WO2022232417A1

WO2022232417A1 - Biomarkers for response to exportin-1 inhibitors in multiple myeloma patients

Info

Publication number: WO2022232417A1
Application number: PCT/US2022/026766
Authority: WO
Inventors: Christopher Walker; Yosef Landesman
Original assignee: Karyopharm Therapeutics Inc.
Priority date: 2021-04-28
Filing date: 2022-04-28
Publication date: 2022-11-03

Abstract

A method of treating multiple myeloma (MM) in a subject in need thereof, comprising the steps of: obtaining a sample from the subject; determining the presence or absence of one or more RAS mutations in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof; and one or more of an additional therapeutic agent to the subject determined to have one or more RAS mutations present. Example values of the variables in structural formula (I) are defined herein.

Description

BIOMARKERS FOR RESPONSE TO EXPORTIN-1 INHIBITORS IN MULTIPLE

MYELOMA PATIENTS

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

63/180,962, filed on April 28, 2021, and U.S. Provisional Application No. 63/185,753, filed on May 7, 2021. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Multiple Myeloma (MM) is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, or M protein in the serum or urine, bone disease, kidney disease, and immunodeficiency. MM is the second most common hematological malignancy (after non- Hodgkin’s lymphoma), representing 1% of all cancers and 2% of all cancer deaths. The treatment of MM has improved in the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation, the introduction of immunomodulatory agents, such as thalidomide, lenalidomide, and pomalidomide, and the proteasome inhibitors, bortezomib and carfilzomib. However, despite the increased effectiveness of these agents, most patients develop resistant MM and succumb to the disease. As such, there remains a high unmet need to develop anti-MM agents and to tailor anti-MM therapies more closely to patients to achieve a higher likelihood of response.

SUMMARY OF THE INVENTION

[0003] In one embodiment, the present invention is a method of treating multiple myeloma (MM) in a subject in need thereof, comprising the steps of: obtaining a sample from the subject; determining the presence or absence of one or more RAS mutations in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:

[0005] and one or more of an additional therapeutic agent to the subject determined to have one or more RAS mutations present.

[0006] In structural formula (I):

Ring A is phenyl or pyridyl; X is -N- or -C(H)-; each R¹ is independently selected from -CN, halo, - OH, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, 3-18 membered heterocycloalkyl, halo- C₁-C₄ alkyl, -NH₂, -NO₂, -NH(C₁-C₄ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)OH, -C(O)O-(C₁- C₆ alkyl), -C(O)-(C₁-C₄ alkyl), -O-(C₁-C₄ alkyl), -O-(C₁-C₄ haloalkyl), and -S-( C₁-C₄ alkyl); R² is selected from -C(O)-O-R³, -C(O)-N(R⁵)(R⁶), -C(O)-N(R⁷)-N(R⁵)(R⁶), -CN, -CF₃, -S(O)i-2(C₁-C₄ alkyl), 5-18 membered heteroaryl, and C₆-C₁₈ aryl; R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R^3’, -C(O)-N(R^5’)(R^6’), -C(O)-N(R^r)-N(R^5’)(R^6’), -CN, -C(S)-O-R^3’, -C( S)-N(R⁵ )(R⁶ ), -C(S)-N(R^7’ )-N(R⁵ )(R⁶ ), and 5-18-membered heteroaryl, wherein: R³ and R³ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; R⁵,

R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18- membered heteroaryl; or R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membered heteroaryl; each R⁷ and R^7’ are each independently hydrogen or C₁-C₄ alkyl; and n is 0, 1, 2, 3, 4 or 5; wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

[0007] In another embodiment, the present invention is a method of treating multiple myeloma in a subject in need thereof. The method comprises administering a therapeutically effective amount of a compound represented by structural formula (I)

[0009] or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, wherein the subject is determined to have a one or more RAS mutation. The example values in structural formula (I) are defined above.

[0010] In another embodiment, the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of: selecting the subject only if the subject has been determined to have one or more RAS mutations; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof,

[0011]

[0012] one or more additional therapeutic agents. Example values in structural formula (I) are defined above.

[0013] In another embodiment, the present invention is a method of treating multiple myeloma in a subject in need thereof, comprising the steps of: receiving information about the absence or presence of one or more RAS mutation in the subject; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

[0014]

[0015] one or more additional therapeutic agents to the subject only if the subject has one or more RAS mutations. The example values in structural formula (I) are defined above. [0016] In another embodiment, the present invention is a use of an XPOl inhibitor described herein or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents for treating multiple myeloma in a subject in need thereof, wherein the subject has been determined to have one or more RAS mutations. [0017] In another embodiment, the present invention is a use of an XPOl inhibitor described herein and one or more additional therapeutic agents for the manufacture of a medicament for treating multiple myeloma in a subject determined to have one or more RAS mutations.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the present invention.

[0019] FIG. 1 A depicts superimposed plots of progression-free survival as a function of time (months) for MM patients, either Ras^mut or Ras^wt, where the patients enrolled in the STORM trial receive the XPOl inhibitor selinexor in combination with the steroid dexamethasone.

[0020] FIG. IB depicts superimposed plots of overall survival as a function of time for MM patients, either Ras^mut or Ras^wt, where the patients enrolled on the STORM trial received the XPOl inhibitor selinexor in combination with the steroid dexamethasone.

[0021] FIG. 2A depicts superimposed plots of progression-free survival as a function of time for Ras^mut MM patients enrolled on the BOSTON trial who either received or did not receive an XPOl inhibitor selinexor, in combination with the proteasome inhibitor bortezomib and the steroid dexamethasone.

[0022] FIG. 2B depicts superimposed plots of progression-free survival as a function of time for MM patients, either Ras^mut or Ras^wt, where the patients enrolled on the BOSTON trial received an XPOl inhibitor selinexor, in combination with the proteasome inhibitor bortezomib and the steroid dexamethasone.

[0023] FIG. 2C depicts superimposed plots of progression-free survival as a function of time for MM patients, either Ras^mut or Ras^wt, where the patients enrolled on the BOSTON trial did not received an XPOl inhibitor selinexor, but were treated with the proteasome inhibitor bortezomib and the steroid dexamethasone.

[0024] FIG. 2D depicts superimposed plots of overall survival as a function of time for MM patients, either Ras^mut or Ras^wt, where the patients enrolled on the BOSTON trial received an XPOl inhibitor selinexor, in combination with the proteasome inhibitor bortezomib and the steroid dexamethasone.

[0025] FIG. 2E depicts superimposed plots of overall survival as a function of time for MM patients, either Ras^mut or Ras^wt, where the patients enrolled on the BOSTON trial did not received an XPOl inhibitor selinexor, but were treated with the proteasome inhibitor bortezomib and the steroid dexamethasone.

DETAILED DESCRIPTION OF THE INVENTION

[0026] A description of example embodiments of the invention follows.

[0027] Targeting exportin 1 (XPOl) is a promising therapeutic option for patients with multiple myeloma (MM). Exemplary XPOl inhibitors useful for practicing the present invention are compounds represented by structural formula (I):

wherein:

Ring A is phenyl or pyridyl;

X is -N- or -C(H)-; each R¹ is independently selected from -CN, halo, - OH, C₁-C₄ alkyl, C₃- C₆ cycloalkyl, 3-18 membered heterocycloalkyl, halo-C₁-C₄ alkyl, -NH₂, -NO₂, -NH(C₁-C₄ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)OH, -C(O)O-(C₁-C₆ alkyl), -C(O)-(C₁-C₄ alkyl), -O-(C₁-C₄ alkyl), -O-(C₁-C₄ haloalkyl), and -S-( C₁-C₄ alkyl);

R² is selected from -C(O)-O-R³, -C(O)-N(R⁵)(R⁶), -C(O)-N(R⁷)-N(R⁵)(R⁶),

-CN, -CF₃, -S(O)I-2(C₁-C₄ alkyl), 5-18 membered heteroaryl, and C₆-C₁₈ aryl;

R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R^3’, -C(O)-N(R^5’)(R^6’), -C(O)-N(R^7’’)-N(R^5’)(R^6’), -CN, -C(S)-O-R^3’, -C( S)-N(R⁵ )(R⁶ ), -C(S)-N(R^7’ )-N(R⁵ )(R⁶ ), and 5-18-membered heteroaryl, wherein:

R³ and R³ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5- 18-membered heteroaryl; or

[0028] R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18- membered heteroaryl;

[0029] each R⁷ and R^7’’ are each independently hydrogen or C₁-C₄ alkyl; and [0030] n is 0, 1, 2, 3, 4 or 5;

[0031] wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions). Specific optional substituents include, but are not limited to, halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C₅-C₆ heteroaryl.

[0032] In a first aspect of compounds of structural formula I, each R⁷ or R7' is hydrogen. The values for the remaining variables are as defined with respect to structural formula I. [0033] In a second aspect of compounds of structural formula I, X is -C(H)-. The values for the remaining variables are as defined with respect to structural formula I, or first aspect thereof.

[0034] In a third aspect of compounds of structural formula I, X is -N-. The values for the remaining variables are as defined with respect to structural formula I, or first or second aspect thereof.

[0035] In a fourth aspect of compounds of structural formula I, n is 0, 1 or 2. The values for the remaining variables are as defined with respect to structural formula I, or first through third aspects thereof.

