Nuclear transport modulators and uses thereof
The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula (I) or their pharmaceutically acceptable salts, and methods of using said compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.
1. A compound of structural formula (Ia), (Ib), or (Ic):
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 , if present, is independently selected from —CF 3 , halo, —OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 3-18-membered heterocyclyl, halo-C 1 -C 3 alkyl, —NH 2 , —NO 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)—(C 1 -C 3 alkyl), —O—(C 1 -C 3 alkyl), —O—(C 1 -C 3 haloalkyl), and —S—(C 1 -C 3 alkyl);
R 2 and R b are each independently selected from: —C(O)—N(R 5 )(R 6 ), halogen, C(O)—O—R 3 , —C(O)—N(R 7 )—N(R 5 )(R 6 ), —C(O)—N(R 7 )—N(R 7 )—C(O)—R 4
and —C(O)—N(R 7 )—N(R 7 )—S(O) 1-2 —R 4 , a 6-18-membered aryl or a 5-18-membered heteroaryl;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-member heterocyclyl and 5-18-member heteroaryl;
R 4 is selected from —N(H)(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-C 3 -C 18 carbocyclyl, —(C 0 -C 4 alkylene)-3-18-member heterocyclyl, —(C 0 -C 4 alkylene)-C 6 -C 18 aryl, and —(C 0 -C 4 alkylene)-5-18-member heteroaryl;
R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 18 carbocyclyl, C 6 -C 18 aryl, 3-18-member heterocyclyl and 5-18-member heteroaryl; or
R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-member heterocyclyl or 5-18-member heteroaryl; and
each R 7 is independently hydrogen or C 1 -C 4 alkyl;
n is 0, 1, 2, 3, 4 or 5;
wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
2. The compound of claim 1 , represented by formula (II)
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , represented by formula (III)
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R b is —C(O)—NH 2 , C(O)—OH, —C(O)—O(C 1 -C 4 )alkyl, —C(O)—N(R 7 )—N(R 5 )(R 6 ), —C(O)—N(R 7 )—N(R 7 )—C(O)—R 4 , or —C(O)—N(R 7 )—N(R 7 )—S(O) 1-2 —R 4 .
5. The compound of claim 4 , wherein R b is —C(O)—NH 2 , —C(O)—OH, C(O)—O(C 1 -C 4 )alkyl; or —C(O)—NH—NH(R 6 ), and R 6 is an optionally substituted 5-18-member heteroaryl; or
—C(O)—NH—NH—C(O)—R 4 or —C(O)—NH—NH—S(O) 1-2 —R 4 , and R 4 is selected from optionally substituted —N(H)(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl, —(C 0 -C 4 alkylene)-3-18-member heterocyclyl and —(C 0 -C 4 alkylene)-5-18-member heteroaryl.
6. The compound of claim 1 , wherein R b is —C(O)NH 2 .
7. The compound of claim 1 , wherein R b is —C(O)OH.
8. The compound of claim 1 , wherein R b is —C(O)OCH 3 or —C(O)OCH 2 CH 3 .
9. The compound of claim 1 , wherein R b is phenyl.
10. The compound of claim 1 , wherein R b is a 5-6-membered heteroaryl.
11. The compound of claim 1 , wherein R b is halo.
12. The compound of claim 11 , wherein R b is bromo.
13. The compound of claim 1 , wherein R 2 is a 6-12-membered aryl or a 5-12-membered heteroaryl.
14. The compound of claim 13 , wherein R 2 is phenyl.
15. The compound of claim 13 , wherein R 2 is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, and oxadiazolyl.
16. The compound of claim 13 , wherein R 2 is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl.
17. The compound of claim 1 , wherein R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, phenyl, 5-6-membered heteroaryl, —S(O) 1-2 —R 8 and N(H)S(O) 1-2 —R 8 , R 8 is selected from —N(R 9 )R 10 , (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, —(C 0 -C 4 alkylene) C 3 -C 18 carbocyclyl, and —(C 0 -C 4 alkylene)-3-18-member heterocyclyl;
R 9 is hydrogen or —C 1 -C 4 alkyl;
R 10 is selected from —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 0 -C 4 alkylene)-C 3 -C 18 carbocyclyl and —(C 0 -C 4 alkylene)-3-18-member heterocyclyl; or
R 9 and R 10 are taken together with the nitrogen atom to which they are commonly attached to form a 4-7-membered heterocyclyl.
18. The compound of claim 17 , wherein R 2 is substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, —CF 3 , amino and cyano.
19. The compound of claim 1 , wherein R 2 is selected from: —C(O)NH 2 , —C(O)OH, —C(O)OCH 3 , —C(O)OCH 2 CH 3 and halo.
20. The compound of claim 1 , wherein n is 1 or 2 and each R 1 is independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and —O—(C 1 -C 4 )alkyl.
21. The compound of claim 1 , wherein the compound is represented by the following structural formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 1a and R 1b are independently selected from —CF 3 , halo, —OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 3-12-membered heterocyclyl, halo-C 1 -C 3 alkyl, —NH 2 , —NO 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)—(C 1 -C 3 alkyl), —O—(C 1 -C 3 alkyl), —O—(C 1 -C 3 haloalkyl), and —S—(C 1 -C 3 alkyl); and
m is 0 or 1.
22. The compound of claim 21 , wherein R 1a is halo or —C 1 -C 3 haloalkyl.
23. The compound of claim 21 , wherein R 1b is —C 1 -C 3 haloalkyl or —O—C 1 -C 3 alkyl.
24. The compound of claim 21 , wherein R 1a is —CF 3 and R 1b is —CF 3 .
25. A compound represented by any one of the following structural formulas:
or a pharmaceutically acceptable salt thereof.
26. A compound represented by any one of the following structural formulas:
or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
28. A method for treating a disorder associated with CRM1 activity, wherein the disorder associated with CRM1 is selected from a proliferative disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, an inflammatory disorder, a disorder of abnormal tissue growth, a disorder related to food intake, an allergic disorder, and a respiratory disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
29. The method of claim 28 , wherein the proliferative disorder is selected from a hematologic malignancy or a solid tumor.
30. The method of claim 29 , wherein the hematologic malignancy is selected from leukemia, lymphoma, myeloma, myelodysplastic syndrome, myeloproliferative syndrome.
31. The method of claim 30 , wherein the hematologic malignancy is selected from chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), T-cell ALL, B-cell non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, follicular lymphoma, and multiple myeloma.
32. The method of claim 31 , wherein the proliferative disorder is multiple myeloma.
33. The method of claim 32 , wherein the proliferative disorder is relapsed or refractory multiple myeloma.
34. The method of claim 29 , wherein the proliferative disorder is selected from prostate cancer, breast cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, renal cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, and stromal tumor.