 9a and R 10a is hydrogen or C 1-6 alkyl and the other of R 9a and R 10a is selected from the group consisting of hydrogen, C 1-6 alkyl and —C(═O)R 7 ;

(ii) taken together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine or azepine ring said azetidine, pyrrolidine, piperidine or azepine ring optionally substituted with hydroxy, amino, C 1-3 alkylamine or C 1-3 dialkylamine; or,

(iii) taken together are (CH 2 ) 2 —X—(CH 2 ) 2 ;

R 9b is defined as R 9a and R 10b is defined as R 10a ;

R 11 is hydrogen, C 1-6 alkyl or C 1-6 acyl;

X is O, S(O) p or NR 11 wherein p is an integer from 0 to 2;

Ar is phenyl optionally substituted with one to three substituents independently selected in each occurrence from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano and nitro; or,

pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein

R 1 is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy, cyano and halogen; or, pharmaceutically acceptable salts thereof.

3. A compound according to claim 2 wherein:

R 1 is 2,6-dimethylphenyl, 2,4-dimethyl-pyridin-3-yl, 2,4-dimethyl-6-cyano-pyridin-3-yl, 4,6-dimethyl-pyrimidin-5-yl or 4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl;

R 2 is A3;

R 3 is hydrogen;

R 4 is —C(═O)R 5 or —SO 2 R 5 ; and,

Ar is phenyl optionally substituted with one to three halogens.

4. A compound according to claim 3 wherein

R 1 is 2,4-dimethyl-pyridin-3-yl, 2,4-dimethyl-6-cyano-pyridin-3-yl, 4,6-dimethyl-pyrimidin-5-yl or 4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl;

R 4 is —SO 2 R 5 ; and,

R 5 is (a) C 1-6 alkyl, (b) C 3-6 cycloalkyl optionally substituted with one or two groups independently selected in each occurrence from the group consisting of hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl and oxo, (c) phenyl, wherein said phenyl is optionally substituted with one to three groups independently selected in each occurrence from the group consisting of C 1-6 alkyl, C 1-6 alkoxyl, halogen, —SO 2 NHR 6a R 6b and —NHSO 2 C 1-6 alkyl, or(d) optionally substituted phenyl-C 1-3 alkyl.

5. A compound according to claim 3 wherein:

R 1 is 2,4-dimethyl-pyridin-3-yl, 2,4-dimethyl-6-cyano-pyridin-3-yl, 4,6-dimethyl-pyrimidin-5-yl or 4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl;

R 4 is —CO 2 R 5 ; and,

R 5 is (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 hydroxyalkyl, (d) C 3-6 cycloalkyl optionally substituted with one or two groups independently selected in each occurrence from the group consisting of hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl and oxo, or (e) C 1-3 alkoxy-C 1-3 alkyl.

6. A compound according to claim 2 wherein:

R 1 is 2,6-dimethylphenyl, 2,4-dimethyl-pyridin-3-yl, 2,4-dimethyl-6-cyano-pyridin-3-yl; 4,6-dimethyl-pyrimidin-5-yl or 4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl;

R 2 is A1 or A2;

R 3 is hydrogen;

R 4 is —C(═O)R 5 or —SO 2 R 5 ; and,

Ar is phenyl optionally substituted with one to three halogens.

7. A compound according to claim 2 wherein:

R 1 is 2,6-dimethylphenyl, 2,4-dimethyl-pyridin-3-yl, 2,4-dimethyl-6-cyano-pyridin-3-yl, 4,6-dimethyl-pyrimidin-5-yl or 4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl;

R 2 and R 3 together are (CH 2 ) m NR 4 (CH 2 ) n ;

m and n are independently one or two;

R 4 is —C(═O)R 5 or —SO 2 R 5 ; and,

Ar is phenyl optionally substituted with one to three halogens.

8. A compound according to claim 7 wherein:

m and n are one;

R 4 is —C(═O)R 5 or —SO 2 R 5 ; and,

R 5 is (a) C 1-6 alkyl, (b) C 1-6 haloalkyl, (c) C 3-6 cycloalkyl optionally independently substituted with one or two C 1-6 alkyl, halogen, hydroxy, cyano, oxo or C 1-6 haloalkyl, (d) tetrahydropyranyl, (c) tetrahydrofuranyl.