[0036] In a fifth aspect of compounds of structural formula I, each R¹ is independently selected from halo, -C₁-C₄ alkyl, -C₁-C₄ haloalkyl, and -O-C₁-C₄ alkyl, or is absent. The values for the remaining variables are as defined with respect to structural formula I, or first through fourth aspects thereof. [0037] In a sixth aspect of compounds of structural formula I, each R¹ is independently selected from -CF₃, -Cl and -OCH3, or is absent. The values for the remaining variables are as defined with respect to structural formula I, or first through fifth aspects thereof.

[0038] In a seventh aspect of compounds of structural formula I:

R² is -C(O)-O-R³, and R³ is selected from optionally substituted C₁-C₄ alkyl and optionally substituted C₂-C₄ alkenyl; or

R² is -C(O)-N(R⁵)(R⁶), and R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated 3- 18-membered heterocyclyl; or

R² is -C(O)-NH-NH(R⁶), and R⁶ is an optionally substituted 5-18-membered heteroaryl; or

R² is optionally substituted 5-6-membered heteroaryl. The values for the remaining variables are as defined with respect to structural formula I, or first through sixth aspects thereof.

[0039] In an eighth aspect of compounds of structural formula I:

R² is -C(O)-O-R³, and R³ is selected from ethyl, isopropyl and -CH₂-CH=CH₂; or

R² is -C(O)-N(R⁵)(R⁶), and R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted azetidin-l-yl, pyrrolidin-l-yl, or piperidin-l-yl; or

R² is -C(O)-NH-NH(R⁶), and R⁶ is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or

R² is optionally substituted oxadiazolyl. The values for the remaining variables are as defined with respect to structural formula I, or first through seventh aspects thereof.

[0040] In a ninth aspect of compounds of structural formula I, R² is selected from -C(O)-O-R³, -C(O)-N(R⁵)(R⁶), -C(O)-N(R⁷)-N(R⁵)(R⁶), and 5-18-membered heteroaryl. The values for the remaining variables are as defined with respect to structural formula I, or first through sixth aspects thereof.

[0041] In a tenth aspect of compounds of structural formula I, Ring A is phenyl. The values for the remaining variables are as defined with respect to structural formula I, or first through ninth aspects thereof. [0042] In an eleventh aspect of compounds of structural formula I, Ring A is pyridyl.

The values for the remaining variables are as defined with respect to structural formula I, or first through tenth aspects thereof.

[0043] In a twelfth aspect of compounds of structural formula I, Ring A is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl. The values for the remaining variables are as defined with respect to structural formula I, or first through ninth and eleventh aspects thereof.

[0044] In a thirteenth aspect of compounds of structural formula I, Ring A is pyrid-4-yl. The values for the remaining variables are as defined with respect to structural formula I, or first through ninth, eleventh and twelfth aspects thereof.

[0045] In a fourteenth aspect of compounds of structural formula I:

R² is -C(O)-O-R³, and R³ is selected from unsubstituted C₁-C₄ alkyl, Ci alkyl substituted with a 5-6-membered monocyclic heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and C₂-C₄ alkenyl; or

R² is optionally substituted 5-6-membered heteroaryl. The values for the remaining variables are as defined with respect to structural formula I, or first through sixth and ninth through thirteenth aspects thereof.

[0046] In any of the above embodiments or aspects thereof of formula I, R^b is hydrogen. [0047] In one aspect, the compounds of structural formula I are represented by structural formula (II):

[0048] or a pharmaceutically acceptable salt thereof. The values for the variables and optional substituents on each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl (heterocycloalkyl) and heteroaryl are as defined with respect to structural formula I, or any aspect thereof. For example, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions). Specific optional substituents include, but are not limited to, halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁- C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl.

[0049] In another aspect, the compound of structural formula I are represented by structural formula (III):

or a pharmaceutically acceptable salt thereof. Each R^1a and R^1b is independently selected from -CN, halo, - OH, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, 3-18 membered heterocycloalkyl, halo-C₁-C₄ alkyl, -NH₂, -NO₂, -NH(C₁-C₄ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)OH, -C(O)O-(C₁-C₆ alkyl), -C(O)-(C₁-C₄ alkyl), -O-(C₁-C₄ alkyl), -O-(C₁-C₄ haloalkyl), and -S-( C₁-C₄ alkyl); and m is 0 or 1. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.

[0050] In a first aspect of the structural formula (III), R^1a is halo or -C₁-C₄ haloalkyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0051] In a second aspect of the structural formula (III), R^1b is -C₁-C₄ haloalkyl or -O-C₁- C₄ alkyl, or is absent. The values for the remaining variables are as defined above for the structural formula I or any aspect thereof.

[0052] In a third aspect of the structural formula (III), m is 0. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof. [0053] In a fourth aspect of the structural formula (III), m is 1. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof. [0054] In a fifth aspect of the structural formula (III), R^1a and R^1b are each independently selected from -CF₃, -CN, halo, - OH, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C₁2 heterocycloalkyl, halo-C₁-C₃ alkyl, -NH₂, -NO₂, -NH(C₁-C₃ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)OH, -C(O)O-(C₁-C₆ alkyl), -C(O)-(C₁-C₃ alkyl), -O-(C₁-C₃ alkyl), -O-(C₁-C₃ haloalkyl), and -S-( C₁-C₃ alkyl). The values for the remaining variables are as defined above for structural formula I, or any of aspects one through fourth and seventh through sixth thereof.

[0055] In a sixth aspect of the structural formula (III), R^1a and R^1b are each -CF₃. The values for the remaining variables are as defined above for structural formula I, or any of aspects one through four and seventh through sixth thereof.

[0056] In a seventh aspect of the structural formula (III):

R² is optionally substituted 5-6-membered heteroaryl. The values for the remaining variables are as defined above for structural formula I, or any of the first through sixth and ninth through thirteenth aspects thereof.

[0057] In any of the above embodiments or aspects thereof of formula II, R^b is hydrogen. [0058] In another aspect of structural formula I, the compound is represented by structural formula (IIIA):

R² is an optionally substituted 5-18-membered heteroaryl, wherein: optionally substitution is on on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions). Specific optional substituents include, but are not limited to, halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl. [0059] In a first aspect of the structural formulas (IIIA), R² is an optionally substituted 5- 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0060] In a second aspect of the structural formula (IIIA), R² is an optionally substituted

5-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0061] In a third aspect of the structural formula (IIIA), R² is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.

[0062] In a fourth aspect of the structural formula (IIIA), R² is an optionally substituted

6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0063] In a fifth aspect of the structural formula (IIIA), R² is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl ortriazinyl.

[0064] In a sixth aspect of the structural formula (IIIA), R² is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁- C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl.

[0065] In a seventh aspect of the structural formula (IIIA), R² is optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy or oxo.

[0066] In an eighth aspect of the structural formula (IIIA), R² is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C₁-C₄ alkyl, -CF₃, amino, oxo and cyano.

[0067] In another aspect of structural formula I, the compound is represented by structural formula (IIIB): or a pharmaceutically acceptable salt thereof, wherein:

R⁵ and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18- membered heteroaryl; or

R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membred heteroaryl, wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions). Specific optional substituents include, but are not limited to, halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0068] For example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB) R⁵ is hydrogen or methyl and R⁶ is an optionally substituted 5-6-membered heteroaryl; or R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-7-membered heterocyclyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0069] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB), R⁵ is hydrogen or methyl and R⁶ is an optionally substituted 5-6-membered heteroaryl having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur; or R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-6-membered heterocyclyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof. [0070] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB), R⁵ is hydrogen or methyl and R⁶ is an optionally substituted 5-6-membered heteroaryl having 1-3 nitrogen atoms; or R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-6-membered heterocyclyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof. [0071] In yet another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB) R⁵ is methyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0072] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB) R⁵ is hydrogen. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0073] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB), R⁵ is selected from hydrogen and methyl and R⁶ is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, and quinoxalin-2-yl, pyrimidin-4-yl, l,l-dioxotetrahydrothiophen-3-yl and cyclopropyl and is optionally substituted with one or more substituents independently selected from methyl and halogen. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0074] In another example, R⁵ is selected from hydrogen and methyl and R⁶ is selected from pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl and pyrimidin-4-yl and is optionally substituted with a single substituent selected from methyl and chloro. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0075] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB), R⁵ is selected from hydrogen and R⁶ is selected from pyridin-2-yl and pyrazin-2-yl and is optionally substituted with one or more substituents independently selected from methyl, halogen and oxo. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0076] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB), R⁵ is selected from hydrogen and R⁶ is selected from pyrazin-2-yl and is optionally substituted with one or more substituents independently selected from methyl, halogen and oxo. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof. [0077] In another example, for -C(O)-N(H)-N(R⁵)(R⁶) in formula (IIIB), R⁵ is selected from hydrogen and R⁶ is selected from pyridine-2-yl and is optionally substituted with one or more substituents independently selected from methyl, halogen and oxo. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

In a particular embodiment, the substituent is oxo.

