| (11) | EP 2 419 426 B1 |
(12) | EUROPEAN PATENT SPECIFICATION |
|
|
(54) | (PYRAZOL-3-YL)-1,3,4-THIADIAZOL-2-AMINE AND (PYRAZOL-3-YL)-1,3,4-THIAZOL-2-AMINE COMPOUNDS (PYRAZOL-3-YL)-1,3,4-THIADIAZOL-2-AMIN- UND (PYRAZOL-3-YL)-1,3,4-THIAZOL-2- AMINVERBINDUNGEN COMPOSÉS DE (PYRAZOL-3-YL)-1,3,4-THIADIAZOL-2-AMINE ET DE (PYRAZOL-3-YL)-1,3,4-THIAZOL-2-AMINE |
|
| |||||||||||||||||||||||||||||||
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
Field of the invention
Background of the invention
Detailed description of the invention
either X is N and Y is CR5; or X is C and Y is S;
Z is selected from N and CH;
R1 is selected from H and Me,
R2 is selected from H, OH, OMe and Me;
each R3 is independently selected from C1-3alkyl, F, Cl, Br, CF3 and NH2;
R4 is selected from Me, CF3, NO2 and CHF2;
R5 is selected from H, Me and CHF2;
R6 is selected from H and Me; and
p is 0-3.
72 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(methyloxy)-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
73 N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(methyloxy)(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amine
74 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-methyl-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
75 5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
76 N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-y1)ethyl]-1,3,4-thiadiazol-2-amine
77 5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2,3,6-trifluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
78 1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4,thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
79 1-[5-({1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
80 1-[5-({1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
81 N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine and
82 5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(ethyloxy)-3,6-difluorophenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine,
or a pharmaceutically acceptable salt thereof.83 1-[5-({1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
84 1-[5-({1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
85 N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
86 N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
87 N-{1-[(3-amino-2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine and
88 1-[5-({1-[(3-amino-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol,
or a pharmaceutically acceptable salt thereof.66 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1R)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
67 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
68 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1R)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
69 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
70 (1S)-1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol and
71 (1R)-1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol,
or a pharmaceutically acceptable salt thereof.89 (1S)-1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol and
90 (1R)-1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol,
or a pharmaceutically acceptable salt thereof.67 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
69 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
70 (1S)-1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol and
89 (1S)-1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol,
or a pharmaceutically acceptable salt thereof.38 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)-ethyl]-1,3,4-thiadiazol-2-amine
39 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
40 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
41 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-1,3,4-thiadiazol-2-amine
42 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
43 5-{1-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
44 5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
45 5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
46 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
47 N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
48 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazot-2-amine
49 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
50 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
51 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
52 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
53 N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
54 N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
55 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
56 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
57 N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
58 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
59 N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
60 5-[(3-methyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
61 N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
62 5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
63 N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
64 5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3.4-thiadiazol-2-amine and
65 N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine,
or a pharmaceutically acceptable salt thereof.either X is N and Y is CR5; or X is C and Y is S;
Z is selected from N and CH;
R1 is selected from H and Me,
R2 is selected from H, OH, OMe and Me;
One R3 group is NHRA and the remaining R3 groups are independently selected from C1-3alkyl, F, Cl, Br, CF3 and NHRA;
R4 is selected from Me, CF3, N02 and CHF2;
R5 is selected from H, Me and CHF2;
R6 is selected from H and Me;
Each RA is independently selected from -C(O)C1-4alkyl or -C(O)OC1-4alkyl; and
p is 0-3.
either X is N and Y is CR5; or X is C and Y is S;
R1 is selected from H and Me,
R2 is selected from H, OH, OMe and Me;
each R3 is independently selected from C1-3alkyl, F, Cl, Br, CF3 and NH2;
R4 is selected from Me, CF3, NO2 and CHF2;
R5 is selected from H, Me and CHF2;
R6 is selected from H and Me; and
p is 0-3,
comprising the step of reacting of compound of Formula (II) with a compound of Formula (III):either X is N and Y is CR5; or X is C and Y is S;
R1 is selected from H and Me;
R2 is selected from H, OH, OMe and Me;
each R3 is independently selected from C1-3alkyl, F, Cl, Br, CF3 and NH2;
R4 is selected from Me, CF3, NO2 and CHF2;
R5 is selected from H, Me and CHF2;
R6 is selected from H and Me; and
p is 0-3,
comprising the step of reacting a compound of Formula (IIb) with a compound of Formula (IIIb)Terms and definitions
Compound Preparation
Preparation of Compounds of Formula (I)
Synthesis of isothiacyanate intermediates of Formula (II)
Synthesis of hydrazine intermediates of Formula (III)
Compositions and formulations
Abbreviations
EtOAc | ethyl acetate |
Ac | acetyl |
AcOH | acetic acid |
Ac2O | acetic anhydride |
anh | anhydrous |
Boc | N-tert-butoxycarbonyl |
Boc anhydride | di-tert-butyl dicarbonate |
Celite® | a filter aid composed of acid-washed diatomaceous silica, |
(a trademark of Manville Corp., Denver, Colorado) | |
DME | dimethoxyethane |
DCM | dichloromethane |
DIBAL-H | diisobutyl aluminium hydride |
DMF | dimethylformamide |
DMSO-d6 | deuterated dimethylsulfoxide |
DMSO | dimethylsulfoxide |
ES MS | Electrospray mass spectrometry |
Et | Ethyl |
EtOH | ethanol |
h | hours |
HPLC | high performance liquid chromatography |
Int. | Intermediate |
LCMS | Liquid chromatography mass spectroscopy |
Mesylate | methylsulfonate |
Me | methyl |
MeOH | methanol |
Ms | methylsulfonate |
min(s) | minutes |
NaBH(OAc)3 | sodium triacetoxyborohydride |
NMR | Nuclear Magnetic Resonance spectroscopy |
Rt | retention time |
t-BuOMe | methyl t-butyl ether |
t-BuO | tert-butyloxy |
TFA | trifluoroacetic acid |
THF | tetrahydrofuran |
uv | ultraviolet |
Examples
Intermediates
Intermediate 1 : N-1H-pyrazol-3-ylacetamide.
Intermediate 2 : 1,1-dimethylethyl [4-chloro-3-(hydroxymethyl)phenyl]carbamate
Intermediate 3 : 1,1-dimethylethyl [3-(hydroxymethyl)-2-methylphenyl]carbamate
Intermediate 4 : 1,1-dimethylethyl [3-(bromomethyl)-4-chlorophenyl]carbamate
Intermediate 5 : 1,1-dimethylethyl [3-(bromomethyl)-2-methylphenyl]carbamate
Intermediate 6 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}acetamide
Int. | Structure | Benzyl bromide | Physical data |
