➤ Get the DrugPatentWatch Daily Briefing

Get Daily Updates on Generic Entry, Litigation, Biosimilars, and more …

Serving leading biopharmaceutical companies globally:

Dow
Harvard Business School
Moodys
Johnson and Johnson
McKesson
Baxter

Last Updated: October 31, 2020

DrugPatentWatch Database Preview

Claims for Patent: 9,079,865

➤ Get the DrugPatentWatch Daily Briefing
» See Plans and Pricing

« Back to Dashboard

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).

Make Better Decisions: Try a trial or see plans & pricing

Serving leading biopharmaceutical companies globally:

Baxter
Boehringer Ingelheim
AstraZeneca
Moodys
Johnson and Johnson
Colorcon

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.