WO2021252874A1 - Xpo1 inhibitors for use in treating cancer - Google Patents

Abstract

A method of treating a AML in a subject in need thereof. The method comprises administering a therapeutically effective amount of a compound represented by formula (I), for example Selinexor to the subject, wherein the subject has a mutation in the IDH2 gene, for example a IDH2 p.R172K mutation.

Description

XPO1 INHIBITORS FOR USE IN TREATING CANCER RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 63/037,964, filed on June 11, 2020. The entire teachings of the above application are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Hematological malignancies are cancers that affect the blood and lymph system. Some types of hematologic malignancies include: Multiple myeloma, Hodgkin lymphoma, Non-Hodgkin lymphoma and Leukemia. The cancer may begin in blood-forming tissue (e.g., bone marrow), or in the cells of the immune system. For example, leukemia originates in blood-forming tissue. Leukemia is characterized by the uncontrolled growth of blood cells, usually white blood cells (leukocytes), in the bone marrow. White blood cells are a fundamental component of the body's immune response. The leukemia cells crowd out and replace normal blood and marrow cells. [0003] There are four main types of leukemia: Acute myeloid leukemia (AML); Chronic myeloid leukemia (CML); Acute lymphocytic leukemia (ALL); and Chronic lymphocytic leukemia (CLL). The primary differences between the four main types of leukemia have to do with their rates of progression and where the cancer develops. Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, is a fast-growing form of cancer of the blood and bone marrow. AML is the most common type of acute leukemia. It occurs when the bone marrow begins to make blasts, cells that have not yet completely matured. These blasts normally develop into white blood cells. However, in AML, these cells do not develop and are unable to ward off infections. In AML, the bone marrow may also make abnormal red blood cells and platelets. The number of these abnormal cells increases rapidly, and the abnormal (leukemia) cells begin to crowd out the normal white blood cells, red blood cells and platelets that the body needs. [0004] The standard treatment for AML includes remission-induction treatment consisting of administration of the chemotherapeutic agents cytarabine and daunorubicin (7+3). This treatment has been the standard of care for decades. Few other therapeutic approaches for malignant disease have remained so unchanged for such a long period. In addition, the co-morbidities and high susceptibility to treatment-related toxicity still limit treatment success. Despite advances in treatment strategies for AML there remains a need to identify novel, potent and well-tolerated therapies either a single agent therapy or a combination therapy in order to maximize the therapeutic benefit and minimize treatment- related toxicity. SUMMARY OF THE INVENTION [0005] The present invention relates to a method of treating AML in a subject in need thereof. [0006] Accordingly, in one embodiment the present invention is a method of treating a subject suffering from a AML, comprising the steps of: obtaining a sample from the subject; determining a sequence of an IDH2 gene in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof as described herein

to the subject determined to have a mutation in the IDH2 gene. In one aspect, the mutation in the IDH2 gene is IDH2 p.R172K. In another aspect, the compound of formula (I) is represented by structural formula (A)

(A), or a salt thereof. [0007] In another embodiment, the present invention is a method of treating AML in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) as described herein

to the subject, wherein the subject is determined to have a mutation in a IDH2 gene. In one aspect, the mutation in the IDH2 gene is IDH2 p.R172K. In another aspect, the compound of formula (I) is represented by structural formula (A)

(A), or a salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0008] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [0009] FIG.1A is a plot showing the median overall survival of the patients treated in the SOPRA Study stratified by IDH2 gene mutation status. [0010] FIG.1B is a plot of time on treatment for evaluable patients treated with selinexor who harbor IDH2 p.R172K mutations, IDH2 p.R140Q/W mutations or are wild-type for IDH2. . [0011] FIG.2 illustrates the clinical time course from April 2015-September 2019 for the patient detailed in the Case Study. [0012] FIG.3 shows the VAFs of detected somatic mutations in the Case Study patient. DETAILED DESCRIPTION OF THE INVENTION [0013] A description of example embodiments of the invention follows. [0014] SINE COMPOUNDS [0015] In a first embodiment, compounds useful for practicing the present invention are represented by structural formula (I): [0016]

