2,5-substituted pyrimidine derivatives-CCR-3 receptor antagonists

1. A compound of Formula (I):

wherein:

Ar 1 is aryl;

Ar 2 is hydrogen, cycloalkyl, aryl or heteroaryl;

Z is —C(═O)— or a single bond;

R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen or alkyl optionally substituted with hydroxy;

alk is an alkylene chain of one to six carbon atoms;

X is —O—, —NR b -(where R b is hydrogen or alkyl), (CR 6 R 7 ) m (where R 6 and R 7 are independently in each occurrence hydrogen or alkyl and m is an integer from 0 to 3), or —S(O) n — (wherein n is an integer from 0 to 2);

or predrugs and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , where Z is a single bond and R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen.

3. The compound of claim 2 , wherein X is —S—.

4. The compound of claim 3 , wherein alk is methylene.

5. The compound of claim 4 , wherein Ar 2 is 3,4-dimethoxy-phenyl, 4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, or phenyl.

6. The compound of claim 4 , wherein Ar 2 is 3,4-dichloro-phenyl, 2,3-dichloro-phenyl, 3,4-dibromo-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 4-chloro-3trifluoromethyl-phenyl, benzo[1,3]dioxol-5-yl, indan-5-yl, or indol-6-yl.

7. The compound of claim 2 , wherein X is —O.

8. The compound of claim 7 , wherein alk is methylene.

9. The compound of claim 8 , wherein Ar 2 is 3,4-dimethoxy-phenyl, 4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, or phenyl.

10. The compound of claim 8 , wherein Ar 2 is 3,4-dichloro-phenyl, 2,3-dichloro-phenyl, 3,4-dibromo-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, benzo[1,3]dioxol-5-yl, indan-5-yl, or indol-6-yl.

11. The compound of claim 2 , wherein X is —(CR 6 R 7 ) n —.

12. The compound of claim 11 , wherein alk is methylene.

13. The compound of claim 12 , wherein Ar 2 is 3,4-dimethoxy-phenyl, 4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, or phenyl.

14. The compound of claim 12 , wherein Ar 2 is 3,4-dichloro-phenyl, 2,3-dichloro-phenyl, 3,4-dibromo-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, benzo[1,3]dioxol-5-yl, indan-5-yl, or indol-6-yl.

15. The compound of claim 2 , wherein X is —NR b —.

16. The compound of claim 15 , wherein alk is methylene.

17. The compound of claim 16 , wherein Ar 2 is 3,4-dimethoxy-phenyl, 4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, or phenyl.

18. The compound of claim 16 , wherein Ar 2 is 3,4-dichloro-phenyl, 2,3-dichloro-phenyl, 3,4-dibromo-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, benzo[1,3]dioxol-5-yl, indan-5-yl, or indol-6-yl.

19. Tho compound of claim 1 , selected from the group consisting of:

2-[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-[1-(1H-indol-6-ylmethyl) piperidin-3-ylmethyl-acetamide;

N-[1-(3,4-Dichloro-benzyl)-piperidin-3-ylmethyl]-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-[1-(3,4-Dibromo-benzyl)-piperidin-3-ylmethyl]-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin 2-ylsulfanyl]-acetamide;

N-[1-(4-Chloro-3-trifluoromethyl-benzyl)-piperidin-3-ylmethyl]-2-[5-(3,4 -dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-[1-(3,4-Dichloro-benzyl)-piperidin-3-ylmethyl]-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

2-[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-[1-(1H-indol-6-ylmethyl)-piperidin-3-ylmethyl]-acetamide;

N-[1-(2,3-Dichloro-benzyl)-piperidin-3-ylmethyl]-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamideacetamide;

N-[1-(3,4-Dibromo-benzyl)-piperidin-3-ylmethyl]-3-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-propionamide;

N-[1-(3,4-Dichloro-benzyl)-piperidin-3-ylmethyl]-3-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-propionamide;

N-[1-(3,4-Dichloro-benzyl)-piperidin-3-ylmethyl]-3-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-propionamide;

N-[1-(3-Chloro-benzyl)-piperidin-3-ylmethyl]2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-[1-(4-Chloro-3-trifluoromethyl-benzyl)-piperidin-3-ylmethyl]-3-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-propionamide;

N-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-3-ylmethyl]2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-[1-(3,4-Dichloro-benzyl)-piperidin-3-ylmethyl]-3-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-propionamide;

2-[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-(1-naphthalen-2-ylmethyl-piperidin-3-ylmethyl)-acetamide;

2-[5-(3,4-Dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-(1-indan-5-ylmethyl-piperidin-3-ylmethyl)-acetamide;

N-[1-(4-Chloro-3-trifluoromethyl-benzyl)-piperidin-3-ylmethyl]-2-[5-(4-methoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-[1-(4,5-Dibromo-thiophen2-ylmethyl)-piperidin-3-ylmethyl]-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-[1-(4,5-Dichloro-thiophen-2-ylmethyl)-piperidin-3-ylmethyl]-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-{1-[3-(4-Chloro-phenyl)-propionyl]-piperidin-3-ylmethyl}-2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetamide;

N-(1-Cyclopentylmethyl-piperidin-3-ylmethyl)-2-[4-(4,5-dimethoxy-pyrimidin-2-yl)-phenylsulfanyl]-acetamide;

N-[1-(2-Cyclopentyl-ethyl)-piperidin-3-ylmethyl]-2-[4-(4,5-dimethoxy-pyrimidin-2-yl)-phenylsulfanyl]-acetamide;

N-(1-Cyclohexylmethyl-piperidin-3-ylmethyl)-2-[4-(4,5-dimethoxy-pyrimidin-2-yl)-phenylsulfanyl]-acetamide;

and N-[1-(2-Cyclohexy-ethyl)-piperidin-3-ylmethyl]-2-[4-(4,5-dimethoxy-pyrimidin-2-yl)-phenylsulfanyl]-acetamide.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

21. A method of treatment of asthma, in a mammal comprising administration to the mammal of a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

22. A process for preparing a compound of claim 2 which comprises reacting a compound of formula d:

wherein Ar 1 and X are as described in claim 1 , with a compound of formula OHC Ar 2 wherein Ar 2 is as described in claim 1 , under reductive amination conditions, to prepare a compound of Formula (I):

wherein Ar 1 , X, and Ar 2 are as described in claim 1 .