Pyridin-2yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus

1. A compound of general Formula I

or a salt thereof, wherein:

R 13 is a polyhydroxy-(2-6C) alkyl, methoxy(polyhydroxy-(3-6C)alkyl) or polyhydroxy-(5-6C)cycloalkyl;

L is O or S;

D 2 is N or CH;

R 2 is Ar 1 , hetAr 1 , hetAr 2 , or hetAr 3 ;

Ar 1 is phenyl or naphthyl, each of which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, CF 3 , OH, CN, SO 2 Me, C(═O)NH(1-3C alkyl)N(alkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc l ;

hetAr 1 is a 5-6 membered heteroaryl group having 1-3 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (1-6C alkyl), Cl, CF 3 and (1-6C alkyl)OH;

hetAr 2 is a partially unsaturated 5,6 or 6,6 bicyclic heteroaryl ring system having 1-2 ring nitrogen atoms and optionally having a ring oxygen atom;

hetAr 3 is a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms;

R 3 is Cl, Br, CF 3 , aryl, hetAr a , SR 6 or OR 6 ;

hetAr a is a 6-membered heteroaryl having 1-2 ring nitrogen atoms;

R 6 is Ar 2 , hetAr 4 , (1-6C alkyl), -(1-6C alkyl)OH, polyhydroxy(1-6C alkyl), —CH(R 9 )—Ar 3 , —CH(R 10 )-hetAr 5 , hetAr 6 , (5-6C)cycloalkyl substituted with 1 to 4 OH, (1-3 C alkoxy)(1-6C alkyl), or cyclopropyl(1-6C alkyl);

Ar 2 is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 ;

hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 nitrogen atoms and optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 ;

Ar 3 is phenyl optionally substituted with one or more groups independently selected from F, Cl, Br, and (1-6C)alkyl;

hetAr 5 is a 5-6-membered heteroaryl having 1-2 ring nitrogen atoms;

hetAr 6 is a 9-10 membered bicyclic heteroaromatic ring having 2-3 heteroatoms independently selected from N, S and O (provided the ring does not contain an O—O bond) which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, —O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl) and C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 ;

R 9 and R 10 are independently hydrogen, (1-6C)alkyl, (1-6C)alkylOH, or CF 3 ; and

hetCyc 1 and hetCyc 2 are independently a 5-7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O.

2. The compound of claim 1 , wherein:

R 13 is polyhydroxy-(2-6C) alkyl or polyhydroxy-(5-6C)cycloalkyl;

L is O or S;

D 2 is N or CH;

R 2 is Ar 1 , hetAr 1 , hetAr 2 , or hetAr 3 ;

Ar 1 is phenyl or naphthyl, each of which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, CF 3 , OH, CN, SO 2 Me, C(═O)NH(1-3C alkyl)N(alkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 1 ;

hetAr 1 is a 5-6 membered heteroaryl group having 1-3 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (1-6C alkyl), Cl, CF 3 and (1-6C alkyl)OH;

hetAr 2 is a partially unsaturated 5,6 or 6,6 bicyclic heteroaryl ring system having 1-2 ring nitrogen atoms and optionally having a ring oxygen atom;

hetAr 3 is a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms;

R 3 is Cl, Br, CF 3 , aryl, hetAr a , SR 6 or OR 6 ;

hetAr a is a 6-membered heteroaryl having 1-2 ring nitrogen atoms;

R 6 is Ar 2 , hetAr 4 , (1-6C alkyl), -(1-6C alkyl)OH, polyhydroxy(1-6C alkyl), —CH(R 9 )—Ar 3 , —CH(R 10 )-hetAr 5 , hetAr 6 or (5-6C)cycloalkyl substituted with 1-4 OH;

Ar 2 is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 ;

hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 nitrogen atoms and optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 ;

Ar 3 is phenyl optionally substituted with one or more groups independently selected from F, Cl, Br, and (1-6C)alkyl;

hetAr 5 is a 5-6-membered heteroaryl having 1-2 ring nitrogen atoms;

hetAr 6 is a 9-10 membered bicyclic heteroaromatic ring having 2-3 heteroatoms independently selected from N, S and O (provided the ring does not contain an O—O bond) which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, —O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl) and C(═O)NH(1-3C alkyl)N(1-3Calky) 2 ;

R 9 and R 10 are independently hydrogen, (1-6C)alkyl, (1-6C)alkylOH, or CF 3 ; and

hetCyc 1 and hetCyc 2 are independently a 5-7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O.