[0017] In structural formula (I): [0018] Ring A is phenyl or pyridyl; [0019] X is -N- or -C(H)-; [0020] each R¹ is independently selected from -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); [0021] R² is selected from -C(O)-O-R³, -C(O)-N(R⁵)(R⁶), -C(O)-N(R⁷)-N(R⁵)(R⁶), [0022] -CN, -CF₃, -S(O)_1-2( C₁-C₄ alkyl), optionally substituted C₅-C₁₈ heteroaryl, and optionally substituted C₆-C₁₈ aryl; [0023] R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R³, -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(R^5’)(R^6’), -C(S)- N(R^7’)-N(R^5’)(R^6’), and C₅-C₁₈ heteroaryl, wherein: [0024] R³ and R^3’ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl,C₆-C₁₈ aryl,C₃-C₁₈ heterocyclyl and C₅-C₁₈ heteroaryl; [0025] R⁵, R^5’, R⁶ and R^6’ are each independently selected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, C₃-C₁₈ heterocyclyl and C₅- C₁₈ heteroaryl; or [0026] R⁵ and R⁶ or R^5’ and R^6’ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C₁₈ heterocyclyl or C₅-C₁₈ heteroaryl; [0027] each R⁷ and R^7’ are each independently hydrogen or C₁-C₄ alkyl; and [0028] n is 0, 1, 2, 3, 4 or 5; [0029] wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted. [0030] In a first aspect of the first embodiment, each R⁷ is hydrogen. The values for the remaining variables are as defined in the second embodiment. [0031] In a second aspect of the first embodiment, X is -C(H)-. The values for the remaining variables are as defined in the first embodiment, or the first aspect thereof. [0032] In a third aspect of the first embodiment, X is -N-. The values for the remaining variables are as defined in the first embodiment, or the first aspect thereof. [0033] In a fourth aspect of the first embodiment, n is 0, 1 or 2. The values for the remaining variables are as defined in the first embodiment, or the first through third aspects thereof. [0034] In a fifth aspect of the first embodiment, each R¹ is independently selected from halo, -C₁-C₃ alkyl, -C₁-C₃ haloalkyl, and -O-C₁-C₃ alkyl, or is absent. The values for the remaining variables are as defined in the first embodiment, or the first through fourth aspects thereof. [0035] In a sixth aspect of the first embodiment, each R¹ is independently selected from -CF₃, -Cl and -OCH₃, or is absent. The values for the remaining variables are as defined in the first embodiment, or the first through fifth aspects thereof. [0036] In a seventh aspect of the first embodiment: 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 heterocyclyl; or R² is -C(O)-NH-NH(R⁶), and R⁶ is an optionally substituted heteroaryl; or R² is optionally substituted 5-6-membered heteroaryl. The values for the remaining variables are as defined in the first embodiment, or the first through sixth aspects thereof. [0037] In an eighth aspect of the first embodiment: R² is -C(O)-NH-NH(R⁶), and R⁶ is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or R² is optionally substituted pyrimidinyl and R^b is -C(O)-N(R^5’)(R^6’),. The values for the remaining variables are as defined in the firt embodiment, or the first through seventh aspects thereof. [0038] In a ninth aspect of the first embodiment: R² is -C(O)-NH-NH(R⁶), wherein R⁶ is optionally substituted pyrazinyl and R^b is hydrogen; or R² is optionally substituted pyrimidinyl and R^b is -C(O)-N(R^5’)(R^6’) wherein R^5’ and R^6’ are both hydrogen. The values for the remaining variables are as defined in the first embodiment, or the first through seventh aspects thereof. [0039] In a tenth aspect of the first embodiment, Ring A is phenyl. The values for the remaining variables are as defined in the first embodiment, or the first through ninth aspects thereof. [0040] In an eleventh aspect of the first embodiment, Ring A is pyridyl. The values for the remaining variables are as defined in the first embodiment, or the first through ninth aspects thereof. [0041] In a second embodiment, the compound of formula I is represented by structural formula (II):

