Intermediates for the preparation of pyridin-2-yl-amino-1,2,4-thiadiazole derivatives
Provided are intermediates having the formulas wherein R 2 , R 3 , and L are as defined in the specification, which are useful in the preparation of pyridin-2-yl-amino-1,2,4-thiadiazole derivatives.
1. A compound of formula:
where:
L is O or S;
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 1 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 19 )-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(1-3 Calkyl) 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(1-3 Calkyl) 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(1-3 Calkyl) 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;
provided that the compound is not:
1-(5-chloro-3-phenoxypyridin-2-yl)thiourea,
1-(5-bromo-3-phenoxypyridin-2-yl)thiourea,
1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea,
1-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea,
1-(5-bromo-3-(4-cyanophenoxyl)pyridin-2-yl)thiourea, or
1-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea.
2. The compound of claim 1 where L is O.
3. The compound of claim 1 where R 2 is
4. The compound of claim 1 , where:
R 3 is SR 6 ; and
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, (1-3C alkoxy)(1-6C alkyl), or cyclopropyl(1-6C alkyl).
5. The compound of claim 1 , where:
R 3 is SR 6 ;
R 6 is hetAr 4 ; and
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 .
6. The compound of claim 1 , where R 3 is
7. A compound of formula:
where:
L is O or S;
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 , (5-6C)cycloalkyl substituted with 1 to 4 OH, (1-3C 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(1-3 Calkyl) 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;
provided that the compound is not
5-chloro-3-phenoxypyridin-2-amine,
5-bromo-3-(4-fluorophenoxyl)pyridin-2-amine,
5-Bromo-3-(phenylthio)pyridin-2-amine,
3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-amine, or
5-bromo-3-phenoxypyridin-2-amine.
8. The compound of claim 7 where L is O.
9. The compound of claim 7 where R 2 is
10. The compound of claim 7 , where:
R 3 is SR 6 ; and
R 6 is Ar e , 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, (1-3C alkoxy)(1-6C alkyl), or cyclopropyl(1-6C alkyl).
11. The compound of claim 7 , where:
R 3 is SR 6 ;
R 6 is hetAr 4 ; and
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(1-3 Calkyl) 2 and C(═O)NH(1-3C alkyl)hetCyc 2 .
12. The compound of claim 7 , where R 3 is