Compounds as nuclear transport modulators and uses thereof
Nuclear transport modulators are disclosed. The compounds can inhibit nuclear transporters such as the exportin-1 transporter. The compounds and pharmaceutical compositions comprising the compounds can be used to treat neurological diseases and cancer.
1. A compound selected from:
I
(Z)-3-(3-(3- (pentafluoro-sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyrazin-2- yl)acrylohydrazide
II
(Z)-3-(3-(3- (pentafluoro-sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- N′-(pyridin-2- yl)acrylohydrazide
III
(Z)-3-(3-(3- (pentafluoro-sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)-N′- pivaloyl- acrylohydrazide
IV
(E)-3-(3-(3- (pentafluoro-sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)-2 -(pyrimidin-5- yl)acrylamide
VI
(Z)-3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)- N′-(thiazol-2- yl)acrylohydrazide
VII
(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclopropane- carbohydrazide
VIII
(Z)-N′-isobutyryl-3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylohydrazide
IX
(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)acryloyl) butyrohydrazide
X
(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1- yl)acryloyl) cyclobutane- carbohydrazide
XI
(Z)-1-methyl-N′-(3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)acryloyl) cyclopropane-1- carbohydrazide
XII
(Z)-N′-(3-chloro-2- (hydroxymethyl)- 2-methylpropanoyl)-3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylohydrazide
or a pharmaceutically acceptable salt of any of the foregoing.
2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, support or combination of any of the foregoing.
3. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is an oral formulation.
4. A method of treating cancer in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the cancer is glioblastoma.
5. A compound selected from:
XIII
(Z)-3-methyl- N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl)acryloyl) butanehydrazide
XIV
(Z)-N′-acetyl-3- (3-(3-(pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylohydrazide
XV
(Z)-3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H- 1,2,4-triazol- 1-yl)-N′- propionyl- acrylohydrazide
XVI
(Z)-N′-(3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1yl)acryloyl)- cyclopentane- carbohydrazide
XVII
(Z)-N′-(2-methyl- 2-(methyl- d3)propanoyl- 3,3,3-d3)-3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylohydrazide
XVIII
(Z)-3-(3-(3- (difluoromethyl)-5- (pentafluoro- sulfaneyl)phenyl)-1H- 1,2,4-triazol-1- yl)-N′-(pyrazin-2- yl)acrylohydrazide
XIX
(Z)-3-(3-(3- (difluoromethyl)-5- (pentafluoro- sulfaneyl)phenyl)-1H- 1,2,4-triazol-1- yl)-N′-(pyridin-2- yl)acrylohydrazide
XX
(Z)-3-(3-(3- (difluoromethyl)-5- (pentafluoro- sulfaneyl)phenyl)-1H- 1,2,4-triazol-1-yl)-N′- pivaloylacrylo- hydrazide
XXI
(Z)-3-(3-(3- (pentafluoro- sulfaneyl)- 5-(trifluoromethyl) phenyl)-1H- 1,2,4-triazol-1-yl)- N′-(pyridazin-3- yl)acrylohydrazide
XXII
(Z)-N′-(2-hydroxy-2- methylpropanoyl)- 3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylohydrazide
XXIII
(Z)-N′-(2-fluoro-2- methylpropanoyl)- 3-(3-(3- (pentafluoro- sulfaneyl)-5- (trifluoromethyl) phenyl)-1H-1,2,4- triazol-1-yl) acrylohydrazide
or a pharmaceutically acceptable salt of any of the foregoing.
6. A pharmaceutical composition comprising the compound of claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, support or combination of any of the foregoing.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is an oral formulation.
8. The compound of claim 1 , wherein the compound is (Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide (I), or a pharmaceutically acceptable salt thereof:
9. The compound of claim 1 , wherein the compound is (Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide (II), or a pharmaceutically acceptable salt thereof:
10. The compound of claim 1 , wherein the compound is (Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide (III), or a pharmaceutically acceptable salt thereof:
11. The compound of claim 1 , wherein the compound is (E)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide (IV), or a pharmaceutically acceptable salt thereof:
12. The compound of claim 1 , wherein the compound is (Z)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(thiazol-2-yl)acrylohydrazide (VI), or a pharmaceutically acceptable salt thereof:
13. The compound of claim 1 , wherein the compound is (Z)—N′-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropanecarbohydrazide (VII), or a pharmaceutically acceptable salt thereof:
14. The compound of claim 1 , wherein the compound is (Z)—N′-isobutyryl-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (VIII), or a pharmaceutically acceptable salt thereof:
15. The compound of claim 1 , wherein the compound is (Z)—N′-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)butyrohydrazide (IX), or a pharmaceutically acceptable salt thereof:
16. The compound of claim 1 , wherein the compound is (Z)—N′-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclobutanecarbohydrazide (X), or a pharmaceutically acceptable salt thereof:
17. The compound of claim 1 , wherein the compound is (Z)-1-methyl-N′-(3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)cyclopropane-1-carbohydrazide (XI), or a pharmaceutically acceptable salt thereof:
18. The compound of claim 1 , wherein the compound is (Z)—N′-(3-chloro-2-(hydroxymethyl)-2-methylpropanoyl)-3-(3-(3-(pentafluoro-sulfaneyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (XII), or a pharmaceutically acceptable salt thereof:
19. The pharmaceutical composition of claim 2 , wherein the composition comprises another chemotherapeutic agent, a TK or RTK inhibitor, a BCL2 inhibitor, a FLT3 inhibitor, an EGFR inhibitor, a pro-apoptotic drug, an antibody-drug conjugate (ADC), an immune checkpoint inhibitor, CAR-T, a personalized cancer vaccine, or a chemokine/cytokine, or a combination of any of the foregoing.