or a pharmaceutically acceptable salt thereof. The values for the variables are as defined in the first embodiment, or the first through ninth aspects thereof. [0042] In a third embodiment, the compound is represented by structural formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R^1a and R^1b are each independently selected from -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); m is 0 or 1. The values for the remaining variables are as defined above for the first embodiment, or the first through tenth aspects thereof. [0043] In a first aspect of the third embodiment, R^1a is halo or halo-C₁-C₃. The values for the remaining variables are as defined above for the first embodiment, or the first through tenth aspects thereof. [0044] In a second aspect of the third embodiment, 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 first embodiment or the first through tenth aspects thereof. [0045] In a third aspect of the third embodiment, m is 1. The values for the remaining variables are as defined above for the first embodiment, or the first through tenth apects thereof or the first through third aspects of the third embodiment. [0046] In a fourth aspect of the third embodiment, R^1a and R^1b are each -CF₃. The values for the remaining variables are as defined above for the first embodiment, or the first through tenth apects thereof or the third aspect of the thirdembodiment. [0047] In a fifth aspect of the third embodiment: R² is -C(O)-NH-NH(R⁶), wherein R⁶ is optionally substituted pyrazinyl and R^b is hydrogen; or R² is optionally substituted pyrimidinyl and R^b is -C(O)-N(R^5’)(R^6’) wherein R^5’ and R^6’ are both hydrogen. The values for the remaining variables are as defined above for the first embodiment, or the first through ninth aspects thereof or the first through fourth aspects of the third embodiment. [0048] In a fourth embodiment, the compound of formula I is represented by structural formula (IIIA):

or a pharmaceutically acceptable salt thereof, wherein: the remaining variables are as defined above for the first embodiment. [0049] In a first aspect of the fourth embodiment, R² is an optionally substituted 5-6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. [0050] In a second aspect of the fourth embodiment, R² is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.. [0051] In a third aspect of the fourth embodiment, R² is an optionally substituted 6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. [0052] In a fourth aspect of the fourth embodiment, R² is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. [0053] In a fifth aspect of the fourth embodiment, R² is optionally substituted pyrimidinyl. [0054] In an sixth aspect of the fourth embodiment, R² is a 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C₁-C₄ alkyl, halo-C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl, cyano, aryl and 5-6 membered heteroaryl. [0055] In a seventh aspect of the fourthembodiment, R² is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C₁-C₄ alkyl, -CF₃, amino and cyano. [0056] In an eighth aspect of the fourth embodiment, the compouond represented by structural formula (IIIA) or a pharmaceutically acceptable salt thereof has the following structure:

[0057] In a fifth embodiment, the compound of formula (I) is represented by structural formula (IV):

or a pharmaceutically acceptable salt thereof. The remaining variables are as defined above for the first embodiment. [0058] In a sixth embodiment, the compound of formula (I) is represented by structural formuls (IVA):

or a pharmaceutically acceptable salt thereof, wherein the values for R^1a, R^1b, R⁵, R⁶ and m are as defined above for the first and second embodiments and any aspect thereof. [0059] In a seventh embodiment, the compound of formula (I) is represented by structural formula IVB