7 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.43 (br.s, 1H), 7.75 (d, 1H), 7.51-7.54 (m, 1H), 7.41-7.45 (m, 1H), 7.08 (m, 1H), 6.51 (d, 1H), 5.31 (s, 2H), 1.96 (s, 3H). [ES+ MS] m/z 285 (MH+). |
LANCASTER | |||
8 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.37 (br.s, 1H), 7.61 (d, 1H), 7.14-7.20 (m, 3H), 6.94-7.13 (m, 1H), 6.46 (d, 1H), 5.21 (s, 2H), 2.26 (s, 3H), 1.95 (s, 3H), [ES+ MS] m/z 230 (MH+). |
ALDRICH | |||
9 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.42 (br.s, 1H), 7.71 (d, 1H), 7.62-7.65 (m, 1H), 7.33-7.38 (m, 1H), 7.22-7.28 (m, 1H), 6.93-6.96 (m, 1H), 6.50 (d, 1H), 5.29 (s, 2H), 1.96 (s, 3H). [ES+ MS] m/z 295 (MH+). |
ALDRICH | |||
10 |
|
|
1H NMR (300 MHz, CDCl3) δ ppm: 7.68-7.73 (m, 2H), 7.37- 7.51 (m, 2H), 7.35 (d, 2H), 6.91 (d, 1H), 6.77 (d, 1H), 5.41 (br.s, 2H), 2.15 (s, 3H) [ES+ MS] m/z 284 MH+) |
ALDRICH | |||
11 |
|
|
1H NMR (300 MHz, CDCl3) δ ppm: 7.70 (br. s, 1H), 7.32-7.39 (m, 2H), 7.00-7.08 (m, 2H), 6.72 (d, 1H), 5.24 (s, 2H), 2.14 (s, 3H). [ES+ MS] m/z 268 MH+). |
ALFAAESAR | |||
12 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.44 (br.s, 1H), 7.91-8.05 (m, 2H), 7.80 (d, 1H), 7.28 ( br.s, 1H), 6.56 (d, 1H), 5.52 (s, 2H), 1.96 (s, 3H). [ES+ MS] m/z 352 MH+). |
JRD | |||
13 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.44 (br.s, 1H), 7.83-7.88 (m, 1H), 7.78 (d, 1H), 7.35-7.41 (m, 1H), 6.66-6.69 (m, 1H), 6.55 (d, 1H), 5.43 (s, 2H) 1.96 (s, 3H). [ES+ MS] m/z 302 MH+). |
ALFAAESAR | |||
14 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.41 (br.s, 1 H), 7.73 (d, 1H), 7.34-7.43 (m, 1H), 7.15-7.22 (m, 1 H), 6.98-7.03 (m, 1H), 6.47 (d, 1 H), 5.31 (s, 2H) 1.94 (s, 3H). [ES+ MS] m/z 252 MH+). |
ALDRICH | |||
15 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.43 (br.s, 1H), 7.78 (d, 1H), 7.74 (m, 2H), 7.43 (br.s, 1H), 6.52 (d, 1H), 5.41 (s, 2H), 1.95 (s, 3H). [ES+ MS] m/z 318 MH+). |
ALFAAESAR | |||
16 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.38 (br.s, 1H), 7.66 (d, 1H), 7.23-7.34 (m, 2H), 6.43 (d, 1H), 5.31 (d, 2H), 2.22 (d, 3H), 1.92 (s, 3H), [ES+ MS] m/z 282 MH+). |
FLUOROCHEM | |||
17 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.37 (br.s, 1H), 7.67 (d, 1H), 7.38-7.43 (m, 1H), 7.16-7.22 (m, 1H), 6.43 (d, 1H), 5.34 (d, 2H), 2.31 (s, 3H), 1.92 (s, 3H), [ES+ MS] m/z 282 MH+). |
FLUOROCHEM | |||
18 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.39 (br.s, 1H), 7.68 (d, 1H), 7.20-7.25 (m, 1 H), 6.97-7.07 (m, 2H), 6.45 (d, 1H), 5.23 (br.s, 2H), 2.22 (d, 3H), 1.94 (s, 3H). [ES+ MS] m/z 248 (MH+). |
ALFAAESAR | |||
19 |
|
|
1H NMR (300 MHz, CDCl3) δ ppm:: 10.37 (s, 1H), 7.69 (d, 1H), 7.38 (d, 2H), 7.19 (d, 2H), 6.46 (d, 2H), 1.93 (s, 3H); [ES+ MS] m/z: 250 (MH+). |
ALDRICH | |||
21 |
|
|
1H NMR (300 MHz, CDCl3) δ ppm:: 7.80 (s, 1H), 7.39 (d, 1H), 7.35 (dd, 1H), 6.96 (m, 1H), 6.76 (d, 1H), 6.62 (dd, 1H), 5.26 (s, 2H), 2.15 (s, 3H); [ES+ MS] m/z: 268 (MH+). |
ALDRICH | |||
22 |
|
Intermediate 4 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.42 (br.s, 1H), 9.51 (br.s, 1H), 7.68 (d, 1H), 7.26-7.50 (m, 3H), 6.47 (d, 1 H), 5.23 (br.s, 2H), 1.95 (s, 3H), 1.45 (s, 9H). [ES+ MS] m/z 365 [MH+] |
| |||
23 |
|
Intermediate 5 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.37 (br.s, 1H), 8.60 (br.s, 1H), 7.60 (d, 1H), 7.17-7.20 (m, 1H), 7.06-7.11 (m, 1H), 6.77-6.80 (m, 1H), 6.46 (d, 1H), 5.21 (br.s, 2H), 2.10 (s, 3H), 1.95 (s, 3H), 1.44 (s, 9H), . [ES+ MS] m/z 345 [MH+] |
| |||
24 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.41 (br.s, 1H), 7.71 (d, 1H), 7.46-7.50 (m, 1H), 7.19-7.26 (m, 1H), 7.10-7.15 (m, 1H), 6.49 (d, 1H), 5.29 (s, 2H), 1.96 (s, 3H). [ES+ MS] m/z 253 (MH+) |
ACROS | |||
25 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.39 (s, 1H), 7.74 (d, 1H), 7.69 (d, 2H), 7.35 (d, 2H), 7.08 (m, 1H), 6.48 (d, 1H), 5.31 (s, 2H), 1.94 (s, 3H). [ES+ MS] m/z 284 (MH+). |
ALDRICH |
Intermediate 20: N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}acetamide.
Method B
Intermediate 26 : N-{1-[(2-fluorophenyl)methyl]-1H-pyrazol-3-yl}acetamida
Intermediate 27: 2-(1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione
Intermediate 28 : 2-(5-methyl-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione
Intermediate 29 : 2-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1H-isoindole-1,3(2H)-dione
Intermediate 30 : 2-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-1H-isoindole-1,3(2H)-dione
Intermediate 31 :2-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1H-isoindole-1,3(2H)-dione
Intermediate 32 : 2-{1-[(2-chloro-6-fluorophenyl)methyl]-5-methyl-1H-pyrazol-3-yl}-1H-isoindole-1,3(2H)-dione
Intermediate 33 : 1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-amine
Intermediate 34 : 1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-amine
Intermediate 35 : 1-(phenylmethyl)-1H-pyrazol-3-amine
Intermediate 36 : 1-[(2-chloro-6-fluorophenyl)methyl]-5-methyl-1H-pyrazol-3-amine
Intermediate 37 : 1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-amine
Int. | Structure | Acetyl intermediate to replace Int. 6 | Physical data |
38 |
|
7 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.48-7.51 (m, 2H), 7.36-7.41 (m, 1H), 6.89 (d, 1H), 5.46 (d, 1H), 5.13 (s, 2H), 4.69 (br. s, 2H). [ES+ MS] m/z 243 (MH+). |
39 |
|
8 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.32 (d, 1H), 7.09-7.17 (m, 3H), 6.89-6.91 (m, 1H), 5.41 (d, 1H), 5.02 (s, 2H), 4.5 (br. s, 2H), 2.27 (s, 3H). [ES+ MS] m/z 188 (MH+). |
40 |
|
9 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.60-7.63 (m, 1H), 7.45 (d, 1H), 7.30-7.36 (m, 1H), 7.19-7.25 (m, 1H), 6.85-6.88 (m, 1H), 5.45 (d, 1H), 5.10 (s , 2H), 4.62 (br. s, 2H).[ES+ MS] m/z 253 (MH+). |
41 |
|
10 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.72-7.74 (m, 1H), 7.58-7.63 (m, 1H), 7.45-7.50 (m, 2H), 6.86-6.89 (m, 1H), 5.47 (d, 1H), 5.24 (s, 2H), 4.66 (br. s, 2H). [ES+ MS] m/z 242 (MH+). |
42 |
|
11 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.49-7.54 (m, 1H), 7.45 (d, 1H), 7.16-7.21 (m, 1H), 7.06-7.11 (m, 1H), 5.41 (d, 1H), 5.12 (br.s, 2H), 4.62 (br. s, 2H).[ES MS] m/z 226 (MH+). |
43 |
|
12 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.87-8.02 (m, 2H), 7.55 (d, 1H), 7.11 (br,s, 1H), 5.51 (d, 1H), 5.34 (br.s , 2H), 4.74 (br. s, 2H). [ES+ MS] m/z 310 (MH+). |
44 |
|
13 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.79-7.84 (m, 1H), 7.52 (d, 1H), 7.32-7.36 (m, 1H), 6.53-6.55 (m, 1H), 5.50 (d, 1H), 5.26 (br.s , 2H), 4.76 (br. s, 2H). [ES+ MS] m/z 260 (MH+). |
See footnote (a) | |||
45 |
|
14 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.45 (d, 1H), 7.30-7.39 (m, 1H), 7-12-7.20 (m, 1H), 6.92-6.96 (m, 1H), 5.41 (d, 1H), 5.13 (br.s , 2H), 4.61 (br. s, 2H).[ES MS] m/z 210 (MH+). |
46 |
|
15 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.67-7.74 (m, 2H), 7.51 (d, 1H), 7.22 (br.s, 1H), 5.46 (d, 1H), 5.22 (br.s , 2H), 4.69 (br. s, 2H). [ES+ MS] m/z 276 (MH+). |
47 |
|
16 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.34 (d, 1H), 7.21-7.32 (m, 2H), 5.35 (d, 1H), 5.13 (d, 2H), 4.57 (br. s, 2H), 2.21 (d, 3H). [ES+ MS] m/z 240 (MH+). |
48 |
|
17 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.35-7.41 (m, 2H), 7.13-7.19 (m, 1H), 5.35 (d, 1H), 5.15 (d , 2H), 4.56 (br. s, 2H), 2.30 (s, 3H).[ES MS] m/z 240 (MH+). |
49 |
|
18 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.40 (d, 1H), 7.17-7.22 (m, 1H), 7.00-7.05 (m, 1H), 6.90-6.95 (m, 1H), 5.40 (d, 1H), 5.05 (br.s, 2H), 4.57 (br. s, 2H), 2.22 (d, 3H).[ES+ MS] m/z 206 (MH+). |
50 |
|
19 | 1H NMR (300 MHz, CDCl3) δ ppm: 7.26-7.32 (m, 2H), 7.15 (d, 1H), 7.12 (m, 2H), 5.63 (d, 1H), 5.07 (s, 2H), 3.65 (br s, 2H); [ES+ MS] m/z: 208. |
52 |
|
26 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.41 (d, 1H), 7.29-7.37 (m, 1H), 7.08-7.21 (m, 3H), 5.40 (d, 1H), 5.08 (s, 2H), 4.58 (br. s, 2H). |
53 |
|
24 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.43-7.47 (m,2H), 7.14-7.22 (m, 1H), 6.99-7.18 (m1H), 5.13 (d, 1H), 5.1 (s, 2H), 4.63 (br. S, 2H),. [ES+ MS] m/z 226 (MH+) |
54 |
|
25 | 1H NMR (300 MHz, CDCl3-d6) δ ppm: 7.58 (d, 2H), 7.28 (m, 1H), 7.20 (d, 1H), 5.66 (d, 1H), 5.16 (s, 2H), 3.67 (br. s, 2H). [ES+ MS] m/z 242 (MH+). |
(a) Purified by HPLC preparative using SunFire Chromatography Column, Method (40_00) ACN/H2O, in neutral conditions |
Intermediate 51 : 1-[(2,6-difluorophenyl)methyl]-1 H-pyrazol-3-amine.
