Thiazole carboxamide derivatives and their use to treat cancer
View Patent ↗The present invention relates to novel Heterocyclic Ether or Thioether Derivatives, compositions comprising the Heterocyclic Ether or Thioether Derivatives, and methods for using the Heterocyclic Ether or Thioether Derivatives for treating or preventing a proliferative disorder, an anti-proliferative disorder, inflammation, arthritis, a central nervous system disorder, a cardiovascular disease, alopecia, a neuronal disease, an ischemic injury, a viral infection, a fungal infection, or a disorder related to the activity of a protein kinase.
1. A compound having the formula:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the dashed line indicates an optional and additional bond and wherein:
M is —O— or —S—;
R 1 is H, alkyl, alkenyl, alkynyl, -(alkylene) m -aryl, -(alkylene) m -cycloalkyl, -(alkylene) m -heteroaryl, -(alkylene) m -heterocycloalkyl or -(alkylene) m -heterocycloalkenyl, wherein any aryl, cycloalkyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl group can be optionally substituted on a ring carbon or ring nitrogen atom with up to 3 substituents, which may be the same or different, and are selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, —OR 6 , -(alkylene) m -N(R 6 ) 2 , —C(O)OR 6 , —NHC(O)R 6 , —C(O)N(R 6 ) 2 , —S(O) 2 R 7 , —CN, —OH, —NO 2 , -(alkylene) m -aryl, -(alkylene) m -cycloalkyl, -(alkylene) m -heteroaryl, -(alkylene) m -heterocycloalkyl and -(alkylene) m -heterocycloalkenyl; and wherein any aryl or heteroaryl substituent group can be optionally substituted with up to 5 substituents, which may be the same or different, and are selected from halo, —OH, alkyl, —C(O)OR 6 , —N(R 6 ) 2 , —NHC(O)R 6 , —C(O)N(R 6 ) 2 , —S(O) 2 R 7 , —CN, —OH, —NO 2 , and —O-alkyl; and wherein any aryl, cycloalkyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl group can be optionally fused to an aryl, cycloalkyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl group;
each occurrence of R 2 is independently H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)R 6 or -(alkylene) m -N(R 6 ) 2 ;
R 3 is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)—R 6 or -(alkylene) m -N(R 6 ) 2 ;
R 3a is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)—R 6 or -(alkylene) m -N(R 6 ) 2 ;
each occurrence of R 5 is independently H, alkyl, -(alkylene) m -aryl, -(alkylene) m -heteroaryl, -(alkylene) m -heterocycloalkyl, -(alkylene) m -N(R 6 ) 2 , -(alkylene) m -OH, -(alkylene) m -NHC(O)R 6 , hydroxyalkyl, haloalkyl, —C(O)R 6 , —C(O)OR 6 , —C(O)-(alkylene) m -N(R 6 ) 2 , -(alkylene) m -NHC(O)R 6 , —NHC(O)OR 6 or —NHS(O) 2 R 7 ;
each occurrence of R 6 is independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl;
each occurrence of R 7 is independently H, alkyl, aryl, cycloalkyl or haloalkyl;
R 8 is H, alkyl, —OH, —O-alkyl or haloalkyl;
R 10 is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)R 6 or -(alkylene) m -N(R 6 ) 2 ;
R 10a is H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)—R 6 or -(alkylene) m -N(R 6 ) 2 ;
each occurrence of R 11 is independently H, alkyl, haloalkyl, hydroxyalkyl, -(alkylene) m -C(O)N(R 6 ) 2 , -(alkylene) m -NHC(O)—R 6 or -(alkylene) m -N(R 6 ) 2 ;
W is —C(R 5 ) 2 ;
Y is H, halo, alkyl or —CN; and
each occurrence of m is independently 0 or 1.
2. The compound of claim 1 , wherein M is —O—.
3. The compound of claim 1 , wherein M is —S—.
4. The compound of claim 1 , wherein R 1 is aryl, -alkylene-aryl, cycloalkyl, heteroaryl or heterocycloalkenyl, each of which can be optionally substituted with up to 3 groups, each independently selected from halo, alkyl, —OH, —NH 2 , heteroaryl, or —O-haloalkyl.
5. The compound of claim 1 , wherein R 1 is:
6. The compound of claim 1 , R 2 , R 3 , R 3a R 10 , R 10a and R 11 are each —H.
7. The compound of claim 1 , wherein W is —CH(NH 2 )—, —CH(OH)— or CH(NHSO 2 CH 3 ).
8. The compound of claim 1 , wherein the group
is
R 1 is:
9. The compound of claim 1 having the formula:
and pharmaceutically acceptable salts and stereoisomers thereof, wherein
M is —O— or —S—;
W is —C(R 5 ) 2 —;
R 1 is aryl, -alkylene-aryl or heteroaryl, wherein any aryl or heteroaryl group may be optionally substituted with up to 3 substituents, each independently selected from alkyl, halo, —OH, —O-haloalkyl, —N(R 9 ) 2 , heteroaryl and —C(O)OR 9 ; and
R 5 is H, —OR 9 or —N(R 9 ) 2 .
10. The compound of claim 9 , wherein M is —O—.
11. The compound of claim 9 , wherein M is —S—.
12. The compound of claim 11 , wherein R 1 is:
R 5 is —NH 2 , —NHSO 2 -alkyl or —OH.
13. A compound having the structure,
or a pharmaceutically acceptable salt or stereoisomer thereof.
14. A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.