9. A compound according to claim 2 wherein:

R 1 is 2,6-dimethylphenyl, 2,4-dimethyl-pyridin-3-yl, 2,4-dimethyl-6-cyano-pyridin-3-yl, 4,6-dimethyl-pyrimidin-5-yl or 4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl;

R 2 and R 3 together are (CH 2 ) m NR 4 (CH 2 ) n ;

m and n are independently one or two;

R 4 is C 1-6 alkyl or C 1-6 haloalkyl; and,

Ar is phenyl optionally substituted with one to three halogens.

10. A pharmaceutical composition comprising a therapeutically effective quantity of a compound according to claim 1 or claim 2 and at least one pharmaceutically acceptable carrier, excipient or diluent.

11. A compound according to claim 2 , wherein said compound is either a free base or a pharmaceutically acceptable acid addition salt of a compound selected from group consisting of:

4-{2-[5(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester;

4-{2-[5(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester;

(5-{2-[1-Benzoyl-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[2-(1-Benzoyl-4-phenyl-piperidin-4-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

1-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidin-1-yl)-2,2-dimethyl-propan-1-one;

1-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrro[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-2,2-dimethyl-propan-1-one;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(3-fluoro-benzenesulfonyl)-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(3-fluoro-benzenesulfonyl)-4-phenyl-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

4-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-benzenesulfonamide;

4-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-N-methyl-benzenesulfonamide;

4-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-N,N-dimethyl-benzenesulfonamide;

3-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-benzenesulfonamide;

3-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-N-methyl-benzenesulfonamide;

3-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-N,N-dimethyl-benzenesulfonamide;

4-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carbonyl]-N-methyl-benzenesulfonamide;

4-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carbonyl]-N,N-dimethyl-benzenesulfonamide;

3-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carbonyl]-benzenesulfonamide;

3-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carbonyl]-N-methyl-benzenesulfonamide;

3-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carbonyl]-N,N-dimethyl-benzenesulfonamide;

N-[4-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidine-1-carbonyl)-phenyl]-methanesulfonamide;

N-{4-[4-{2-[5-(4,6Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidine-1-carbonyl]-phenyl}-methanesulfonamide;

1-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-ethanone;

1-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidin-1-yl)-ethanone;

1-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrolo-2-yl]-ethyl}-4-phenyl-piperidin-1-yl)-2-methyl-propan-1-one;

1-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-2-methyl-propan-1-one;

{5-[2-(1-Cyclopropanecarbonyl-4-phenyl-piperidin-4-yl-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[2-(1-Cyclobutanecarbonyl-4-phenyl-piperidin-4-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[2-(1-Cyclopentanecarbonyl-4-phenyl-piperidin-4-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[2-(1-Cyclohexanecarbonyl-4-phenyl-piperidin-4-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[4-phenyl-1-(tetrahydro-pyran-4-carbonyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidin-1-yl)-3,3-dimethyl-butan-1-one;

2-Cyclopentyl-1-(4-{2-[5(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidin-1-yl)-ethanone;

1-(4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-phenyl-piperidin-1-yl)-3,3,3-trifluoro-propan-1-one;

(5-{2-[1-Cyclopropanecarbonyl-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(5-{2-[1-Cyclobutanecarbonyl-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(5-{2-[1-Cyclopentanecarbonyl-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(5-{2-[1-Cyclohexanecarbonyl-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[4-(3-fluoro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-3,3-dimethyl-butan-1-one;

2-Cyclopentyl-1-[4-{2-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-ethanone;

1-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-3,3,3-trifluoro-propan-1-one;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[4-(3-fluoro-phenyl)-1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[4-(3-fluoro-phenyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-[4-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-1-yl]-3-hydroxy-2,2-dimethyl-propan-1-one;

{5-[2-(1-Cyclopentanecarbonyl-3-phenyl-azetidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[2-(1-Cyclopentanecarbonyl-3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

2-Cyclopentyl-1-(3-{2-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-ethanone;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-ethanone;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-2,2-dimethyl-propan-1-one;

5-{5-[2-(1-Cyclopentanecarbonyl-3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile;

