Chiral
The present invention relates to novel compounds of Formula I and their use in therapeutic treatments. The invention further relates to a novel chiral synthesis of 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines using N-sp3 protective groups. The invention also provides intermediates for use in the synthesis of compounds of Formula I.
1. A compound of Formula I:
and pharmaceutically acceptable solvates thereof, wherein
Ar 1 is unsubstituted thiophen-2-yl, unsubstituted phenyl, or 4-fluorophenyl;
R 1 is H or methyl;
Ar 2 is of general Formula (i), (ii) or (iii):
wherein
R 2 is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl or di(C1-C2 alkyl)amino;
X 1 is N or C—R 6 wherein R 6 is H, fluoro or C1-C2 alkyl;
X 2 is O or S;
X 3 is N, or X 3 is CH under the condition that X 1 is N and X 2 is N—R 7 wherein R 7 is linear or branched C1-C3 alkyl or cyclopropyl;
R 3 is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl;
X 4 is N or C—R 8 wherein R 8 is H or C1-C2 alkyl;
X 5 is O or S;
X 6 is N, or X 6 is CH under the condition that X 4 is N and X 5 is N—R 9 wherein R 9 is linear or branched C1-C3 alkyl or cyclopropyl;
R 4 is halo, cyano, methyl, or hydroxyl;
R 5 is H or halo;
with the condition that when Ar 2 is of Formula (iii), then R 1 is methyl; and
the compound of Formula I is not
(3-(2-isobutylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;
[1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;
(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone.
2. The compound of claim 1 having Formula I′:
and pharmaceutically acceptable solvates thereof, wherein
Ar 1 is unsubstituted thiophen-2-yl, unsubstituted phenyl, or 4-fluorophenyl;
R 1 is H or methyl;
R 2 is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl or di(C1-C2 alkyl)amino;
X 1 is N or C—R 6 wherein R 6 is H, fluoro or C1-C2 alkyl;
X 2 is O or S;
X 3 is N, or X 3 is CH under the condition that X 1 is N and X 2 is N—R 7 wherein R 7 is linear or branched C1-C3 alkyl or cyclopropyl.
3. The compound of claim 1 having Formula I′1
and pharmaceutically acceptable solvates thereof.
4. The compound of claim 1 selected from Formulae I′a and I′b
and pharmaceutically acceptable solvates thereof.
5. The compound of claim 1 selected from Formulae I′c, I′d
and pharmaceutically acceptable solvates thereof.
6. The compound of claim 1 selected from Formulae I′e, I′f
and pharmaceutically acceptable solvates thereof.
7. The compound of claim 1 selected from Formulae I′e-1, I′e-2, I′f-1, I′f-2
and pharmaceutically acceptable solvates thereof.
8. The compound of claim 1 having Formula I′e-3
and pharmaceutically acceptable solvates thereof.
9. The compound of claim 1 having Formula I′f-3
and pharmaceutically acceptable solvates thereof.
10. The compound of claim 1 having Formulae I′g, I′h and I′i
and pharmaceutically acceptable solvates thereof.
11. The compound of claim 1 having Formula I″:
and pharmaceutically acceptable solvates thereof, wherein
Ar 1 is unsubstituted thiophen-2-yl, unsubstituted phenyl, or 4-fluorophenyl;
R 1 is H or methyl;
R 3 is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl;
X 4 is N or C—R 8 wherein R 8 is H or C1-C2 alkyl;
X 5 is O or S;
X 6 is N, or X 6 is CH under the condition that X 4 is N and X 5 is N—R 9 wherein R 9 is linear or branched C1-C3 alkyl or cyclopropyl.
12. The compound of claim 1 selected from Formulae I″a, I″b
and pharmaceutically acceptable solvates thereof.
13. The compound of claim 1 selected from Formulae II″c, I″d
and pharmaceutically acceptable solvates thereof.
14. The compound of claim 1 selected from Formulae II″e, I″f, I″g, I″h and I″i
and pharmaceutically acceptable solvates thereof.
15. The compound of claim 14 selected from Formulae I″e-1, I″f-1, I″g-1, I″h-1, I″i-1, I″e-2, I″f-2, I″g-2, I″h-2 and I″i-2
and pharmaceutically acceptable solvates thereof.