Intermediate 55 : 1,1-dimethylethyl {3-[(3-amino-1H-pyrazol-1-yl)methyl]-4-chlorophenyl}carbamate.
Intermediate 56 : 1,1-dimethylethyl {3-[(3-amino-1H-pyrazol-1-yl)methyl]-2-methylphenyl}carbamate.
Intermediate 57 : 1-[(2-chloro-6-fluorophenyl)methyl]-3-isothiocyanato-1H-pyrazole
Int | Structure | Starting intermediate to replace Int. 37 | Physical data |
58 |
|
38 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.96 (d, 1H), 7.53-7.56 (m,1H), 7.45-7.48 (m, 1H), 7.21 (d, 1H), 6.49 (d, 1H), 5.40 (s, 2H). [MS] m/z 285 (MH+) |
59 |
|
39 | 1H NMR (300 MHz, DMSO-d6) 8 ppm: 7.86 (d, 1H), 7.17-7.23 (m,3H), 6.97-6.99 (m, 1H), 6.46 (d, 1H), 5.30 (s, 2H), 2.28 (s, 3H). [ES+ MS] m/z 230 [MH+] |
60 |
|
40 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.93 (d, 1H), 7.65-7.68 (m, 1H), 7.36-7.41 (m, 1H), 7.26-7.32 (m, 1H), 7.02-7.05 (m, 1H), 6.48 (d, 1H), 5.38 (s, 2H). [ES+ MS] m/z 295 [MH+] |
61 |
|
54 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.50 (s, 2H), 6.51 (d, 1H), 7.01-7.04 (m, 1H), 7.52-7.57 (m, 1H), 7.64-7.69 (m, 1H), 7.77-7.80 (m, 1H), 7.96 (d, 1H) [ES+ MS] m/z 284 (MH+) |
62 |
|
33 or 42 | 1H NMR (300 MHz, DMSO-d6) δ, ppm: 5.40 (d, 2H), 6.46 (d, 1H), 7.19-7.27 (m, 2H), 7.55-7.61 (m, 1H), 7.96 (d, 1H) [ES+ MS] m/z 268 (MH+) |
From 33 - see notes (a) & (b) | |||
63 |
|
43 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.60 (s, 2H), 6.53 (d, 1H), 7.46 (br.s, 1H), 7.96-8.01 (m, 3H). |
64 |
|
44 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.99 (d, 1H), 7.86-7.90 (m, 1H), 7.39-7.44 (m, 1H), 6.82-6.86 (m, 1H), 6.53 (d, 1H), 5.51 (br.s, 2H). |
65 |
|
45 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.95 (d, 1H), 7.37-7.46 (m, 1H), 7.17-7.23 (m, 1H), 7.03-7.08 (m, 1H), 6.46 (d, 1H), 5.40 (s, 2H). [ES+ MS] m/z 252 (MH+). |
See footnote (b) | |||
66 |
|
46 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.99 (d, 1H), 7.76 (br.s, 2H), 7.57 (br.s,1H), 6.49 (d, 1H), 5.50 (s, 2H). |
67 |
|
47 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.91 (d, 1H), 7.21-7.39 (m, 2H), 6.43 (d, 1H), 5.39 (s, 2H), 2.22 (d, 3H),. [ES+ MS] m/z 282 [MH+] |
68 |
|
48 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.91 (d, 1H), 7.42-7.47 (m, 1H), 7.19-7.25 (m, 1H), 6.41 (d, 1H), 5.42 (s, 2H), 2.31 (s, 3H), [ES+ MS] m/z 282 [MH+] |
69 |
|
34 or 49 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.90 (d, 1H), 7.22-7.28 (m, 1H), 7.02-7.10 (m, 2H), 6.44 (d, 1H), 5.32 (s, 2H), 2.22 (d, 3H). [ES+ MS] m/z 248 (MH+). |
71 |
|
52 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.92 (d, 1H), 7.35-7.43 (m, 1H), 7.17-7.27 (m, 3H), 6.45 (d, 1H), 5.35 (s, 2H). [ES+ MS] m/z 234 [MH+] |
72 |
|
35 | 1H NMR (300 MHz, CDCl3) δ ppm: 7.21-7.40 (m, 5H), 6.19 (d, 1H), 5.22 (s, 2H). [ES+ MS] [MH+] 216 |
73 |
|
53 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.38 (s, 2H), 6.47 (d, 1H), 7.23-7.26 (m, 2H), 7.49-7.53 (m, 1H), 7.90 (d, 1H). |
74 |
|
55 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.51 (br.s, 1H), 7.91 (d, 1H), 7.44-7.48 (m, 1H), 7.33-7.37 (m, 1H), 7.17 (m, 1H), 6.48 (d, 1H), 5.33 (s, 2H), 1.45 (s, 9H). [ES+ MS] m/z 365 (MH+) |
75 |
|
56 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.62 (br.s, 1H), 7.83 (d, 1H), 7.21-7.23 (m, 1H), 7.09-7.14 (m, 1H), 6.81-6.83 (m, 1H), 6.45 (d, 1H), 5.31 (s, 2H), 2.11 (s, 3H), 1.44 (s, 9H). [ES+ MS] m/z 345 (MH+) |
76 |
|
36 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.25-7.49 (m, 3H), 6.23 (s, 1H), 5.28 (d, 2H), 2.37 (s, 3H). [ES+ MS] m/z 282 (MH+). |
See footnote (a) |
(a) Organic phase was washed with water (b) Crude was purified in silica gel cartridge with gradient Hex/ETOAc (0-10%) |
Intermediate 70: 1-[(2,6-difluorophenyl)methyl]-3-isothiocyanato-1 H-pyrazole
Intermediate 77 : Ethyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoate
Intermediate 78 : 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanohydrazide
Intermediate 79 : Ethyl 3-amino-2-methyl-3-thioxopropanoate
Intermediate 80 : Ethyl 2-(4-methyl-1,3-thiazol-2-yl)propanoate
Intermediate 81 : 2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide and
Intermediate 82 : 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide
Intermediate 83 : Ethyl 2-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanoate
Intermediate 84 : 2-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propanohydrazide
Intermediate 85 : 2-chloro-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3-thiazole
Intermediate 86: ethyl 2-bromo-2-(4-methyl-1,3-thiazol-2-yl)propanoate
Intermediate 87: ethyl 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanoate
Intermediate 82 (alternative procedure): 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide
Intermediate 88: ethyl 2-(methyloxy)-2-(4-methyl-1,3-thiazol-2-yl)propanoate
Intermediate 89: ethyl diazo(4-methyl-1,3-thiazol-2-yl)acetate
Intermediate 90: ethyl (methyloxy)(4-methyl-1,3-thiazol-2-yl)acetate
Intermediate 91: ethyl 3-amino-2,2-dimethyl-3-thioxopropanoate
Intermediate 92: ethyl 2-methyl-2-(4-methyl-1,3-thiazol-2-yl)propanoate
Int. | Structure | Ester to replace Int. 83 | Physical data |
93 |
|
Intermediate 88 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.24 (br s, 1H), 7.24 (s, 1H), 4.10-4.50 (m, 2H), 3.16 (s, 3H), 2.32 (s, 3H), 1.70 (s, 3H). [ES+ MS] m/z 216 (MH+). |
| |||
94 |
|
Intermediate 90 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.57 (br s, 1H), 7.26 (d, 1H), 4.94 (s, 3H), 4.38 (br s, 2H), 2.32 (s, 3H). |
| |||
95 |
|
Intermediate 92 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.95 (br s, 1H), 7.13 (s, 1H), 4.24 (br s, 2H), 2.31 (s, 3H), 1.54 (s, 6H). [ES+MS] m/z 200 (MH+). |
|
a) Residue was pre-absorbed on silica and loaded on a 10g silica gel cartridge, eluted with a linear gradient, 0-20%MeOH-DCM. |
Intermediate 96: (2,6-difluoro-3-nitrophenyl)methanol
Intermediate 97: (3-amino-2,6-difluorophenyl)methanol
Intermediate 98: [3-(acetylamino)-2,6-difluorophenyl]methyl acetate
Intermediate 99: N-[2,4-difluoro-3-(hydroxymethyl)phenyl]acetamide
Intermediate 100: [3-(acetylamino)-2,6-difluorophenyl]methyl methanesulfonate
Intermediate 101: (3-amino-2-fluorophenyl)methanol
Intermediate 102: ethyl [2-fluoro-3-(hydroxymethyl)phenyl]carbamate
Intermediate 103: ethyl [3-(bromomethyl)-2-fluorophenyl]carbamate
Intermediate 104: ethyl (3-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1H-pyrazol-1-yl]methyl}-2-fluorophenyl)carbamate
Intermediate 105: N-(3-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1H-pyrazol-1-yl]methyl}-2,4-difluorophenyl)acetamide
Int. | Structure | Benzyl bromide | Physical data |
106 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.37 (br s, 1H), 7.70 (d, 1H), 7.11-7.29 (m, 4H), 6.45 (d, 1H), 5.17 (s, 2H), 1.94 (s, 3H). [ES+ MS] m/z 234 (MH+). |
ALDRICH | |||
a) | |||
107 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.39 (br s, 1H), 7.70 (d, 1H), 7.45-7.58 (m, 1H), 7.12-7.22 (m, 1H), 6.44 (d, 1H), 5.30 (s, 2H), 1.92 (s, 3H), [ES+ MS] m/z 270 (MH+). |
ALDRICH | |||
b) | |||
108 |
|
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.39 (br s, 1H), 7.65 (d, 1H), 7.24-7.35 (m, 1H), 6.96-7.05 (m, 1H), 6.42 (d, 1H), 5.24 (s, 2H), 2.18 (s, 3H), 1.91 (s, 3H). [ES+ MS] m/z 266 (MH+). |
APOLLO |
a) Reaction was partitioned between saturated NH4Cl and DCM, and purified by FlashMaster using a 10 g silica gel cartridge with gradient Hexane/AcOEt (0-70%). b) Reaction was partitioned between saturated NH4Cl and DCM, and purified by FlashMaster using a 25 g silica gel cartridge with gradient Hexane/AcOEt (0-50%). |
Int. | Structure | Intermediate (to replace Int. 6) | Physical data |
109 |
|
106 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.42 (d, 1H), 7.08-7.25 (m, 4H), 5.39 (d, 1H), 4.99 (s, 2H), 4.55 (br s, 2H). [ES+ MS] m/z 192 (MH+). |
a) | |||
110 |
|
107 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.42-7.55 (m, 1 H), 7.40 (d, 1H), 7.09-7.19 (m, 1H), 5.36 (d, 1H), 5.11 (s, 2H), 4.60 (br s, 2H). [ES+ MS] m/z 228 (MH+). |
a), b) | |||
111 |
|
108 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.34 (d, 1H), 7.22-7.32 (m, 1H), 6.94-7.02 (m, 1H), 5.35 (d, 1H), 5.05 (s, 2H), 4.57 (br s, 2H), 2.18 (s, 3H). [ES+ MS] m/z 224 (MH+). |
a) | |||
112 |
|
107 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.22-7.33 (m, 2H), 6.91-7.01 (m, 1H), 5.35 (d, 1H), 5.02 (s, 2H), 4.52 (br s, 2H), 4.05 (qd, 2H), 1.29 (t, 3H). [ES+ MS] m/z 254 (MH+). |
