WO2020092965A1 - E2f1 as a biomarker for treatments using xpo1 inhibitors - Google Patents

E2f1 as a biomarker for treatments using xpo1 inhibitors Download PDF

Info

Publication number
WO2020092965A1
WO2020092965A1 PCT/US2019/059483 US2019059483W WO2020092965A1 WO 2020092965 A1 WO2020092965 A1 WO 2020092965A1 US 2019059483 W US2019059483 W US 2019059483W WO 2020092965 A1 WO2020092965 A1 WO 2020092965A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heteroaryl
heterocyclyl
aryl
optionally substituted
Prior art date
Application number
PCT/US2019/059483
Other languages
French (fr)
Inventor
Yosef Landesman
Marsha CROCHIERE
Alessandro LAGANA
Samir PAREKH
Original Assignee
Karyopharm Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Karyopharm Therapeutics Inc. filed Critical Karyopharm Therapeutics Inc.
Publication of WO2020092965A1 publication Critical patent/WO2020092965A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia

Definitions

  • the invention generally relates to the use of nuclear transport modulators, e.g., XPO1 inhibitors, for treating cancer, for example, a hematological cancer in a subject.
  • nuclear transport modulators e.g., XPO1 inhibitors
  • the present invention is a method for treating a cancer in a subject in need thereof, wherein the subject has been determined to have a pre- dose level of a E2F1 gene product less than or equal to a control value, the method comprising administering to the subject an effective amount of a compound represented by structural formula I:
  • ring A is phenyl or pyridyl
  • X is -N- or -C(H)-; each R 1 is independently selected from halo;
  • each Rq is independently selected from hydrogen,C 1-6 aliphatic, -CH 2 -(C3- C12)carbocyclyl, -CH 2 -(C6-C12)aryl, -CH 2 -(4-12 member)heterocyclyl, -CH 2 -(5-12- member)heteroaryl, -O(CH 2 ) 0-1 –(C3-C12)carbocyclyl, -O-(CH 2 ) 0-1 -(C6-C12)carbocyclyl, -O-(CH 2 ) 0-1 -(C6
  • C12)aryl -O(CH 2 ) 0-1 -(4-12 member)heterocyclyl, -O(CH 2 ) 0-1 -(5-12-member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12
  • each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(unsubstituted C 1 -C 3 alkyl), -N(unsubstituted C 1 -C 3 alkyl) 2 , -O-C 1 - C 3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C 1 -C 3 alkyl), -C(O)-(unsubstituted C 1 -C 3 alkyl), -O-(unsubstituted C 1 -C 3 alkyl), and -S-(unsubstituted C 1 -C 3 alkyl,
  • R a is hydrogen and R b is selected from
  • R 3 is selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
  • R 4 is selected from–NR 7 -(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)-(C 3 -C 6
  • cycloalkyl -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-(C3-C12)carbocyclyl, -(C 0 -C 4 alkylene)-(4-12 member)heterocyclyl, -(C 0 -C 4 alkylene)-(C6-C12)aryl, and -(C 0 -C 4 alkylene)- (5-12- member)heteroaryl;
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12-member)heteroaryl;
  • each R 7 and R 9 are independently hydrogen or C 1 -C 4 alkyl
  • R 8 is selected from–N(R 9 ) 2 , -N(R 9 )-(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-(4-12 member)heterocyclyl, -(C 0 -C 4 alkylene)- (5-12-member)heteroaryl;
  • Y is O or S
  • n 0, 1, 2, 3, 4 or 5;
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • the present invention is a method for treating a cancer in a subject in need thereof, the method comprising steps of: receiving information related to a pre-dose level of E2F1 gene product in a subject suffering from the cancer; and administering to the subject an effective amount of a compound represented by structural formula (I):
  • the present invention is a method of treating a subject suffering from a cancer, comprising the steps of: obtaining a sample comprising a cell from the subject; determining a pre-dose level of an E2F1 gene product in the sample; and administering an effective amount of a compound to the subject, wherein the pre-dose level of the E2F1 gene product in the sample is determined to be less than or equal to a control value, wherein the compound is represented by structural formula (I)
  • the present invention is a method for treating a cancer in a subject in need thereof, the method comprising: selecting the subject on the basis of an E2F1 gene product; and administering to the selected subject an effective amount of a compound represented by structural formula I:
  • the present invention a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of formula I
  • FIG.1 is a“heat map” representation of the pre-dose level of expression of the genes listed in the righthmost column, determined by their respective mRNA abundance, in 33 refractory multiple myeloma patients.
  • Each patient is represented by a column; each gene– by a row.
  • the heat map is color-coded by the blue-to-red spectrum according to the Z-score of each gene.
  • the bar above the heat map, color-coded“red or black,” represents the value of the Progression Free Survival (PFS) of each patient after the treatment with a combination of compound C-3 and dexamethasone: red represents PFS greater than or equal to 120 days; black– PFS of fewer than 120 days.
  • PFS Progression Free Survival
  • FIG.2 is a plot representing the numerical range of the pre-treatment values of log2- normalized expression values of the E2F1 gene (measured by the level of mRNA abundance using Affymetryx® U133 microarray) among 26 patients suffering from refractory multiple myeloma and exhibiting progression free survival (PFS) of either greater than 120 days (left) or less than 120 days (right) upon treatment with a combination of compound C-3 and dexamethasone.
  • PFS progression free survival
  • Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
  • 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,
  • aliphatic group can be optionally substituted as described herein.
  • alkyl means a saturated, straight-chain or branched aliphatic group.
  • 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.
  • 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.
  • alkynyl means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -CoC-).
  • 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.
  • cycloaliphatic refers 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.
  • 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.
  • “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.
  • cycloalkyl means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-12 members.
  • a cycloalkyl can be optionally substituted as described herein.
  • a cycloalkyl has 3–6 carbons.
  • a cycloalkyl group can be optionally substituted as described herein.
  • heterocyclyl means a saturated or unsaturated aliphatic ring system having from 3 to 12 members (e.g., a 4-12 member heterocyclyl) 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.
  • 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.
  • 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).
  • alkoxy 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.
  • 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.
  • haloalkyl means an alkyl group that is substituted with one or more halogen atoms.
  • haloalkyl refers to a perhalogenated alkyl group.
  • haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms.
  • Exemplary haloalkyl groups include -CF 3 , -CF 2 H, -CCl 3 , -CF 2 CH 3 , -CH 2 CF 3 , -CH 2 (CF 3 ) 2 , -CF 2 (CF 3 ) 2 , and the like.
  • Preferred haloalkyl groups include -CF 3 and -CF 2 H.
  • a preferred haloalkyl group is -CF 3 .
  • alkylene means a bivalent branched or unbranched saturated hydrocarbon radical.
  • “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.
  • “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.
  • alkynylene means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -CoC-).
  • “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.
  • 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.
  • 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.
  • a heteroaryl has one, two or three rings.
  • the heteroaryl has five to twelve ring atoms.
  • 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.
  • 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.
  • 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.
  • 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.
  • an“optionally substituted group” can be unsubstituted.
  • 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.
  • each Rq may be substituted as defined below and is independently hydrogen, C 1–6 aliphatic,–CH 2 Ph,–O(CH 2 ) 0–1 Ph, -CH 2 -(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 Rq, 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
  • Suitable monovalent substituents on Rq are independently halogen, -(CH 2 ) 0-2 R z ,–(haloR z ),–(CH 2 ) 0–2 OH,–(CH 2 ) 0–2 OR z ,–(CH 2 ) 0–
  • R z is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently selected from C 1–4 aliphatic,–CH 2 Ph,– O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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 *
  • 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 substituents on the aliphatic group of R * include halogen,–
  • each R z is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic,–CH 2 Ph,– O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on a substitutable nitrogen of an“optionally substituted group” include—R ⁇ ,–NR ⁇
  • 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.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen,– R z , -(haloR z ),–OH,–OR z ,–O(haloR z ),–CN,–C(O)OH,–C(O)OR z ,–NH 2 ,–NHR z ,– NR z
  • each R z is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic,–CH2Ph,–O(CH2)0– 1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, the relevant teachings of which are incorporated herein by reference in their entirety.
  • Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of subjects.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, peroxine sodium
  • exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • exemplary organic acids which form suitable salts include the mono-, di- and tricarboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g., hydrochloric, sulfuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
  • inorganic acids e.g., hydrochloric, sulfuric or phosphoric acids
  • organic acids e.g. succinic, maleic, acetic or fumaric acid.
  • non-pharmaceutically acceptable salts e.g., oxalates can be used, for example, in the isolation of compounds of formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • base addition salts such as sodium, potassium and ammonium salts
  • solvates and hydrates of compounds of the invention are included within the scope of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.
  • A“pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by formula I, or any of its intermediates.
  • Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 – 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • stereoisomers is a general term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • the term“subject”, as used herein, means an animal. In some embodiments, the animal is a mammal. In certain embodiments, the subject is a veterinary subject (i.e., a non-human mammal subject), such as a dog, a pig or a horse. In some embodiments, the subject is a dog. In other embodiments, the subject is a human.
  • a veterinary subject i.e., a non-human mammal subject
  • the subject is a dog. In other embodiments, the subject is a human.
  • the term“subject” can be used interchangeably herein with the term“patient.”
  • Hematological cancers are cancers that affect the body’s blood, bone marrow or lymphatic system.
  • the most common forms of hematologic cancers include leukemia, lymphoma and myeloma.
  • Leukemia occurs when the bone marrow overproduces abnormal white blood cells, and is classified by the type of white blood cell affected: myeloid or lymphocytic.
  • Types of leukemia include, but are not limited to, acute lymphoblastic leukemia (ALL) (e.g., B- cell ALL and T-cell ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), acute promyelocytic leukemia (APL), hairy cell leukemia (HCL), large granular lymphocytic leukemia (LGL), te-cell acute lymphoblastic leukemia (T-ALL) and chronic myelomonocytic leukemia (CMML).
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic
  • Lymphoma is a cancer of the lymphatic system that results in uncontrolled growth of malignant white blood cells, forming tumors in the lymph nodes. Lymphoma is classified into two main types: Hodgkin’s and Non-Hodgkins’s lymphoma (HL and NHL). Lymphomas may also be classified by cell type, for example, T-cell lymphoma or B-cell lymphoma. For example, B-Cell HL, T-cell HL, B-cell NHL such as Diffuse large B-cell lymphoma (DLBCL).