16. The compound of claim 1 having Formula I′″:
and pharmaceutically acceptable solvates thereof, wherein
Ar 1 is unsubstituted phenyl, unsubstituted thiophen-2-yl or 4-fluorophenyl;
R 4 is halo, cyano, methyl, or hydroxyl;
R 5 is H or halo.
17. The compound of claim 1 selected from Formulae I′″a and I′″b
and pharmaceutically acceptable solvates thereof.
18. The compound of claim 1 selected from the group consisting of:
1
(R)-(8-methyl-3-(2- methylthiazol-4-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)mcthanone
2
(R)-[1,1′-biphenyl]-4- yl(8-methyl-3-(2- methylthiazol-4-yl)-5,6- dihydro- [1,2,41triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
3
(3-(2-methylthiazol-4- yl)-5,6-dihydro- [1,2.41triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
4
(4-(thiophen-2- yl)phenyl)(3-(2- (trifluoromethyl)thiazol- 4-yl)-5,6-dihydro- [1,2,41triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
5
(R)-(3-(2-ethylthiazol- 4-yl)-8-methyl-5,6- dihydro- [1,2,41triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
6
(R)-[1,1′-biphenyl]-4- yl(3-(2-ethylthiazol-4- yl)-8-methyl-5,6- dihydro-[1,2,4]triazolo [4,3-a]pyrazin-7(8H)- yl)methanone
7
(R)-(8-methyl-3-2- vinylthiazol-4-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
8
(R)-[1,1′-biphenyl]-4- yl(8-methyl-3-(2- vinylthiazol-4-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
9
(4-(thiophen-2- yl)phenyl)(3-(2- vinylthiazol-4-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
10
[1,1′-biphenyl]-4-yl(3- (2-vinylthiazol-4-yl)- 5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
11
(R)-(8-methyl-3-(2- methyloxazol-4-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
12
(R)-[1,1′-biphenyl]-4- yl(8-methyl-3-(2- methyloxazol-4-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
13
(R)-(3-(2- isopropyloxazo1-4-yl)- 8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
14
(3-(2-isopropyloxazol- 4-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
15
(R)-(3-(2- cyclopropyloxazol-4- yl)-8-methyl-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thlophen-2- yl)phenyl)methanone
16
(R)-(3-(2,5- dimethylthiazol-4-yl)-8- methyl-5,6-dihydro- [1,2.4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
17
(R)-(3-(2- (diniethylarnino)thiazol- 4-yl)-8-methyl-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
18
(3-(2-isopropylthiazol- 4-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
19
(R)-(8-nnethyl-3-(4- methylthiazol-2-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
20
(R)-[1,1′-biphenyl]-4- yl(8-methyl-3-(4- methylthiazol-2-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
21
[1,1′-biphenyl]-4-yl(3- (4-methylthiazol-2-yl)- 5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
22
(R)-(3-(4,5- dimethylthiazol-2-yl)-8- methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
23
(R)-(8-nnethyl-3- methyl-1,2,4- (oxadiazol-5-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
24
(R)-(8-methyl-3-(3- methyl-1,2,4-thiadiazol- 5-yl)-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
25
(R)-(3-(3-isopropyl- 1,2,4-thiadiazol-5-yl)-8- methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
26
(R)-(8-methyl-3-(4- methyloxazol-2-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
27
(R)-[1,1′-biphenyl]-4- yl(8-methyl-3-(4- methyloxazol-2-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
28
(R)-(3-(1,3-dimethyl- 1H-pyrazol-5-yl)-8- methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
29
(R)-[1,1′-biphenyl]-4- yl(8-methyl-3-(6- methylpyridin-2-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
30
(R)-(8-methyl-3-(6- methylpyridin-2-yl)-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
31
(R)-(3-(6- hydroxypyridin-2-yl)-8- methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2- yl)phenyl)methanone
32
(R)-[1,1′-biphenyl]-4- yl(3-(6-hydroxypyridin- 2-yl)-8-methyl-5,6- dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone
33
(R)-6-(8-methyl-7-(4- (thiophen-2- yl)benzoyl)-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyrazin-3- yl)picolinonitrile
and pharmaceutically acceptable solvates thereof.
19. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
20. Medicament comprising a compound according to claim 1 or a pharmaceutically acceptable solvate thereof.