a), b) |
a) Remaining aqueous fraction was diluted with distilled water and EtOAc. Aqueous layer was extracted with EtOAc (x3); organic layers were combined and dried over MgSO4 anh, and concentrated. b) Purified by preparative HPLC using XTERRA Chromatography Column (30x150mm), Method (0_80) ACN (0.1%TFA) /H2O (0.1%TFA). |
Intermediate 113 : ethyl {3-[(3-amino-1H-pyrazol-1-yl)methyl]-2-fluorophenyl}carbamate
Intermediate 114 : N-{3-[(3-amino-1H-pyrazol-1-yl)methyl]-2,4-difluorophenyl}acetamide
Int. | Structure | Starting intermediate (to replace Int. 37) | Physical data |
115 |
|
109 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.93 (d, 1H), 7.27-7.35 (m, 2H), 7.13-7.23 (m, 2H), 6.44 (d, 1H), 5.26 (s, 2H). [MS] m/z 234 (MH+). |
a) | |||
116 |
|
110 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.95 (s, 1H), 7.46-7.62 (m, 1H), 7.12-7.25 (m, 1H), 6.38-6.46 (m, 1H), 5.39 (s, 2H). [ES+ MS] m/z 270 (MH*). |
a) | |||
117 |
|
111 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.90 (d, 1H), 7.28-7.39 (m, 1H), 6.99-7.09 (m, 1H), 6.41 (dd, 1H), 5.33 (s, 2H), 2.19 (s, 3H). [ES+ MS] m/z 266 (MH+). |
a) | |||
118 |
|
112 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.86 (d, 1H), 7.29-7.40 (m, 1H), 6.97-7.06 (m, 1H), 6.41 (dd, 1H), 5.28 (s, 2H), 4.08 (q, 2H), 1.28 (t, 3H). [ES+ MS] m/z 296 (MH+). |
a) | |||
119 |
|
113 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.33 (br s, 1H), 7.92 (d, 1H), 7.55-7.64 (m, 1H), 7.07-7.15 (m, 1H), 6.91-6.99 (m, 1H), 6.44 (d, 1H), 5.33 (s, 2H), 4.11 (q, 2H), 1.22 (t, 3H). [ES+ MS] m/z 321 (MH+). |
120 |
|
114 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.77 (br s, 1H), 7.92 (d, 1H), 7.77-7.90 (m, 1 H), 7.05-7.15 (m, 1H), 6.42 (d, 1H), 5.36 (s, 2H), 2.05 (s, 3H). |
a) Reaction was diluted with DCM and aqueous sodium bicarbonate. Phases were separated and organic phase was dried over MgSO4 (anh), filtrated and concentrated. b) Reaction was diluted with DCM and distilled water. Phases were separated and organic phase was dried over Na2SO4 (anh), filtrated and concentrated. |
Intermediate 121. Ethyl (2-fluoro-3-{[3-({5-[1-hydroxy-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-yl}amino)-1H-pyrazol-1-yl]methyl}phenyl)carbamate
Examples
Method A
Example 1 : 5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(trifluoromethyl) phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
Ex. | Structure | Isothiocyanate Intermediate | Hydrazide intermediate | Physical data |
2 |
|
58 0.231 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.79 (d, 1H), 7.51-7.54 (m, 1H), 7.41-7.45 (m, 1H), 7.15 (d, 1H), 6.01 (d, 1H), 5.83 (s, 1H), 5.77 (q, 1H), 5.32 (s, 2H), 2.25 (s, 3H), 2.08 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 448 (MH+). |
N-{1-[(2,5-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnote (a) |
| |||
0.231 mmol | ||||
3 |
|
60 0.255 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.76 (d, 1H), 7.63-7.66 (m, 1H), 7.23-7.37 (m, 2H), 7.02-7.05 (m, 1H), 5.99 (d, 1H), 5.84 (br s, 1H), 5.76 (q, 1H), 5.29 (s, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 458 (MH+). |
N-{1-[(2-bromophenyl)methyl-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine amine See footnote (a) |
| |||
0.255 mmol | ||||
4 |
|
58 0.197 mmol |
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.93 (br s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.51-7.54 (m, 1H), 7.41-7.45 (m, 1H), 7.13 (d, 1H), 6.01-6.06 (m, 2H), 5.83 (q, 1H), 5.32 (s, 2H), 2.15 (s, 3H), 1.82 (d, 3H). [ES+ MS] m/z 434 (MH+). |
N-{1-[(2,5-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.197 mmol ARTCHEM | |||
5 |
|
60 0.258 mmol |
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.91 (br s, 1H), 7.75-7.76 (m, 2H), 7.63-7.66 (m, 1H), 7.23-7.37 (m, 2H), 6.99-7.02 (m, 1H), 6.06 (d, 1H), 5.99 (d, 1H), 5.83 (q, 1H), 5.29 (br s, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.82 (d, 3H). [ES+ MS] m/z 445 (MH+). |
N-{1-[(2-bromophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.258 mmol ARTCHEM | |||
6 |
|
71 0.343 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br s. 1H), 7.73 (d, 1H), 7.13-7.25 (m, 3H), 5.97 (d, 1H), 5.85 (s, 1H), 5.77 (q, 1H), 5.26 (br s, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 448 (MH+). |
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine See footnote (a) |
| |||
0.343 mmol | ||||
7 |
|
62 0.530 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.89 (br s, 1H), 7.77 (d, 1H), 7.52-7.58 (m, 1H), 7.17-7.23 (m, 2H), 5.99 (d, 1H), 5.84 (s, 1H), 5.77 (q, 1H), 5.32 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 432 MH+). |
N-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine |
| |||
0.530 mmol | ||||
8 |
|
63 0.683 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.94 (br s, 1H), 7.92-8.05 (m, 2H), 7.86 (d,1H), 7.45 (s, 1H), 6.04 (d, 1H), 5.72-5.80 (m, 2H), 5.51 (br s, 2H), 2.22 (s, 3H), 2.04 (s, 3H), 1.77 (d, 3H). [ES+ MS] m/z 516 (MH+). |
N-(1-{[2,5-bis(trifluoromethyl)phenyl] methyl)-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnote (b) |
| |||
0.683 mmol | ||||
9 |
|
64 0.531 mmo |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.94 (br s, 1H), 7.82-7.88 (m, 2H), 7.36-7.42 (m, 1H), 6.82-6.84 (m, 1H), 6.03 (d, 1H), 5.75-5.81 (m, 2H), 5.42 (br s, 2H), 2.23 (s, 3H), 2.06 (s, 3H), 1.78 (d, 3H).[ES+ MS] m/z 516 (MH+). |
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[5-fluoro-2-(trifluoromethyl)phenyl] methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine |
| |||
0.531 mmol | ||||
10 |
|
65 0.8 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.90 (br s, 1H), 7.77 (d, 1H), 7.01-7.44 (m, 3H), 5.98 (d, 1H), 5.84 (s, 1H), 5.77 (q, 1H), 5.32 (br s, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 416 (MH+). |
N-{1-[(2,3-difluorophenyl)methyl)-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnote (a) |
| |||
0.8 mmol | ||||
11 |
|
66 0.604 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.92 (br s, 1H), 7.83 (d, 1H), 7.74 (br s, 2H), 7.45 (br s, 1H), 6.01 (d, 1H), 5.75-5.82 (m, 2H), 5.41 (br s, 2H), 2.24 (s, 3H), 2.06 (s, 3H), 1.77 (d, 3H). [ES+ MS] m/z 482 (MH+). |
N-(1-{[2-chloro-5-(trifluoromethyl)phenyl] methyl}-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-thiadiazol-2-amine See footnote (a) |
| |||
0.604 mmol | ||||
12 |
|
70 0.299 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.84 (br s, 1H), 7.71 (d, 1H), 7.39-7.50 (m, 1H), 7.07-7.12 (m, 2H), 5.92 (d, 1H), 5.86 (s, 1H), 5.75 (q, 1H), 5.24 (s, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.78 (d, 3H). [ES+ MS] m/z 416 (MH+). |
N-{1-[(2,6-difluorophenyl)methyl)-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnotes (b) and (d) |
| |||
0.358 mmol | ||||
13 |
|
69 0.309 mmol |
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br s, 1H), 7.74 (d, 1H), 7.71 (d, 1H), 7.19-7.25 (m, 1H), 6.97-7.06 (m, 2H), 6.06 (d, 1H), 5.96 (d, 1H), 5.83 (q, 1H), 5.23 (s, 2H), 2.23 (d, 3H), 2.15 (s, 3H), 1.81 (d, 3H). [ES+ MS] m/z 398 (MH+). |
N-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-yl)ethyl]-1.3.4-thiadiazol-2-amine See footnote (a) |
0.309mmol ARTCHEM | |||
14 |
|
62 0.297 mmol |
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.88 (br s, 1H), 7.77 (d, 1H), 7.74 (d, 1H), 7.51-7.57 (m, 1H), 7.13-7.21 (m, 2H), 6.06 (d, 1H), 5.99 (d, 1H), 5.82 (q, 1H), 5.31 (s, 2H), 2.15 (s, 3H), 1.81 (d, 3H). [ES+ MS] m/z 418 (MH+). |
N-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnote (a) |
0.297 mmol ARTCHEM | |||
15 |
|
65 0.191 mmol |
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.88 (br s, 1H), 7.77 (d, 1H), 7.74 (d, 1H), 7.33-7.43 (m, 1H), 7.12-7.20 (m, 1H), 6.99-7.03 (m, 1H), 6.06 (d, 1H), 5.98 (d, 1H), 5.83 (q, 1H), 5.31 (s, 2H), 2.15 (s, 3H), 1.81 (d, 3H). [ES+ MS] m/z 402 (MH+). |
N-{1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnote (a) |
0.191 mmol ARTCHEM | |||
16 |
|
65 0.178 mmol |
81 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.89 (br s, 1H), 7.77 (d, 1H), 7.33-7.42 (m, 1H), 7.12-7.21 (m, 2H), 6.99-7.04 (m, 1H), 5.99 (d, 1H), 5.32 (s, 2H), 4.89 (q, 1H) 2.33 (s, 3H), 1.72 (d, 3H). [ES+ MS] m/z 419 (MH+). |
N-{1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl)-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine See footnotes (c) and (b) |
