Pyridine derivatives substituted by heterocyclic ring and amino group
Described herein are pyridine derivatives substituted by heterocycle and amino groups and pharmaceutical compositions comprising said compounds. The disclosed compounds are antifungal agents. The subject compounds and compositions are useful for the treatment of fungal diseases and infections.
1. A compound having formula (Ib), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
wherein:
one of X 1 and Y is nitrogen while the other is nitrogen or oxygen;
W is N or N + —R 15 ;
A is substituted or unsubstituted phenyl or substituted or unsubstituted pyridinyl;
Z is a bond, —(CH 2 )—, —(CH 2 ) 2 —, —O—, —S—, —CH 2 O—, —OCH 2 —, —NH—, —CH 2 NH—, —NHCH 2 —, —CH 2 S—, or —SCH 2 —;
R 1 is hydrogen, halogen, —NR 1B R 1C , —C(O)NR 1B R 1C , —OR 1A , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
X 2 is selected from —O—, —S—, or —NR 13B ;
R 15 is —SO n15 R 15A , —SO v15 NR 15B R 15C , —C(O)R 15D , —C(S)R 15D , —C(O)OR 15D , —C(S)OR 15D , —C(O)SR 15D , —C(O)NR 15B R 15C , —C(S)NR 15B R 15C , —CH 2 OPO 3 H 2 , —CH 2 OSO 3 H, —CH 2 OPO 3 H − , —CH 2 OSO 3 − , —C(O)CH 2 X 3 , or substituted or unsubstituted heteroalkyl;
X 3 is —F, —Cl, —Br, —I, —CHF 2 , —CHCl 2 , —CHBr 2 , —CHI 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , or —NO 2 ;
n15 is an integer from 0 to 4;
v15 is 1 or 2; and
R 1A , R 1B , R 1C , R 13B , R 13C , R 15A , R 15B , R 15C , and R 15D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
R 13B and R 13C or R 15B and R 15C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
2. The compound of claim 1 , wherein W is N + —R 15 .
3. The compound of claim 2 , wherein R 15 is:
wherein:
Ra is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a side chain of a natural amino acid; and
Rb and Rc are independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
4. The compound of claim 1 , wherein W is N.
5. The compound of claim 1 , wherein:
X 2 is —O—; and
R 13C is substituted or unsubstituted phenyl.
6. The compound of claim 1 , wherein:
Z is —O—, —CH 2 O—, or —OCH 2 —;
R 3 is unsubstituted pyridine;
A is unsubstituted phenyl; and
R 1 and R 2 are independently hydrogen.
7. The compound of claim 1 , wherein R 13C is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl.
8. The compound of claim 7 , wherein:
Z is —O—, —CH 2 O—, or —OCH 2 —;
R 3 is unsubstituted pyridine;
A is unsubstituted phenyl; and
R 1 and R 2 are independently hydrogen.
9. The compound of claim 1 , wherein the compound has structural Formula (Ibb):
10. A pharmaceutical composition, comprising:
the compound of claim 1 ; and
at least one pharmaceutically acceptable carrier.
11. A method of treating a subject having a fungal disease or infection, the method comprising:
administering to therapeutically effective amount of the compound of claim 1 .
12. The method of claim 11 , wherein the fungal disease or infection is caused by a Cryptococcus, Aspergillus, Candida, Fusarium , or Scedosporium fungus or a fungus from the Mucorales order.
13. The method of claim 11 , wherein the fungal disease or infection is azole-resistant and/or echinocandin-resistant.
14. The method of claim 11 , comprising:
administering at least one additional antifungal agent in combination with the compound of claim 1 .