[0078] In another example, for -C(O)-N(H)-N(R⁵)(R⁶), R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl, wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions). Specific optional substituents include, but are not limited to, halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0079] In a particular embodiment, for -C(O)-N(H)-N(R⁵)(R⁶), R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form 6-membered heterocyclyl wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl (heterocycloalkyl) and heteroaryl is optionally and independently substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3, 4 or 5 positions). Specific optional substituents include, but are not limited to, halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0080] In an even more particular embodiment, for -C(O)-N(H)-N(R⁵)(R⁶), R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form 6- membered heterocyclyl selected from the following structures:

, wherein the 6-membered heterocyclyl is substituted on any substitutable position (e.g., optional substituents can be present at 1, 2, 3 or 4 positions including the heteroatom) with halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl. In a very specific embodiment, the substituent is oxo. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.

[0081] Exemplary compounds for use in the methods of the invention are set forth in Tables 1 A, IB, IC and IF. Methods of making compounds disclosed in Table 1 A and compounds of formula (I) wherein R² is -C(O)-O-R³ are disclosed, for example, in International Application No. PCT/US2011/027328, the entire contents of which are incorporated herein by reference.

[0082] Table 1A. Exemplary Compounds.

[0083] Table 1A. Exemplary Compounds (Cont.).

-

[0084] Methods of making the compounds of Table IB and compounds of formula (I) wherein R² is -C(O)-N(R⁵)(R⁶) are disclosed, for example, in International Application No. PCT/US2012/048368, the entire contents of which are incorporated herein by reference.

[0085] Table IB. Exemplary Compounds.

[0086] In some embodiments, the compound i

s

[0087] Methods of making the compounds of Table 1C and compounds of formula (I) wherein R² is -C(O)-N(R⁷)-N(R⁵)(R⁶) are disclosed, for example, in International Application No. PCT/US2012/048319, the entire contents of which are incorporated herein by reference.

Table 1C. Exemplary Compounds.

[0088] In some embodiments, the compound is selected from

referred to herein selinexor or XPOVIO

referred to herein as verdinexor

[0089] Methods of making the compounds of Table IF and compounds of formula (I) wherein R² is -C(O)-N(R⁵)(R⁶) are disclosed, for example, in International Application No. PCT/2014/04479, the entire contents of which are incorporated herein by reference.

[0090] Table IF. Exemplary Compounds

[0091] In some embodiments, the compound is selected from

[0092] In some embodiments, the compound i

referred to herein as eltanexor.

[0093] Definition of Substituents relating to Formulas I, II, III, IIIA and IIIB of the XPOl Inhibitor Compounds described herein: [0094] The term “aliphatic” or “aliphatic group,” as used herein, denotes a monovalent hydrocarbon radical that is straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic). An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 carbon atoms. However, in some embodiments, an aliphatic group contains 1-10 or 2-8 carbon atoms. In some embodiments, aliphatic groups contain 1- 4 carbon atoms and, in yet other embodiments, aliphatic groups contain 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. An aliphatic group can be optionally substituted as described herein. [0095] The term “alkyl,” as used herein, means a saturated, straight-chain or branched aliphatic group. In one aspect, an alkyl group contains 1-6 or 1-4 carbon atoms. Alkyl includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, and the like. An alkyl group can be optionally substituted as described herein.

[0096] The term “alkenyl,” as used herein, means a straight-chain or branched aliphatic group having one or more carbon-carbon double bonds {i.e., -CH=CH-). In one aspect, an alkenyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like. The term “alkenyl” encompasses radicals having carbon-carbon double bonds in the “cis” and “trans” or, alternatively, the “E” and “Z” configurations. If an alkenyl group includes more than one carbon-carbon double bond, each carbon-carbon double bond is independently a cis or trans double bond, or a mixture thereof. An alkenyl group can be optionally substituted as described herein.

[0097] The term “alkynyl,” as used herein, means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -C≡C-). In one aspect, an alkyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like. An alkynyl group can be optionally substituted as described herein.

[0098] The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic,” used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. In some embodiments, a cycloaliphatic group has 3-6 carbon atoms. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. The terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic” also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane. These aliphatic rings can be optionally substituted as described herein.

[0099] The term “cycloalkyl,” as used herein, means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-18, for example 3-12 members. A cycloalkyl can be optionally substituted as described herein. In some embodiments, a cycloalkyl has 3-6 carbons. A cycloalkyl group can be optionally substituted as described herein.

[00100] The term “heterocyclyl,” as used herein, means a saturated or unsaturated aliphatic ring system having from 3 to 18, for example 3-12 members in which at least one carbon atom is replaced with a heteroatom selected from N, S and O. A heterocyclyl can contain one or more rings, which may be attached together in a pendent manner or may be fused. In one aspect, a heterocyclyl is a three- to seven-membered ring system and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like. A heterocyclyl group can be optionally substituted as described herein.

[00101] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, and includes any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl).

[00102] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[00103] The term “alkoxy,” as used herein, means -O-alkyl. “Alkoxy” can include a straight-chained or branched alkyl. In one aspect, “alkoxy” has from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like. An alkoxy group can be optionally substituted as described herein. [00104] The term “halo” or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.

[00105] The term “haloalkyl,” as used herein, means an alkyl group that is substituted with one or more halogen atoms. In some embodiments, haloalkyl refers to a perhalogenated alkyl group. In some embodiments, haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms. Exemplary haloalkyl groups include -CF₃, -CF₂H, -CCI₃, - CF₂CH₃, -CH₂CF₃, -CH₂(CF 3)2, -CF₂(CF₃)2, and the like. Preferred haloalkyl groups include -CF₃ and -CF₂H. A preferred haloalkyl group is -CF₃.

[00106] The term “alkylene,” as used herein, means a bivalent branched or unbranched saturated hydrocarbon radical. In one aspect, “alkylene” has one to six carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like. An alkylene group can be optionally substituted as described herein. [00107] The term “alkenylene,” as used herein, means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon double bonds {i.e., -CH=CH-). In one aspect, “alkenylene” has two to six carbon atoms, and includes, for example, and without being limited thereto, ethenylene, n-propenylene, n-butenylene and the like. An alkenylene group can be optionally substituted as described herein.

[00108] The term “alkynylene,” as used herein, means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -CºC-). In one aspect, “alkynylene” has two to six carbon atoms, and includes, for example, and without being limited thereto, ethynylene, n-propynylene, n-butynylene and the like. An alkynylene group can be optionally substituted as described herein.

[00109] The term “aryl,” alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused. In some embodiments, an aryl has one, two or three rings. In one aspect, the aryl has six to twelve ring atoms. The term “aryl” encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl and acenaphthyl. An “aryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.

[00110] The term “heteroaryl,” alone or in combination, as used herein, means an aromatic system wherein at least one carbon atom is replaced by a heteroatom selected from N, S and O. A heteroaryl can contain one or more rings, which may be attached together in a pendent manner or may be fused. In some embodiments, a heteroaryl has one, two or three rings. In one aspect, the heteroaryl has five to twelve ring atoms. The term “heteroaryl” encompasses heteroaromatic groups such as triazolyl, imidazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, oxadiazolyl, isoxazolyl, and the like. A “heteroaryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.

[00111] It is understood that substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted group” can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an “optionally substituted group” can be unsubstituted. [00112] Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[00113] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted group” are independently halogen; haloalkyl; -(CH₂)_0-4R°; -(CH₂)_0-4OR°; - 0(CH₂)_0-4R°, -O- (CH₂)_0-4C(O)OR°; -(CH₂)_0-4CH(OR°)₂; -(CH₂)_0-4SR °; -(CH₂)_0-4Ph, which may be substituted with R°; -(CH₂)_0-40(CH₂)_0-1Ph which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH₂)_0-40(CH₂)_0-1-pyridyl which may be substituted with R°; -NO₂; -CN; -Ns; -(CH₂)_0-4N(R°)2; -(CH₂)_0-4N(R°)C(O)R°; - N(R°)C(S)R°; -(CH₂)_0-4N(R°)C(O)NR°₂; -N(R°)C(S)NR°₂; -(CH₂)O- 4N(R°)C(O)0R°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)0R°; - (CH₂)_0-4C(O)R°; -C(S)R°; -(CH₂)_0-4C(O)OR°; -(CH₂)_0-4C(O)SR°; -(CH₂)o-₄C(O)OSiR°₃; - (CH₂)_0-4OC(O)R°; -OC(O)(CH₂)_0-4SR- SC(S)SR°; -(CH₂)_0-4SC(O)R°; -(CH₂)_0-4C(O)NR°₂; -C(S)NR°₂; -C(S)SR°; -SC(S)SR°, -(CH₂)_0-4OC(O)NR°₂; -C(O)N(0R°)R°; - C(O)C(O)R°; -C(O)CH₂C(O)R°; -C(NOR°)R°;-(CH₂)_0-4SSR°; -(CH₂)_0-4S(O)₂R°; -(CH₂)O- ₄S(O)₂0R°; -(CH₂)_0-4OS(O)₂R°; -S(O)₂NR°₂; -(CH₂)_0-4S(O)R°; -N(R°)S(O)₂NR°₂; - N(R°)S(O)₂R°; -N(OR°)R°; -C(NH)NR°₂; -P(O)₂R°; -P(O)R°₂; -0P(O)R°₂; -0P(O)(0R°)₂; SiR°3; — ( C I -4 straight or branched alkylene)0-N(R°)₂; or -(C_1-4 straight or branched alkylene)C(O)O-N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, C₁-₆ aliphatic, -CH₂Ph, -0(CH₂)_0-1Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.

