Claims for Patent: 9,079,865

Summary for Patent: 9,079,865

Title:	Hydrazide containing nuclear transport modulators and uses thereof
Abstract:	The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by structural formula (I): or a pharmaceutically acceptable salt thereof, wherein the values and alternative values for 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. ##STR00001##
Inventor(s):	Sandanayaka; Vincent P. (Northboro, MA), Shacham; Sharon (Newton, MA), McCauley; Dilara (Cambridge, MA), Shechter; Sharon (Andover, MA)
Assignee:	Karyopharm Therapeutics Inc. (Newton, MA)
Application Number:	14/235,306
Patent Claims:	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: ##STR00174## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is selected from hydrogen and methyl; R.sup.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.sup.2 is optionally substituted with one or more substituents independently selected from methyl and halogen; or R.sup.1 and R.sup.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.sup.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: ##STR00175## 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.sub.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.sub.2--, --C(S)--, --C(NOR)--or --C(NR)--; each R is independently hydrogen or an optionally substituted group selected from C.sub.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.sup.1, V.sup.2 and V.sup.3 is independently C(R.sup.y) or N; each R.sup.x and R.sup.y is independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, --SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; each R.sup.1 and R.sup.2 is independently hydrogen, deuterium, tritium or halogen; W is --CN, haloalkyl, --NO.sub.2 or --C(.dbd.Z)R.sup.3; Z is O, S, or NR; R.sup.3 is hydrogen, --R, --OR, --SR or --N(R.sup.4)2; each R.sup.4 is independently --R, or two R.sup.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.sup.5).sub.n; each R.sup.5 is independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, --SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; 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: ##STR00176## wherein each of Ring A, R.sup.x, Y, V.sup.1, V.sup.2, V.sup.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: ##STR00177## wherein: LG is halogen, --OSO.sub.2R or --OSO.sub.2CF.sub.3; and each of W, R, R.sup.1 and R.sup.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: ##STR00178## or a pharmaceutically acceptable salt thereof, wherein: each R.sup.x and R.sup.y is independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, --SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; each R is independently hydrogen or an optionally substituted group selected from C.sub.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.sup.1 and R.sup.2 is independently hydrogen, deuterium, tritium or halogen; W is --CN, haloalkyl, --NO.sub.2 or --C(.dbd.Z)R.sup.3; Z is O, S, or NR; R.sup.3 is hydrogen, --R, --OR, --SR or --N(R.sup.4).sub.2; each R.sup.4 is independently --R, or two R.sup.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.sup.5).sub.n; each R.sup.5 is independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, --SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; 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: ##STR00179## wherein each of R.sup.x, R.sup.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: ##STR00180## wherein: LG is halogen, --OSO.sub.2R or --OSO.sub.2CF.sub.3; and each of W, R, R.sup.1 and R.sup.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: ##STR00181## or a pharmaceutically acceptable salt thereof, wherein: each R.sup.xand R.sup.yis independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, --SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; each R is independently hydrogen or an optionally substituted group selected from C.sub.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.sup.1and R.sup.2 is independently hydrogen, deuterium, tritium or halogen; each R.sup.4 is independently --R, or two R.sup.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.sup.5).sub.n; each R.sup.5 is independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, --SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; 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: ##STR00182## wherein each of R.sup.x, R.sup.yand 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: ##STR00183## wherein: LG is halogen, --OSO.sub.2R or --OSO.sub.2CF.sub.3; and each of R, R.sup.1, R.sup.2 and R.sup.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: ##STR00184## or a pharmaceutically acceptable salt thereof, wherein: each R.sup.x and R.sup.Yis independently selected from --R, halogen, --OR, --SR, --N(R).sub.2, --CN, --NO.sub.2, --N.sub.3, -SOR, --SO.sub.2R, --SO.sub.2NR, --C(O)R, --CO.sub.2R, --C(O)OR, --C(O)N(R).sub.2, --NRC(O)R, --OC(O)R, --OC(O)N(R).sub.2, --NRC(O)OR, --NRC(O)NR.sub.2 and --NRSO.sub.2R; each R is independently hydrogen or an optionally substituted group selected from C.sub.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.sup.1 and R.sup.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: ##STR00185## wherein each of R.sup.x, R.sup.yand 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: ##STR00186## wherein: LG is halogen, --OSO.sub.2R or --OSO.sub.2CF.sub.3; and each of R, R.sup.1 and R.sup.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: ##STR00187## wherein R.sup.2 is as defined for the compound of formula V; (b) reacting said compound of formula L with ##STR00188## to form a compound of formula R: ##STR00189## wherein R.sup.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: ##STR00190## wherein R.sup.2is 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: ##STR00191## wherein each of R and R.sup.2is as defined for the compound of formula V; (c) reacting said compound of formula M to provide a compound of formula N: ##STR00192## wherein: LG is halogen, --OSO.sub.2R or --OSO.sub.2CF.sub.3; and each of R, R.sup.1and R.sup.2is as defined for the compound of formula V; (d) hydrolyzing said compound of formula N to form a compound of formula Q: ##STR00193## wherein: LG is halogen, --OSO.sub.2R or --OSO.sub.2CF.sub.3; and each of R, R.sup.1and R.sup.2is as defined for the compound of formula V; and (e) reacting said compound of formula Q with ##STR00194## 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).