or a pharmaceutically acceptable salt thereof, wherein the values for R⁵ and R⁶ as defined above for the first and second embodiments and any aspect thereof. [0060] In a first aspect of the seventh embodiment, R² is -C(O)-N(H)-N(R⁵)(R⁶) wherein 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 first and second embodiments and any aspect thereof. [0061] In a second aspect of the seventh embodiment, R² is -C(O)-N(H)-N(R⁵)(R⁶) wherein 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 first and second embodiments and any aspect thereof. [0062] In a third aspect of the seventh embodiment, R² is -C(O)-N(H)-N(R⁵)(R⁶) wherein 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 first and second embodiments and any aspect thereof. [0063] In a fourth aspect of the seventh embodiment, R² is -C(O)-N(H)-N(R⁵)(R⁶) wherein R⁵ is hydrogen. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0064] In a fifth aspect of the seventh embodiment, 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; or R⁵ and R⁶ are taken together to form 4-hydroxypiperdin-1-yl. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0065] In a sixth aspect of the seventh embodiment, R² is an optionally substituted 5- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0066] In a seventh aspect of the seventh embodiment, R² is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0067] In an eight aspect of the seventh embodiment, R² is an optionally substituted 6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0068] In a ninth aspect of the seventh embodiment, R² is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. [0069] In a tenth aspect of the seventh embodiment, R² is optionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, hydroxyl, amino, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, sulfhydryl or cyano. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0070] In a eleventh aspect of the seventh embodiment, R² is optionally substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0071] In a twelfth aspect of the seventh embodiment, R² is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C₁-C₄ alkyl, -CF₃, amino and cyano. The values for the remaining variables are as defined above for the first and second embodiments and any aspect thereof. [0072] In an thirteenth aspect of the seventh embodiment, the compouond represented by structural formula (IVB) or a pharmaceutically acceptable salt thereof has the following structure:

. [0073] 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. [0074] 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. [0075] 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. [0076] 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. [0077] 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. [0078] 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. [0079] 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. [0080] 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 quaternized 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). [0081] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0082] 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. [0083] 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. [0084] 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, -CCl₃, - CF₂CH₃, -CH₂CF₃, -CH₂(CF₃)₂, -CF₂(CF₃)₂, and the like. Preferred haloalkyl groups include -CF₃ and -CF₂H. A preferred haloalkyl group is -CF₃. [0085] 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. [0086] 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. [0087] The term “alkynylene,” as used herein, means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -C≡C-). 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. [0088] 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. [0089] 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. [0090] 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. [0091] 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. [0092] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted group” are independently halogen; haloalkyl; –(CH₂)_0–4R°; –(CH₂)_0–4OR°; - O(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)_0–4O(CH₂)_0–1Ph which may be substituted with R°; – CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO₂; –CN; –N₃; -(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)_{0– 4}N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; – (CH₂)_0–4C(O)R°; –C(S)R°; -(CH₂)_0–4C(O)OR°; –(CH₂)_0–4C(O)SR°; -(CH₂)_0–4C(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(OR°)R°; – C(O)C(O)R°; -C(O)CH₂C(O)R°; –C(NOR°)R°;-(CH₂)_0–4SSR°; –(CH₂)_0–4S(O)₂R°; –(CH₂)0– 4S(O)₂OR°; -(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; -OP(O)R°₂; –OP(O)(OR°)₂; SiR°₃; –(C_1–4 straight or branched alkylene)O–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, C_1–6 aliphatic, –CH₂Ph, –O(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. [0093] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen,

wherein each 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, –O(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 =O and =S. [0094] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted group” include the following: =O, =S, =NNR^* ₂, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, –O(C(R^* ₂))_2–3O–, and –S(C(R^* ₂))_2–3S–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 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: –O(CR^* ₂)_2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 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. [0095] Suitable substituents on the aliphatic group of R^* include halogen, –

and –NO₂, wherein each

is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(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. [0096] 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, C_1–6 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. [0097] Suitable substituents on the aliphatic group of R^† are independently halogen, –

or -NO₂, wherein each

is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(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. [0098] Example embodiments of the XPO1 inhibitors of the invention are Selinexor, Eltanexor and Verdinexor. [0099] Eltanexor is a compound represented by the following structural formula,