  • Exemplary lymphomas include precursor T-cell lymphoma, follicular lymphoma, cutaneous T-cell lymphoma (CTCL), Mantle cell lymphoma (MCL), B-cell chronic lympohocytic lymphoma, MALT lymphoma, Burkitt’s lymphoma, mycosis fungoides, peripheral T-cell lymphoma-Not-Otherwise Specified, nodular sclerosis from of Hodgkin’s lymphoma and mixed-cellularity subtype of Hodgkin’s lymphoma.
  • Myeloma (also referred to as multiple myeloma) occurs when abnormal plasma cells (a type of white blood cell that produces antibodies) accumulate in the bone marrow.
  • abnormal plasma cells a type of white blood cell that produces antibodies
  • the accumulation of abnormal plasma cells causes tumors in many bones of the body that damage and weaken the bone. The tumors can also keep the bone marrow from making enough healthy blood cells.
  • the disclosed methods are useful in the prevention and treatment of cancer, including for example, hematological malignancies (e.g., (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic and myeloproliferative syndromes), solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others.
  • hematological malignancies e.g., (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic and myeloproliferative syndromes), solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others.
  • Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, liver and ovary as well as osteoscarcoma.
  • Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, pancreas, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.
  • Breast cancer can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC.
  • breast cancer can include invasive or non-invasive ductal or lobular carcinoma, tubular, medullary, mucinous, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast and Paget’s disease of the nipple.
  • Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia;, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia; Acute Myeloid Leukemia, Adult;
  • Carcinoid Tumor Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Leukemia; Chronic Lymphocytic Leukemia; Chronic
  • Lymphoma Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors;
  • Extracranial Germ Cell Tumor Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma;
  • Gallbladder Cancer Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;
  • Glioma Childhood Brain Stem
  • Glioma Childhood Visual Pathway and Hypothalamic
  • Hairy Cell Leukemia Head and Neck Cancer
  • Hepatocellular (Liver) Cancer
  • Lymphoblastic Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;
  • Leukemia Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell;
  • Lymphoblastic Leukemia Adult Acute
  • Lymphoblastic Leukemia Childhood Acute
  • Lymphocytic Leukemia Chronic; Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non- Hodgkin's,
  • Lymphoma Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma;
  • Retinoblastoma Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary
  • Further exemplary cancers include diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Yet further exemplary cancers include endocervical cancer, B-cell ALL, T-cell ALL, B- or T-cell lymphoma, mast cell cancer, glioblastoma, neuroblastoma, follicular lymphoma and Richter’s syndrome.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • endocervical cancer B-cell ALL, T-cell ALL, B- or T-cell lymphoma
  • mast cell cancer glioblastoma, neuroblastoma, follicular lymphoma and Richter’s syndrome.
  • Exemplary sarcomas include fibrosarcoma, alveolar soft part sarcoma (ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing’s sarcoma, neuroectodermal sarcoma, phyllodes/osteogenic sarcoma and chondroblastic osteosarcoma.
  • Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
  • “treat” or“treating” means to alleviate one or more symptoms, to eliminate the causation of one or more symptoms, either on a temporary or permanent basis, or to prevent or delay the onset of one or more symptoms associated with a disorder or condition.
  • “treating a cancer” can mean administering to a subject suffering from a cancer a therapeutically effective amount of a compound defined herein, alone or in combination with one or more agents, for a sufficient duration of time to achieve a desired response.
  • a desired response can be, for example, achieving at least a stable disease (“SD”), as this term is defined by the relevant Response Criteria accepted by persons of ordinary skill in the art of a cancer of interest (e.g., as defined by International Myeloma Working Group Response Criteria, described herein below).
  • SD stable disease
  • treating a cancer means achieving at least a“partial response” (“PR”).
  • treating a cancer means achieving a complete response (“CR”).
  • a desired response can be, for example, achieveing“minimal response” (“MR”).
  • MR minimal response
  • the terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound which, when administered in a proper dosing regimen, is sufficient to treat the target disorder (i.e., a hematological or solid cancer).
  • a therapeutically effective amount can relieve to some extent one or more of the symptoms of the disease or condition being treated.
  • the result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of compound required to provide a clinically significant decrease in disease symptoms.
  • a therapeutically effective amount can be an amount that is sufficient to achieve at least a“minimal response,” (“MR”) as this term is defined by the Response Criteria accepted by persons of ordinary skill in the art of a cancer of interest.
  • MR minimal response
  • the MR is defined in Example 1.
  • an effective amount” or“a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
  • the term“differential expression” of a gene refers to either an overexpression or an underexpression of a gene as compared to a pre-determined control.
  • E2F1 refers to a gene coding for a transcription factor that regulates cell cycle G1/S progression.
  • E2F1 is complexed with its negative regulator retinoblastoma (RB) protein.
  • RB negative regulator retinoblastoma
  • pRB is inactivated allowing E2F1 to commence transcription of target genes allowing G1/S progression.
  • E2F transcription factors are exported by XPO1 from the nucleus to cytoplasm.
  • Human E2F1 is listed in the NCBI database under Gene ID 1869.
  • gene product refers to a nucleic acid or a protein that results from the gene expression.
  • gene products include mRNA, DNA, cDNA, transcript and proteins.
  • expression level in the context of a gene expression refers to the measurable quantity (such as number of molecules or concentration) of a particular gene or a gene product (including any of DNA, cDNA, RNA, transcript, or a polypeptide encoded by the gene) in an individual or a sample taken from the individual.
  • expression level refers to the amount of mRNA of the particular gene.
  • expression level refers to the amount of a particular gene in a sample from an individual, such as a tumor sample, blood sample, serum sample, etc., and can, for example, be detected de novo or correspond to a previous determination.
  • the expression level can be expressed as a value normalized relative to a control, e.g. an expression level of a“housekeeping” gene.
  • control value when used in the context of the expression level of a gene (measured, for example, by the abundance of its gene product), refers to a level of gene expression that defines the dividing line between two subsets of a population of patients suffering from the condition being treated (e.g., responders and non-responders). Thus, a value that is equal to or higher than the control value defines one subset of the population; and a value that is lower than the cutoff value defines the other subset of the population.
  • control values are the levels of expression of a gene product of E2F1 above which the subject exhibits progressive disease (PD), stable disease (SD), or, minimal response (MR), as defined by the Response Criteria accepted by persons of ordinary skill in the art of a cancer of interest.
  • Control values can be expressed in any convenient units or be unitless. For example, where the control value is used in the context of gene expression level, control values can be expressed in units of“copies per unit volume,”“moles per unit volume,” “weight per unit volume,”“RPM” (Reads per million mapped reads),“RPKM” (Reads per kilo base per million mapped reads),“TPM” (Transcript per million),“FPKM” (Fragments per kilo base per million mapped reads), or“log2 normalized fluorescence intensity.” Control values can alos be expressed with reference to median values of gene expression obtained for an ensemble of samples (for example, a pool of patients suffereing from the same condition).
  • the control value can be defined relative to a median value of the pre-dose expression levels of the E2F1 gene product (e.g., the E2F1 mRNA) in a population of subjects having Progression Free Survival of not less than 120 days.
  • the control value can be from about 150%, about 140%, about 130%, about 125%, about 120%, about 115%, about 110%, about 105%, about 104%, about 103%, about 102%, about 101%, or about 100% of the median value to about the lowest gene expression level of the E2F1 gene measured in the population of patients.
  • control value can be 150%, 140%, 130%, 125%, 120%, 115%, 110%, 105%, 104%, 103%, 102%, 101%, or 100% of the median value.
  • control value can be derived from the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
  • the control value can be defined in the units of log2 normalized fluorescence intensity (also referred to as“log2-normalized expression”).
  • the control value defined in these units can be from about 50 to about 0.5.
  • the control value sdefined in these units can be 10, 9.95, 9.5, 8, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5.
  • pre-dose refers to the expression level of the gene product measured prior to the commencement of treatment regimen with compounds described herein.
  • sample or“biological sample” refer to any specimen from a subject that contains, or can contain, the biomarkers of interest, e.g., E2F1or an encoded peptide thereof, including, for example, tumor, blood, serum, or plasma.
  • the sample is a tumor biopsy sample.
  • nucleic acid refers to deoxyribonucleotides, deoxyribonucleosides, ribonucleosides, or ribonucleotides and polymers thereof in either single- or double- stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides which have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • oligonucleotide analogs including PNA (peptidonucleic acid), analogs of DNA used in antisense technology (e.g., phosphorothioates, phosphoroamidates).
  • PNA peptidonucleic acid
  • analogs of DNA used in antisense technology e.g., phosphorothioates, phosphoroamidates.
  • a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (including but not limited to, degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated.
  • degenerate codon substitutions are achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al. (1991)Nucleic Acid Res.19:5081; Ohtsuka et al. (1985) J. Biol. Chem.
  • the nucleic acid or a fragment thereof encodes a protein.
  • probe refers to a nucleic acid molecule that comprises a sequence of nucleotides (such as 10 or more, 15 or more, 20 or more, or 10-25, 26-50, 51- 75, 76-100, or 101-500 bases or nucleotides) that will hybridize specifically to a target nucleic acid sequence, such as a gene disclosed herein.
  • nucleotides such as 10 or more, 15 or more, 20 or more, or 10-25, 26-50, 51- 75, 76-100, or 101-500 bases or nucleotides
  • primer refers to a nucleic acid sequence, whether occurring naturally as in a purified restriction digest or produced synthetically, that is capable of acting as a point of synthesis when placed under conditions in which synthesis of a primer extension product, which is complementary to a nucleic acid strand is induced (e.g. in the presence of nucleotides and an inducing agent such as DNA polymerase and at a suitable temperature and pH).
  • chromatography can be used to determine the expression level of a gene, including the E2F1 gene.
  • expression of the gene can be determined by measuring all or a portion of nucleic acid (e.g., DNA, mRNA) of the gene and/or protein (polypeptide) expressed by the gene. The level, expression and/or activity of a gene or its encoded polypeptide can be measured.