| |||
0.178 mmol | ||||
17 |
|
73 0.347 mmol |
78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.75 (d, 1H); 7.46-7.49 (m, 1H), 7.18-7.21 (m, 2H), 5.97 (d, 1H), 5.85 (s, 1H), 5.76 (q, 1H), 5.29 (br.s, 2H), 2.25 (s, 3H), 2.09 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 432 (MH+). |
N-{1-[(2-chloro-4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadlezol-2-amine See footnote (a) |
| |||
0.347 mmol | ||||
18 |
|
73 0.273 mmol |
|
1H NMR (300 MHz, DMSO-d6) δ ppm: 10.92 (br.s, 1H), 7.75-7.76 (m, 2H), 7.46-7.50 (m, 1 H), 7.17-7.21 (m, 2H), 6.06 (m,1H), 5.98 (d, 1H), 5.83 (q, 1H), 5.29 (br.s, 2H), 2.16 (s, 3H), 1.82 (d, 3H). [ES+ MS] m/z 418 (MH+). |
N-{1-[(2-chloro-4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-(1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.273 mmol ARTCHEM |
(a) The initial precipitate did not need EtOAc/water treatment (b) Precipitate was purified by HPLC preparative using SunFire Chromatography Column (30mmx 150mm), Method (40 100) ACN/H2O, in neutral conditions. (c) Initial precipitate was partitioned between DCM/water. (d) Product was dissolved in DCM (HPLC grade) and precipitated with Hexane (HPLC grade). |
Example 19 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-5-methyl-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Method B
Example 20 : 5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-methylphenyl) methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine.
Ex. | Structure | Isothiocyanate intermediate | Hydrazide intermediate | Physical data |
21 |
|
72 | 78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.85 (br s. 1H), 7.74 (d, 1H), 7.24-7.33 (m, 2H) 5.96 (d, 1H), 5.85 (br s, 1H), 5.78 (q, 1H), 5.20 (br s, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 1.80 (d, 3H). [ES+ MS] m/z 380 (MH+). |
| ||||
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl-N-[1-(phenylmethyl)-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine | 0.813 mmol | 0.813 mmol | ||
See footnote (a) | ||||
22 |
|
67 | 78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br s. 1H), 7.71 (d, 1H), 7.22-7.34 (m, 2H), 5.90 (d, 1H), 5.85 (br s, 1H), 5.76 (q, 1H), 5.31 (d, 2H), 2.24-2.26 (m, 3H), 2.07-2.11 (m, 3H), 1.80 (d, 3H). [ES+ MS] m/z 446 (MH+). |
| ||||
N-{1-[(6-chloro-2-fluoro-3-methylphenyl) methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.838 mmol | 0.838 mmol | ||
23 |
|
68 | 78 | 1 H NMR (300 MHz, DMSO-d6) δ ppm: 10.85 (br s, 1H), 7.71 (d, 1H), 7.38-7.43 (m, 1H), 7.13-7.19 (m, 1H), 5.90 (d, 1H), 5.87 (br s, 1H), 5.75 (q, 1H), 5.33 (d, 2H), 2.32 (br s, 3H), 2.26 (br s, 3H), 2.12 (br s, 3H), 1.80 (d, 3H). [ES+ MS) m/z 446 (MH+). |
| ||||
N-{1-[(2-chloro-6-fluoro-3-methylphenyl) methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.609 mmol | 0.609 mmol | ||
24 |
|
69 | 78 | 1 H NMR (300 MHz, DMSO-d6) δ ppm: 10.86 (br s, 1H), 7.72 (d, 1H), 7.20-7.26 (m, 1 H), 7.02-7.07 (m, 2H), 5.96 (d, 1H), 5.84 (br s, 1H), 5.77 (q, 1H), 5.24 (d, 2H), 2.25 (br s, 3H), 2.10 (br s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 412 (MH+). |
| ||||
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine | 0.505 mmol | 0.505 mmol | ||
See footnote (a) | ||||
25 |
|
69 | 81 | 1H-NMR (δ, ppm, CDCl3): 7.37 (d, 1H), 7.18-7.13 (m, 1H), 7.04-7.00 (m, 2H), 6.85 (m, 1H), 6.15 (d, 1H), 5.25 (s, 2H), 4.81 (q, 1H), 2.46 (s, 3H), 2.28 (d, 3H), 1.89 (d, 3H). [ES+ MS] m/z 421 (MH+) |
| ||||
N-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.238 mmol | 0.238 mmol | ||
See footnote (a) | ||||
26 |
|
74 | 78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.88 (br.s, 1H), 7.67 (d, 1H), 7.05 (d, 1H), 6.47-6.50 (m, 1H), 6.02 (d, 1H), 6.19 (d, 1H), 5.83 (br.s, 1H), 5.77 (q, 1H), 5.26 (br.s, 2H), 5.15 (br.s, 2H), 2.25 (s, 3H), 2.09 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 429 (MH+) |
| ||||
N-{1-[(5-amino-2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.244 mmol | 0.244 mmol | ||
See footnote (b) | ||||
27 |
|
75 | 78 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.84 (br.s, 1H), 7.54 (d, 1H), 6.80-6.85 (m, 1H), 6.57-6.60 (m, 1H), 6.30-6.32 (m, 1H), 5.91 (d, 1H), 5.85 (br.s, 1H), 5.78 (q, 1H), 5.12 (br.s, 2H), 4.83 (br.s, 2H), 2.26 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 1.80 (d, 3H),. [ES+ MS] m/z 409 (MH+) |
| ||||
N-{1-[(3-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.186 mmol | 0.186 mmo | ||
See footnote (c). |
(a) Method (40_100) ACN/H2O, in neutral conditions. (b) Method (30_100) ACN (0.1%TFA) /H2O (0.1%TFA). Obtaining corresponding salt, that was basified with NH3 (aq, 32%) partitioned between AcOEt/H2O. Organic layer was dried over MgSO4 (anh), filtered and solvent was eliminated. (c) Method (20_100) ACN/H2O, in neutral conditions. |
Method C
Example 28 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Ex. | Structure | Isothiocyanate intermediate | Hydrazide intermediate | Physical data |
29 |
|
57 | 81 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.71 (s, 1H), 7.46-7.21 (m, 5H), 5.92 (d, 1H), 5.32 (s, 2H), 4.87 (q, 1H), 2.35 (s, 3H), 1.71 (d, 3H). [ES+ MS] m/z 435 (MH+) |
| ||||
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.702 mmol | 0.702 mmol | ||
See footnote (a) | ||||
30 |
|
57 | 82 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.84 (s, 1H), 7.69 (s, 1H), 7.43-7.21 (m, 5H), 5.90 (d, 1H), 5.32 (s, 2H), 2.29 (s, 3H), 1.97 (s, 3H). [ES+ MS] m/z 451 (MH+) |
| ||||
1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol | 0.328 mmol | 0.328 mmol | ||
See footnote (a) | ||||
31 |
|
57 | 84 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.50 (s, 1H), 7.72 (s, 1H), 7.45-7.20 (m, 4H), 5.92 (d, 1H), 5.33 (s, 2H), 5.06 (q, 1H), 1.76 (d, 3H). [ES+ MS] m/z 489 (MH+) |
| ||||
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[4-(trifluoromethyl)-1,3-thiazol-2-yl]ethyl}-1,3,4-thiadiazol-2-amine | 0.773 mmol | 0.773 mmol | ||
32 |
|
57 |
|
1H NMR (300 MHz, CDCl3) δ ppm: 7.36-7.20 (m, 4H), 7.07-7.01 (m, 1 H), 6.83 (m, 1 H), 6.01 (d, 1 H), 5.36 (d, 2H), 4.66 (s, 2H), 2.48 (s, 3H). [ES+ MS] m/z 415 (MH+) |
0.209 mmol | ENAMINE | |||
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amine | 0.209 mmol | |||
33 |
|
62 | 81 | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.90 (s, 1H), 7.66 (d, 1H), 7.56-7.50 (m, 1H), 7.20-7.15 (m. 3H), 5.99 (d, 1H), 5.31 (s, 2H), 4.88 (q, 1H), 2.33 (s, 3H), 1.72 (d, 3H). [ES+ MS] m/z 435 (MH+) |
| ||||
N-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-Pyrazol-3-yl)-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.238 mmol | 0.238 mmol | ||
See footnote (b) |
(a) Resulting suspension was diluted with EtOAc and water. Organic phase was separated, washed with brine, dried over sodium sulphate and concentrated Crude was purified by chromatography on silica gel using a DCM/MeOH gradient to yield title compound. (b) Aqueous mixture was extracted with ethyl acetate. Organic extract was washed with brine, dried over sodium sulphate and concentrated. Residue was triturated with ethyl ether and resulting solid was filtered and washed with ethyl ether. |
Example 34 : N-{1-[(4-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Example 35 : 5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine.
Example 36 : N-{1-[(2-chloro-5-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Example 37 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3-thiazol-2-amine
Example | Structure | Name |
38 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine |
39 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
40 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine |
41 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-1,3,4-thiadiazol-2-amine |
42 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine |
43 |
|
5-{1-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine |
44 |
|
5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine |
45 |
|
5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-N-[1-(phenylmethyl)-1H pyrazol-3-yl]-1,3,4-thiadiazol-2-amine |
46 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine |
47 |
|
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
48 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine |
49 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
