Benzofuro[3,2-
View Patent ↗The present invention relates to benzofuro[3,2-c]pyridine and azepine analogs as serotonin sub-type 6 (5-HT 6 ) modulators, pharmaceutical compositions including these compounds, methods of preparation, and use thereof. These compounds are useful in the treatment of central nervous system disorders including obesity, metabolic syndrome, cognition, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, rare and orphan diseases, and sleep disorders. The subject compounds have the structure of formula (I) with the substituents being described herein.
1. A compound of formula (I):
wherein:
G is —(CR 5 R 6 ) n —, where n=1,2
Z is —(CR 10 R 11 ) m —, where m=1,2
P is N—R 7 or CR 21 —OR 22
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 2 and R 3 are independently H, R 14 S(O) 2 —, or R 14 S(O)—;
R 5 , R 6 , R 10 , and R 11 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 10 , or R 11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)OR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 6 and R 10 can combine to form a —(CH 2 ) n —, wherein n represents an integer from 2 to 3;
R 7 is independently H, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O)R 15 , —S(O) 2 R 15 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 7 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 14 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each R 14 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of the R 14 substituents further optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, H, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl;
R 21 and R 22 are independently H or C 1 -C 6 alkyl;
with the provisos that (a) when n=2, m=1 (b) at least one of R 2 and R 3 , but not both, is H;
or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
2. The compound according to claim 1 which has the formula (Ia):
3. The compound according to claim 2 , wherein
R 1 and R 4 are H or C 1 -C 6 alkyl;
R 2 is R 14 S(O) 2 —;
R 3 is H;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
4. The compound according to claim 3 , wherein
R 7 is H, methyl, or ethyl.
5. The compound according to claim 2 , wherein
R 1 and R 4 are H or C 1 -C 6 alkyl;
R 2 is H;
R 3 is R 14 S(O) 2 —;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
6. The compound according to claim 5 , wherein R 7 is methyl.
7. The compound according to claim 5 , wherein R 7 is H.
8. The compound according to claim 2 , wherein
R 1 is Br, Cl, F, or I;
R 4 is H;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
9. The compound according to claim 2 , wherein
R 1 is OMe, OEt, OCF 3 , or OBn;
R 4 is H or C 1 -C 6 alkyl;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
10. The compound according to claim 2 , wherein
R 1 is H, C 1 -C 6 alkyl, Cl, O—C 1 -C 6 alkyl;
R 2 is R 14 S(O)—;
R 3 is H
R 4 is H;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
11. The compound according to claim 2 , wherein
R 1 is H, C 1 -C 6 alkyl, Cl, O—C 1 -C 6 alkyl;
R 2 is H;
R 3 is R 14 S(O)—;
R 4 is H;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
12. The compound according to claim 1 which has the formula (Ib):
wherein:
m is 1 or 2;
R 1 is H or C 1 -C 6 alkyl;
R 4 is H or C 1 -C 6 alkyl;
R 7 is H or C 1 -C 6 alkyl; and
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
13. The compound according to claim 12 , wherein m is 1.
14. The compound according to claim 13 , wherein R 2 is H and R 3 is R 14 S(O) 2 —.
15. The compound according to claim 14 , wherein R 2 is R 14 S(O) 2 — and R 3 is H.
16. The compound of claim 12 , wherein m is 2.
17. The compound of claim 16 , wherein R 2 is H and R 3 is R 14 S(O) 2 —.
18. The compound according to claim 16 , wherein R 2 is R 14 S(O) 2 — and R 3 is H.
19. The compound according to claim 1 which has the formula (Ic):
R 1 is H, C 1 -C 6 alkyl, Cl, O—C 1 -C 6 alkyl;
R 2 is R 14 S(O) 2 —;
R 3 is H
R 4 is H;
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
20. The compound according to claim 19 wherein:
R 1 is H, C 1 -C 6 alkyl, Cl, O—C 1 -C 6 alkyl;
R 2 is H;
R 3 is R 14 S(O) 2 —;
R 4 is H;
R 14 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl.
21. The compound according to claim 1 , wherein R 14 is a substituted or unsubstituted monocyclic aryl.
22. The compound according to claim 21 , wherein the monocyclic aryl is a substituted or unsubstituted phenyl.
23. The compound according to claim 21 , wherein R 14 is a substituted or unsubstituted polycyclic aryl.
24. The compound according to claim 23 , wherein the substituted or unsubstituted polycyclic aryl is selected from the group consisting of naphthyl, azulenyl, fluorenyl, phenanthrenyl, anthracenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.