[00114] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH₂)_0-2R^●, -(haloR^●), -(CH₂)_0-2OH, -(CH₂)_0-2OR^●, -(CH₂)o- ₂CH(OR^●)₂; -O(haloR^●), -CN, -Ns, -(CH₂)_0-2C(O)R^●, -(CH₂)_0-2C(O)OH, -(CH₂)o- ₂C(O)OR·, -(CH₂)_0-2SR^●, -(CH₂)_0-2SH, -(CH₂)_0-2NH₂, -(CH₂)_0-2NHR·, -(CH₂)_0-2NR^● ₂, - NO₂, -SiR^●3, -OSiR^●3, -C(O)SR^● -(C_1-4 straight or branched alkylene)C(O)OR·, or-SSR^● wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_1-4 aliphatic, -CH₂Ph, -0(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[00115] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted group” include the following: =0, =S, =NNR^* ₂, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, -0(C(R^● ₂))_2-3O-, and -S(C(R^* ₂))_2-3S-, wherein each independent occurrence of R^* is selected from hydrogen, C₁-₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR^* 2)_2-3O-, wherein each independent occurrence of R^* is selected from hydrogen, C₁-₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00116] Suitable substituents on the aliphatic group of R^* include halogen, - R^●, -(haloR^●), -OH, -OR^●, -O(haloR^●), -CN, -C(O)OH, -C(O)OR^●, -NH₂, NHR*, -NR^● _2, and -NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, -CH₂Ph , -0(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00117] Suitable substituents on a substitutable nitrogen of an “optionally substituted group” include -R^†, -NR^† ₂, -C(O)R^†, -C(O)OR^†, -C(O)C(O)R^†, -C(O)CH₂C(O)R^†, - S(O)₂R^†, -S(O)₂NR^†2, -C(S)NR^†2, -C(NH)NR^†2, and -N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C₁-₆ aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00118] Suitable substituents on the aliphatic group of R^† are independently halogen, - R^●, -(haloR^●), -OH, -OR^●, -O(haloR^●), -CN, -C(O)OH, -C(O)OR^●, -NH₂, -NHR^●, -NR^● _2, or -NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, -CH₂Ph , -0(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00119] Example embodiments of compounds of structural formula (I) are selinexor, eltanexor, and vedinexor. [00120] Eltanexor is a compound represented by the following structural formula,

pharmaceutically acceptable salt thereof.

[00121] XPOl inhibitor selinexor is represented by the following structural formula,

pharmaceutically acceptable salt thereof.

[00122] Verdinexor, represented by structural formula (3), is an oral inhibitor or XPOl also described in WO₂013/019548.

pharmaceutically acceptable salt thereof.

The Ras Family of Genes

[00123] The 3 canonical members of the Ras gene family (hRas, nRas, and kRas) were identified more than a quarter century ago because of their frequent oncogenic activation in human tumors. They are the founding members of the wider Ras superfamily including more than 150 small GTPases, divided into at least 5 distinct subfamilies (Ras, Rho/Rac, Rab, Arf, and Ran) on the basis of primary sequence relationships. In particular, the Ras subfamily encompasses the hRas, nRas, and kRas genes together with the closely related rRas/TC21, Ral, and Rap loci.

[00124] All Ras superfamily proteins share very similar molecular structures and a common ability to bind and hydrolyze guanine nucleotides. The Ras proteins are continually cycling between active (GTP bound) and inactive (GDP bound) conformational states dependent on structural changes occurring mostly in the 2 motile switch I and switch II regions, which are also responsible for the functional interactions of these proteins with negative (GAP) and positive (GEF) cellular regulators. The binary behavior aspects of these proteins enable them to function as molecular switches in a broad range of signaling processes related to the transduction of extracellular signals to the interior of cells. Oncogenic mutations at positions 12, 13, or 61 of the HRAS , NRAS and KRAS genes are among the most common genetic lesions in mammalian tumors. These mutations result in significant impairment of the overall GTPase activity of the carrier RAS proteins and lock them into a constitutively activated state in which they signal to downstream effectors, even in the absence of extracellular stimuli.

[00125] NRAS, KRAS and HRAS are three separate human genes. Activating mutations within any one of these genes result in constitutively active gene products implinated in various malignancies. The frequencies of the different activating mutations in the different genes are variable across cancer types - HRAS mutations are less commonly mutated compared to KRAS and NRAS across human cancers, and HRAS mutations are rare in multiple myeloma (MM).

[00126] As used herein, the kRas, nRas, and hRas gene products refer to, but is not limited to, the following.

[00127] Human KRAS Isoform 2A (canonical), accessible at https://www.uniprot.org/uniprot/P01116,

[00128] and having the following amino acid sequence (SEQ ID NO: 1):

[00129] KRAS can also refer to human Isoform 2B (SEQ ID NO: 2). The sequence of this isoform differs from the canonical sequence as follows:

151-153: RVE GVD

165-189: QYRLKKISKEEKTPGC VKIKKCIIM → KHKEKMSKDGKKKKKKSKTKCVIM [00130] Human NBAS, accessible as https://www.uniprot.org/uniprot/P01111, and having the following amino acid sequence (SEQ ID N0:3):

[00131]

..

[00132] Human HRAS Isoform 1 (canonical), accessible as https://www.uniprot.org/uniprot/P01112,

[00133] and having the following amino acid sequence (SEQ ID NO:4):

[00134]

[00135] HRAS can also refer to human Isoform 2 differs from the canonical sequence as follows:

152-189: VEDAFYTLVREIRQHKLRKLNPPDESGPGCMSCKCVLS SRSGSSSSS GTL WDPPGPM (SEQ ID NO: 5)

[00136] Determination of mutation status

[00137] Prior to onset of treatment as described herein, DNA or RNA from cells of the patient’s (subject’s) tumor are assessed to determine RAS (e.g., NRAS, KRAS or HRAS) mutation status to identify patients who are likely to benefit from the methods described herein. Mutation status is determined using standard sequencing methods known to those skilled in the art including, for example, Sanger sequencing, next generation sequencing (NGS, also called massive parallel sequencing.). In certain embodiments, the tumor mutation is determined by a diagnostic assay selected from FoundationOne^®CDx, Oncomine™Dx Target Test, Guardant360^®CDx. Tumors demonstrating an activating mutation at codon 12, 13 or 61 of RAS (e.g., NRAS, KRAS or HRAS) could be used to identify a subgroup of multiple myeloma patients warranting treatment as described herein. Additional details relating to sequencing methods suitable for use can be found at the following url: https ://www. illumina. com/ content/ dam/illumina- marketing/documents/products/research reviews/sequencing-methods-review.pdf [00138] As used herein, “RAS nucleotide” encompasses the RAS genes, RAS mRNAs, RAS cDNAs and amplification products, mutations, variations and fragments thereof. Unless otherwise specified “RAS” refers to hRAS, kRAS and nRAS (e.g., the term “RAS gene” refers to the HRAS gene, the KRAS gene and the NRAS gene or RAS protein refers to the HRAS, KRAS and NRas protein). “RAS Protein” refers to the polypeptide sequence that is produced by the translation of the RAS nucleotide or a portion thereof. As used herein, a “RAS mutation” refers to alterations to a wild-type or parent RAS gene (i.e., the HRAS ,

KRAS or NRAS gene) located on a genome or extrachromosomal element, or to the corresponding cDNA, mRNA or protein. For example, alterations can be in the parent polynucleotide sequence encoding RAS, alterations to the parent polypeptide sequence of RAS, alterations to the parent polynucleotide sequence involved in RAS expression, multiplication or amplification in the number of RAS genes, multiplication or amplification in the number of RAS genes having one or more polynucleotide sequence mutations, or the like. Examples of polynucleotide sequence mutations include missense mutations, nonsense mutations, splice site mutations, silent mutations, insertion mutations, nonsense mutations, splice site mutations, silent mutations, insertion mutations, deletion mutations, substitution mutations, promoter mutations, partial or whole gene duplication (or amplification) mutations, frameshift mutations, repeat expansion mutations, inversion mutations and translocation mutations. A sequence mutation can affect a single nucleotide (point mutations) a few nucleotides, tens of nucleotides, the entire gene sequence or a chromosomal segment. In some embodiments, when discussing RAS mutations in a nucleotide sequence that encodes a RAS polypeptide, mutations are described in terms of the change that is produced in the sequence of the polypeptide that is encoded by the nucleotide. For example, a G12C KRAS mutation refers to point mutation(s) of the basepairs comprising codon 12 of KRAS that causes the glycine of the wild-type KRAS protein to be substituted by a cysteine.

A RAS mutated cancer cell can comprise one or more RAS mutations. A plurality of RAS- mutated cancer cells in a subject can be composed of populations of cells that each comprise the same RAS mutation or a population of cells having heterogeneous RAS mutation. [00139] Mutations in a RAS gene, such as an NRAS, KRAS or HRAS , that cause increased activity of the RAS protein or increased expression of encoded product (e.g., polypeptide/protein product) are known as “activating mutations.” For example, an activating mutation increases expression of a protein product which can result in inappropriate expression of the protein product or can result in increased or inappropriate activity of the protein product. Such mutations can be constitutive (i.e., always causing increased activity) or transient (e.g., pulsed for a limited duration or inducible). An activating mutation can result from a constitutively acting protein product, gain in copy number (e.g., amplification mutation), inappropriate expression of the gene due to mutation of or switching of expression control elements (e.g., promoter).