  • nucleic acids such as genes, mRNA or a combination thereof, can be determined using PCR (e.g., RT-PCR, RT- qPCR), gene chips or microarray analysis (DNA arrays, gene expressin arrays,
  • next generation sequencing e.g., next generation RNA sequencing
  • in situ hybridization blotting techniques, and the like.
  • Protein can be determined using immunoassys (e.g., immunohistochemistry, immunofluorescence, immunoprecipitation), arrays (e.g., reverse phase protein microarrays), blotting techniques (e.g., western blots), SDS-PAGE, and the like.
  • the level of the E2F1 mRNA in a subject can be determined by a method comprising the steps of: a) obtaining total mRNA from a biological sample from the subject; b) appending to each mRNA molecule additional nucleotides not naturally appended to such mRNA molecules to enable the mRNA molecules to bind to a solid support; c) sequencing the mRNA molecules; and d) determining the level of the mRNA.
  • the level of E2F1 mRNA in a subject can be determined by a method comprising the steps of: (a) obtaining total RNA from sample; (b) hybridizing RNA to array that contains probes for many RNAs; and (c) determining the relative level of E2F1 RNA that bind to the specific array probes.
  • the level of E2F1 in a subject can be determined by a method comprising the steps of: a) obtaining total mRNA from a biological sample from the subject; b) creating a cDNA library from the total mRNA; and c) combining the cDNA library with (i) a primer pair that is specific for cDNA created from the E2F1 mRNA; (ii) a DNA polymerase; and (iii) a component for detection of any DNA molecules produced from the primer pair and the DNA polymerase.
  • the component for detection is a dye.
  • the component for detection is a labelled (e.g., radiolabelled or dye-labelled or oligonucleotide).
  • the level of the E2F1 mRNA detected in the subject is compared to a (pre-determined) control level.
  • the subject is suffering from a hematological cancer.
  • the subject is suffering from a hematological cancer and is administered any one or more compounds described herein, optionally in combination with one or more second agents (e.g., compound C-3 in combination with dexamethasone) if the determined E2F1 level is above the pre-determined control value.
  • the pre-determined control value is a E2F1 level determined by measuring the E2F1 mRNA levels in a sample or an ensemble of samples obtained from subjects having the same hematological cancer; and identifying at least one subject that is non-responsive to any one or more compounds described herein, optionally in combination with one or more second agents.
  • the invention provides a differential method of treating a set of subjects suffering from a hematological cancer comprising administering any one or more compounds described herein, optionally in combination with one or more second agents to a subset of subjects whose cancer is characterized by a E2F1 level that is above a control value; and not administering any one or more compounds described herein, optionally in combination with one or more second agents to a subset of subjects whose cancer is characterized by a E2F1 level that is below that control value.
  • the present invention is a method for treating a cancer in a subject in need thereof, wherein the subject has been determined to have a pre- dose level of a E2F1 gene product less than or equal to a control value, the method comprising administering to the subject an effective amount of a compound represented by structural formula I:
  • the present invention is a method for treating a cancer in a subject in need thereof, the method comprising steps of: receiving information related to a pre-dose level of E2F1 gene product in a subject suffering from the cancer; and administering to the subject an effective amount of a compound represented by structural formula (I): [00119] ,
  • the present invention is a method of treating a subject suffering from a cancer, comprising the steps of: obtaining a sample comprising a cell from the subject; determining a pre-dose level of an E2F1 gene product in the sample; and administering an effective amount of a compound to the subject, wherein the pre-dose level of the E2F1 gene product in the sample is determined to be less than or equal to a control value, wherein the compound is represented by structural formula (I
  • the present invention is a method for treating a cancer in a subject in need thereof, the method comprising: selecting the subject on the basis of an E2F1 gene product; and administering to the selected subject an effective amount of a compound represented by structural formula I:
  • the present invention a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of formula I
  • selecting the subject includes receiving information related to a pre-dose level of an E2F1 gene product in the subject.
  • the E2F1 gene product is an E2F1 mRNA.
  • control value is from 150% to 100% of the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
  • control value is equal to 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110%, or 105% of the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
  • the cancer is a solid tumor.
  • the cancer is a hematological cancer.
  • the hematological cancer is selected from leukemia, lymphoma and myeloma.
  • the hematological cancer is multiple myeloma, for example, a refractory multiple myeloma.
  • the level of the E2F1 gene product has been determined in a CD138 + cell.
  • the cancer is a multiple myeloma refractory after prior treatment with an imunomodulatory drug or a proteasome inhibitor.
  • the multiple myeloma is refractory to one or more of bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (up to penta- refractory).
  • Ring A is phenyl or pyridyl
  • X is -N- or -C(H)-
  • each R 1 is independently selected from halo; haloalkyl; -(CH 2 ) 1-4 Rq; -(CH 2 ) 0-4 ORq;
  • each Rq is independently selected from hydrogen,C 1-6 aliphatic,
  • each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(unsubstituted C 1 -C 3 alkyl), -N(unsubstituted C 1 -C 3 alkyl) 2 , -O-C 1 -C 3 alkyl, -C(O)OH, -C(O)O- (unsubstituted C 1 -C 3 alkyl), -C(O)-(unsubstituted C 1 -C 3 3
  • R 2 is selected from -C(O)-O-R 3 , -C(O)-N(R 5 )(R 6 ), -C(O)-N(R 7 )-N(R 5 )(R 6 ), -CN, -CF 3 , -S(O) 1-2 (C 1 -C 4 alkyl), optionally substituted heteroaryl and optionally substituted aryl;
  • R a is hydrogen and R b is selected from hydrogen, -C(O)-O-R 3 ,
  • R 3 is selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl;
  • R 4 is selected from–NR 7 -(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)-(C 3 -C 6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-carbocyclyl, -(C0-C4
  • alkylene -heterocyclyl, -(C 0 -C 4 alkylene)-aryl, and -(C 0 -C 4 alkylene)-heteroaryl;
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl;
  • each R 7 and R 9 are independently hydrogen or C 1 -C 4 alkyl
  • R 8 is selected from–N(R 9 ) 2 , -N(R 9 )-(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 - C 4 alkylene)-heterocyclyl, -(C 0 -C 4 alkylene)-heteroaryl;
  • Y is O or S
  • n 0, 1, 2, 3, 4 or 5;
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • each R 7 is hydrogen.
  • the values for the remaining variables are as defined with respect to 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.
  • X is -N-.
  • the values for the remaining variables are as defined with respect to structural formula I, or first or second aspect thereof.
  • 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.
  • each R 1 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.
  • each R 1 is independently selected from -CF 3 , -Cl and -OCH 3 , or is absent.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through fifth aspects thereof.
  • R 2 is -C(O)-O-R 3 , and R 3 is selected from optionally substituted C1-C4 alkyl and optionally substituted C 2 -C 4 alkenyl; or
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated heterocyclyl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted heteroaryl; or
  • R 2 is -C(O)-NH-NH-C(O)-R 4 , and R 4 is selected from -NH-(C 3 -C 6
  • cycloalkyl -N(C 1 -C 4 alkyl)-(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-heterocyclyl and -(C 0 -C 4 alkylene)-heteroaryl, each of which is optionally substituted; or
  • R 2 is optionally substituted C 5 -C 6 heteroaryl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through sixth aspects thereof.
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or
  • R 2 is -C(O)-NH-NH-C(O)-R 4
  • R 4 is selected from -C(CH 3 ) 3 , -NH-cyclopropyl, and optionally substituted -(CH 2 ) 0-1 -pyrazinyl,
  • R 2 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.
  • R 2 is selected
  • 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. [00151] 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.
  • 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 eleventh aspects thereof.
  • Ring A is pyrid-4-yl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through twelfth aspects thereof.
  • each R 1 is
  • R 2 is -C(O)-O-R 3
  • R 3 is selected from unsubstituted C 1 -C 4 alkyl, C 1 alkyl
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated heterocyclyl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted heteroaryl; or
  • R 2 is -C(O)-NH-NH-C(O)-R 4 , and R 4 is selected from -NH-(C 3 -C 6
  • cycloalkyl -N(C 1 -C 4 alkyl)-(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-heterocyclyl and -(C 0 -C 4 alkylene)-heteroaryl, each of which is optionally substituted; or
  • R 2 is optionally substituted C 5 -C 6 heteroaryl.
  • the values for the remaining variables are as defined with respect to structural formula I, or first through fourteenth aspects thereof.
  • R 1a and R 1b are each independently selected from halo
  • each Rq is independently hydrogen, C 1-6 aliphatic, -CH 2 -carbocyclyl, -CH 2 -aryl, -CH 2 -heterocyclyl, -CH 2 -heteroaryl, -O(CH 2 ) 0-1 -carbocyclyl, -O
  • each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(unsubstituted C 1 -C 3
  • m 0 or 1.
  • R 1a is halo or -C 1 -C 4 haloalkyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 1b is -C 1 -C 4 haloalkyl or -O-C 1 - C 4 alkyl, or is absent.
  • the values for the remaining variables are as defined above for the structural formula I or any aspect thereof.
  • m is 0. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • m is 1.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 1a and R 1b are each independently selected from -CF 3 , -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 12
  • heterocycloalkyl halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkyl), -O-(C 1 -C 3 haloalkyl), and -S-( C 1 -C 3 alkyl).
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 1a and R 1b are each -CF 3 .
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 2 is -C(O)-O-R 3
  • R 3 is selected from unsubstituted C 1 -C 4 alkyl, C 1 alkyl
  • R 2 is -C(O)-N(R 5 )(R 6 ), and R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted saturated heterocyclyl; or
  • R 2 is -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted heteroaryl; or
  • R 2 is -C(O)-NH-NH-C(O)-R 4 , and R 4 is selected from -NH-(C 3 -C 6
  • cycloalkyl -N(C 1 -C 4 alkyl)-(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-heterocyclyl and -(C 0 -C 4 alkylene)-heteroaryl, each of which are optionally substituted; or
  • R 2 is optionally substituted C 5 -C 6 heteroaryl.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R b is selected from -C(O)OH, -C(O)NH 2 , -C(O)-N(R 7 )-N(R 5 )(R 6 ),
  • R 4 is selected from -N(H)(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-carbocyclyl, -(C0-C4
  • alkylene -heterocyclyl, -(C 0 -C 4 alkylene)-aryl, and -(C 0 -C 4 alkylene)-heteroaryl;
  • R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; or R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl; and
  • each R 7 is independently hydrogen or C 1 -C 4 alkyl
  • R 2 is an optionally substituted C 5 -C 15 heteroaryl, wherein:
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • R b is -C(O)OH; or -C(O)NH 2 ; or -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted heteroaryl; or
  • R b is or -C(O)-NH-NH-C(O)-R 4 or -C(O)-NH-NH-S(O)1-2-R 4
  • R 4 is selected from– N(H)(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-heterocyclyl and -(C 0 -C 4 alkylene)-heteroaryl, each of which are optionally substituted.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R b is -C(O)NH 2 .
