NUCLEAR TRANSPORT MODULATORS AND USES THEREOF
The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by formula I: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.
1 . A compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring B is an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
X is selected from O, S, N—CN, and NR;
R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Y is a covalent bond or an optionally substituted bivalent C 1-4 hydrocarbon group, wherein one methylene unit of Y is optionally replaced by —O—, —S—, —N(R 6 )—, —C(O)—, —C(S)—, —C(O)N(R 6 )—, —N(R 6 )C(O)N(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )C(O)O—, —OC(O)N(R 6 )—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 6 )—, —N(R 6 )S(O) 2 —, —OC(O)— or —C(O)O—;
each of R 1 and R 2 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
R 1 and R 2 are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed thereby is substituted with —(R 5 ) p ;
each of n, m, and p is independently an integer selected from 0, 1, 2, 3 and 4;
q is an integer selected from 0, 1 and 2;
each of R 3 , R 4 , and R 5 is independently halogen, —NO 2 , —CN, —N 3 , -L-R 6 , or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R 3 groups on Ring B are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R 4 groups on Ring A are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R 5 groups on the ring formed by R 1 and R 2 are taken together with their intervening atoms to form a fused 4-8 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L is a covalent bond or an optionally substituted bivalent C 1-6 hydrocarbon group, wherein one or two methylene units of L is optionally and independently replaced by —Cy-, —O—, —S—, —N(R 6 )—, —C(O)—, —C(S)—, —C(O)N(R 6 )—, —N(R 6 )C(O)N(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )C(O)O—, —OC(O)N(R 6 )—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 6 )—, —N(R 6 )S(O) 2 —, —OC(O)— or —C(O)O—; —Cy- is an optionally substituted bivalent ring selected from a 3-7 membered saturated or partially unsaturated cycloalkylenylene ring, a 4-7-membered saturated or partially unsaturated heterocycloalkylene ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenylene, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic arylene, and an 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 6 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R 6 on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
provided the compound is not (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-N-cyclopentylacrylamide, (Z)-1-(azetidin-1-yl)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one, (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)prop-2-en-1-one, (Z)-1-(3,3-difluoroazetidin-1-yl)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one, (Z)-1-(3,3-difluoroazetidin-1-yl)-3-(3-(3-isopropoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one, (Z)-3-(5-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-N-phenylacrylamide, (Z)-3-(5-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-N-methyl-N-phenylacrylamide, (E)-tert-butyl (4-(3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylamido)phenyl)carbamate, (E)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-N-(4-methoxyphenyl)acrylamide, (E)-N-(3-chlorophenyl)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylamide, (E)-N-(4-aminophenyl)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylamide, (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-N-isopropyl-N-methylacrylamide, (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-N-fluoro-N-isopropylacrylamide, (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylamide, (E)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-N-phenylacrylamide, (E)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)-N-methyl-N-phenylacrylamide, (E)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylamide or (Z)-3-(3-(3-isopropoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide.
2 . The compound according to claim 1 , wherein Ring A is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
3 . The compound according to claim 1 , wherein Ring A is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl.
4 . The compound according to claim 3 , wherein Ring A is triazolyl.
5 - 7 . (canceled)
8 . The compound according to claim 3 , wherein Ring A is selected from:
9 - 11 . (canceled)
12 . The compound according to claim 1 , wherein Ring B is phenyl.
13 . The compound according to claim 12 , wherein Ring B is substituted and is represented by the following structural formula
14 . The compound according to claim 1 , wherein X is O.
15 . The compound according to claim 1 , wherein Y is a covalent bond.
16 . The compound according to claim 1 , wherein R 1 and R 2 are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
17 . The compound according to claim 16 , wherein the 4-8 membered saturated heterocyclic ring formed by R 1 , R 2 and their intervening atoms is represented by the following structural formula
18 . The compound according to claim 17 , wherein p is 2.
19 . The compound according to claim 18 , wherein R 5 is —F.
20 . The compound according to claim 19 , wherein the 4-8 membered saturated heterocyclic ring formed by R 1 , R 2 and their intervening atoms is represented by the following structural formula
21 - 25 . (canceled)
26 . A composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
27 . A method for modulating CRM1, the method comprising contacting CRM1 with a therapeutically effective amount of the compound of claim 1 .
28 . A method for treating, modulating, and/or preventing a disorder associated with CRM1, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 .
29 - 31 . (canceled)