Metalloenzyme inhibitor compounds
Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof; wherein
A is N or CR 5 ;
W is N or CR 6 ;
X is N or CR 6 ;
Y is N or CR 6 ;
Z is N or CR 6 ;
provided that no more than two of W, X, Y, and Z are N;
R 1 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO 2 R c , (CH 2 ) n NR a R b , (CH 2 ) n NHSO 2 R d , (CH 2 ) n NHCO 2 R d , CO 2 R e , COR f , (CH 2 ) n OR f , or CR e R f OH;
R 2 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO 2 R c , CH 2 NR a R b , CH 2 NHSO 2 R d , CO 2 R e , COR f , CH 2 OR f , or CR e R f OH;
R 3 is hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, NR a R b , NHSO 2 R c , (CH 2 ) n NR a R b , (CH 2 ) n NHSO 2 R d , CO 2 R e , COR f , (CH 2 ) n OR f , or CR e R f OH;
each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R 4 is cyclopropyl;
R 5 is hydrogen, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;
each occurrence of R 6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl; and
each occurrence of R a , R b , R c , R d , R e , and R f are, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC 1-6 alkyl, C(O)C 1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atoms to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atoms to which they are attached form a cycloalkyl ring.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, NR a R b , or CH 2 NR a R b .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, cyano, alkyl, NR a R b , or haloalkyl; and R a and R b are, independently, hydrogen, alkyl, or heteroalkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl or haloalkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is haloalkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are hydrogen.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is, independently, hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy or alkylsulfonyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 6 is, independently, hydrogen, halogen, or cyano.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is CR 5 and R 5 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is N.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein no more than one of W, X, Y, and Z is N.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W, X, Y, and Z are each CR 6 .
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is N.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula I-b:
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein X is CR 6 .
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein X is CR 6 , wherein R 6 is halogen; and
each of W, Y, and Z is N or CR 6 , wherein each occurrence of R 6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl.
18. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein Y is CR 6 .
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein Y is CR 6 , wherein R 6 is halogen; and
each of W, X, and Z is N or CR 6 , wherein each occurrence of R 6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl.
20. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein X and Y are CR 6 .
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein each of X and Y are CR 6 , wherein each R 6 is halogen; and
each of W and Z is N or CR 6 , wherein each occurrence of R 6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl.
22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein each of W and Z is CR 6 , wherein each occurrence of R 6 is, independently, hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl.
23. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, NR a R b , or CH 2 NR a R b .
24. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, cyano, alkyl, NR a R b , or haloalkyl; and R a and R b are, independently, hydrogen, alkyl, or heteroalkyl.
25. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl or haloalkyl.
26. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is haloalkyl.
27. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoroalkyl.
28. A pharmaceutical composition comprising a compound or a pharmaceutical salt thereof of any one of claims 1 - 6 , 7 - 14 , and 15 - 27 , and a pharmaceutically acceptable carrier.