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted 5-6- 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 structural formula I, or any aspect thereof.
  • R 2 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 structural formula I, or any aspect thereof.
  • R 2 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 structural formula I, or any aspect thereof.
  • R 2 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 structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 2 is optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl or cyano.
  • halogen C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl or cyano.
  • R 2 is optionally substituted with halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R b is -C(O)OH; or -C(O)NH 2 ; or -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted C5-C6 heteroaryl;
  • R 4 is selected from optionally substituted–N(H)(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 - C 4 alkylene)-(C 3 -C 7 )heterocyclyl and -(C 0 -C 4 alkylene)-(C 5 -C 6 )heteroaryl.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
  • substituents independently selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, -CF 3 , amino and cyano.
  • substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, -CF 3 , amino and cyano.
  • the values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
  • R 2 is selected from optionally substituted heteroaryl and optionally substituted aryl.
  • R 2 is optionally substituted C 5 -C 15 heteroaryl.
  • R 2 is an optionally substituted 5- 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 2 is an optionally substituted 5- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 2 is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.
  • R 2 is an optionally substituted 6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R 2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, -CF 3 , amino and cyano.
  • Ring A is phenyl or pyridyl
  • each of X 1 , X 2 , X 3 and X 4 is independently -N-, -N(H)-, -(C)- or -C(H)-, wherein at least one of X 1 , X 2 , X 3 and X 4 is -N- or -NH-;
  • each R 1 is independently selected from halo; haloalkyl; -(CH 2 ) 1-4 Rq; -(CH 2 ) 0-4 ORq;
  • each Rq is independently
  • each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(unsubstituted C 1 -C 3 alkyl), -N(unsubstituted C 1 -C 3 alkyl) 2 , -O-C 1 -C 3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C 1 -C 3 alkyl), -C(O)-(unsubstituted C 1 -C 3 alkyl), -O-(unsubstituted C 1 -C 3 alkyl), and -S-(unsubstituted C 1 -C 3 alkyl);
  • R 3 is selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, carbocyclyl, aryl,
  • R 4 is selected from -NH-(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)-(C 3 -C 6 cycloalkyl),
  • R 5 and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; or R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl;
  • each R 7 is independently hydrogen or C 1 -C 4 alkyl
  • n 0, 1, 2, 3, 4 or 5
  • each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
  • X 4 is -C-.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • one of X 1 , X 2 and X 3 is -N(H)-, and the remaining two are each -N-.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • X 1 is -N-
  • X 2 is -N(H)-
  • X 3 is -N-
  • X 4 is -C-.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • X 1 is -N-
  • X 2 is -N-
  • X 3 is -N(H)-
  • X 4 is -C-.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • structural formula (V) is selected from:
  • the compound useful for practicing the methods defined herein is represented by structural formula (I), (II), (III), (IIIB), (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R 2 is -C(O)OR 3 .
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 3 is -CH(CH 3 ) 2 .
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 3 is -CH 2 -(5-6 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur).
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 3 is -CH 2 -(6 membered monocyclic heterocyclic ring having 1-3 nitrogen atoms).
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • the compound of structural formula I is represented by structural formula (VI):
  • R 1a , R 1b , m and R 3 are as defined above for structural formula I or any aspect thereof.
  • the compound useful for practicing methods defined herein is represented by structural formula (I), (II), (III), (IIIA), (IIIB), (IV) or (V), or a
  • R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or two substituents independently selected from halo, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkyl, -OH, pyridin-2-yl, -CH 2 -N(C 1 -C 3
  • alkyl 2 , -CH 2 -NH(C 1 -C 3 alkyl), -CH 2 -NH 2 , -CN, -CO 2 H and -C(O)-O-(C 1 -C 3 alkyl).
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • the 4-8 membered saturated heterocyclic ring formed by R 5 , R 6 and their intervening atoms is an azetidin-1-yl ring optionally substituted at the 3-position with one or two substituents independently selected from halo, (C 1 -C 3 )haloalkyl, (C 1 - C 3 )alkyl, -OH, pyridin-2-yl, -CH 2 -N(C 1 -C 3 alkyl) 2 , -CH 2 -NH(C 1 -C 3
  • the 4-8 membered saturated heterocyclic ring formed by R 5 , R 6 and their intervening atoms is an azetidin-1-yl ring substituted at the 3-position with two fluoro substituents.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is hydrogen and R 6 is selected
  • R 5 and R 6 are taken together with the nitrogen atom to which they are bound to form , , , 4-hydroxypiperidin-1-yl, pyrrolidiny-1-yl, or azetidin-1-yl, wherein the pyrrolidiny-1-yl and azetidin-1-yl are each optionally and independently substituted at the 3-position with up to two substituents independently selected from fluoro, -CF 3 , -CH 3 , -OH, pyridin-2- yl, -CH 2 -N(CH 3 ) 2 , -CH 2 -NH-CH 3 , -CH 2 -NH 2 , -CN and -C(O)-O-CH 3 .
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 1 , R 5 , R 6 and n are as defined above for structural formula I or any aspect thereof.
  • R 1a , R 1b , R 5 , R 6 and m are as defined above for structural formula I or any aspect thereof.
  • the compound useful for parcticing methods defined herein is represented by structural formula (I), (II), (III), (IIIB), (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R 2 is -C(O)-N(R 7 )-N(R 5 )(R 6 ).
  • R 2 is -C(O)-N(R 7 )-N(R 5 )(R 6 ).
  • the values for the remaining variables are as defined above for structural formula I or any aspect thereof.
  • R 2 is -C(O)-N(H)-N(R 5 )(R 6 ) wherein R 5 is hydrogen or methyl and R 6 is an optionally substituted 5-6-membered heteroaryl; or R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-7-membered heterocyclyl.
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form an optionally substituted 4-7-membered heterocyclyl.
  • R 2 is -C(O)-N(H)-N(R 5 )(R 6 ) wherein R 5 is hydrogen or methyl and R 6 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 R 5 and R 6 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.
  • R 2 is -C(O)-N(H)-N(R 5 )(R 6 ) wherein R 5 is hydrogen or methyl and R 6 is an optionally substituted 5-6-membered heteroaryl having 1-3 nitrogen atoms; or R 5 and R 6 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.
  • R 2 is -C(O)-N(H)-N(R 5 )(R 6 ) wherein R 5 is methyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is -C(O)-N(H)-N(R 5 )(R 6 ) wherein R 5 is hydrogen.
  • R 5 is hydrogen.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is
  • R 8 is selected from -N(R 9 )-(C 3 -C 6 cycloalkyl), -C 3 -C 6 alkyl, -(C 0 -C 1 alkylene)-heterocyclyl, and -(C 0 -C 1 alkylene)-heteroaryl, wherein any alkyl or alkylene portion of R 2 is optionally substituted with -N(R 7 ) 2 , wherein each R 7 and R 9 is
  • any heterocyclyl, and heteroaryl portion of R 2 comprises at least one nitrogen atom in a ring; and any heterocyclyl, and heteroaryl portion of R 2 is optionally substituted with C 1 -C 4 alkyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 8 is selected from -C(CH 3 ) 3 ,
  • any alkyl or alkylene portion of R 8 is optionally substituted with -N(R 7 ) 2 ;
  • any heterocyclyl or heteroaryl portion of R 8 comprises at least one nitrogen
  • any heterocyclyl or heteroaryl portion of R 8 is optionally substituted with C 1 -C 4 alkyl.
  • any alkyl or alkylene portion of any R 8 is optionally and independently substituted with one or more substituents selected from oxo and -N(R 7 ) 2 , wherein each R 7 is independently selected from hydrogen and C 1 -C 4 alkyl;
  • any heterocyclyl portion of R 8 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from C 1 -C 4 alkyl and oxo; and any heteroaryl portion of R 8 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C 1 -C 4 alkyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 8 is -(C 0 - C 1 alkylene)-heterocyclyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 8 is -(C 0 -C 1
  • alkylene-heterocyclyl wherein the heterocyclyl is selected from pyrazinyl, piperidinyl, morpholinyl, and pyrazolyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 8 is -(C 0 -C 1
  • R 5 is selected from hydrogen and methyl and R 6 is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, and quinoxalin-2-yl, pyrimidin- 4-yl, 1,1-dioxotetrahydrothiophen-3-yl and cyclopropyl and is optionally substituted with one or more substituents independently selected from methyl and halogen; or R 5 and R 6 are taken together with their intervening atoms to form 4-hydroxypiperidin-1-yl, pyrrolidin-1- yl, azepan-1-yl, 4-benzylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-hydroxyazetidin-1-yl, or morpholin-4-yl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and methyl and R 6 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 R 5 and R 6 are taken together to form 4-hydroxypiperdin-1-yl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 1 , R 5 , R 6 and n are as defined above for structural formula I or any aspect thereof.
  • R 1a , R 1b , R 5 , R 6 and m are as defined above for structural formula I or any aspect thereof.
  • the compound useful for practicing methods defined herein is represented by structural formula (I), (II), (III), (IIIb), (IV) or (V), or a
  • R 2 is an optionally substituted 5-6 membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted 5-membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted 6-membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is a heteroaryl (e.g., a C 5 -C 6 heteroaryl or a 5-6 membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur) optionally substituted with one or more substituents selected from (C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocyclyl, cyano, (C 1 -C 3 )haloalkyl, halogen, nitro, (C 1 -C 3 )haloalkoxy and (C 1 -C 3 )alkoxy.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • the compound useful for practicing the methods defined herein is represented by structural formula (I), (II), (III), (IIIB), (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R b is selected
  • R b is selected from
  • R b is selected from -C(O)-OH; or-C(O)-NH 2 ;
  • R 6 is an optionally substituted heteroaryl
  • each R 4 is independently selected from -N(H)(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-heterocyclyl and -(C 0 -C 4 alkylene)-heteroaryl, each of which are optionally substituted.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R b is -C(O)NH 2 .