[00140] In certain aspects of the first through fourth example embodiments, a mutation is a mutation in any one of codons 12, 13, or 61 of any one of KRAS, NRAS or HRAS. In a specific aspect, the mutation is an activating mutation.

[00141] In certain aspects of the first through fourth example embodiments, a mutation is any one or more of the following mutations resulting from an amino acid substitution in the protein expressed by the wild-type gene a) in nRas: Q61I, Q61K, Q61L, Q61H, Q61R, G12D, G12R, G12S, G13R,

A83G, D54Y, D57A, M72I, E62K, G12A, G12V, G13K; b) in kRas: Q61H, Q61R, Q61K, Q61E, G12H, G12A, G12R, G12S, G12V, G12C, G12D, G13D, G13C, G13V, A59T, A59G, A146T, K117N, L19F, E63K, Q22K, K88*, R123*, E3K, G60R, G60D, V7*, G12M, Y64N; c) In hRas: G13V, G13R, G12C, G12D, G12V, K117N, Q61R, Q61L, E91K, K167E .

In one aspect, the mutation is an activating mutation.

[00142] For example, the one or more RAS mutations (e.g., an activation mutation) can be an amino acid substitution of the protein product of the RAS gene at position G12, G13, G60, Q61, LI 9, Y64 or any combination thereof. For example, the one or more RAS mutations (e.g., an activating mutation) can be an NRAS mutation (e.g., an activating mutation) having one or more of the following amino acid substitutions: Q61I, Q61K, Q61L, Q61H, Q61R, G12D, G12R, G12S, G13R, A83G, D54Y, D57A, M72I, E62K, G12A, G12V, G13K in SEQ ID NOS: 3 or 4 described herein. In a specific aspect, the at least one NRAS mutation (e.g. activating mutation) is one or more of the following amino acid substitutions: Q61K, Q61L, Q61H, Q61R, G13R, G12A, G12V of SEQ ID NOS: 3 or 4. In another embodiment, the RAS activating mutation can be one or more kRAS mutations (e.g., an activating mutation) having one or more of the following amino acid substitutions: Q61H, Q61R, Q61K, Q61E, G12H, G12A, G12R, G12S, G12V, G12C, G12D, G13D, G13C, G13V, A59T, A59G, A146T, K117N, L19F, E63K, Q22K, K88*, R123*, E3K, G60R, G60D, V7*, G12M, Y64N of SEQ ID NOS: 1 or 2 described herein. In a specific aspect, the one or more KRAS mutations (e.g., activating mutation) is one or more of the following amino acid substitutions: Q61H, Q61R, G12A, G12V, G12C, G12D, G13D, G13V, L19F, G60R, G60D, V7*, G12M, Y64N of SEQ ID NOS: 1 or 2.

[00143] Methods for determining the presence of a RAS mutation (e.g., a mutation within a RAS nucleotide sequence encoding a mutant RAS polypeptide, or within a mutant RAS polypeptide) in a patient (subject) sample (e.g., in a tumor cell or tissue) are known in the art. In one embodiment, the sample is a nucleic acid sample. In one aspect, the nucleic acid sample comprises DNA or RNA, e.g., genomic DNA or cDNA or RNA e.g., mRNA. In other embodiments, the sample is a protein sample.

[00144] In some embodiments, where the RAS mutation is to be detected in a nucleic acid molecule, one or more methods selected from nucleic acid hybridization assays (e.g., in situ hybridization, comparative genomic hybridization, microarray, Southern blot, northern blot), amplification-based assays (e.g., PCR, PCR-RFLP assay or real-time PCR), sequencing and genotyping (e.g., sequence-specific primers, high-performance liquid chromatography or mass spectrometric genotyping), and screening analysis (including metaphase cytogenetic analysis by karyotype methods) can be used.

[00145] In another embodiment, the RAS mutation is detected in a RAS protein. The method comprises the steps of obtaining a patient sample (e.g., a tumor sample) and exposing the sample to at least on reagent that detects RAS protein containing a mutation (e.g., an antibody that recognizes the mutated RAS protein, but does not recognize the wild-type RAS protein) to determine whether the mutation RAS protein is present in the sample. For example, the mutant RAS protein can be detected in a patient sample by a method selected from any one of: antibody-based detection (e.g., western blot, ELISA, immunohistochemistry), size based detection methods (e.g., HPLC or mass spectrometry), or protein sequencing.

[00146] Methods of Treating [00147] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. In particular, subjects are humans, such as adult humans.

[00148] In one embodiment, the subject is an adult human. In a specific aspect, the adult human subject is suffering from multiple myeloma. In a further aspect, the adult human subject has received at least one prior therapy to treat the multiple myeloma.

[00149] In another embodiment, the subject is an adult human suffering from relapsed or refractory multiple myeloma. In a further aspect, the adult human suffering from relapsed or refractory multiple myeloma has received at least four prior therapies. In a specific aspect, the adult human subject is suffering from relapsed or refractory multiple myeloma has received at least four prior therapies for multiple myeloma and the multiple myeloma is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

[00150] The term “treating” means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. Treatment includes treating a symptom of a disease, disorder or condition.

[00151] The phrase “combination therapy” or “co-administration” embraces the administration of the XPOl inhibitors of the present invention and one or more additional therapeutic agents as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each. For example, combination therapy includes the administration of one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc. When administered as a combination, the XPOl inhibitors of the present invention and the one or more additional therapeutic agents can be formulated as separate compositions. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). [00152] “Combination therapy” or “co-administration” is intended to embrace administration of the XPOl inhibitors of the present invention and one or more additional therapeutic agent, (e.g., one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc.) in a sequential manner, that is, wherein each therapeutic agent (e.g., the XPOl inhibitor described herein and the at least one additional therapeutic agent) is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, an injection route (e.g., intravenous, subcutaneous), intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, the XPOl inhibitor of the combination may be administered by orally while the at least one additional therapeutic agent of the combination (e.g., bortezomib) may be administered by injection (intravenous or subcutaneous) or vice versa. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence wherein the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with non-drug therapies (e.g., surgery or radiation).

[00153] As used herein, additional therapeutic agents include agents other than XPOl Inhibitors. The one or more additional therapeutic agents (one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc.) can be selected from a glucocorticoid or anti-cancer agents (e.g., anti-cancer agents typically used to treat multiple myeloma). Exemplary glucocorticoids include beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone. In a particular embodiment, the glucocorticoid is dexamethasone. Further the at least one additional therapeutic agent (e.g, one additional therapeutic agent, two additional therapeutic agents, three additional therapeutic agents, four additional therapeutic agents, five additional therapeutic agents etc.) can include anti-cancer agents typically used to treat multiple myeloma. Such anti-cancer agents include, but are not limited to, proteosome inhibitors (e.g., bortezomib, earfilzomib and ixazomib citrate), monoclonal antibodies (e.g., Darzalex (anti-CD38), elotuzumab, sarclisa (anti-CD38) and belantamab mafodotin), immunomodulatory imide drugs (IMiD) (e.g., lenalidomide and pomalidomide, thalidomide), alkylating agents (e.g. melphalan, cyclophosphamide, carmustine), topoisomerase 2 inhibitors (e.g., etoposide, doxorubicin, Doxil, idarubicin), and HDAC inhibitors (e.g, Panobinostat) [00154] In a particular embodiment, combination treatment comprises the administration of the XPOl inhibitors of the present invention (e.g., selinexor) in combination with dexamethasone. The XPOl inhibitor (e.g., selinexor at about 80 mg) is orally administered on Days 1 and 3 of each week of treatment in combination with 20 mg of dexamethasone taken orally also on Days 1 and 3 of each week of treatment. The dose of selinexor can be adjusted to 100 mg once weekly, 80 mg once weekly or 60 mg once weekly as needed. Dexamethasone administration is continued with each dose of selinexor.

[00155] In another embodiment, combination treatment comprises the administration of the XPOl inhibitors of the present invention (e.g., selinexor) in combination with one or more (e.g,, 1, 2 or 3) of the following additional therapeutic agents: lenalidomide, pomalidomide, earfilzomib, bortezomib or duratumumab, and dexamethasone. In one aspect the XPOl inhibitor of the present invention (e.g., selinexor) is

[00156] In a particular embodiment the one or more additional therapeutics agents are two additional therapeutic agents being the combination of a glucocorticoid (e.g., dexamethasone) and a proteasome inhibitor (e.g., bortezomib).