3. The compound of claim 1 , wherein R 13 is a polyhydroxy-(2-6C) alkyl.

4. The compound of claim 1 , wherein R 13 is 1,2-dihydroxy(2-6C alkyl) or methoxy(polyhydroxy(3-6C)alkyl).

5. The compound of claim 4 , wherein R 13 is selected from:

6. The compound according to claim 1 , wherein R 2 is phenyl or naphthyl, each of which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, CF 3 , OH, CN, SO 2 Me, C(═O)NH(1-3C alkyl)N(alkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 1 .

7. The compound according to claim 1 , wherein R 2 is hetAr 1 optionally substituted with one or more groups independently selected from (1-6C alkyl), Cl, CF 3 and (1-6C alkyl)OH.

8. The compound according to claim 4 , wherein R 2 is hetAr 1 optionally substituted with one or more groups independently selected from (1-6C alkyl), Cl, CF 3 and (1-6C alkyl)OH.

9. The compound of claim 8 , wherein R 2 is pyridyl or pyrazole optionally substituted with (1-6C alkyl).

10. The compound according to claim 1 , wherein R 3 is SR 6 .

11. The compound according to claim 8 , wherein R 3 is SR 6 .

12. The compound according to claim 10 , wherein R 6 is Ar 2 optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 .

13. The compound according to claim 11 wherein R 6 is Ar 2 optionally substituted with one or more groups independently selected from (1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 .

14. The compound according to claim 10 , wherein R 6 is hetAr 4 optionally substituted with one or more groups independently selected from(1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 .

15. The compound according to claim 11 , wherein R 6 is hetAr 4 optionally substituted with one or more groups independently selected from(1-6C)alkyl, F, Br, Cl, CF 3 , CN, OH, O-(1-6C alkyl), C(═O)OH, C(═O)O(1-6C alkyl), C(═O)NH(1-3C alkyl)N(1-3Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 .

16. The compound according to claim 11 , wherein R 6 is -(1-6C alkyl)OH, polyhydroxy(1-6C alkyl), hetAr 6 , or (5-6C)cycloalkyl substituted with 1-4 OH.

17. The compound of claim 1 , wherein R 3 is SR 6 and R 6 is (1-3C alkoxy)(1-6C alkyl), cyclopropyl(1-6C alkyl), or pyridyl optionally substituted with one or more groups independently selected from (1-6C alkyl).

18. The compound according to claim 1 , wherein R 3 is selected from Cl, Br, or CF 3 .

19. The compound according to claim 1 wherein R 3 is OR 6 .

20. The compound according to claim 1 , having the formula

or a pharmaceutically acceptable salt thereof wherein:

R 13 is 1,2-dihydroxyethyl;

D 2 is N or CH;

R 2 is phenyl, pyridyl or pyrazolyl, each of which is optionally substituted with one or more (1-6C)alkyl groups; and

R 6 is phenyl, pyridyl or (1-6C alkyl)OH, wherein said phenyl and pyridyl are optionally substituted with one or more (1-6C)alkyl groups.

21. The compound according to claim 1 wherein D 2 is N.

22. The compound according to claim 1 having the Formula Ic

or a pharmaceutically acceptable salt thereof, wherein:

R 13 is dihydroxy(2-6C)alkyl or methoxy(dihydroxy(3-6C)alkyl);

R 2 is a pyridyl or pyrazolyl ring, each of which is optionally substituted with one or more groups independently selected from (1-6C)alkyl; and

R 6 is (1-3C alkoxy)(1-6C alkyl), cyclopropyl(1-6 C alkyl), or pyridyl optionally substituted with one or more groups independently selected from (1-6C alkyl).

23. The compound according to claim 1 having the Formula Id:

or a pharmaceutically acceptable salt thereof, wherein:

R 13 is a 1,2-dihydroxy(2-6C)alkyl or methoxy(1,2-dihydroxy(3-6C)alkyl);

R 2 is pyrid-3-yl, pyrazol-4-yl or pyrazol-5-yl, each of which is optionally substituted with one or more groups independently selected from (1-6C)alkyl; and

R 6 is methoxy(2-3C alkyl), cyclopropylmethyl, or pyridyl-2-yl optionally substituted with (1-6C alkyl).

24. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 or pharmaceutically acceptable salt thereof, selected from:

(S)-1-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-trifluoromethyl-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-phenylthio-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl) ethane-1,2-diol;

(S)-1-(5-(5-phenylthio-3-(pyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethane-1,2-diol;

(S)-1-(5-(5-(2-hydroxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(4-fluorophenoxy)-5-pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol;

(S)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol;

(R)-1-(2-(3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol;

(1S)-1-(5-(5-bromo-3-(5,6,7,8-tetrahydroquinolin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-bromo-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(R)-1-(2-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol;

(S)-1-(5-(5-(2-hydroxyethylthio)-3-(pyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-bromo-3-(1-methyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(1-methyl-1H-pyrazol-4-yloxy)-5-(2-methylpyridin-3-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; or

(S)-1-(5-(5-(2-methylpyridin-3-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol.

