Therapeutic thiophene-, furan-, and pyridine-fused azolopyrimidin-5-(6H)-ones
Described herein are compounds of Formula I and Formula II, methods of their synthesis, compositions comprising the compounds, and use of the compounds and compositions in treating numerous diseases and disorders, including cognitive deficits associated with CNS diseases and disorders.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein
X and Y are independently nitrogen or carbon, but at least one is nitrogen;
M =0-4;
each occurrence of R 1 and R 2 is independently selected from H, halo, aryl, heteroaryl, heterocycle, —(C 1 -C 6 alkyl) aryl, —(C 1 -C 6 alkyl) heteroaryl, —CN, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 thiohaloalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NO 2 , —SO 2 C 1 -C 6 alkyl, —SOC 1 -C 6 alkyl, —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 alkyl)aryl, —OC(O)(C 1 -C 6 alkyl), —OC(O)(C 1 - C 6 alkyl)aryl, —SO 2 NH 2 , —CONH 2 , —CO 2 H, —COH, —NH 2 , C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, —N 3 , cyanate, isocyanate, thiocyanate, isothiocyanate, —(C 2 -C 6 alkenyl)O(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), aryloxy, arylthio, —CO(C 1 -C 6 alkyl), —CO(aryl), —CO(heteroaryl), and —CO(heterocycle);
or R 1 and R 2 are on adjacent carbons and taken together with the carbons to which they are attached form a 5-6 member saturated or unsaturated monocylic ring system comprising one or more oxygen or nitrogen atoms, wherein the ring system is optionally substituted with one or more groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;
R 3 and R 4 are independently selected from H, halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, —(C 1 -C 6 alkyl) aryl, —(C 1 -C 6 alkyl) heteroaryl, heterocycle, —NO 2 , —SO 2 C 1 -C 6 alkyl, —SO 2 N(C 1 -C 6 alkyl) 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 ; —(CR 7 R 8 ) 0-3 NR 5 R 6 ;
or R 3 and R 4 taken together with the carbons to which they are attached form a 5-6 member monocylic ring system comprising one or more oxygen atoms;
R 5 , R 6 , R 7 , and R 8 are independently selected from H, F, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —SO 2 C 1 -C 6 alkyl, —SO 2 N(C 1 -C 6 alkyl) 2 , —CO 2 (C 1 -C 6 alkyl), —CO 2 CH 2 C 6 H 5 , —CONH(C 1 -C 6 alkyl), and —CON(C 1 -C 6 alkyl) 2 , or optionally R 5 and R 6 and the nitrogen to which they are attached form a ring taken from azetidine, pyrollidine, piperidine, homopiperidine, morpholine, morpholinone, homomorpholine, homomorpholinone, piperazine, piperazinone, homopiperazine and homopiperazinone with the ring optionally substituted with up to three independent occurrences of R 1 ;
or any two of R 5 , R 6 , R 7 , and R 8 taken together with the atoms to which they are attached form a 3-7 member monocyclic ring containing up to two heteroatoms selected from nitrogen, oxygen, and sulfur.
2. The compound of claim 1 , wherein M=1 or 2.
3. The compound of claim 1 , wherein X is N, and Y is CH.
4. The compound of claim 1 , wherein one or more of R 1 , R 2 , R 3 , and R 4 is halomethyl.
5. The compound of claim 1 , wherein
R l is H, and R 2 is —C 1 -C 6 alkoxy;
or R 1 is halo, and R 2 is C 1 -C 6 alkoxy.
6. The compound of claim 1 , wherein R 1 is F, Cl, or Br, and R 2 is —CF 3 or —CHF 2 .
7. The compound of claim 1 , wherein R 3 is C 1 -C 6 alkyl, and R 4 is H.
8. A compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein
X and Y are independently nitrogen or carbon, but at least one is nitrogen;
M=0-4;
each occurrence of R 1 and R 2 is independently selected from H, halo, —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OH, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, —NO 2 , —SO 2 C 1 -C 3 alkyl, —SO 2 N(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), —CON(C 1 -C 3 alkyl) 2 , aryl, and heteroaryl;
or R 1 and R 2 are on adjacent carbons and taken together with the carbons to which they are attached form a 5-6 member monocylic ring system comprising one or more oxygen atoms, wherein the ring system is optionally substituted with one or more groups selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkoxy;
R 3 and R 4 are independently selected from H, halo, —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OH, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, —NO 2 , —SO 2 C 1 -C 3 alkyl, —SO 2 N(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), —CON(C 1 -C 3 alkyl) 2 , —(CR 7 R 8 ) 0-3 NR 5 R 6 ; and aryl or heteroaryl, either optionally substituted with one or more groups selected from halo, CN, C 1 -C 3 alkyl, OH, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, NO 2 , and SO 2 C 1 -C 3 alkyl;
or R 3 and R 4 taken together with the carbons to which they are attached form a 5-6 member monocylic ring system comprising one or more oxygen atoms;
R 5 , R 6 , R 7 , and R 8 are independently selected from H, F, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OH, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, —SO 2 C 1 -C 3 alkyl, —SO 2 N(C 1 -C 3 alkyl) 2 , —CONH(C 1 -C 3 alkyl), and —CON(C 1 -C 3 alkyl) 2 ;
or any two of R 5 , R 6 , R 7 , and R 8 taken together with the atoms to which they are attached form a 3-7 member monocyclic ring containing up to two heteroatoms selected from nitrogen, oxygen, and sulfur.
9. The compound of claim 8 , wherein M=1.
10. The compound of claim 8 , wherein M=2.
11. The compound of claim 8 , wherein X is N, and Y is CH.
12. The compound of claim 8 , wherein one or more of R 1 , R 2 , R 3 , and R 4 is halomethyl.
13. The compound of claim 8 , wherein R l is H, and R 2 is C 1 -C 3 alkoxy.
14. The compound of claim 8 , wherein R 1 is halo, and R 2 is C 1 -C 3 alkoxy;
or R 1 is F, Cl, or Br and R 2 is CF 3 or CHF 2 .
15. The compound of claim 8 , wherein R 3 is C 1 -C 3 alkyl, and R 4 is H.
16. A compound selected from the group consisting of Examples 220, 222, 223, 225, 229, 247, 248, 266, 267, 268, 270, 272, 277, 290, 294 and 295, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 1 ; and a pharmaceutically acceptable carrier.