Hydrazide containing nuclear transport modulators and uses thereof

1. A method for treating a disorder associated with CRM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from hydrogen and methyl;

R 2 is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, and quinoxalin-2-yl, pyrimidin-4-yl, 1,1-dioxotetrahydrothiophen-3-yl and cyclopropyl,

wherein R 2 is optionally substituted with one or more substituents independently selected from methyl and halogen; or

R 1 and R 2 are taken together with their intervening atoms to form 4-hydroxypiperidin-1-yl, pyrrolidin-1-yl, azepan-1-yl, 4-benzylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-hydroxyazetidin-1-yl, or morpholin-4-yl;

R 3 is selected from hydrogen and halo; and

represents a single bond wherein a carbon-carbon double bond bound thereto is in an (E)- or (Z)-configuration.

2. The method according to claim 1 , wherein the disorder is selected from a proliferative disorder, an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a disorder related to food intake, allergies, and a respiratory disorder.

3. The method according to claim 2 , wherein the disorder is cancer.

4. The method according to claim 3 , wherein the compound is administered together with a second therapeutic useful for treating cancer.

5. A method for preparing a compound of formula Z:

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;

Y is a covalent bond or —L—;

L is a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon radical, wherein one or two methylene units of L is optionally replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(S)—, —C(NOR)—or —C(NR)—;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated carbocyclic ring, a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of V 1 , V 2 and V 3 is independently C(R y ) or N;

each R x and R y is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , —SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R;

each R 1 and R 2 is independently hydrogen, deuterium, tritium or halogen;

W is —CN, haloalkyl, —NO 2 or —C(═Z)R 3 ;

Z is O, S, or NR;

R 3 is hydrogen, —R, —OR, —SR or —N(R 4 )2;

each R 4 is independently —R, or

two R 4 on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring thereby formed is optionally substituted with —(R 5 ) n ;

each R 5 is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , —SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R; and

each m and n is independently an integer selected from 0, 1, 2, 3 and 4;

comprising the steps of:

(a) providing a compound of formula A:

wherein each of Ring A, R x , Y, V 1 , V 2 , V 3 and m is as defined above for the compound of formula Z; and

(b) reacting said compound of formula A with an olefin of formula B:

wherein:

LG is halogen, —OSO 2 R or —OSO 2 CF 3 ; and

each of W, R, R 1 and R 2 is as defined above for the compound of formula Z;

in the presence of a sterically-hindered nucleophilic base to form a compound of formula Z.

6. The method of claim 5 , wherein the compound of formula Z is represented by a compound of formula Y:

or a pharmaceutically acceptable salt thereof, wherein:

each R x and R y is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , —SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated carbocyclic ring, a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 1 and R 2 is independently hydrogen, deuterium, tritium or halogen;

W is —CN, haloalkyl, —NO 2 or —C(═Z)R 3 ;

Z is O, S, or NR;

R 3 is hydrogen, —R, —OR, —SR or —N(R 4 ) 2 ;

each R 4 is independently —R, or

two R 4 on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring thereby formed is optionally substituted with —(R 5 ) n ;

each R 5 is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , —SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R; and

each m and n is independently an integer selected from 0, 1, 2, 3 and 4;

comprising the steps of:

(a) providing a compound of formula E:

wherein each of R x , R y and m is as defined above for the compound of formula Y; and

(b) reacting said compound of formula E with an olefin of formula B:

wherein:

LG is halogen, —OSO 2 R or —OSO 2 CF 3 ; and

each of W, R, R 1 and R 2 is as defined above for the compound of formula Y,

in the presence of a sterically-hindered nucleophilic base to form the compound of formula Y.

7. The method of claim 6 , wherein the compound of formula Y is represented by a compound of formula X:

or a pharmaceutically acceptable salt thereof, wherein:

each R x and R y is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , —SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated carbocyclic ring, a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 1 and R 2 is independently hydrogen, deuterium, tritium or halogen;

each R 4 is independently —R, or

two R 4 on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring thereby formed is optionally substituted with —(R 5 ) n ;

each R 5 is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , —SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R; and

each m and n is independently an integer selected from 0, 1, 2, 3 and 4;

comprising the steps of:

(a) providing a compound of formula E:

wherein each of R x , R y and m is as defined above for the compound of formula X; and

(b) reacting said compound of formula E with an olefin of formula G:

wherein:

LG is halogen, —OSO 2 R or —OSO 2 CF 3 ; and

each of R, R 1 , R 2 and R 4 is as defined above for the compound of formula X, in the presence of a sterically-hindered nucleophilic base to form the compound of formula X.

8. The method according to claim 7 , wherein the compound of formula X is represented by a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

each R x and R Y is independently selected from —R, halogen, —OR, —SR, —N(R) 2 , —CN, —NO 2 , —N 3 , -SOR, —SO 2 R, —SO 2 NR, —C(O)R, —CO 2 R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —OC(O)R, —OC(O)N(R) 2 , —NRC(O)OR, —NRC(O)NR 2 and —NRSO 2 R;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7-membered saturated or partially unsaturated carbocyclic ring, a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 1 and R 2 is independently hydrogen, deuterium, tritium or halogen; and

m is an integer selected from 0, 1, 2, 3 and 4;

comprising the steps of:

(a) providing a compound of formula E:

wherein each of R x , R y and m is as defined above for the compound of formula V; and

(b) reacting said compound of formula E with an olefin of formula J:

wherein:

LG is halogen, —OSO 2 R or —OSO 2 CF 3 ; and

each of R, R 1 and R 2 is as defined above for the compound of formula V, in the presence of a sterically-hindered nucleophilic base to form the compound of formula V.

9. The method of claim 8 , further comprising the steps of:

(a) providing a compound of formula L:

wherein R 2 is as defined for the compound of formula V;

(b) reacting said compound of formula L with

 to form a compound of formula R:

wherein R 2 is as defined for the compound of formula V; and

(c) reacting said compound of formula R to provide the compound of formula J.

10. The method of claim 8 , further comprising the steps of:

(a) providing a compound of formula L:

wherein R 2 is as defined for the compound of formula V;

(b) reacting said compound of formula L with an alcohol having the formula HO—R to form a compound of formula M:

wherein each of R and R 2 is as defined for the compound of formula V;

(c) reacting said compound of formula M to provide a compound of formula N:

wherein:

LG is halogen, —OSO 2 R or —OSO 2 CF 3 ; and

each of R, R 1 and R 2 is as defined for the compound of formula V;

(d) hydrolyzing said compound of formula N to form a compound of formula Q:

wherein:

LG is halogen, —OSO 2 R or —OSO 2 CF 3 ; and

each of R, R 1 and R 2 is as defined for the compound of formula V; and

(e) reacting said compound of formula Q with

 to form the compound of formula J.

11. The method of claim 5 , wherein the sterically-hindered nucleophilic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-dicyclohexylmethylamine, 2,6-di-tert-butyl -4-methylpyridine, quinuclidine, 1,2,2,6,6-pentamethylpiperidine (PMP), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), triphenylphosphine, tri-tert-butylphosphine and tricyclohexylphosphine.

12. The method of claim 11 , wherein the sterically-hindered nucleophilic base is selected from 1,8-diazabicyclo [5.4.0, ]undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0 ]non-5-ene (DBN) and 1,4-diazabicyclo(2.2.2)octane (DABCO).

13. The method of claim 12 , wherein the sterically-hindered nucleophilic base is 1,4-diazabicyclo(2.2.2)octane (DABCO).