5-(5-{2-[1-(2-Cyclopentyl-acetyl)-3-phenyl-pyrrolidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridine-2-carbonitrile;

5-{5-[2-(1-Acetyl-3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile;

5-(5-{2-[1-(2,2-Dimethyl-propionyl)-3-phenyl-pyrrolidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridine-2-carbonitrile;

5-(5-{2-[1-(3,3-Difluoro-cyclobutanecarbonyl)-3-phenyl-pyrrolidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridine-2-carbonitrile;

1-[3-(2-{5-[3,5-Dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-ethanone;

{5-[2-(1-Cyclopentanecarbonyl-3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-[3,5-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanone;

(5-{2-[1-(3,3-Difluoro-cyclobutanecarbonyl)-3-phenyl-pyrrolidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,5-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanone;

5-(5-{2-[1-(2,2-Dimethyl-propionyl)-4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridine-2-carbonitrile;

3-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-azetidine-1-carboxylic acid tert-butyl ester;

{5-[3-(1-Cyclopentanecarbonyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-phenyl-3-[1-(2,2,2-trifluoro-ethyl)-azetidin-3-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-(3-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-azetidin-1-yl)-3-methyl-butan-1-one;

(5-{3-[1-(3,3-Difluoro-cyclobutanecarbonyl)-azetidin-3-yl]-3-phenyl-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-phenyl-3-[1-(propane-2-sulfonyl)-azetidin-3-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-phenyl-3-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidine-1-carboxylic acid tert-butylamide;

4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolol[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidine-1-carboxylic acid isopropylamide;

4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidine-1-carboxylic acid ethylamide;

4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidine-1-carboxylic acid cyclopentylamide;

4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidine-1-carboxylic acid 3-hydroxy-cyclopentyl ester;

4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidine-1-carboxylic acid methyl ester;

{5-[3-(1-Benzenesulfonyl-piperidin-4-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-phenyl-3-[1-(propane-2-sulfonyl)-piperidin-4-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[3-phenyl-3-(1-phenylmethanesulfonyl-piperidin-4-yl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[3-(1-ethanesulfonyl-piperidin-4-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[3-(1-methanesulfonyl-piperidin-4-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

1-(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-propan-1-one;

1-(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-3-methyl-butan-1-one;

1-(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-2,2-dimethyl-propan-1-one;

1-(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-2-methoxy-ethanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[3-(1-methanesulfonyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

{5-[3-(1-Cyclopentanesulfonyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

2-Cyclopentyl-1-(4-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-ethanone;

{5-[3-(1-Cyclopentanesulfonyl-piperidin-4-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

1-(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-2-methyl-propan-1-one;

{5-[3-(1-Cyclopropanesulfonyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[3-(1-Cyclopropanesulfonyl-piperidin-4-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(5-{3-[1-(2,2-Difluoro-ethyl)-piperidin-4-yl]-3-phenyl-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(3-fluoro-benzenesulfonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(3-fluoro-benzoyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[3-phenyl-1-(tetrahydro-pyran-4-carbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[3-phenyl-1-(tetrahydro-furan-3-carbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

2-Cyclopentyl-1-(3-{2-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-ethanone;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-2,2-dimethyl-propan-1-one;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-3,3,3-trifluoro-propan-1-one;

(5-{2-[1-(3,3-Difluoro-cyclobutanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(4-hydroxy-cyclohexanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-2-(tetrahydro-pyran-4-yl)-ethanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[3-phenyl-1-(tetrahydro-furan-2-carbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(1-methyl-cyclopropanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolor[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidine-1-carbonyl)-cyclopropanecarbonitrile;

(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-(1-trifluoromethyl-cyclopropyl)-methanone;

1-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-3-hydroxy-2,2-dimethyl-propan-1-one;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(1-hydroxy-cyclopropanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

3-(3-{2-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidine-1-carbonyl)-cyclopentanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[3-phenyl-1-(propane-2-sulfonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

{5-[2-(1-Cyclopropanesulfonyl-3-phenyl-azetidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[1-(3-hydroxy-cyclopentanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

{5-[2-(1-Cyclopentanesulfonyl-3-phenyl-azetidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