26. The compound of claim 1 selected from:

(S)-1-(5-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(R)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(S)-1-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol;

(1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol;

(S)-1-(5-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; or

pharmaceutically acceptable salts thereof.

27. The compound

(1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition, which comprises a compound of Formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

29. A pharmaceutical composition, which comprises (1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

30. A method of treating diabetes comprising administering to a mammal a therapeutically effective amount of a compound of Formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

31. The method of claim 30 wherein the compound is (1S,2S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-3-methoxypropane-1,2-diol, or a pharmaceutically acceptable salt thereof.

32. A method for preparing a compound of claim 1 or a salt thereof, comprising:

(a) reacting a corresponding compound of the formula (II)

with a compound of the formula (III)

in the presence of a base catalyst or metal catalyst; or

(b) reacting a corresponding compound of the formula (IV)

with a compound of the formula (V)

wherein X is a leaving atom or group in the presence of a base catalyst or metal catalyst; or

(c) for a compound of Formula I wherein D 2 is CH, reacting a corresponding compound of the formula (VI)

with a compound of the formula R 13 COCH 2 X, wherein X is a leaving group or atom in the presence of a base; or

(d) for a compound of Formula I wherein D 2 is N, reacting a corresponding compound of the formula (VII)

with a compound having the formula (VIII)

where R′ is C1-C6 alkyl or aryl optionally substituted with C1-C6 alkyl, in the presence of a base; or

(e) for compounds of Formula I where R 3 is SR 6 , reacting a corresponding compound having the formula (IX)

with a compound having the formula R 6 SH in the presence of a suitable base; or

(f) reacting a corresponding compound having the formula (XI)

wherein X a is a leaving atom or group, with a compound having the formula R 3 -X b wherein X b is a leaving atom or a leaving group, in the presence of a suitable base; or

(g) for compounds of Formula I where R 3 is SR 6 , reacting a corresponding compound having the formula (XII)

with a compound having the formula R 6 -X c wherein X c is a leaving atom or group in the presence of a suitable base; or

(h) for compounds of Formula I where L is O reacting a corresponding compound having the formula (XIII)

with a compound having the formula R 2 -X d , wherein X d is a leaving atom or group in the presence of a base or in the presence of a copper or palladium catalyst; or

(i) reacting a corresponding compound having the formula (XIV)

wherein X e is a leaving group or atom, with a compound having the formula R 2 LH wherein L is O, in the presence of a palladium catalyst and a suitable base; or

(j) for a compound of Formula I where R 13 has the formula

wherein each R x is independently selected from hydrogen and a (1-2C alkyl) group and n is 0-2, reacting a corresponding compound having the formula (XV)

with an oxidizing agent; or

(k) for a compound of Formula I where R 13 has the formula

hydrolyzing a corresponding compound having the formula (XVI)

wherein each R x is independently selected from hydrogen and a (1-2C alkyl) group and n is 0-2; or

(l) for a compound of Formula I wherein R 13 has the formula

wherein each R x is independently selected from hydrogen and a (1-2C alkyl) group and n is 0-2, reacting a corresponding compound having the formula (XVII)

with two equivalents of a metal hydride reagent or an organometallic reagent having the formula R x M or (R x ) 2 M where each R x is independently selected from hydrogen and a (1-2C alkyl) group and M is a metal anion; or

(m) for a compound of Formula I wherein R 13 has the formula

wherein each R x is independently selected from hydrogen and a (1-2C alkyl) group and n is 0-2, reacting a corresponding compound having the formula (XVIII)

with a metal hydride reagent or an organometallic reagent having the formula R x M or (R x ) 2 M where each R x is independently selected from hydrogen and a (1-2C alkyl) group and M is a metal anion; or

(n) for a compound of Formula I wherein R 13 has the formula

wherein each R x is independently selected from hydrogen and a (1-2C alkyl) group and n is 0-2, reacting a corresponding compound having the formula (XIX)

with two equivalents of a metal hydride reagent or an organometallic reagent having the formula R x M or (R x ) 2 M where each R x is independently selected from hydrogen and a (1-2C alkyl) group and M is a metal anion; or

(o) for a compound of Formula I wherein R 13 has the formula

wherein each R x is independently selected from hydrogen and a (1-2C alkyl) group and n is 0-2, reacting a corresponding compound having the formula (XX)

with a metal hydride reagent or an organometallic reagent having the formula R x M or (R x ) 2 M where ach R x is independently selected from hydrogen and a (1-2C alkyl) group and M is a metal anion; and

removing any protecting group or groups and, if desired, forming a salt.