50 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
51 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
52 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
53 |
|
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
54 |
|
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine |
55 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluoromethyl}-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine |
56 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
57 |
|
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
58 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
59 |
|
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(tifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine |
60 |
|
5-[(3-methyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine |
61 |
|
N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine |
62 |
|
5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine |
63 |
|
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine |
64 |
|
5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine |
65 |
|
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine |
Chiral separation of racemate Example 38
Example 66 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1R)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Example 67 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Chiral separation of racemate Example 28
Example 68 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1R)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Example 69 : N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Chiral separation of racemate Example 30
Example 70: (1S)-1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
Example 71: (1R)-1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
Ex. | Structure | Isothiocyanate intermediate | Hydrazide intermediate | Example method | Purification | Physical data |
72 |
|
57 | 92 | Example 28 | a), b) and c) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.00 (br.s, 1H), 7.72 (d, 1H), 7.18-7.47 (m, 4H), 5.89 (d, 1H), 5.32 (s, 2H), 3.23 (s, 3H), 2.30 (s, 3H), 1.99 (s, 3H). [ES+ MS] m/z 465 (MH+) |
0.172 mmol |
0.172 | |||||
N-{1-[(2-chloro-6-fluorophenyl)methy]-1H-pyrazol-3-yl}-5-[1-(methyloxy)-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine | mmol | |||||
73 |
|
70 | 92 | Example 28 | a) and d) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.95 (br.s, 1 H), 7.72 (d, 1 H), 7.37-7.48 (m, 2H), 7.05-7.14 (m, 2H), 5.93 (d, 1 H), 5.91 (s, 1H), 5.26 (s, 2H), 3.40 (s, 3H), 2.32 (s, 3H). [ES+ MS] m/z 435 (MH+) |
1.043 mmol |
1.043 | |||||
N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(methyloxy)(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amine | mmol | |||||
74 |
|
57 | 94 | Example 28 | a) and c) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.85 (br.s, 1H), 7.72 (d, 1H), 7.20-7.46 (m, 4H), 5.91 (d, 1H), 5.32 (s, 2H), 2.35 (s, 3H), 1.82 (s, 6H). [ES+ MS] m/z 449 (MH+) |
0.703 mmol |
| |||||
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-methyl-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1.3,4-thiadiazol-2-amine | 0.703 mmol | |||||
75 |
|
114 | 78 | Example 1 | c) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.85 (br.s, 1H), 7.73 (d, 1H), 7.25-7.32 (m, 2H), 7.10-7.18 (m, 2H), 5.96 (d, 1H), 5.84 (s, 1H), 5.77 (q, 1H), 5.18 (s, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.79 (d, 3H). [ES+ MS] m/z 398 (MH+) |
| ||||||
5-[1-(3, 5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine | 0.917 mmol | 1.101 mmol | ||||
76 |
|
70 |
|
Example 1 | c) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.85 (br.s, 1 H), 7.74 (d, 1H), 7.70 (d, 1H), 7.39-7.50 (m, 1H), 7.05-7.15 (m, 2H), 6.09 (d, 1 H), 5.93 (d, 1H), 5.81 (q, 1H), 5.24 (s, 2H), 2.18 (s, 3H), 1.81 (d, 3H). [ES+ MS] m/z 402 (MH+) |
N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 0.297 mmol | 0.297 mmol | ||||
ARTCHEM | ||||||
77 |
|
115 | 78 | Example 1 | b) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br.s, 1 H), 7.75 (d, 1H), 7.45-7.58 (m, 1H), 7.10-7.19 (m, 1 H), 5.93 (d, 1 H), 5.84 (s, 1H), 5.75 (q, 1H), 5.29 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 1.78 (d, 3H). [ES+ MS] m/z 434 (MH+) |
0.557 mmol |
| |||||
5-[1-(3,5-dimethyl-1H-pyrazd-1-yl)ethyl]-N-{1-[(2,3,6-trifluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine | 0.613mmol | |||||
79 |
|
62 | 82 | Example 28 | e) and b) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.88 (br.s, 1H), 7.76 (d, 1H), 7.49-7.56 (m, 1H), 7.10-7.29 (m, 4H), 5.98 (d, 1H), 5.32 (s, 2H), 2.29 (s, 3H), 1.97 (s, 3H). [ES+ MS] m/z 451 (MH+) |
0.730 mmol |
| |||||
1-[5-({1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol | 0.730 mmol | |||||
80 |
|
65 | Example 28 | e) and b) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.88 (br.s, 1H), 7.76 (d, 1H), 6.96-7.43 (m, 5H), 5.98 (d, 1H), 5.32 (s, 2H), 2.29 (s, 3H), 1.97 (s, 3H). [ES+ MS] m/z 435 (MH+) | |
0.919 mmol |
| |||||
1-[5-({1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol | 0.919 mmol | |||||
81 |
|
116 | 78 | Example 1 | b) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.84 (br.s, 1H), 7.70 (d, 1H), 7.25-7.35 (m, 1H), 6.95-7.03 (m, 1 H), 5.92 (d, 1H), 5.84 (s, 1H), 5.75 (q, 1H), 5.23 (s, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.78 (d, 3H). [ES+ MS] m/z 430 (MH+) |
1.086 mmol |
| |||||
N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | 1.086mmol | |||||
82 |
|
117 | 78 | Example 20 | b) and f) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.85 (br.s, 1H), 7.68 (d, 1H), 7.26-7.36 (m, 1H), 6.92-7.01 (m, 1 H), 5.90 (d, 1 H), 5.83 (s, 1H), 5.74 (q, 1 H), 5.21 (s, 2H), 4.11 (q, 2H), 2.23 (s, 3H), 2.09 (s, 3H), 1.78 (d, 3H), 1.31 (t, 3H). [ES+ MS] m/z 460 (MH+) |
0.271 mmol |
| |||||
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(ethyloxy)-3,6-difluorophenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiezol-2-amine | 0.271mmol |
a) Aqueous mixture was extracted with EtOAc. Organic extract was washed with brine, dried over sodium sulphate and concentrated. b) Crude was purified by chromatography on silica gel using a Hexane/EtOAc gradient. c) Crude was purified by chromatography on silica gel using a DCM/MeOH gradient. d) Residue was triturated with ethanol, filtered and dried under vacuum. e) Resulting precipitate was filtered, washed with water several times, and dried under vacuum. f) Preparative HPLC using XTERRA Chromatography Column (19mmx150mm), Method (40_80) ACN (0.1 %TFA) /H2O (0.1 %TFA). |
Example 78: 1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
Ex. | Structure | Isothiocyanate intermediate | Hydrazide intermediate | Example method | Purification | Physical data |
83 | 1-[5-({1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol | 69 | 82 | Example 28 | No further purification | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.70 (d, 1H), 7.18-7.29 (m, 3H), 6.95-7.06 (m, 2H), 5.94 (d, 1 H), 5.24 (s, 2H), 2.29 (s, 3H), 2.23 (d, 3H), 1.97 (s, 3H). [ES+ MS] m/z 431 (MH+) |
|
0.189 mmol |
| ||||
0.189 mmol | ||||||
84 | 1-[5-({1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol | 116 | 82 | Example 28 | a) and b) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.82 (br.s, 1H), 7.68 (d, 1H), 7.19-7.34 (m, 3H), 6.95-7.03 (m, 1H), 5.92 (d, 1H), 5.23 (s, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 1.97 (s, 3H). [ES+ MS] m/z 449 (MH+) |
|
0.199 mmol |
| ||||
0.199 mmol | ||||||
85 | N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine | 116 | 81 | Example 1 | c) | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.70 (d, 1H), 7.19-7.34 (m, 2H), 6.95-7.04 (m, 1H), 5.94 (d, 1H), 5.24 (s, 2H), 4.87 (q, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 1.72 (d, 3H). [ES+ MS] m/z 433 (MH+) |
|
0.520 mmol |
| ||||
0.520 mmol | ||||||
86 |
|
116 |
|
Example 1 | No further purification | 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.73 (d, 1H), 7.69 (d, 1H), 7.25-7.35 (m, 1H), 6.95-7.04 (m, 1H), 6.07 (d, 1H), 5.93 (d, 1H), 5.82 (q, 1H), 5.23 (s, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 1.81 (d, 3H). [ES+ MS] m/z 416 (MH+) |
0.520 mmol | 0.520 mmol | |||||
N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine | ARTCHEM |