[00157] In other embodiments, the XPOl inhibitor (e.g., selinexor) is administered in the following regimens:

(1) XPOl inhibitor (e.g. selinexor) and the following additional therapeutic agents: a. Lenalidomide and methylprednisolone, prednisone or dexamethasone; b. Liposomal doxorubicin and dexamethasone; c. Carfilzomib and dexamethasone; d. Pomalidomide and dexamethasone; e. Daratumumab and dexamethasone; f. Melphalan and dexamethasone; g. Bortezomib and dexamethasone; h. Dexamethasone; i. Ixazomib and dexamethasone; j . Daratumumab, bortezomib and dexamethasone; k. Dexamethasone, pomalidomide and bortezomib; l. Dexamethasone, pomalidomide and elotuzumab; m. Dexamethasone and belantamab mafodotin; n. Dexamethasone, pomalidomide and daratumumab; o. Dexamethasone, pamalidomide and carfilzomib; p. Dexamethasone, lenalidomide and bortezomib; and q. Dexamethasone, daratumumab and lenalidomide;

[00158] In one aspect, the treatment comprises administering a combination of the XPOl inhibitors of the present invention (e.g., selinexor (also referred to herein as XPOVIO)), bortezomib and dexamethasone. In a particular aspect of this embodiment, the subject has not been previously treated with a proteasome inhibitor (PI naive). In an example embodiment having a 35 day cycle, selinexor is orally administered on Days 1, 8, 15, 22, and 29 of a 35-day cycle (e.g., at 100 mg per dose); bortezomib is subcutaneously administered on Days 1, 8, 15, and 22 of a 35-day cycle (e.g., at 1.3 mg/m2) and dexamethasone is orally administered on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle at 20 mg per dose. The length of the cycle can be adjusted accordingly, maintaining the once weekly administration for selinexor and bortezomib and the twice weekly administration of dexamethasone. If needed the dose of selinexor can be reduced to 80 mg once weekly, 60 mg once weekly or 40 mg once weekly.

[00159] In certain embodiments, the combined administration of the compound of XPOl inhibitor and one or more additional therapeutic agents (e.g., dexamethasone and bortezomib) can provide an enhanced therapeutic effect or can demonstrate synergy ( i.e . show a therapeutic effect that is greater than the additive effect resulting from separate administration of each component of the combination). An advantage of a synergistic effect of the combination therapy is the ability to use less of each agent than is needed when each is administered alone. As such, undesirable side effects associated with the agents are reduced (partially or completely). The presence of synergistic effects can be determined using suitable method for assessing drug interaction. Suitable methods include, for example, the Sigmoid-Emax equation, the equation of Loewe additivity and the median-effect equation. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. [00160] As used herein, “an enhanced therapeutic effect” includes an improved therapeutic profile or increased clinical benefit. Examples of enhanced therapeutic effects include the ability to use a less of one or a portion of or all agents administered in the combination therapy than is needed when each is used alone, a prolonged therapeutic window of one or both compounds of the combination therapy, reduced side effects following administration of the combination therapy, reduced resistance of the target disorder (e.g., multiple myeloma) to one or both compounds of the combination, sensitization of target cells to the action of one or both compounds of the combination therapy, an increase in progression free survival (PFS) as compared to use of the agents not in combination (e.g. and increased PFS for patients treated with selinexor, dexamethasone and bortezomib in combination versus dexamethasone and bortezomib together).

Suitable doses of the XPOl inhibitor per administration include doses of about or greater than about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg. In another embodiment, a suitable dose of the XPOl inhibitor can be from about 50 mg to about 300 mg (such as 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg). Doses can be administered one or more time per day (e.g. once per day, twice per day, three times per day etc.). Dosing regimens can range from one to three time per week (e.g., once per week, twice per week, three times per week etc.).

[00161] The one or more additional therapeutic agents can be administered at the typical dose used in practice or can be determined by one of skill in the medical art using known methods and medical judgment. For example, one or more of the additional therapeutics agents is glucocorticoid (e.g., dexamethasone), it can be administered from about 1 mg to about 100 mg per dose, such as from about 10 mg to about 50 mg per dose, such as 10 mg, 20 mg, 30 mg, 40 mg or 50 mg per dose. In a particular embodiment, the glucocorticoid (e.g., dexamethasone) can be administered at about 20 mg per dose. In another example embodiment, the one or more of addition the additional therapeutic agents is a proteasome inhibitor (e.g., bortezomib) and can be administered from about 100 mg/m² to about 1 mg/m2, such as from about 40 mg/m2 to about 1 mg/m2 such as about 1.3 mg/m².

[00162] The XPOl inhibitors of the present invention can be present in the form of pharmaceutically acceptable salt. For use in medicines, the salts of the XPOl inhibitors of the present invention refer to non-toxic “pharmaceutically acceptable salts.”

Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

[00163] Pharmaceutically acceptable acidic/anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

[00164] The XPOl inhibitors of the present invention can be administered orally, nasally, ocularly, transdermally, topically, intravenously (both bolus and infusion), and via injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) either as alone or as part of a pharmaceutical composition comprising the XPOl inhibitors of the present invention and a pharmaceutically acceptable excipient. The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.

[00165] In a particular embodiment, the XPOl inhibitors of the present invention and the additional therapeutic agent (e.g., dexamethasone) is administered orally. Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. [00166] As used herein, “prior therapies” refers to known therapies for multiple myeloma involving administration of a therapeutic agent. Prior therapies can include, but are not limited to, treatment with proteasome inhibitors (PI), Immunomodulatory agents, anti-CD38 monoclonal antibodies or other agents typically used in the treatment of multiple myeloma such as glucocorticoids. Specific prior therapies can include bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, glucocorticoids or an alkylating agent [00167] In a first example embodiment, the present invention is a method of treating multiple myeloma (MM) in a subject in need thereof, comprising the steps of: obtaining a sample from the subject; determining the presence or absence of one or more RAS mutations in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:

[00168]

[00169] and one or more of an additional therapeutic agent to the subject determined to have one or more RAS mutations present.

[00170] In a first aspect of the first example embodiment:

[00171] Ring A is phenyl or pyridyl;

[00172] X is -N- or -C(H)-;

[00173] each R¹ is independently selected from -CN, halo, - OH, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, 3-18 membered heterocycloalkyl, halo-C₁-C₄ alkyl, -NH₂, -NO₂, -NH(C₁-C₄ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)OH, -C(O)O-(C₁-C₆ alkyl), -C(O)-(C₁-C₄ alkyl), -O-(C₁-C₄ alkyl), -O-(C₁-C₄ haloalkyl), and -S-( C₁-C₄ alkyl);

[00174] R² is selected from -C(O)-O-R³, -C(O)-N(R⁵)(R⁶), -C(O)-N(R⁷)-N(R⁵)(R⁶), [00175] -CN, -CF₃, -S(O)I-2(C₁-C₄ alkyl), 5-18 membered heteroaryl, and C₆-C₁₈ aryl; [00176] R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R^3’, -C(O)-N(R^5’)(R^6’), -C(O)-N(R^r)-N(R^5’)(R^6’), -CN, -C(S)-O-R^3’, -C( S)-N(R⁵ )(R⁶ ), -C(S)-N(R^7’ )-N(R⁵ )(R⁶ ), and 5-18-membered heteroaryl, wherein: [00177] R³ and R³ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl;

[00178] R⁵, R⁵ , R⁶ and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; or

[00179] R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18- membered heteroaryl;

[00180] each R⁷ and R^7’ are each independently hydrogen or C₁-C₄ alkyl; and [00181] n is 0, 1, 2, 3, 4 or 5;

[00182] wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

[00183] In a second example embodiment, the present invention is a method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a compound represented by structural formula (I)

[00185] or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, wherein the subject is determined to have a one or more RAS mutations. [00186] In a 1^st aspect of the 2^nd example embodiment, the values and example values of the variables in structural formula (I) of the second example embodiment are defined above with respect to the first aspect of the first example embodiment.

[00187] In a third example embodiment, the present invention is a method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of: selecting the subject only if the subject has been determined to have one or more RAS mutations; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof,

[00189] one or more additional therapeutic agents.

[00190] In a 1^st aspect of the 3^rd example embodiment, the values and example values of the variables in structural formula (I) of the third example embodiment are defined above with respect to the first aspect of the first example embodiment.

[00191] In a fourth example embodiment, the present invention is a method of treating multiple myeloma in a subject in need thereof, comprising the steps of: receiving information about the absence or presence of one or more RAS mutations in the subject; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

[00192]

[00193] one or more additional therapeutic agents to the subject only if the subject has one or more RAS mutations.

[00194] In a 1^st aspect of the 4^th example embodiment, the values and example values of the variables in structural formula (I) of the second example embodiment are defined above with respect to the first aspect of the first example embodiment.

[00195] In a 2^nd aspect of any one of the 1^st through 4^th example embodiments, the compound of structural formula (I) is represented by structural formula (IIIB):

[00197] or a pharmaceutically acceptable salt thereof, wherein: [00198] R⁵ and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5- 18-membered heteroaryl; or

[00199] R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membred heteroaryl, wherein, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally and independently substituted on any substitutable position with a substituent selected from halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl.

[00200] The remainder of the features, values and example values are as defined above with respect to the 1^st aspect of any of the example embodiments.

[00201] In a 3^rd aspect of any of the 1^st through 4^th example embodiments, the compound of structural formula (I) is represented by the following structural formula

[00202]

[00203]

[00204] or a pharmaceutically acceptable salt thereof.

[00205] The remainder of the features, values and example values are as defined above with respect to the 1^st through 2^nd aspects of any of the example embodiments.

[00206] In a 4^th aspect of any of the example embodiments, the additional therapeutic agent is selected from a glucocorticoid, a proteosome inhibitor, an anti-CD38 monoclonal antibody, an immunomodulatory imide drug (IMiD), an alkylating agent, a topoisomerase 2 inhibitor and an HD AC inhibitor.

[00207] The remainder of the features, values and example values are as defined above with respect to the 1^st through 3^rd aspects of any of the example embodiments.

