Azaindoles as inhibitors of c-Jun N-terminal kinases
View Patent ↗The present invention relates to novel 5-substituted 7-azaindole compounds of formula (I), their use in the inhibition of c-Jun N-terminal kinases, their use in medicine and particularly in the prevention and/or treatment of neurodegenerative disorders related to apoptosis and/or inflammation. The invention also provides processes for manufacture of said compounds, compositions containing them and processes for manufacturing such compositions
1. A compound of formula (I) as defined below:
wherein:
R stands for carbocyclyl, substituted carbocyclyl, wherein
the optionally substituted carbocyclyl group is optionally fused to an unsaturated, partially unsaturated or fully saturated five to seven membered ring,
each substitutable carbon atom in R, including the optional fused ring, is optionally and independently substituted by one or more of C 1-12 alkyl, C 2-12 alkenyl, carbocyclyl, or heterocyclyl, halogen, haloalkyl, OR 2 , SR 2 , NO 2 , CN, NR 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 R 2 , NR 2 COR 2 , NR 2 CO 2 R 2 , CO 2 R 2 , COR 2 , CONR 2 R 2 , S(O) 2 R 2 , SONH 2 , S(O)R 2 , SO 2 NR 2 R 2 , NR 2 S(O) 2 R 2 , wherein each R 2 may be the same or different and is as defined below and wherein:
the C 1-12 alkyl optionally incorporates one or two insertions selected from the group consisting of —O—, —C(O)—, —N(R 2 )—, —S(O)— and —S(O 2 )— wherein each R 2 may be the same or different and is as defined below;
the C 1-12 alkyl, carbocyclyl, or heterocyclyl group is optionally substituted by one or more of halogen, haloalkyl, OR 2 , SR 2 , NO 2 , CN, NR 2 R 2 , NR 2 COR 2 , NR 2 CONR 2 R 2 , NR 2 COR 2 , NR 2 CO 2 R 2 , CO 2 R 2 , COR 2 , CONR 2 2 , S(O) 2 R 2 , SONH 2 , S(O)R 2 , SO 2 NR 2 R 2 , NR 2 S(O) 2 R 2 ; wherein each R 2 may be the same or different and is as defined below and
the carbocyclyl, or heterocyclyl group is optionally substituted by one or more C 1-12 alkyl,
each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, ═NNHR 2 , NNR 2 R 2 , ═N—OR 2 , ═NNHCOR 2 , ═NNHCO 2 R 2 , ═NNSO 2 R 2 , or ═NR 2 , wherein each R 2 may be the same or different and is as defined below; and
each substitutable nitrogen atom in R is optionally substituted by R 3 , COR 2 , SO 2 R 2 or CO 2 R 2 , wherein each R 2 and R 3 may be the same or different and is as defined below;
R 2 is hydrogen, C 1-12 alkyl or aryl, optionally substituted by one or more of C 1-4 alkyl, halogen, C 1-4 haloalkyl, OR 4 , SR 4 , NO 2 , CN, NR 4 R 4 , NR 4 COR 4 , NR 4 CONR 4 R 4 , NR 4 COR 4 , NR 4 CO 2 R 4 , CO 2 R 4 , COR 4 , CONR 4 2 , S(O) 2 R 4 , SONH 2 , S(O)R 4 , SO 2 NR 4 R 4 , NR 4 S(O) 2 R 4 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 4 )—, —S(O)— and —S(O 2 )—, wherein each R 4 may be the same or different and is as defined below;
R 3 is C 1-12 alkyl or aryl, optionally substituted by one or more of C 1-4 alkyl, halogen, C 1-4 haloalkyl, OR 4 , SR 4 , NO 2 , CN, NR 4 R 4 , NR 4 COR 4 , NR 4 CONR 4 R 4 , NR 4 COR 4 , NR 4 CO 2 R 4 , CO 2 R 4 , COR 4 , CONR 4 2 , S(O) 2 R 4 , SONH 2 , S(O)R 4 , SO 2 NR 4 R 4 , NR 4 S(O) 2 R 4 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 4 )—, —S(O)— and —S(O 2 )—, wherein each R 4 may be the same or different and is as defined below;
R 4 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; with the proviso that when R is phenyl substituted with branched C 6 -alkyl (—CH(CH 2 —CH(CH 3 )(CH 3 ))—CH 2 —) incorporating two insertions —(CO)— and —NH—, the C 6 -alkyl group is not substituted with —CN;
and the pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1 , wherein R is an aryl, optionally substituted with one or more of alkyl, haloalkyl, halogen, OR 8 , S R 8 , SO R 8 , (NR 8 ) 2 , wherein R 8 is independently selected from hydrogen, C 1-4 alkyl or haloalkyl.
3. A compound as claimed in claim 1 , wherein R is an optionally substituted aryl.
4. A compound as claimed in claim 3 , wherein R is phenyl substituted in the 4-(para) position.
5. A compound as claimed in claim 4 , wherein R is phenyl substituted by NR 6 R 6 ; and wherein each R 6 is independently H or C 1-4 alkyl.
6. A compound as claimed in claim 3 , wherein R is aryl substituted with F, Cl, Br, haloalkyl, or alkyl.
7. A compound as claimed in claim 1 , wherein the compound is selected from the group consisting of:
8. A process for the manufacture of the compounds of claim 1 which comprises hydrogenating a compound of the general formula (II):
wherein R is as defined in claim 1 and hal stands for a halogen atom.
9. A process as claimed in claim 8 , wherein the compound of the general formula (II) is made by halogenating a compound of the general formula (III) in the 2 position
where R is as defined above and hal stands for halogen.
10. A pharmaceutical formulation comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
11. The compound of claim 3 , wherein R is selected from the group consisting of phenyl and naphthyl.
12. The compound of claim 6 , wherein R is aryl substituted with fluorine.
13. The compound of claim 6 , wherein the haloalkyl is CF 3 .
14. The compound of claim 6 , wherein the alkyl is selected from the group consisting of methyl, ethyl, and propyl.