a) Aqueous mixture was extracted with EtOAc. Organic extract was washed with brine, dried over sodium sulphate and concentrated. bc) Crude was purified by chromatography on silica gel using a DCM/MeOH gradient. c) Preparative HPLC using XBRIDGE Chromatography Column (19mmx150mm), Method (40_100) ACN /H2O (0.1% NH4CO3 10 mM). |
Example 87: N-{1-[(3-amino-2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
Intermediate 122 N-(3-{[3-({5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}amino)-1H-pyrazol-1-yl]methyl}-2,4-difluorophenyl)acetamide
Example 88 : 1-[5-({1-[(3-amino-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
Chiral separation of racemate Example 78
Example 89 : (1S)-1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
Example 90 : (1R)-1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
Biological Activity
Mycobacterium tuberculosis H37Rv Inhibition Assay (Whole Cell Assay)
Results of the Mycobacterium tuberculosis H37Rv Inhibition Assay (Whole Cell Assay)
Mycobacterium tuberculosis InhA Inhibition Assay (Enzyme Assay)
Results of the Mycobacterium tuberculosis InhA Inhibition Assay (Enzyme Assay)
either X is N and Y is CR5; or X is C and Y is S;
Z is selected from N and CH;
R1 is selected from H and Me,
R2 is selected from H, OH, OMe and Me;
each R3 is independently selected from C1-3alkyl, F, Cl, Br, CF3 and NH2;
R4 is selected from Me, CF3, NO2 and CHF2;
R5 is selected from H, Me and CHF2;
R6 is selected from H and Me; and
p is 0-3,
for use in therapy.
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-{1-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
5-[(3-methyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amine
5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine and
N-{1-[(2,6-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine,
or a pharmaceutically acceptable salt thereof for use in therapy.either X is N and Y is CR5; or X is C and Y is S;
Z is selected from N and CH;
R1 is Me,
R2 is selected from H, OH, and OMe;
each R3 is independently selected from C1-3alkyl, F, Cl, Br, CF3 and NH2;
R4 is selected from Me, CF3, NO2 and CHF2;
R5 is selected from H, Me and CHF2;
R6 is selected from H and Me; and
p is 0-3.
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine and
(1S)-1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanoland
(1S)-1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol,
or a pharmaceutically acceptable salt thereof.X is C and Y is S;
Z is selected from N and CH;
R1 is selected from H and Me,
R2 is selected from H, OH, OMe and Me;
each R3 is independently selected from C1-3alkyl, F, Cl, Br, CF3 and NH2;
R4 is selected from Me, CF3, NO2 and CHF2;
R6 is selected from H and Me; and
p is 0-3.
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
N-{1-[(2,5-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-bromophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,5-dichlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-bromophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
N-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-(1-{[2,5-bis(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[5-fluoro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
N-{1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-(1-{[2-chloro-5-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-5-methyl-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-methylphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine.
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4 thiadiazol-2-amine
N-{1-[(6-chloro-2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
N-{1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(5-amino-2-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(3-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-frfluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
1-[5-({1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[4-(trifluoromethyl)-1,3-thiazol-2-yl]ethyl}-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(4-chlorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-5-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine and
N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3-thiazol-2-amine,
or a pharmaceutically acceptable salt thereof.N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(methyloxy)-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1, 3,4-thiadiazol-2-am ine
N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(methyloxy)(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2-chloro-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-methyl-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2,3,6-trifluorophenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
1-[5-({1-[(2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
1-[5-({1-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
1-[5-({1-[(2,3-difluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine and
5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(ethyloxy)-3,6-difluorophenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
or a pharmaceutically acceptable salt thereof.1-[5-({1-[(2-fluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
1-[5-({1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(2,6-difluoro-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine
N-{1-[(3-amino-2,6-difluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine and
1-[5-({1-[(3-amino-2-fluorophenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol,
or a pharmaceutically acceptable salt thereof.entweder X N und Y CR5 ist; oder X C und Y S ist;
Z aus N und CH ausgewählt ist;
R1 aus H und Me ausgewählt ist;
R2 aus H, OH, OMe und Me ausgewählt ist;
jedes R3 unabhängig aus C1-3-Alkyl, F, Cl, Br, CF3 und NH2 ausgewählt ist;
R4 aus Me, CF3, NO2 und CHF2 ausgewählt ist;
R5 aus H, Me und CHF2 ausgewählt ist;
R6 aus H und Me ausgewählt ist; und
p 0 bis 3 ist,
zur Verwendung in der Therapie.N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[3-(difluormethyl)-5-methyl-1H-pyrazol-1-yl]ethyl}-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
5-{1-[3-(Difluormethyl)-5-methyl-1H-pyrazol-1-yl]-ethyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin
5-[1-(3-Methyl-1H-pyrazol-1-yl)ethyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin
5-{[3-(Difluormethyl)-5-methyl-1H-pyrazol-1-yl]-methyl}-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluormethyl)-5-methyl-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-{[5-methyl-3-(trifluormethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(difluormethyl)-5-methyl-1H-pyrazol-1-yl]-methyl}-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3-methyl-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluormethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amin
5-[(3-Methyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin
N-[1-(Phenylmethyl)-1H-pyrazol-3-yl]-5-{[3-(trifluormethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amin
5-[(5-Methyl-3-nitro-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-{[3-(trifluormethyl)-1H-pyrazol-1-yl]methyl}-1,3,4-thiadiazol-2-amin
5-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin und
N-{1-[(2,6-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(5-methyl-3-nitro-1H-pyrazol-1-yl)methyl]-1,3,4-thiadiazol-2-amin
oder ein pharmazeutisch annehmbares Salz davon zur Verwendung in der Therapie.
entweder X N und Y CR5 ist; oder X C und Y S ist;
Z aus N und CH ausgewählt ist;
R1 Me ist;
R2 aus H, OH und OMe ausgewählt ist;
jedes R3 unabhängig aus C1-3-Alkyl, F, Cl, Br, CF3 und NH2 ausgewählt ist;
R4 aus Me, CF3, NO2 und CHF2 ausgewählt ist;
R5 aus H, Me und CHF2 ausgewählt ist;
R6 aus H und Me ausgewählt ist; und
p 0 bis 3 ist.N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
(1S)-1-[5-({1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yllamino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol und
(1S)-1-[5-({1-[(2,6-Difluorphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
oder ein pharmazeutisch annehmbares Salz davon.X C und Y S ist;
Z aus N und CH ausgewählt ist;
R1 aus H und Me ausgewählt ist;
R2 aus H, OH, OMe und Me ausgewählt ist;
jedes R3 unabhängig aus C1-3-Alkyl, F, Cl, Br, CF3 und NH2 ausgewählt ist;
R4 aus Me, CF3, NO2 und CHF2 ausgewählt ist;
R6 aus H und Me ausgewählt ist;
p 0 bis 3 ist.
