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.
Inventor(s):	Vincent P. Sandanayaka, Sharon Shacham, Dilara McCauley, Sharon Shechter
Assignee:	Karyopharm Therapeutics Inc
Application Number:	US14/235,306
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,079,865
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: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from hydrogen and methyl; R2 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 R2 is optionally substituted with one or more substituents independently selected from methyl and halogen; or R1 and R2 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; R3 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 C1-8 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—, —SO2—, —C(S)—, —C(NOR)—or —C(NR)—; each R is independently hydrogen or an optionally substituted group selected from C1-6 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 V1, V2 and V3 is independently C(Ry) or N; each Rx and Ry is independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, —SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; each R1 and R2 is independently hydrogen, deuterium, tritium or halogen; W is —CN, haloalkyl, —NO2 or —C(═Z)R3; Z is O, S, or NR; R3 is hydrogen, —R, —OR, —SR or —N(R4)2; each R4 is independently —R, or two R4 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 —(R5)n; each R5 is independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, —SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; 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, Rx, Y, V1, V2, V3 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, —OSO2R or —OSO2CF3; and each of W, R, R1 and R2 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 Rx and Ry is independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, —SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; each R is independently hydrogen or an optionally substituted group selected from C1-6 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 R1 and R2 is independently hydrogen, deuterium, tritium or halogen; W is —CN, haloalkyl, —NO2 or —C(═Z)R3; Z is O, S, or NR; R3 is hydrogen, —R, —OR, —SR or —N(R4)2; each R4 is independently —R, or two R4 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 —(R5)n; each R5 is independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, —SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; 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 Rx, Ry 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, —OSO2R or —OSO2CF3; and each of W, R, R1 and R2 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 Rxand Ryis independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, —SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; each R is independently hydrogen or an optionally substituted group selected from C1-6 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 R1and R2 is independently hydrogen, deuterium, tritium or halogen; each R4 is independently —R, or two R4 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 —(R5)n; each R5 is independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, —SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; 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 Rx, Ryand 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, —OSO2R or —OSO2CF3; and each of R, R1, R2 and R4 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 Rx and RYis independently selected from —R, halogen, —OR, —SR, —N(R)2, —CN, —NO2, —N3, -SOR, —SO2R, —SO2NR, —C(O)R, —CO2R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —OC(O)R, —OC(O)N(R)2, —NRC(O)OR, —NRC(O)NR2 and —NRSO2R; each R is independently hydrogen or an optionally substituted group selected from C1-6 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 R1 and R2 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 Rx, Ryand 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, —OSO2R or —OSO2CF3; and each of R, R1 and R2 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 R2 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 R2 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 R2is 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 R2is 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, —OSO2R or —OSO2CF3; and each of R, R1and R2is 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, —OSO2R or —OSO2CF3; and each of R, R1and R2is 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).