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 method of treating a CNS disorder selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, schizophrenia, mild-cognitive impairment, ADHD, and multiple scleroisis, comprising administration to a patient in need thereof of an effective amount of 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 alky) 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 ; —(CR 7 R 8 ) 0-3 NR 5 R 6 in which R 5 and R 6 and the nitrogen to which they are attached may 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 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 alky) 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 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. A method of treating an injury or disease that results in neuronal degeneration selected from the group consisting of closed head injuries, blunt trauma, penetrating trauma, hemorrhagic stroke, ischemic stroke, glaucoma, cerebral ischemia, and neuronal damage caused by surgical procedures, said method comprising administering to a patient in need thereof an effective amount of 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 alky) 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 ; —(CR 7 R 8 ) 0-3 NR 5 R 6 in which R 5 and R 6 and the nitrogen to which they are attached may 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 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 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.
3. The method of claim 2 , wherein the injury is a primary nervous system injury selected from the group comprising closed head injuries, blunt trauma, penetrating trauma, hemorrhagic stroke, ischemic stroke, glaucoma, cerebral ischemia, and neuronal damage caused by surgical procedures.
4. A method of promoting neurogenesis, comprising administering to an animal an effective amount of 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 - 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 in which R 5 and R 6 and the nitrogen to which they are attached may 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 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 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.
5. The method of claim 1 , wherein M=1.
6. The method of claim 1 , wherein M=2.
7. The method of claim 1 , wherein X is N, and Y is CH.
8. The method of claim 1 , wherein one or more of R 1 , R 2 , R 3 , and R 4 is halomethyl.
9. The method of claim 1 , wherein R 1 is H, and R 2 is C 1 -C 3 alkoxy.
10. The method of claim 1 , wherein R 1 is halo, more specifically F, Cl, or B, 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 .
11. The method of claim 1 , wherein R 3 is C 1 -C 3 alkyl, more specifically methyl, and R 4 is H.
12. The method of claim 1 , wherein the compound of Formula II is selected from the group consisting of Example 220, 222, 223, 225, 229, 247, 248, 266, 267, 268, 270, 272, 277, 290, 294, 295, and pharmaceutically acceptable salts thereof.
13. A method of treating a CNS disorder selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, schizophrenia, mild-cognitive impairment, ADHD, and multiple sclerosis, comprising administration to a patient in need thereof of an effective amount of a compound selected from the group consisting of Examples 186 to 304, and pharmaceutically acceptable salts thereof.
14. The method of claim 13 , comprising administration of a compound selected from the group consisting of Example 220, 222, 223, 225 and pharmaceutically acceptable salts thereof.
15. The method of claim 13 , comprising administration of a compound selected from the group consisting of Example 229, 247, 248, 266, 267, 268, and pharmaceutically acceptable salts thereof.
16. The method of claim 13 , comprising administration of a compound selected from the group consisting of Example 270, 272, 277, 290, 294, 295, and pharmaceutically acceptable salts thereof.
17. The method of claim 13 , wherein the CNS disorder is Parkinson's disease.
18. The method of claim 17 , comprising administration of a compound selected from the group consisting of Example 220, 222, 223, 225, and pharmaceutically acceptable salts thereof.
19. The method of claim 17 , comprising administration of a compound selected from the group consisting of Example 229, 247, 248, 266, 267, 268, and pharmaceutically acceptable salts thereof.
20. The method of claim 17 , comprising administration of a compound selected from the group consisting of Example 270, 272, 277, 290, 294, 295, and pharmaceutically acceptable salts thereof.