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted C 5 -C 15 heteroaryl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted 5-6-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 structural formula I, or any aspect thereof.
  • R 2 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 structural formula I, or any aspect thereof.
  • R 2 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 structural formula I, or any aspect thereof.
  • R 2 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 structural formula I, or any aspect thereof.
  • R 2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl or cyano.
  • halogen C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl or cyano.
  • R 2 is optionally substituted with halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • X is -C(H)-.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • n is 0, 1 or 2.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • each R 1 is independently selected from -CF 3 , -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 12 heterocycloalkyl, halo-C 1 -C 3
  • alkyl -NH 2 , -NO 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)(C 1 -C 3 alkyl), -C(O)OH, -C(O)O-(C 1 - C 6 alkyl), -C(O)-(C 1 -C 3 alkyl), -O-(C 1 -C 3 alkyl),
  • each R 1 is independently selected from halo, -C 1 -C 4 alkyl, -C 1 -C 4 haloalkyl and -O-C 1 -C 4 alkyl, or is absent.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R b is -C(O)OH; or-C(O)NH2; or -C(O)-NH-NH(R 6 ), and R 6 is an optionally substituted C 5 -C 6 heteroaryl; or -C(O)-NH-NH-C(O)-R 4
  • each R 4 is selected from –N(H)(C 3 -C 6
  • cycloalkyl -N(C 1 -C 4 alkyl)(C 3 -C 6 cycloalkyl), -C 1 -C 6 alkyl, -(C 0 -C 4 alkylene)-(C 3 - C 7 )heterocyclyl and -(C 0 -C 4 alkylene)-(C 5 -C 6 )heteroaryl, each of which is optionally substituted.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • each R 7 is hydrogen.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 is selected from hydrogen and C 1 -C 4 alkyl; and R 6 is selected from C 1 -C 4 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 5 and R 6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 3 is selected from optionally substituted C 1 -C 4 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 4 is selected from -N(R 7 )(C 3 -C 6 cycloalkyl), -C 3 -C 6 alkyl, -(C 0 -C 1 alkylene)-heterocyclyl, and -(C 0 -C 1 alkylene)-heteroaryl, wherein R 7 is hydrogen or -C 1 -C 4 alkyl; any alkyl or alkylene portion of R 4 is optionally and
  • any heterocyclyl portion of R 4 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from C 1 -C 4 alkyl and oxo; and any heteroaryl portion of R 4 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C 1 -C 4 alkyl.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
  • substituents independently selected from halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, sulfhydryl, cyano, C 6 aryl and C 5 -C 6 heteroaryl.
  • R 2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, -CF 3 , amino and cyano.
  • substituents independently selected from fluoro, chloro, C 1 -C 4 alkyl, -CF 3 , amino and cyano.
  • the values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
  • Exemplary compounds for use in the methods of the invention are set forth in Tables 1A-1F.
  • the compound is selected from:
  • the compound in some embodiments, the compound
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from [00273] In some embodiments, the compound Pharmaceutically Acceptable Compositions
  • compositions comprising a compound of this invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that it is effective to measurably inhibit CRM1 in a biological sample or in a subject.
  • a composition of this invention is formulated for administration to a subject in need of such composition.
  • compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
  • carboxymethylcellulose polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • Other pharmaceutically acceptable carriers, adjuvants or vehicles include water, saline and dimethylsulfoxide, as well as other hydrophobic or hydrophilic solvents.
  • compositions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • provided compounds or compositions are administrable intravenously and/or intraperitonally.
  • the compounds and compositions described herein are administered orally or parenterally.
  • compositions are administered orally, subcutaneously, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • a provided oral formulation is formulated for immediate release or sustained/delayed release.
  • the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles.
  • a compound disclosed herein can also be in micro-encapsulated form.
  • compositions should be formulated so that a dosage of between about 0.01– about 100 mg/kg body weight/day of the compound can be administered to a subject receiving these compositions.
  • the dosage is from about 0.5 to about 100 mg/kg of body weight, or between about 1 mg and about 1000 mg/dose, about every 4 to 120 hours, or according to the requirements of the particular drug.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day.
  • the compound is formulated for oral administration at a dosage of approximately 5 mg/kg to approximately 10 mg/kg, preferably at a dosage of approximately 7.5 mg/kg.
  • the compound can be formulated for oral administration at a dosage from about 60mg to about 100mg per dose (e.g., an 80 mg dose orally).
  • the dose can be administered daily, every other day, once per week, twice per week etc. for as long as needed.
  • the compound can be dosed orally at about 80 mg twice weekly for four weeks. Four weeks can be considered a cycle and multiple cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) can be administered as needed.
  • the compound is formulated for topical administration at a concentration of approximately 0.3 mM to approximately 10 mM.
  • a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
  • Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • RNAs are carried into and out of the nucleus by specialized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus. Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters. Chromosomal Region Maintenance 1 (CRM1), which is also called exportin-1 or Xpo1, is a major exportin.
  • CCM1 Chromosomal Region Maintenance 1
  • CRM1 blocks the exodus of proteins and/or growth regulators such as p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27, E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or forkhead proteins (e.g. FOXO3a) from the nucleus that are associated with gene expression, cell proliferation, angiogenesis, neurological disorders, and epigenetics.
  • proteins and/or growth regulators such as p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27, E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or forkhead proteins (e.g. FOXO3a) from the nucleus that are associated with gene expression, cell proliferation, angiogenesis, neurological disorders, and epigenetics.
  • proteins and/or growth regulators such as p53, c-Abl, p21
  • the present invention provides a method for treating a hematological cancer comprising the step of administering to a subject in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • the hematological cancer is myeloma.
  • the compounds and compositions described herein can also be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of hematological cancers, including those described herein.
  • the activity of a compound utilized in this invention as an inhibitor of CRM1 may be assayed in vitro, in vivo or in a cell line.
  • Detailed conditions for assaying a compound utilized in this invention as an inhibitor of CRM1 are set forth in US Patent No.9,096,543, and International Application Nos. PCT/US2011/027328; PCT/US2012/048368;
  • a compound described herein is administered together with one or more additional,“second,” therapeutic agent, active pharmaceutical ingredient (API), or treatment.
  • the choice of the second therapeutic agent may be made from any agent that is typically used to treat hematological cancer.
  • the term “administered together” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a therapeutically effective amount of a compound of the present invention may be administered with a therapeutically effective amount of another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a
  • the therapeutically effective amount of the compound of this invention is less than its therapeutically effective amount would be where the second therapeutic agent is not administered. In another embodiment, the therapeutically effective amount of the second therapeutic agent is less than its therapeutically effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • compositions of this invention should be formulated so that a dosage of between about 0.01 – about 100 mg/kg body weight/day of a compound of the invention can be administered.
  • a therapeutically effective amount of a compound described herein may be administered alone or in combination with therapeutically effective amounts of other compounds useful for treating hematological cancer.
  • Examples of a second agent that can be used in combination with the compounds described herein include, but are not limited to immunomodulators and/or check-point modulators.
  • the immunomodulators are immunomodulatory imide drugs (IMiD) such as thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).
  • IiD immunomodulatory imide drugs
  • Other examples include azathioprine and 6-mercaptopurine (6-MP) and their analogs.
  • Still further examples include cyclosporine A, tacrolimus, and methotrexate.
  • check-point modulators include PD-1 inhibitors (Pembrolizumab, Nivolumab), PD-L1 inhibitors (Atezolizumab), and CTLA-4 modulator Ipilimumab.
  • compounds described herein are co- administered with dexamethasone. EXEMPLIFICATION
  • the STORM (Selinexor Treatment of Refractory Myeloma) trial is a clinical trial in which the combination of SelinexorTM (compound C-3) and dexamethasone in multiple myeloma patients refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide (quad-refractory), or in addition, to daratumumab (penta-refractory), was tested.
  • Example 1 International Myeloma Working Group Response Criteria
  • Table A lists International Myeloma Working Group Response Criteria, Myeloma (see Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 2014; 32(6):587-600. )
  • CR complete response
  • FLC free light chain
  • hr hour
  • MR minimal response
  • PD progressive disease
  • PR partial response
  • sCR stringent complete response
  • SD stable disease
  • VGPR very good partial response.
  • Example 2 Differentiatl Expression Analysis of Refractory Multiple Myeloma Patients
  • FEATURECOUNTS a tool for assigning sequence reads to genomic features, available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.
  • Subread http://subread.sourceforge.net
  • Rsubread http://www.bioconductor.org
  • DESeq2 Differential expression analysis was performed using the“DESeq2” tool for differential gene expression analysis, available under the General Public License at the URL https://github.com/mikelove/DESeq2.
  • DESeq2 enables a quantitative analysis of comparative RNA-seq data using shrinkage estimators for dispersion and fold change.
  • E2F1 gene as a biomarker of responsiveness to the compound C- 3 was further confirmed in an independent cohort of 26 MM patients enrolled in the STORM study.
  • the pre-dose E2F1 expression level in these patients was analyzed by Affymetrix® U133 gene expression microarrays, available from Affimetrix® at the URL https://www.affymetrix.com/products_services/arrays/specific/hgu133_array_strip.affx.

Abstract

The invention generally relates to the use of nuclear transport modulators, e.g, XPO1 inhibitors, such as a compound represented by structural formula I or a pharmaceutically acceptable salt thereof, wherein Ring A, X, R1, R2 Ra, Rb and n are as defined and described herein, in a method for treating cancers in a subject.

Description

E2F1 AS A BIOMARKER FOR TREATMENTS USING XPO1 INHIBITORS RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No.62/754,343, filed on November 1, 2018. The entire teachings of the above application are incorporated herein by reference. BACKGROUND OF THE INVENTION
[0002] A great need exists for the discovery of improved methods for treating cancers. SUMMARY OF THE INVENTION
[0003] The invention generally relates to the use of nuclear transport modulators, e.g., XPO1 inhibitors, for treating cancer, for example, a hematological cancer in a subject.