[00100] Eltanexor is a second-generation oral selective inhibitor of nuclear export (SINE) that binds to XPO1 and prevents it from shuttling its cargo from the nucleus to the cytoplasm, resulting in nuclear accumulation of tumor suppressor proteins and oncogene mRNAs. [00101] Selinexor is an oral inhibitor of XPO1 that can cross the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the cell nucleus, inducing cancer cell apoptosis. Selinexor is approved by the US FDA for treatment of patients with refractory multiple myeloma. [00102] International Publication No. WO 2013/019548 describes compounds having inhibitory activity against XPO1, useful in the treatment of disorders associated with XPO1 activity, such as cancer. (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)- 1H-1,2,4-triazol-1-yl)-N'- (pyrazin-2-yl)acrylohydrazide (also referred to as Selinexor) is one of the compounds disclosed in International Publication No. WO 2013/019548, which is incorporated herein by reference in its entirety. Selinexor has the chemical structure shown in Structural Formula 1:

[00103] Verdinexor is an oral inhibitor or XPO1 also described in WO2013/019548.

[00104] Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, is a fast-growing form of cancer of the blood and bone marrow. AML is the most common type of acute leukemia. It occurs when the bone marrow begins to make blasts, cells that have not yet completely matured. These blasts normally develop into white blood cells. However, in AML, these cells do not develop and are unable to ward off infections. In AML, the bone marrow may also make abnormal red blood cells and platelets. The number of these abnormal cells increases rapidly, and the abnormal (leukemia) cells begin to crowd out the normal white blood cells, red blood cells and platelets that the body needs. [00105] An association of IDH2 gene mutations with the response of AML patients to treatment with XPO1 Inhibitors, for example Selinexor has now been demonstrated. Mutations in the IDH2 Gene Can be Predictive of Patient Response to Treatment [00106] To identify patients with AML who are most likely to benefit from selinexor treatment, we assessed associations between somatic mutations and best overall response in patients treated with selinexor on the SOPRA study. Targeted DNA sequencing of a panel of 50 cancer/leukemia genes was performed on pre-selinexor treatment bone marrow mononuclear cells (BM-MNCs) from 62, evaluable, selinexor-treated patients enrolled on SOPRA. Additional exome sequencing was performed on DNA extracted from BM-MNCs from a patient with exceptionally long-term complete remission at six time points. on 57 selinexor-treated patients suffering from the GBM was performed. Associations between gene mutations and response to treatment. [00107] The IDH2 gene provides instructions for making an enzyme called isocitrate dehydrogenase 2. This enzyme is found in mitochondria, which are the energy-producing centers within cells. Within mitochondria, the enzyme participates in reactions that produce energy for cell activities. Specifically, isocitrate dehydrogenase 2 normally converts a compound called isocitrate to another compound called 2-ketoglutarate. A series of additional enzymes further process 2-ketoglutarate to produce energy. The conversion reaction also produces a molecule called NADPH, which is necessary for many cellular processes and helps protect cells from potentially harmful molecules called reactive oxygen species. See NCBI GeneID; 3418. [00108] A “therapeutically effective amount”, as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of diseases or conditions disclosed herein. In a particular embodiment, the therapeutically effective amount of the compound of formula (1) is from about 200 mg to about 2 mg. For example, a therapeutically effect amounts can be about 60 mg twice per week. [00109] 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. Subject and patient are used interchangeably herein. [00110] 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. [00111] The phrase “combination therapy” or “co-administration” embraces the administration of the compound of Formula (I) and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each. When administered as a combination, the compound of Formula (I) and an additional therapeutic agent 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). [00112] Additional therapeutic agents include, but are not limited to, hyrdoxyurea, Ara-C, Azacitidine and Decitabine. [00113] The compounds of formula (1) can be present in the form of pharmaceutically acceptable salt. For use in medicines, the salts of the compounds of formula (1) refer to non- toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. [00114] 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, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. [00115] The compounds of formula (1) 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 compound of formula (1) 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. [00116] In a particular embodiment, the compound of formula (1) and optionally a second agent 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. EXEMPLIFICATION [00117] SOPRA STUDY (NCT02088541): The SOPRA study was a randomized, open label, Phase 2 study of selinexor vs specified physician’s choice (PC) in patients ≥60 years old with relapsed/refractory AML who were ineligible for intensive chemotherapy and/or transplantation. [00118] The Phase 2 SOPRA (Selinexor in Older Patients with Relapsed/Refractory AML) study is a randomized trial evaluating single-agent selinexor (KPT-330), Karyopharm's lead, novel, oral Selective Inhibitor of Nuclear Export / SINE™ compound, versus physician's choice in patients 60 years of age or older with relapsed or refractory AML who were ineligible for intensive chemotherapy and/or transplantation. In the SOPRA study, 176 patients with AML whose disease had relapsed after, or was refractory to, first line therapy were randomized 2:1 to receive either oral selinexor (60 mg twice per week) or one of four physician's choice (PC) therapies. Physician's choice included best supportive care (BSC) alone, or BSC plus either azacytidine (Vidaza^®), decitabine (Dacogen^®), or low dose cytosine arabinoside (LD-AraC). Mutations in the IDH2 Gene Can be Predictive of Patient Response to Treatment [00119] As described above, targeted DNA sequencing of a panel of 50 genes typically mutated in cancer/leukemia was performed by Cancer Genetics Inc., on pre-selinexor treatment bone marrow mononuclear cells (BM-MNCs) from 62 evaluable, selinexor-treated patients enrolled on SOPRA. [00120] The gene-level frequencies of non-silent, non-synonymous mutations were compared between 12 patients treated with selinexor who achieved complete remission (CR) or complete remission with incomplete count recovery (CRi) and 50 patients treated with selinexor who did not (39 with stable disease, and 11 with progressive disease). [00121] Additional whole exome sequencing was performed on DNA extracted from BM- MNCs from a patient with an exceptionally long-term complete remission at six time-points: (1) at diagnosis with therapy-related AML (tAML), (2) after initial low-dose cytarabine treatment, (3) after 6 cycles of azacytidine treatment, and (4-6) after 5, 8, and 12 cycles of selinexor. [00122] RESULTS [00123] Among evaluable patients treated with selinexor, IDH2 p.R172K mutations were observed significantly more common in the patients who achieved CR/CRi. [00124] Table 1 reports the best overall response stratified by IDH2 mutations. TABLE 1:

[00125] FIG.1A is a plot showing the median overall survival of the patients treated in the SOPRA Study stratified by IDH2 gene mutation status. As can be seen in FIG.1A, the median overall survival of the patients with IDH2 p.R172K mutations patients was 11.60 months compared to 4.0 months in patients wild-type for IDH2 (FIG.1A). [00126] FIG.1B is a plot of time on treatment for evaluable patients treated with selinexor who harbor IDH2 p.R172K mutations, IDH2 p.R140Q/W mutations or are wild-type for IDH2. As can be seen in FIG.1B, time on treatment was significantly longer for patients with IDH2 p.R172K mutations compared to patients with wild-type IDH2 (FIB.1B). [00127] CASE STUDY [00128] Among the three patients with IDH2 p.R172K mutations who achieved a CR/CRi was a 73-year-old female with therapy related AML (tAML) with normal karyotype. The patient started to have a hematologic response from cycle 2 of therapy with a durable CRi (and later CR). his patient was on selinexor in remission for ~3.5 years from April of 2016 until she relapsed in September of 2019. The clinical time course from April 2015- September 2019 is shown in FIG.2. [00129] Sequencing was performed on serial samples from the patient with a sustained complete remission. In addition to the IDH2 p.R172K mutation, the DNMT3A p.R882H hotspot mutation and a loss of function BCORL1 p.C489fs mutation were also detected. Variant allele fractions (VAFs) of these mutations were markedly reduced after treatment with selinexor. [00130] FIG.3 shows the VAFs of detected somatic mutations in the Case Study patient who achieved a long-term complete remission after selinexor treatment. Pre-selinexor time points are initial diagnosis, after low-dose cytarabine and after azacytidine treatment. The middle time point is immediately before selinexor C1D1. Post-selinexor time points are after cycles 5, 8 and 12. [00131] CONCLUSIONS [00132] Molecular marker analyses shows that patients with AML harboring IDH2 p.R172K mutations respond more favorably to selinexor treatment. In fact, treatment with selinexor resulted in a remarkable durable response in a patient with tAML harboring an IDH2 p.R172K mutation, who was enrolled on the SOPRA trial and achieved a CRi/CR for ~3.5 years. [00133] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety. [00134] 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 a subject suffering from a AML, comprising the steps of: obtaining a sample from the subject; determining a sequence of one or a IDH2 gene in the sample; and administering a therapeutically effective amount of a compound represented by structural formula (I):