25. The compound according to claim 1 , wherein R 14 is a substituted or unsubstituted monocyclic heteroaryl.
26. The compound according to claim 25 , wherein the substituted or unsubstituted monocyclic heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
27. The compound according to claim 1 wherein R 14 is a substituted or unsubstituted polycyclic heteroaryl.
28. The compound according to claim 27 , wherein the substituted or unsubstituted polycyclic heteroaryl is selected from the group consisting of thienopyrrolyl, furopyrrolyl, indolyl, azaindolyl, isoindolyl, indolinyl indolizinyl, indazolyl, benzimidazolyl, imidazopyridinyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, pyrazolopyridinyl, triazolopyridinyl, thienopyridinyl, benzothiadiazolyl, benzofuyl, benzothiophenyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, quinazolinyl, quinolizilinyl, phthalazinyl, benzotriazinyl, chromenyl, and naphthyridinyl.
29. The compound according to claim 28 , wherein the compound is present in the form of a pharmaceutical acceptable salt.
30. The compound according to claim 1 , wherein the compound is present in the form of an oxide.
31. The compound according to claim 1 , wherein the compound is a (+)-stereoisomer.
32. The compound according to claim 1 , wherein the compound is a (−)-stereoisomer.
33. A pharmaceutical composition comprising:
a compound according to claim 1 and a pharmaceutically acceptable carrier.
34. A process for preparation of a product compound of formula (I):
wherein:
G is —(CR 5 R 6 ) n —, where n=1, 2
Z is —(CR 10 R 11 ) m —, where m=1, 2
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 2 and R 3 are independently H, R 14 S(O) 2 —, R 14 S(O)—, R 14 S—, R 14 —(CR 19 R 20 )—;
R 5 , R 6 , R 10 , and R 11 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 10 , or R 11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 6 and R 10 can combine to form a —(CH 2 ) n —, wherein n represents an integer from 2 to 3;
R 7 is independently H, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O)R 15 , —S(O) 2 R 15 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 7 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 14 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each R 14 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of the R 14 substituents further optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, H, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl;
R 19 and R 20 are independently H or C 1 -C 6 alkyl, wherein R 19 and R 20 can combine to form a —(CH 2 ) n — where n represents an integer from 4-7;
with the proviso that at least one of R 2 and R 3 , but not both, is H;
or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprising:
providing a first intermediate compound having the structure:
wherein X is Br, Cl, or I
and
converting the first intermediate compound to the compound of formula (I).
35. The process according to claim 34 , wherein said converting comprises:
reacting the first intermediate compound with a heteroarylsulfonyl salt, arylsulfonyl salt, thiophenol, aldehyde or ketone under conditions effective to produce the compound of formula (I).
36. The process according to claim 34 , wherein said converting comprises:
sulfonating the first intermediate compound in the presence of an organolithium and sulfur dioxide under conditions effective to produce a lithium sulfinate intermediate compound having the structure:
and
subjecting the lithium sulfinate intermediate compound to arylation or heteroarylation under conditions effective to produce the compound of formula (I).
37. The process according to claim 36 , wherein the organolithium is selected from the group consisting of n-butyllithium, t-butyllithium, sec-butyllithium, phenyl lithium, and lithium diisopropyl amide.
38. The process according to claim 34 , wherein said converting comprises:
sulfonating the first intermediate compound in the presence of an organolithium and sulfur dioxide under conditions effective to produce a lithium sulfinate intermediate compound having the structure:
halogenating the lithium sulfinate intermediate compound under conditions effective to produce a halosulfonyl intermediate compound having the structure:
wherein X 1 is Cl, Br, or I;
and
arylating the halosulfonyl intermediate compound under conditions effective to produce the compound of formula (I).