[0004] In a first example embodiment, the present invention is a method for treating a cancer in a subject in need thereof, wherein the subject has been determined to have a pre- dose level of a E2F1 gene product less than or equal to a control value, the method comprising administering to the subject an effective amount of a compound represented by structural formula I:
Figure imgf000002_0001
[0006] or a pharmaceutically acceptable salt thereof, wherein:
[0007] ring A is phenyl or pyridyl;
[0008] X is -N- or -C(H)-; each R1 is independently selected from halo;
haloalkyl; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O)OR°; -(CH 2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-(C3-C12) carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-(C6-C12) aryl, which is optionally substituted with
R°; -(CH2)0-4-(4-12 member) heterocyclyl, which is optionally substituted with
R°; -(CH2)0-4-(5-12 member) heteroaryl, which is optionally substituted with
R°; -CH=CH-(C3-C12) carbocyclyl, which is optionally substituted with R°; -CH=CH-(C6- C12)aryl, which is optionally substituted with R°; -CH=CH-(4-12-member)heterocyclyl, which is optionally substituted with R°; -CH=CH-(4-12-member)heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq)C(S)Rq; -(CH 2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(Rq)C(O)ORq; -(CH2)0-4N(Rq)N( Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O) Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4O C(O)(CH2)0-4SR°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C( S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O) C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq)Rq; -(CH2)0-4SSRq; -(CH2)0-4S(O)2R q; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(CH2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4 N(Rq)S(O)2NRq2; -(CH2)0-4N(Rq)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH 2)0-4P(O)2Rq; -(CH2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(R q)2; -(CH2)0-4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq; and -(CH2)0-4C(O)O-N(Rq)2; or
[0009] two R1, taken together with their intervening atoms, form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12-member)heterocyclyl or (5-12-member)heteroaryl, wherein: each Rq is independently selected from hydrogen,C1-6 aliphatic, -CH2-(C3- C12)carbocyclyl, -CH2-(C6-C12)aryl, -CH2-(4-12 member)heterocyclyl, -CH2-(5-12- member)heteroaryl, -O(CH2)0-1–(C3-C12)carbocyclyl, -O-(CH2)0-1-(C6
C12)aryl, -O(CH2)0-1-(4-12 member)heterocyclyl, -O(CH2)0-1-(5-12-member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12
member)heteroaryl; and
[0010] each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3 alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1- C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted C1-C3 alkyl); [0011] R2 is selected
from -C(O)-O-R3, -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -CF3, -S(O)1-2(C1-C4 alkyl), optionally substituted (5-12 member)heteroaryl and optionally substituted (C6- C12)aryl;
[0012] Ra is hydrogen and Rb is selected from
hydrogen, -C(O)-O-R3, -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)- N(R5)(R6), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)-C(O)- R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)-N(R7)-N(R7)-S(O)1-2- R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1-C4 alkyl), and (5-12- member)heteroaryl, wherein: R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
[0013] R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6
cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3-C12)carbocyclyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)-(C6-C12)aryl, and -(C0-C4 alkylene)- (5-12- member)heteroaryl;
[0014] R5 and R6 are each independently selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl and (5-12-member)heteroaryl; or
[0015] R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12-member)heteroaryl;
[0016] each R7 and R9 are independently hydrogen or C1-C4 alkyl;
[0017] R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)- (5-12-member)heteroaryl;
[0018] Y is O or S; and
[0019] n is 0, 1, 2, 3, 4 or 5;
[0020] wherein, unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
[0021] In a second example embodiment, the present invention is a method for treating a cancer in a subject in need thereof, the method comprising steps of: receiving information related to a pre-dose level of E2F1 gene product in a subject suffering from the cancer; and administering to the subject an effective amount of a compound represented by structural formula (I):
Figure imgf000005_0001
[0023] or a pharmaceutically acceptable salt thereof, wherein the information indicates that the pre-dose level of E2F1 gene product is less than or equal to a control value. The values and example values of the variables in formula (I) are as defined above with respect to the first example embodiment.
[0024] In a third example embodiment, the present invention is a method of treating a subject suffering from a cancer, comprising the steps of: obtaining a sample comprising a cell from the subject; determining a pre-dose level of an E2F1 gene product in the sample; and administering an effective amount of a compound to the subject, wherein the pre-dose level of the E2F1 gene product in the sample is determined to be less than or equal to a control value, wherein the compound is represented by structural formula (I)
Figure imgf000005_0002
[0026] or a pharmaceutically acceptable salt thereof. The values and example values of the variables in formula (I) are as defined above with respect to the first example embodiment.
[0027] In a fourth example embodiment, the present invention is a method for treating a cancer in a subject in need thereof, the method comprising: selecting the subject on the basis of an E2F1 gene product; and administering to the selected subject an effective amount of a compound represented by structural formula I:
Figure imgf000005_0003
[0029] or a pharmaceutically acceptable salt thereof. The values and example values of the variables in formula (I) are as defined above with respect to the first example embodiment.
[0030] In the fifth example embodiment, the present invention a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of formula I
Figure imgf000006_0001
[0032] or a pharmaceutically acceptable salt thereof to the subject. The values and example values of the variables in formula (I) are as defined above with respect to the first example embodiment.
[0033] The novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific examples presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various changes and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG.1 is a“heat map” representation of the pre-dose level of expression of the genes listed in the righthmost column, determined by their respective mRNA abundance, in 33 refractory multiple myeloma patients. Each patient is represented by a column; each gene– by a row. The heat map is color-coded by the blue-to-red spectrum according to the Z-score of each gene. The bar above the heat map, color-coded“red or black,” represents the value of the Progression Free Survival (PFS) of each patient after the treatment with a combination of compound C-3 and dexamethasone: red represents PFS greater than or equal to 120 days; black– PFS of fewer than 120 days.
[0035] FIG.2 is a plot representing the numerical range of the pre-treatment values of log2- normalized expression values of the E2F1 gene (measured by the level of mRNA abundance using Affymetryx® U133 microarray) among 26 patients suffering from refractory multiple myeloma and exhibiting progression free survival (PFS) of either greater than 120 days (left) or less than 120 days (right) upon treatment with a combination of compound C-3 and dexamethasone. DETAILED DESCRIPTION OF THE INVENTION
[0036] A description of exemplary embodiments of the invention follows.
Definitions
[0037] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and“March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0038] Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by reference herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program such as ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada, or Chem Draw, Versions 15.1 and lower, PerkinElmer, Waltham, Massachusetts.
[0039] If there is a discrepancy between a structural formula of a compound and the name of a compound, the structural formula should be assumed correct.
[0040] Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention. [0041] 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.
[0042] 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.
[0043] 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.
[0044] The term“alkynyl,” as used herein, means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -CºC-). 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.
[0045] 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.
[0046] The term“cycloalkyl,” as used herein, means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 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.
[0047] The term“heterocyclyl,” as used herein, means a saturated or unsaturated aliphatic ring system having from 3 to 12 members (e.g., a 4-12 member heterocyclyl) 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.
[0048] 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).
[0049] The term“unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.
[0050] 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. [0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] 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.
[0060] Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted group” are independently halogen; haloalkyl;–(CH2)0–4Rq;–(CH2)0–4ORq; - O(CH2)0-4Ro, -O–(CH2)0–4C(O)OR°;–(CH2)0–4CH(ORq)2;–(CH2)0–4SRq;–(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(Rq)2;–(CH2)0–4N(Rq)C(O)Rq;– N(Rq)C(S)Rq; -(CH2)0–4N(Rq)C(O)NRq2; -N(Rq)C(S)NRq2;–(CH2)0–
4N(Rq)C(O)ORq; -N(Rq)N(Rq)C(O)Rq; -N(Rq)N(Rq)C(O)NRq2; -N(Rq)N(Rq)C(O)ORq;– (CH2)0–4C(O)Rq;–C(S)Rq; -(CH2)0-4C(O)ORq;–(CH2)0–4C(O)SRq; -(CH2)0–4C(O)OSiRq3;– (CH2)0–4OC(O)Rq; -OC(O)(CH2)0–4SR–, SC(S)SR°;–(CH2)0–4SC(O)Rq;–(CH2)0–
4C(O)NRq2;–C(S)NRq2; -C(S)SR°;–SC(S)SR°, -(CH2)0–4OC(O)NRq2; -C(O)N(ORq)Rq;– C(O)C(O)Rq; -C(O)CH2C(O)Rq;–C(NORq)Rq;-(CH2)0–4SSRq;–(CH2)0–4S(O)2Rq;– (CH2)0–4S(O)2ORq; -(CH2)0–4OS(O)2Rq;–S(O)2NRq2; -(CH2)0–4S(O)Rq; -N(Rq)S(O)2NRq2; –N(Rq)S(O)2Rq; -N(ORq)Rq;–C(NH)NRq2;–P(O)2Rq; -P(O)Rq2; -OP(O)Rq2;–
OP(O)(ORq)2; SiRq3;–(C1–4 straight or branched alkylene)O–N(Rq)2; or–(C1–4 straight or branched alkylene)C(O)O-N(Rq)2, wherein each Rq may be substituted as defined below and is independently hydrogen, C1–6 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 Rq, 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.
[0061] Suitable monovalent substituents on Rq (or the ring formed by taking two independent occurrences of Rq together with their intervening atoms), are independently halogen, -(CH2)0-2Rz,–(haloRz),–(CH2)0–2OH,–(CH2)0–2ORz,–(CH2)0–
2CH(ORz)2; -O(haloRz),–CN,–N3,–(CH2)0–2C(O)Rz,–(CH2)0–2C(O)OH,–(CH2)0– 2C(O)ORz,–(CH2)0–2SRz,–(CH2)0–2SH,–(CH2)0–2NH2,–(CH2)0–2NHRz,–(CH2)0–2NRz
2,– NO2,–SiRz
3,–OSiRz
3, -C(O)SRz
,–(C1–4 straight or branched alkylene)C(O)ORz, or– SSRz wherein each Rz is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently selected from C1–4 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 Rq include =O and =S.