[00208] In a 5^th aspect of any of the example embodiments, the additional therapeutic agent is selected from a glucocorticoid and a proteasome inhibitor.

[00209] The remainder of the features, values and example values are as defined above with respect to the 1^st through 4^th aspects of any of the example embodiments. [00210] In a 6^th aspect of any of the example embodiments, two additional therapeutic agents are administered and are dexamethasone and bortezomib.

[00211] The remainder of the features, values and example values are as defined above with respect to the 1^st through 5^th aspects of any of the example embodiments.

[00212] In a 7^th aspect of any of the example embodiments, the RAS mutation comprises one or more mutations of kRAS, one or more mutations of nRAS or a combination thereof. [00213] The remainder of the features, values and example values are as defined above with respect to the 1^st through 6^th aspects of any of the example embodiments.

[00214] In an 8^th aspect of any of the example embodiments, the RAS mutation comprises a point mutation at one of more of codons 12, 13 or 61 of kRAS, nRAS or a combination thereof.

[00215] The remainder of the features, values and example values are as defined above with respect to the 1^st through 7^th aspects of any of the example embodiments.

[00216] In a 9^th aspect of any of the example embodiments, the one or more RAS mutation is a kRAS mutation comprising an amino acid substitution at one or more of the following positions of the kRAS polypeptide of SEQ ID NO. 1 or SEQ ID NO. 2: Q61H, G12C,

G12D, G12R, G12V, G13D, G60D, L19F, G60R, Q61R, Y64N, G12A, G12M and G13V. [00217] The remainder of the features, values and example values are as defined above with respect to the 1^st through 8^th aspects of any of the example embodiments.

[00218] In a 10^th aspect of any of the example embodiments, the one or more RAS mutation is a nRAS mutation comprising an amino acid substitution at one or more of the following positions of the nRAS polypeptide of SEQ ID NO. 3: G12A, Q61H, Q61K, Q61L, Q61R, G12V and G13R.

[00219] The remainder of the features, values and example values are as defined above with respect to the 1^st through 9^th aspects of any of the example embodiments.

[00220] In an 11^th aspect of any of the example embodiments, the multiple myeloma is a relapsed or refractory multiple myeloma.

[00221] The remainder of the features, values and example values are as defined above with respect to the 1^st through 10^th aspects of any of the example embodiments.

[00222] In a 12^th aspect of any of the example embodiments, the subject has received from 1 to 7 prior therapies. [00223] The remainder of the features, values and example values are as defined above with respect to the 1^st through 11^th aspects of any of the example embodiments.

[00224] In a 13 ^th aspect of any of the example embodiments, the subject has received at least one prior therapy.

[00225] The remainder of the features, values and example values are as defined above with respect to the 1^st through 12^th aspects of any of the example embodiments.

[00226] In a 14^th aspect of any of the example embodiments, the subject is a human, for example an adult human.

[00227] The remainder of the features, values and example values are as defined above with respect to the 1^st through 13^th aspects of any of the example embodiments.

[00228] In the 15^th aspect of any of the example embodiments, the compound of structural formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[00229] The remainder of the features, values and example values are as defined above with respect to the 1^st through 14^th aspects of any of the example embodiments.

[00230] In a 16^th aspect of any of any of the example embodiments, the compound of structural formula (I) or a pharmaceutically acceptable salt thereof is represented by the following structural formula:

[00231]

[00232] The remainder of the features, values and example values are as defined above with respect to the 1^st through 15^th aspects of any of the example embodiments.

[00233] In a 17^th aspect of any of the example embodiments, the compound of structural formula (I) or a pharmaceutically acceptable salt thereof is orally administered using a dosing regimen comprising multiple weeks of treatment and 100 mg/per day is administered on day 1 of each week of treatment.

[00234] The remainder of the features, values and example values are as defined above with respect to the 1^st through 16^th aspects of any of the example embodiments.

[00235] In a 18^th aspect of any of the example embodiments, two additional therapeutics agents are administered and are dexamethasone and bortezomib. For example, the dexamethasone is orally administered at an amount of 20 mg/day on days 1 and 2 of each week of treatment. In another example, bortezomib is administered at 1.3 mg/m² on day 1 of each week of treatment.

[00236] The remainder of the features, values and example values are as defined above with respect to the 1^st through 17^th aspects of any of the example embodiments.

[00237] EXEMPLIFICATION

[00238] Example 1: Effects of weekly selinexor. bortezomib. dexamethasone (XVd) versus stand twice weekly bortezomib and dexamethasone (Vd) on RAS-mutated previously treated multiple myeloma (MM)

[00239] The experimental data presented below was derived from the analysis of patients involved in the clinical studies described at the following URLs: https://clinicaltrials.gov/ct2/show/NCT02336815 (STORM), and https://clinicaltrials.gov/ct2/show/NCT03110562 (BOSTON).

[00240] BOSTON: The efficacy of XPOVIO in combination with bortezomib and dexamethasone (XVd) was evaluated in BOSTON (NCT03110562). BOSTON was a global, randomized, open label, active-controlled trial in adult patients who had received 1 to 3 prior anti-Multiple Myeloma (MM) regimens. Prior treatment with bortezomib or other Proteosome Inhibitors (PI) was allowed.

[00241] Patients were randomized to receive one of the following:

XPOVIO 100 mg orally once weekly on Days 1, 8, 15, 22, 29 in combination with bortezomib 1.3 mg/m² administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle [SVd arm]; or

Bortezomib 1.3 mg/m² administered subcutaneously twice weekly on Days 1, 4, 8, 11 and dexamethasone 20 mg taken orally four times weekly on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for the first 8 cycles, followed by bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle (Cycle >9) [Vd arm],

[00242] Treatment continued in both arms until disease progression or unacceptable toxicity. Randomization was stratified based on prior proteasome inhibitor therapies exposure (yes versus no), number of prior regimens (1 versus >1), Stage (III versus I or II) according to the Revised-International Staging System (R- ISS) and region. Upon confirmed progressive disease (PD), patients in the Vd arm could receive XPOVIO in combination with bortezomib and dexamethasone (SVd) or XPOVIO 100 mg taken orally on Days 1, 8, 15, 22, 29 with dexamethasone 20 mg taken orally on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35- day cycle. A total of 402 patients were randomized: 195 to SVd arm and 207 to Vd arm. [00243] Efficacy was based on progression free survival (PFS) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma, as assessed by an Independent Review Committee (IRC).

[00244] XPOVIO in combination with bortezomib and dexamethasone (XVd) is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The recommended dosage of XPOVIO is 100 mg taken orally once weekly on Day 1 of each week until disease progression or unacceptable toxicity in combination with: Bortezomib 1.3 mg/m² administered subcutaneously once weekly on Day 1 of each week for 4 weeks followed by 1 week off; and dexamethasone 20 mg taken orally twice weekly on Days 1 and 2 of each week.

[00245] STORM: The efficacy of XPOVIO plus dexamethasone (Sd or Xd) was evaluated in STORM (NCT02336815). STORM was a multicenter, single-arm, open-label study of adults with relapsed or refractory multiple myeloma (RRMM). STORM Part 2 included 122 patients with RRMM who had previously received three or more anti-myeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy. [00246] In STORM Part 2, a total of 122 patients received XPOVIO 80 mg orally in combination with dexamethasone 20 mg orally on Days 1 and 3 of every week (. Treatment continued until disease progression or unacceptable toxicity. Eighty -three patients had RRMM that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab.

[00247] Efficacy was based on overall response rate (ORR), as assessed by an Independent Review Committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. The approval of XPOVIO was based upon the efficacy and safety in a prespecified subgroup analysis of the 83 patients whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, as the benefit-risk ratio appeared to be greater in this more heavily pretreated population than in the overall trial population.

[00248] XPOVIO in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. The recommended dosage of XPOVIO is 80 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity in combination with dexamethasone 20 mg taken orally with each dose of XPOVIO on Days 1 and 3 of each week.

[00249] Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS (RAS^mut) occur in up to 50% of MM and portend poor survival and high recurrence rates. [00250] Methods: In the randomized BOSTON study, patients with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study, patients with penta-treated, triple-class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 patients from BOSTON and STORM, respectively. More specifically, whole exome sequencing was performed on cryopreserved CD 138+ cells from patients treated on the BOSTON or STORM trials by researchers at the JP Sulzberger Columbia Genome Center. FASTQ files were aligned to the human genome (hg38) using BWA, then variants were called according the genome analysis toolkit best practices with mutect2. All RAS mutations were manually examined in BAM files using integrated genomics viewer. Patients were considered RAS^mut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61.

[00251] Results: There were 54 patients (45%) with RAS^mut in BOSTON (XVd=26, Vd=28), and 17 (33%) in STORM.

[00252] In BOSTON, patients with RAS^mut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med]=12.9 vs 6.7 months [mo], hazard ratio [HR]=0.48 [95% Cl 0.24-0.97], p=0.039).

[00253] For patients treated with Vd, those with RAS^mut had significantly shorter overall survival (OS) compared to RAS^wild-type (WT) (med=16.8 mo vs not reached [NR], HR=2.87 [95% Cl 1.03-7.99], p=0.035). PFS was not significantly different (med=6.74 vs 9.82 mo, HR=1.64 [95% Cl 0.88-3.07], p=0.122).