wherein: ring A is phenyl or pyridyl; X is -C(H)- or -N-; each R¹ is independently selected from halo-C₁-C₃ alkyl, -CN, halo, - OH, C₁- C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C₁₂ heterocycloalkyl, -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); 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), optionally substituted C₅-C₁₈ heteroaryl, and optionally substituted C₆-C₁₈ aryl; R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R³, -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(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C₅-C₁₈ heteroaryl, wherein: R³ and R^3’ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, C₃-C₁₈ heterocyclyl and C₅-C₁₈ heteroaryl; R⁵, R^5’, R⁶ and R^6’ are each independently selected from hydrogen, C₅- C₁₈ heteroaryl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, and C₃-C₁₈ heterocyclyl; or R⁵ and R⁶ or R^5’ and R^6’ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C₁₈ heterocyclyl or C₅-C₁₈ 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 each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted, to the subject determined to have a mutation in the IDH2 gene.

2. The method of Claim 1, wherein the compound of formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

3. The method of any one of Claims 1 or 2, wherein the mutation in the IDH2 gene result in a p.R172K mutation.

4. The method of any one of Claims 1-3, wherein the subject is 60 years of age or greater.

5. The method of any one of Claims 1-4, wherein the subject is suffering from relapsed/refractory AML.

6. The method of Claim 5, wherein the subject is ineligible for intensive chemotherapy and/or transplantation.

7. A method of treating a subject suffering from a AML, comprising administering a therapeutically effective amount of a compound represented by structural formula (I):

wherein: ring A is phenyl or pyridyl; X is -C(H)- or -N-; each R¹ is independently selected from halo-C₁-C₃ alkyl, -CN, halo, - OH, C₁- C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C₁₂ heterocycloalkyl, -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); 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), optionally substituted C₅-C₁₈ heteroaryl, and optionally substituted C₆-C₁₈ aryl; R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R³, -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(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C₅-C₁₈ heteroaryl, wherein: R³ and R^3’ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, C₃-C₁₈ heterocyclyl and C₅-C₁₈ heteroaryl; R⁵, R^5’, R⁶ and R^6’ are each independently selected from hydrogen, C₅- C₁₈ heteroaryl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, and C₃-C₁₈ heterocyclyl; or R⁵ and R⁶ or R^5’ and R^6’ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C₁₈ heterocyclyl or C₅-C₁₈ 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 each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted, wherein the subject is determined to have a mutation in the IDH2 gene.