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(trifluormethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amin
N-{1-[(2,5-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Bromphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,5-Dichlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Bromphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-fluorphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
N-{1-[(3-Chlor-2-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-(1-{[2,5-bis(trifluormethyl)phenyl]methyl}-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)-ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[5-fluor-2-(trifluormethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amin
N-{1-[(2,3-Difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-(1-{[2-Chlor-5-(trifluormethyl)phenyl]methyl}-1H-pyrazol-3-yl)-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)-ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Fluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(3-Chlor-2-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,3-Difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,3-Difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-4-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-4-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-5-methyl-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)-ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-methylphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-[1-(phenylmethyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amin
N-{1-[(6-Chlor-2-fluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)-ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)-ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2-fluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
N-{1-[(2-Fluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(5-Amino-2-chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(3-Amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amin
1-[5-({1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-{1-[4-(trifluormethyl)-1,3-thiazol-2-yl]ethyl}-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(3-Chlor-2-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(4-Chlorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[4-(trifluormethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-5-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin und
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-1,3-thiazol-2-amin
oder ein pharmazeutisch annehmbares Salz davon.N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(methyloxy)-1-(4-methyl-1,3-thiazol-2-yl)-ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[(methyloxy)(4-methyl-1,3-thiazol-2-yl)methyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2-Chlor-6-fluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-methyl-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(4-fluorphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-{1-[(2,3,6-trifluorphenyl)methyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amin
1-[5-({1-[(2,6-Difluorphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
1-[5-({1-[(3-Chlor-2-fluorphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
1-[5-({1-[(2,3-Difluorphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
N-{1-[(2,6-Difluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin und
5-[1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-N-(1-{[2-(ethyloxy)-3,6-difluorphenyl]methyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amin
oder ein pharmazeutisch annehmbares Salz davon.1-[5-({1-[(2-Fluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
1-[5-({1-[(2,6-Difluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
N-{1-[(2,6-Difluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(2,6-Difluor-3-methylphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin
N-{1-[(3-Amino-2,6-difluorphenyl)methyl]-1H-pyrazol-3-yl}-5-[1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amin und
1-[5-({1-[(3-Amino-2-fluorphenyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol
oder ein pharmazeutisch annehmbares Salz davon.X est N et Y est CR5 ; ou X est C et Y est S ;
Z est choisi parmi N et CH ;
R1 est choisi parmi H et Me ;
R2 est choisi parmi H, OH, OMe et Me ;
chaque R3 est choisi indépendamment parmi alkyle en C1-C3, F, Cl, Br, CF3 et NH2 ;
R4 est choisi parmi Me, CF3, NO2 et CHF2 ;
R5 est choisi parmi H, Me et CHF2 ;
R6 est choisi parmi H et Me ; et
p vaut 0 à 3,
destiné à une utilisation en thérapie.
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3-méthyl-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(5-méthyl-3-nitro-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-{1-[3-(difluorométhyl)-5-méthyl-1H-pyrazol-1-yl]éthyl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-{1-[(3-(difluorométhyl)-5-méthyl-1H-pyrazol-1-yl]éthyl}-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
la 5-{[3-(difluorométhyl)-5-méthyl-1H-pyrazol-1-yl]méthyl}-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-{[3-(difluorométhyl)-5-méthyl-1H-pyrazol-1-yl]méthyl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-{[5-méthyl-3-(trifluorométhyl)-1H-pyrazol-1-yl]méthyl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(5-méthyl-3-nitro-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3,5-diméthyl-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3-nitro-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3,5-diméthyl-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-{[3-(difluorométhyl)-5-méthyl-1H-pyrazol-1-yl]méthyl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3,5-diméthyl-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3-méthyl-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(5-méthyl-3-nitro-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-{[3-(trifluorométhyl)-1H-pyrazol-1-yl]méthyl}-1,3,4-thiadiazol-2-amine
la 5-[(3-méthyl-1H-pyrazol-1-yl)méthyl]-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
la N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-5-{[3-(trifluorométhyl)-1H-pyrazol-1-yl]méthyl}-1,3,4-thiadiazol-2-amine
la 5-[(5-méthyl-3-nitro-1H-pyrazol-1-yl)méthyl]-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-{[3-(trifluorométhyl)-1H-pyrazol-1-yl]méthyl}-1,3,4-thiadiazol-2-amine
la 5-[(3,5-diméthyl-1H-pyrazol-1-yl)méthyl]-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine et
la N-{1-[(2,6-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(5-méthyl-3-nitro-1H-pyrazol-1-yl)méthyl]-1,3,4-thiadiazol-2-amine,
ou un sel pharmaceutiquement acceptable de celui-ci destiné à une utilisation en thérapie.X est N et Y est CR5 ; ou X est C et Y est S ;
Z est choisi parmi N et CH ;
R1 est Me ;
R2 est choisi parmi H, OH et OMe ;
chaque R3 est choisi indépendamment parmi alkyle en C1-C3, F, Cl, Br, CF3 et NH2 ;
R4 est choisi parmi Me, CF3, NO2 et CHF2 ;
R5 est choisi parmi H, Me et CHF2 ;
R6 est choisi parmi H et Me ; et
p vaut 0 à 3.
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine et
le (1S)-1-[5-({1-[(2-chloro-6-fluorophényl) méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol et
le (1S)-1-[5-({1-[(2,6-difluorophényl)méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol,
ou un sel pharmaceutiquement acceptable de celui-ci.X est C et Y est S ;
Z est choisi parmi N et CH ;
R1 est choisi parmi H et Me ;
R2 est choisi parmi H, OH, OMe et Me ;
chaque R3 est choisi indépendamment parmi alkyle en C1-C3, F, Cl, Br, CF3 et NH2 ;
R4 est choisi parmi Me, CF3, NO2 et CHF2 ;
R6 est choisi parmi H et Me ; et
p vaut 0 à 3.
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-(1-{[2-(trifluorométhyl)phényl]méthyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
la N-{1-[(2,5-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-bromophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,5-dichlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-bromophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(2-fluorophényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
la N-{1-[(3-chloro-2-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-(1-{[2,5-bis(trifluorométhyl)phényl]méthyl}-1H-pyrazol-3-yl)-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-(1-{[5-fluoro-2-(trifluorométhyl)phényl]méthyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
la N-{1-[(2,3-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-(1-{[2-chloro-5-(trifluorométhyl)phényl]méthyl}-1H-pyrazol-3-yl)-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-fluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(3-chloro-2-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,3-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,3-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-4-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-4-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-5-méthyl-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(2-méthylphényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-[1-(phénylméthyl)-1H-pyrazol-3-yl]-1,3,4-thiadiazol-2-amine
la N-{1-[(6-chloro-2-fluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(2-fluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2-fluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(5-amino-2-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(3-amino-2-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
le 1-[5-({1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-{1-[4-(trifluorométhyl)-1,3-thiazol-2-yl]éthyl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(4-méthyl-1,3-thiazol-2-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(3-chloro-2-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(4-chlorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-(1-{[4-(trifluorométhyl)phényl]méthyl}-1H-pyrazol-3-yl)-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-5-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine, et
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3-thiazol-2-amine,
ou un sel pharmaceutiquement acceptable de celui-ci.la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(méthyloxy)-1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[(méthyloxy)(4-méthyl-1,3-thiazol-2-yl)méthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2-chloro-6-fluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-méthyl-1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(4-fluorophényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(4-fluorophényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(4-fluorophényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-{1-[(2,3,6-trifluorophényl)méthyl]-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine
le 1-[5-({1-[(2,6-difluorophényl)méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
le 1-[5-({1-[(3-chloro-2-fluorophényl)méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
le 1-[5-({1-[(2,3-difluorophényl)méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
la N-{1-[(2,6-difluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine, et
la 5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-N-(1-{[2-(éthyloxy)-3,6-difluorophényl]méthyl}-1H-pyrazol-3-yl}-1,3,4-thiadiazol-2-amine,
ou un sel pharmaceutiquement acceptable de celui-ci.le 1-[5-({1-[(2-fluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yllamino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
le 1-[5-({1-[(2,6-difluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
la N-{1-[(2,6-difluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(4-méthyl-1,3-thiazol-2-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(2,6-difluoro-3-méthylphényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3-méthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine
la N-{1-[(3-amino-2,6-difluorophényl)méthyl]-1H-pyrazol-3-yl}-5-[1-(3,5-diméthyl-1H-pyrazol-1-yl)éthyl]-1,3,4-thiadiazol-2-amine, et
le 1-[5-({1-[(3-amino-2-fluorophényl)méthyl]-1H-pyrazol-3-yllamino)-1,3,4-thiadiazol-2-yl]-1-(4-méthyl-1,3-thiazol-2-yl)éthanol
ou un sel pharmaceutiquement acceptable de celui-ci.REFERENCES CITED IN THE DESCRIPTION
Non-patent literature cited in the description