39. A process for the preparation of a compound of formula (VI) having the structure:
wherein:
G is —(CR 5 R 6 ) n —, where n=1, 2
Z is —(CR 10 R 11 ) m —, where m=1, 2
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 5 , R 6 , R 10 , and R 11 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 10 , or R 11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 6 and R 10 can combine to form a —(CH 2 ) n —, wherein n represents an integer from 2 to 3;
R 7 is independently H, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O)R 15 , —S(O) 2 R 15 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 7 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 14 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each R 14 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of the R 14 substituents further optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, H, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl;
R 19 is independently H or C 1 -C 6 alkyl;
with the proviso that at least one of R 2 and R 3 , but not both, is H;
or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprising:
providing a first intermediate compound having the structure:
wherein X is Br, Cl, or I
reacting the first intermediate compound (II) with a lithiating agent;
quenching the lithiated first intermediate compound with an aldehyde or ketone under conditions effective to produce the second intermediate compound (VII) of the following formula:
and
reacting the second intermediate compound (VII) under conditions effective to de-oxygenate a hydroxyl group attached to the carbon adjacent to R 14 and produce the compound of formula (VI).
40. A process for the preparation of a compound of formula (VIII):
wherein
X is Br, Cl, or I;
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 5 , R 6 , R 8 , and R 9 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 8 , or R 9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or
R 6 and R 8 can combine to form a —(CH 2 ) n —, wherein n represents an integer from 2 to 3;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
providing a phenoxylamine derivative compound having the formula:
and
reacting the phenoxylamine derivative compound with a piperidone derivative compound having the structure:
wherein PG is H or a protective group under conditions effective to form the compound of formula (VIII).
41. A process for preparation of a compound of formula (XI):
wherein
X is Br, Cl, or I;
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 5 , R 6 , R 8 , and R 9 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 8 , or R 9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
providing a starting compound having the structure:
and
converting said starting compound under conditions effective to form the compound of formula (XI).
42. The process according to claim 41 , wherein said providing a starting compound comprises:
providing a precursor compound having the structure:
and
converting the precursor compound under conditions effective to form the starting compound.
43. The process according to claim 42 , wherein said providing a precursor compound comprises:
providing a reactant compound having the structure:
and
converting the reactant compound under conditions effective to form the precursor compound.
44. The process according to claim 43 , wherein said providing a reactant compound comprises:
reacting a phenoxylamine derivative having the formula (IX) with a diketone compound having the structure:
under conditions effective to form said reactant compound.
45. The process according to claim 44 , wherein the phenoxylamine is prepared by reacting a phenol derivative having the formula:
with an aminating reagent under conditions effective to form said phenoxylamine.
46. The process according to claim 45 , wherein the aminating reagent is hydroxylamine-O-sulfonic acid or O-mesitylsulfonyl-hydroxylamine.
47. A process for preparation of a compound formula (XVII):
wherein
X is Br, Cl, or I;
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 5 , R 6 , R 8 , and R 9 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 8 , and R 9 are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 47 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 10 and R 11 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 10 or R 11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
providing a starting compound having the structure:
and
converting said starting compound under conditions effective to form the compound of formula (XVII).
48. The process according to claim 47 , wherein said providing a starting compound comprises:
providing a precursor compound having the structure:
and
converting the precursor compound under conditions effective to form the starting compound.
49. The process according to claim 48 , wherein said providing a precursor compound comprises:
providing a reactant compound having the structure:
and
converting the reactant compound under conditions effective to form the precursor compound.
50. A process for preparation of a compound formula (XXI):
wherein
PG is a protecting group that can be removed under acidic or basic conditions
X is Br, Cl, or I;
R 1 and R 4 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 45 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 1 or R 4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 5 , R 6 , R 8 , and R 9 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 5 , R 6 , R 8 , and R 9 are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR 17 , —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —NHR 17 , —NR 17 R 18 , —SR 17 , —S(O)R 17 , —S(O) 2 R 17 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 12 and R 13 are independently H, halogen, CF 3 , CHF 2 , CH 2 F, OH, OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)NR 15 R 16 , —NHR 15 , —NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R 12 or R 13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
R 15 , R 16 , R 17 , and R 18 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R 15 , R 16 , R 17 , or R 18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and a monocyclic aryl; or R 15 and R 16 or R 17 and R 18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO 2 , NH 2 , H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
providing a starting compound having the structure:
and
converting said starting compound under conditions effective to form the compound of formula (XXI).
51. The process according to claim 50 , wherein said providing a starting compound comprises:
providing a precursor compound having the structure:
and
converting the precursor compound under conditions effective to form the starting compound.
52. The process according to claim 51 , wherein said providing a precursor compound comprises:
reacting a phenoxylamine derivative having the formula (IX)
with a diketone derivative compound having the structure:
under conditions effective to form said precursor compound.