1-(3-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-azetidin-1-yl)-2-methyl-propan-1-one;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-[1-(2-methyl-propane-1-sulfonyl)-azetidin-3-yl]-3-phenyl-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{2-[3-phenyl-1-(2,2,2-trifluoro-ethyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(5-{2-[1-(2,2-Difluoro-ethyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(5-{2-[1-(4,4-Difluoro-cyclohexanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(3-{2-[5-(4,6-Dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-(tetrahydro-furan-3-yl)-methanone

(5-{2-[1-(3,5-Difluoro-benzoyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(2,4-Dimethyl-pyridin-3-yl)-(5-{2-[3-phenyl-1-(tetrahydro-furan-3-carbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

1-(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1-yl)-2,2,2-trifluoro-ethanone;

4,6-Dimethyl-5-(5-{2-[3-phenyl-1-(tetrahydro-furan-3-carbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-pyridine-2-carbonitrile;

(5-{2-[1-(4,4-Difluoro-cyclohexanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl)-methanone;

(5-{2-[1-(3,3-Difluoro-cyclobutanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-2-trifluoromethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-phenyl-3-[1-(2,2,2-trifluoro-ethanesulfonyl)-piperidin-4-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

5-{5-[3-(1-Methanesulfonyl-piperidin-4-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile;

5-{5-[3-(1-Cyclopropanesulfonyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile;

5-{5-[3-(1-Cyclopentanesulfonyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile;

(4,4-Difluoro-cyclohexyl)-(3-{2-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1yl)-methanone;

(3,3-Difluoro-cyclobutyl)-(3-{2-[5-(2,4-dimethyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethyl}-3-phenyl-azetidin-1-yl)-methanone;

(5-{2-[3-(3-Chloro-phenyl)-1-(4,4-difluoro-cyclohexanecarbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(5-{2-[3-(3-Chloro-phenyl)-1-(3,3-difluoro-cyclobutanecarbonyl)-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[3-[1-(2,2-Difluoro-ethyl)-piperidin-4-yl]-3-(3-fluoro-phenyl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[3-[1-(3-fluoro-benzenesulfonyl)-azetidin-3-yl]-3-(3-fluoro-phenyl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

{5-[3-(1-Cyclopentanesulfonyl-azetidin-3-yl)-3-(3-fluoro-phenyl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

{5-[3-(1-Cyclopropanesulfonyl-azetidin-3-yl)-3-(3-fluoro-phenyl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(4,6-dimethyl-pyrimidin-5-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[3-(3-fluoro-phenyl)-3-(1-methanesulfonyl-piperidin-4-yl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

5-(5-{2-[1-(4,4-Difluoro-cyclohexanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridine-2-carbonitrile;

5-(5-{2-[1-(3,3-Difluoro-cyclobutanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyridine-2-carbonitrile;

(5-{2-[1-(4,4-Difluoro-cyclohexanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,4-dimethyl-6-trifluoromethyl-pyridin-3-yl)-methanone;

(5-{2-[1-(3,3-Difluoro-cyclobutanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,4-dimethyl- 6 -trifluoromethyl-pyridin-3-yl)-methanone;

5-(5-{2-[1-(4,4-Difluoro-cyclohexanecarbonyl)-3-phenyl-azetidin-3-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-4,6-dimethyl-pyran-2-one;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-(3-fluoro-phenyl)-3-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-(5-{3-(3-fluoro-phenyl)-3-[1-(pyridine-2-sulfonyl)-azetidin-3-yl]-propyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone;

3-[3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-azetidine-1-sulfonic acid dimethylamide;

4-[3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-piperidine-1-sulfonic acid dimethylamide;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[(R)-3-(3-fluoro-phenyl)-3-(1-methanesulfonyl-piperidin-4-yl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

(4,6-Dimethyl-pyrimidin-5-yl)-{5-[(S)-3-(3-fluoro-phenyl)-3-(1-methanesulfonyl-piperidin-4-yl)-propyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;

{3-[3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-azetidin-1-yl}-acetonitrile;

5-{5-[3-(1-Acetyl-azetidin-3-yl)-3-phenyl-propyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-4,6-dimethyl-pyridine-2-carbonitrile; and,

(4-{3-[5-(4,6-Dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-phenyl-propyl}-piperidin-1 -yl)-acetonitrile.