[00254] Amongst patients on XVd, there was no difference in survival between RAS^mut and RAS^WT patients (PFS: med=12.8 vs 12.9 mo, HR=1.08 [95% Cl 0.52-2.26], p=0.83; OS: med=NR vs NR, HR=0.94 [95% Cl 0.36-2.45], p=0.91).

[00255] In STORM, patients with RAS^mut had shorter OS compared to RAS^wt pts (med=6.1 vs NR, HR=2.05 [95% Cl 1.22-5.19], p=0.010).

[00256] Conclusions: Despite typically having the worst outcomes, patients with RAS^mut MM had a similar benefit from XVd as RAS^wild-type MM, showing that the XVd combination can overcome RAS^mut. With a manageable safety profile, the XVd regimen provides a viable treatment option to improve survival of pts with MM with RAS mutations.

[00257] The results of this study are presented in Table 1 :

[00258] Table 1

[00259] The results of the analysis are also graphically represented in FIG. 1 A and FIG.

IB, which demonstrate that activating RAS mutations in MM patients are associated with poor prognosis, and in FIG. 2A through FIG. 2D, which demonstrate that a combination of selinexor, bortezomib, and dexamethasone improves the chances of survival of RAS^mut MM patients as compared to RAS^wild-type.

[00260] More specifically, patients with RAS mutation who were treated with either the Vd double (BOSTON) or Xd doublet (STORM) had shorter OS compared to those who were RAS wild-type. However, among patients treated with XVd on the BOSTON study, those with RAS mutations had similar PFS and OS as those who were RAS wild-type. As such, the selinexor, bortezomib and dexamethasone combination treatment is able to overcome the therapeutic resistance caused by RAS mutations in multiple myeloma.

[00261] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMS What is claimed is:

1. A method of treating multiple myeloma (MM) in a subject in need thereof, comprising the steps of: obtaining a sample from the subject; determining the presence or absence of one or more RAS mutations in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:

and one or more of an additional therapeutic agent to the subject determined to have one or more RAS mutations present, wherein:

Ring A is phenyl or pyridyl;

X is -C(H)- or -N-; each R¹ is independently selected from halo-C₁-C₄ alkyl, -CN, halo, - OH, C₁- C₄ alkyl, C₃-C₆ cycloalkyl, 3-18 membered heterocycloalkyl, -NH₂, -NO₂, -NH(C₁-C₄ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)0H, -C(O)O-(C₁-C₆ alkyl), -C(O)-(C₁-C₄ alkyl), -O-(C₁-C₄ alkyl), -O-(C₁-C₄ haloalkyl), and -S-( C₁-C₄ alkyl);

R² is selected from

-C(O)-N(R⁷)-N(R⁵)(R⁶), -C(O)-O-R³, -C(O)-N(R⁵)(R⁶),

-CN, -CF₃, -S(O)_1-2(C₁-C₄ alkyl), 5-18 membered heteroaryl, and C₆-C₁₈ aryl;

R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R^3’, -C(O)-N(R^5’)(R^6’), -C(O)-N(R^r)-N(R^5’)(R^6’), -CN, -C(S)-O- R³ , -C(S)-N(R⁵ )(R⁶ ), -C(S)-N(R^7’ )-N(R⁵ )(R⁶ ), and 5-18-membered heteroaryl, wherein: R³ and R³ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5- 18-membered heteroaryl;

R⁵ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃- C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl;

R⁶ is selected from a 5-18-membered heteroaryl, hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, and 3-18-membered heterocyclyl;

R⁶ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃- C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; or

R⁵ and R⁶ or R⁵ and R⁶ are each independently taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membered heteroaryl; each R⁷ and R^7’ are each independently hydrogen or C₁-C₄ alkyl; and n is 2, 0, 1, 3, 4 or 5; wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

2. A method of treating multiple myeloma in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and and one or more additional therapeutic agents wherein the subject is determined to have a one or more RAS mutations, wherein:

Ring A is phenyl or pyridyl;

R² is selected from

-C(O)-N(R⁷)-N(R⁵)(R⁶), -C(O)-O-R³, -C(O)-N(R⁵)(R⁶),

R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R^3’, -C(O)-N(R^5’)(R^6’), -C(O)-N(R^r)-N(R^5’)(R^6’), -CN, -C(S)-O- R³ , -C(S)-N(R⁵ )(R⁶ ), -C(S)-N(R^7’ )-N(R⁵ )(R⁶ ), and 5-18-membered heteroaryl, wherein:

R³ and R³ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5- 18-membered heteroaryl;

R⁵ is selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃- C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; R⁶ is selected from a 5-18-membered heteroaryl, hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, and 3-18-membered heterocyclyl;

3. A method of selecting and treating a subject suffering from multiple myeloma (MM), comprising the steps of: selecting the subject only if the subject has been determined to have one or more RAS mutations; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof,

one or more additional therapeutic agents wherein:

Ring A is phenyl or pyridyl; X is -C(H)- or -N-; each R¹ is independently selected from halo-C₁-C₄ alkyl, -CN, halo, - OH, C₁- C₄ alkyl, C₃-C₆ cycloalkyl, 3-18 membered heterocycloalkyl, -NH₂, -NO₂, -NH(C₁-C₄ alkyl), -N(C₁-C₃ alkyl)(C₁-C₃ alkyl), -C(O)0H, -C(O)O-(C₁-C₆ alkyl), -C(O)-(C₁-C₄ alkyl), -O-(C₁-C₄ alkyl), -O-(C₁-C₄ haloalkyl), and -S-( C₁-C₄ alkyl);

R² is selected from

-C(O)-N(R⁷)-N(R⁵)(R⁶), -C(O)-O-R³, -C(O)-N(R⁵)(R⁶),

4. A method of treating multiple myeloma in a subject in need thereof, comprising the steps of: receiving information about the absence or presence of one or more RAS mutations in the subject; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof

one or more additional therapeutic agents to the subject only if the subject has one or more RAS mutations, wherein:

Ring A is phenyl or pyridyl;

R² is selected from

-C(O)-N(R⁷)-N(R⁵)(R⁶), -C(O)-O-R³, -C(O)-N(R⁵)(R⁶),

5. The method of any one of claims 1-4, wherein the compound of structural formula I, is represented by structural formula (IIIB):

or a pharmaceutically acceptable salt thereof, wherein: R⁵ and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, 3-18-membered heterocyclyl and 5-18-membered heteroaryl; or

R⁵ and R⁶ are taken together with the nitrogen atom to which they are commonly attached to form a 3-18-membered heterocyclyl or 5-18-membred heteroaryl, wherein, each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally and independently substituted on any substitutable position with a substituent selected from halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, oxo (=0), cyano, C₆ aryl and C5-C₆ heteroaryl.

6. The method of any one of claims 1-5, wherein the compound of Formula I is represented by the following structural formula

or a pharmaceutically acceptable salt thereof.

7. The method of any one of Claims 1-6, wherein the additional therapeutic agent is selected from a glucocorticoid, a proteosome inhibitor, an anti-CD38 monoclonal antibody, an immunomodulatory imide drug (IMiD), an alkylating agent, a topoisomerase 2 inhibitor and an HD AC inhibitor.

8. The method of any one of Claims 1-7, wherein the additional therapeutic agent is selected from a glucocorticoid and a proteasome inhibitor.

9. The method of Claim 8, wherein two additional therapeutic agents are administered and are dexamethasone and bortezomib.

10. The method of any one of claims 1-9, wherein the RAS mutation comprises one or more mutations of kRAS, one or more mutations of nRAS or a combination thereof.

11. The method of any one of claims 1-8, wherein the RAS mutation comprises as point mutation at one of more of codons 12, 13 or 61 of kRAS, nRAS or a combination thereof.

12. The method of any one of claims 1-9, wherein the one or more RAS mutation is a kRAS mutation comprising an amino acid substitution at one or more of the following positions of the kRAS polypeptide of SEQ ID NO. 1 or SEQ ID NO. 2: Q61H,

G12C, G12D, G12R, G12V, G13D, G60D, L19F, G60R, Q61R, Y64N, G12A, G12M and G13V.

13. The method of any one of claim 1-8, wherein the one or more RAS mutation is a nRAS mutation comprising an amino acid substitution at one or more of the following positions of the nRAS polypeptide of SEQ ID NO. 3: G12A, Q61H, Q61K, Q61L, Q61R, G12V and G13R.

14. The method of any one of Claims 1-13, wherein the multiple myeloma is a relapsed or refractory multiple myeloma.

15. The method of any one of Claims 1-14, wherein the subject has received from 1 to 7 prior therapies.

16. The method of Claim 15, wherein the subject has received at least one prior therapy.

17. The method of any one of Claims 1-16, wherein the subject is a human.

18. The method of Claim 17, wherein the human is an adult.

19. The method of any one of Claim 1-18, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

20 The method of Claim 19, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by the following structural formula:

21 The method of Claim 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered using a dosing regimen comprising multiple weeks of treatment and 100 mg/per day is administered on day 1 of each week of treatment.

22. The method of Claim 21, wherein two additional therapeutics agents are administered and are dexamethasone and bortezomib.

23. The method of Claim 22 wherein the dexamethasone is orally administered at an amount of 20 mg/day on days 1 and 2 of each week of treatment.

24. The method of Claim 22 or 23, wherein bortezomib is administered at 1.3 mg/m² on day 1 of each week of treatment.