8. The method of Claim 7, wherein the compound of formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

9. The method of any one of Claims 7 or 8, wherein the mutation in the IDH2 gene result in a p.R172K mutation.

10. The method of any one of Claims 7-9, wherein the subject is 60 years of age or greater.

11. The method of any one of Claims 7-10, wherein the subject is suffering from relapsed/refractory AML.

12. A method of selecting and treating a subject suffering from AML, comprising the steps of: selecting the subject only if the subject has been determined to have a mutation in a IDH2 gene; and administering to the selected subject a therapeutically effective amount of a compound represented by structural formula (1):

wherein: ring A is phenyl or pyridyl; X is -C(H)- or -N-; each R¹ is independently selected from halo-C₁-C₃ alkyl, -CN, halo, - OH, C₁- C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C₁₂ heterocycloalkyl, -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); 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), optionally substituted C₅-C₁₈ heteroaryl, and optionally substituted C₆-C₁₈ aryl; R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R³, -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(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C₅-C₁₈ heteroaryl, wherein: R³ and R^3’ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, C₃-C₁₈ heterocyclyl and C₅-C₁₈ heteroaryl; R⁵, R^5’, R⁶ and R^6’ are each independently selected from hydrogen, C₅- C₁₈ heteroaryl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, and C₃-C₁₈ heterocyclyl; or R⁵ and R⁶ or R^5’ and R^6’ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C₁₈ heterocyclyl or C₅-C₁₈ 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 each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

13. The method of Claim 12, wherein the compound of formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

14. The method of any one of Claims 12 or 13, wherein the mutation in the IDH2 gene result in a p.R172K mutation.

15. The method of any one of Claims 12-14, wherein the subject is 60 years of age or greater.

16. The method of any one of Claims 12-15, wherein the subject is suffering from relapsed/refractory AML.

17. A method of treating a subject suffering from AML, comprising the steps of: receiving information about a mutation in a IDH2 gene present in the patient; and administering a therapeutically effective amount of a compound represented by structural formula (I) to the patient only if the subject has a mutation the IDH2 gene, wherein

ring A is phenyl or pyridyl; X is -C(H)- or -N-; each R¹ is independently selected from halo-C₁-C₃ alkyl, -CN, halo, - OH, C₁- C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C₁₂ heterocycloalkyl, -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); 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), optionally substituted C₅-C₁₈ heteroaryl, and optionally substituted C₆-C₁₈ aryl; R^a is hydrogen and R^b is selected from hydrogen, -C(O)-O-R³, -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(R^5’)(R^6’), -C(S)-N(R^7’)-N(R^5’)(R^6’), and C₅-C₁₈ heteroaryl, wherein: R³ and R^3’ are each independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, C₃-C₁₈ heterocyclyl and C₅-C₁₈ heteroaryl; R⁵, R^5’, R⁶ and R^6’ are each independently selected from hydrogen, C₅- C₁₈ heteroaryl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₁₈ carbocyclyl, C₆-C₁₈ aryl, and C₃-C₁₈ heterocyclyl; or R⁵ and R⁶ or R^5’ and R^6’ are each independently taken together with the nitrogen atom to which they are commonly attached to form a C₃-C₁₈ heterocyclyl or C₅-C₁₈ 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 each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.

18. The method of Claim 17, wherein the compound of formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

19. The method of any one of Claims 17 or 18, wherein the mutation in the IDH2 gene result in a p.R172K mutation.

20. The method of any one of Claims 17-19, wherein the subject is 60 years of age or greater.

21. The method of any one of Claims 17-20, wherein the subject is suffering from relapsed/refractory AML.

22. The method of any one of Claims 1-21, wherein the patient has received from 1-7 previous systemic therapies.

23. The method of Claim 22, wherein the patient has received at least one previous systemic therapies.

24. The method of Claim 22, wherein the patient has received at least two previous systemic therapies.

25. The method of any one of Claims 1-24, wherein the subject is administered 60 mg of the compound of structural formula (1) twice per week.

26. The method of Claim 18, wherein the subject is treated for a four week cycle.

27. The method of Claim 26, wherein the four week cycle is repeated one or more times.

28. The method of any one of Claims 1-27, wherein the compound of Formula (1) is administered orally.

29. The method of any Claims 1-28, wherein the method comprising further administering a second therapeutic agent.

30. The method of Claim 29, wherein the second therapeutic agent is selected from hyrdoxyurea, Ara-C, Azacitidine and Decitabine.