[0062] 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, 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:–O(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.
[0063] Suitable substituents on the aliphatic group of R* include halogen,–
Rz, -(haloRz), -OH,–ORz,–O(haloRz),–CN,–C(O)OH,–C(O)ORz,–NH2,–NHRz,– NRz
2, and–NO2, wherein each Rz is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1–4 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.
[0064] 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.
[0065] Suitable substituents on the aliphatic group of R† are independently halogen,– Rz, -(haloRz),–OH,–ORz,–O(haloRz),–CN,–C(O)OH,–C(O)ORz,–NH2,–NHRz,– NRz
2, or -NO2, wherein each Rz is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1–4 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.
[0066] As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, the relevant teachings of which are incorporated herein by reference in their entirety.
Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of subjects.
[0067] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.
[0068] In some embodiments, exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
[0069] In some embodiments, acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g., hydrochloric, sulfuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.
[0070] Other non-pharmaceutically acceptable salts, e.g., oxalates can be used, for example, in the isolation of compounds of formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.
[0071] A“pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by formula I, or any of its intermediates. Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
[0072] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
[0073] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
[0074] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
[0075] The term“stereoisomers” is a general term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
[0076] The term“subject”, as used herein, means an animal. In some embodiments, the animal is a mammal. In certain embodiments, the subject is a veterinary subject (i.e., a non-human mammal subject), such as a dog, a pig or a horse. In some embodiments, the subject is a dog. In other embodiments, the subject is a human. The term“subject” can be used interchangeably herein with the term“patient.”
Hematological Cancers
[0077]“Hematological cancers” are cancers that affect the body’s blood, bone marrow or lymphatic system. The most common forms of hematologic cancers include leukemia, lymphoma and myeloma.
[0078] Leukemia occurs when the bone marrow overproduces abnormal white blood cells, and is classified by the type of white blood cell affected: myeloid or lymphocytic. Types of leukemia include, but are not limited to, acute lymphoblastic leukemia (ALL) (e.g., B- cell ALL and T-cell ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), acute promyelocytic leukemia (APL), hairy cell leukemia (HCL), large granular lymphocytic leukemia (LGL), te-cell acute lymphoblastic leukemia (T-ALL) and chronic myelomonocytic leukemia (CMML).
[0079] Lymphoma is a cancer of the lymphatic system that results in uncontrolled growth of malignant white blood cells, forming tumors in the lymph nodes. Lymphoma is classified into two main types: Hodgkin’s and Non-Hodgkins’s lymphoma (HL and NHL). Lymphomas may also be classified by cell type, for example, T-cell lymphoma or B-cell lymphoma. For example, B-Cell HL, T-cell HL, B-cell NHL such as Diffuse large B-cell lymphoma (DLBCL).
[0080] Exemplary lymphomas include precursor T-cell lymphoma, follicular lymphoma, cutaneous T-cell lymphoma (CTCL), Mantle cell lymphoma (MCL), B-cell chronic lympohocytic lymphoma, MALT lymphoma, Burkitt’s lymphoma, mycosis fungoides, peripheral T-cell lymphoma-Not-Otherwise Specified, nodular sclerosis from of Hodgkin’s lymphoma and mixed-cellularity subtype of Hodgkin’s lymphoma.
[0081] Myeloma (also referred to as multiple myeloma) occurs when abnormal plasma cells (a type of white blood cell that produces antibodies) accumulate in the bone marrow. The accumulation of abnormal plasma cells (myeloma cells) causes tumors in many bones of the body that damage and weaken the bone. The tumors can also keep the bone marrow from making enough healthy blood cells.
[0082] Solid and Additional Hematological Tumors
[0083] The disclosed methods are useful in the prevention and treatment of cancer, including for example, hematological malignancies (e.g., (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic and myeloproliferative syndromes), solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, liver and ovary as well as osteoscarcoma.. Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, pancreas, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine. Breast cancer (BC) can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC. In addition, breast cancer can include invasive or non-invasive ductal or lobular carcinoma, tubular, medullary, mucinous, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast and Paget’s disease of the nipple.
[0084] Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia;, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia; Acute Myeloid Leukemia, Adult;
Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; Lymphoma; AIDS- Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma; Glioma; Brain Stem Glioma, Childhood; Brain Tumor; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood;
Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Leukemia; Chronic Lymphocytic Leukemia; Chronic
Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CeIl
Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors;
Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma;
Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;
Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer;
Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma; Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer;
Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic; Leukemia, Acute
Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;
Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell;
Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute;
Lymphocytic Leukemia, Chronic; Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non- Hodgkin's,
Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma;
Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary;
Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Multiple Myeloma; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma; Non- Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous
Histiocytoma of Bone; Ovarian Cancer; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer;
Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary
Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin
Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- CeIl Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor.
[0085] Further exemplary cancers include diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Yet further exemplary cancers include endocervical cancer, B-cell ALL, T-cell ALL, B- or T-cell lymphoma, mast cell cancer, glioblastoma, neuroblastoma, follicular lymphoma and Richter’s syndrome.
[0086] Exemplary sarcomas include fibrosarcoma, alveolar soft part sarcoma (ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing’s sarcoma, neuroectodermal sarcoma, phyllodes/osteogenic sarcoma and chondroblastic osteosarcoma.
[0087] Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
[0088] The term“treat” or“treating” means to alleviate one or more symptoms, to eliminate the causation of one or more symptoms, either on a temporary or permanent basis, or to prevent or delay the onset of one or more symptoms associated with a disorder or condition.
[0089] In the case of cancers,“treating a cancer” can mean administering to a subject suffering from a cancer a therapeutically effective amount of a compound defined herein, alone or in combination with one or more agents, for a sufficient duration of time to achieve a desired response. A desired response can be, for example, achieving at least a stable disease (“SD”), as this term is defined by the relevant Response Criteria accepted by persons of ordinary skill in the art of a cancer of interest (e.g., as defined by International Myeloma Working Group Response Criteria, described herein below). In another aspect, treating a cancer means achieving at least a“partial response” (“PR”). In yet another aspect, treating a cancer means achieving a complete response (“CR”). In the embodiment in which the hematological cancer is a refractory multiple myeloma, a desired response can be, for example, achieveing“minimal response” (“MR”). The terms“SD,”“MR,”“CR,” and“PR” are defined in Example 1 with respect to multiple myeloma.
[0090] The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound which, when administered in a proper dosing regimen, is sufficient to treat the target disorder (i.e., a hematological or solid cancer). For example, a therapeutically effective amount can relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of compound required to provide a clinically significant decrease in disease symptoms.
[0091] For example, a therapeutically effective amount can be an amount that is sufficient to achieve at least a“minimal response,” (“MR”) as this term is defined by the Response Criteria accepted by persons of ordinary skill in the art of a cancer of interest. In the embodiment in which the hematological cancer is a refractory multiple myeloma, the MR is defined in Example 1.
[0092] It is understood that“an effective amount” or“a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
[0093] As used herein, the term“differential expression” of a gene refers to either an overexpression or an underexpression of a gene as compared to a pre-determined control.
[0094] As used herein, the term“E2F1” refers to a gene coding for a transcription factor that regulates cell cycle G1/S progression. At rest, E2F1 is complexed with its negative regulator retinoblastoma (RB) protein. Upon phosphorylation of RB by the Cyclin D1- CDK4/6 complex, pRB is inactivated allowing E2F1 to commence transcription of target genes allowing G1/S progression. E2F transcription factors are exported by XPO1 from the nucleus to cytoplasm. Human E2F1 is listed in the NCBI database under Gene ID 1869.
[0095] As used herein,“gene product” refers to a nucleic acid or a protein that results from the gene expression. Examples of gene products include mRNA, DNA, cDNA, transcript and proteins.
[0096] As used herein, the term“expression level” in the context of a gene expression refers to the measurable quantity (such as number of molecules or concentration) of a particular gene or a gene product (including any of DNA, cDNA, RNA, transcript, or a polypeptide encoded by the gene) in an individual or a sample taken from the individual. In some embodiments, expression level refers to the amount of mRNA of the particular gene. In some embodiments, expression level refers to the amount of a particular gene in a sample from an individual, such as a tumor sample, blood sample, serum sample, etc., and can, for example, be detected de novo or correspond to a previous determination. In some embodiments, the expression level can be expressed as a value normalized relative to a control, e.g. an expression level of a“housekeeping” gene.
[0097] As used herein, the term“control value,” when used in the context of the expression level of a gene (measured, for example, by the abundance of its gene product), refers to a level of gene expression that defines the dividing line between two subsets of a population of patients suffering from the condition being treated (e.g., responders and non-responders). Thus, a value that is equal to or higher than the control value defines one subset of the population; and a value that is lower than the cutoff value defines the other subset of the population.
[0098] Examples of a control values are the levels of expression of a gene product of E2F1 above which the subject exhibits progressive disease (PD), stable disease (SD), or, minimal response (MR), as defined by the Response Criteria accepted by persons of ordinary skill in the art of a cancer of interest.
[0099] Control values can be expressed in any convenient units or be unitless. For example, where the control value is used in the context of gene expression level, control values can be expressed in units of“copies per unit volume,”“moles per unit volume,” “weight per unit volume,”“RPM” (Reads per million mapped reads),“RPKM” (Reads per kilo base per million mapped reads),“TPM” (Transcript per million),“FPKM” (Fragments per kilo base per million mapped reads), or“log2 normalized fluorescence intensity.” Control values can alos be expressed with reference to median values of gene expression obtained for an ensemble of samples (for example, a pool of patients suffereing from the same condition).
[00100] In an example embodiment, where a subject is suffering from multiple myeloma, e.g.,refractory multiple myeloma, the control value can be defined relative to a median value of the pre-dose expression levels of the E2F1 gene product (e.g., the E2F1 mRNA) in a population of subjects having Progression Free Survival of not less than 120 days. For example, the control value can be from about 150%, about 140%, about 130%, about 125%, about 120%, about 115%, about 110%, about 105%, about 104%, about 103%, about 102%, about 101%, or about 100% of the median value to about the lowest gene expression level of the E2F1 gene measured in the population of patients. For example, the control value can be 150%, 140%, 130%, 125%, 120%, 115%, 110%, 105%, 104%, 103%, 102%, 101%, or 100% of the median value. For example, the control value can be derived from the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
[00101] In example embodiments, where a subject is suffering from multiple myeloma, e.g, refractory multiple myeloma, the control value can be defined in the units of log2 normalized fluorescence intensity (also referred to as“log2-normalized expression”). For example, the control value defined in these units can be from about 50 to about 0.5. In certain examples, the control value sdefined in these units can be 10, 9.95, 9.5, 8, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5.
[00102] As used herein, the term“pre-dose” refers to the expression level of the gene product measured prior to the commencement of treatment regimen with compounds described herein.
[00103] The terms“sample” or“biological sample” refer to any specimen from a subject that contains, or can contain, the biomarkers of interest, e.g., E2F1or an encoded peptide thereof, including, for example, tumor, blood, serum, or plasma. In some embodiments, the sample is a tumor biopsy sample.
[00104] The term“nucleic acid” refers to deoxyribonucleotides, deoxyribonucleosides, ribonucleosides, or ribonucleotides and polymers thereof in either single- or double- stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides which have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless specifically limited otherwise, the term also refers to oligonucleotide analogs including PNA (peptidonucleic acid), analogs of DNA used in antisense technology (e.g., phosphorothioates, phosphoroamidates). Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (including but not limited to, degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions are achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al. (1991)Nucleic Acid Res.19:5081; Ohtsuka et al. (1985) J. Biol. Chem.
260:2605-2608; and Cassol et al. (1992)Mol. Cell. Probes 6, 327-331; and Rossolini et al. (1994) Mol. Cell. Probes 8:91-98). In some embodiments, the nucleic acid or a fragment thereof encodes a protein.
[00105] The term“probe” as used herein refers to a nucleic acid molecule that comprises a sequence of nucleotides (such as 10 or more, 15 or more, 20 or more, or 10-25, 26-50, 51- 75, 76-100, or 101-500 bases or nucleotides) that will hybridize specifically to a target nucleic acid sequence, such as a gene disclosed herein.
[00106] The term“primer” as used herein refers to a nucleic acid sequence, whether occurring naturally as in a purified restriction digest or produced synthetically, that is capable of acting as a point of synthesis when placed under conditions in which synthesis of a primer extension product, which is complementary to a nucleic acid strand is induced (e.g. in the presence of nucleotides and an inducing agent such as DNA polymerase and at a suitable temperature and pH).
[00107] When introducing elements disclosed herein, the articles“a,”“an,”“the,” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,”“having” and“including” are intended to be open-ended and mean that there may be additional elements other than the listed elements.
Determination of Gene Expression Level and of Control Value
[00108] A variety of methods (e.g., spectroscopy, colorimetry, electrophoresis,
chromatography) can be used to determine the expression level of a gene, including the E2F1 gene. As is apparent to those of skill in the art, expression of the gene can be determined by measuring all or a portion of nucleic acid (e.g., DNA, mRNA) of the gene and/or protein (polypeptide) expressed by the gene. The level, expression and/or activity of a gene or its encoded polypeptide can be measured. For example, nucleic acids such as genes, mRNA or a combination thereof, can be determined using PCR (e.g., RT-PCR, RT- qPCR), gene chips or microarray analysis (DNA arrays, gene expressin arrays,
nanostrings), next generation sequencing (e.g., next generation RNA sequencing), in situ hybridization, blotting techniques, and the like. Protein can be determined using immunoassys (e.g., immunohistochemistry, immunofluorescence, immunoprecipitation), arrays (e.g., reverse phase protein microarrays), blotting techniques (e.g., western blots), SDS-PAGE, and the like.
[00109] In certain example embodiments, the the level of the E2F1 mRNA in a subject can be determined by a method comprising the steps of: a) obtaining total mRNA from a biological sample from the subject; b) appending to each mRNA molecule additional nucleotides not naturally appended to such mRNA molecules to enable the mRNA molecules to bind to a solid support; c) sequencing the mRNA molecules; and d) determining the level of the mRNA.
[00110] For example, the the level of E2F1 mRNA in a subject can be determined by a method comprising the steps of: (a) obtaining total RNA from sample; (b) hybridizing RNA to array that contains probes for many RNAs; and (c) determining the relative level of E2F1 RNA that bind to the specific array probes.
[00111] In another example embodiment, the level of E2F1 in a subject can be determined by a method comprising the steps of: a) obtaining total mRNA from a biological sample from the subject; b) creating a cDNA library from the total mRNA; and c) combining the cDNA library with (i) a primer pair that is specific for cDNA created from the E2F1 mRNA; (ii) a DNA polymerase; and (iii) a component for detection of any DNA molecules produced from the primer pair and the DNA polymerase. In some aspects, the component for detection is a dye. In other aspects, the component for detection is a labelled (e.g., radiolabelled or dye-labelled or oligonucleotide).
[00112] In various embodiments of the present invention, the level of the E2F1 mRNA detected in the subject is compared to a (pre-determined) control level. In some aspects, the subject is suffering from a hematological cancer. In more specific aspects, the subject is suffering from a hematological cancer and is administered any one or more compounds described herein, optionally in combination with one or more second agents (e.g., compound C-3 in combination with dexamethasone) if the determined E2F1 level is above the pre-determined control value.
[00113] In some aspects, the pre-determined control value is a E2F1 level determined by measuring the E2F1 mRNA levels in a sample or an ensemble of samples obtained from subjects having the same hematological cancer; and identifying at least one subject that is non-responsive to any one or more compounds described herein, optionally in combination with one or more second agents.
[00114] In an example embodiment, the invention provides a differential method of treating a set of subjects suffering from a hematological cancer comprising administering any one or more compounds described herein, optionally in combination with one or more second agents to a subset of subjects whose cancer is characterized by a E2F1 level that is above a control value; and not administering any one or more compounds described herein, optionally in combination with one or more second agents to a subset of subjects whose cancer is characterized by a E2F1 level that is below that control value. Exemplary Embodiments
[00115] In a first example embodiment, the present invention is a method for treating a cancer in a subject in need thereof, wherein the subject has been determined to have a pre- dose level of a E2F1 gene product less than or equal to a control value, the method comprising administering to the subject an effective amount of a compound represented by structural formula I:
[00116]
Figure imgf000026_0001
,
[00117] or a pharmaceutically acceptable salt thereof. The values and example values of the variables in formula (I) are as defined hereinbelow.
[00118] In a second example embodiment, the present invention is a method for treating a cancer in a subject in need thereof, the method comprising steps of: receiving information related to a pre-dose level of E2F1 gene product in a subject suffering from the cancer; and administering to the subject an effective amount of a compound represented by structural formula (I): [00119]
Figure imgf000027_0001
,
[00120] or a pharmaceutically acceptable salt thereof, wherein the information indicates that the pre-dose level of E2F1 gene product is less than or equal to a control value. The values and example values of the variables in formula (I) are as defined hereinbelow.
[00121] In a third example embodiment, the present invention is a method of treating a subject suffering from a cancer, comprising the steps of: obtaining a sample comprising a cell from the subject; determining a pre-dose level of an E2F1 gene product in the sample; and administering an effective amount of a compound to the subject, wherein the pre-dose level of the E2F1 gene product in the sample is determined to be less than or equal to a control value, wherein the compound is represented by structural formula (I
[00122]
Figure imgf000027_0002
,
[00123] or a pharmaceutically acceptable salt thereof. The values and example values of the variables in formula (I) are as defined hereinbelow.
[00124] In a fourth example embodiment, the present invention is a method for treating a cancer in a subject in need thereof, the method comprising: selecting the subject on the basis of an E2F1 gene product; and administering to the selected subject an effective amount of a compound represented by structural formula I:
[00125]
Figure imgf000027_0003
,
[00126] or a pharmaceutically acceptable salt thereof. The values and example values of the variables in formula (I) are as defined hereinbelow. [00127] In the fifth example embodiment, the present invention a method of treating a cancer in a subject in need thereof, the method comprising: administering an effective amount of a compound of formula I
[00128]
Figure imgf000028_0001
[00129] or a pharmaceutically acceptable salt thereof to the subject. The values and example values of the variables in formula (I) are as defined hereinbelow.
[00130] In one aspect of any of the first through fifth embodiments, selecting the subject includes receiving information related to a pre-dose level of an E2F1 gene product in the subject.
[00131] In another aspect of any of the first through fifth embodiments, the E2F1 gene product is an E2F1 mRNA.
[00132] In another aspect of any of the first through fifth embodiments, the control value is from 150% to 100% of the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
[00133] In another aspect of any of the first through fifth embodiments, the control value is equal to 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110%, or 105% of the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
[00134] In another aspect of any of the first through fifth embodiments, the cancer is a solid tumor.
[00135] In another aspect of any of the first through fifth embodiments, the cancer is a hematological cancer.
[00136] In another aspect of any of the first through fifth embodiments, the hematological cancer is selected from leukemia, lymphoma and myeloma.
[00137] In another aspect of any of the first through fifth embodiments, the hematological cancer is multiple myeloma, for example, a refractory multiple myeloma.
[00138] In another aspect of any of the first through fifth embodiments, the level of the E2F1 gene product has been determined in a CD138+ cell. [00139] In one aspect of the embodiments described herein, the cancer is a multiple myeloma refractory after prior treatment with an imunomodulatory drug or a proteasome inhibitor. In an example embodiment, the multiple myeloma is refractory to one or more of bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (up to penta- refractory).
[00140] Structural formula I is reproduced below:
Figure imgf000029_0001
wherein:
Ring A is phenyl or pyridyl;
X is -N- or -C(H)-;
each R1 is independently selected from halo; haloalkyl; -(CH2)1-4Rq; -(CH2)0-4ORq;
-O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O)OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SR q; -(CH2)0-4-carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-aryl, which is optionally substituted with R°; -(CH2)0-4-heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-heteroaryl, which is optionally substituted with R°; -CH=CH-carbocyclyl, which is optionally substituted with R°; -CH=CH-aryl, which is optionally substituted with
R°; -CH=CH-heterocyclyl, which is optionally substituted with
R°; -CH=CH-heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq;
-(CH2)0-4N(Rq)C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(Rq)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq) C(O)NRq2; -(CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O) (CH2)0-4SR°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2;
-(CH2)0-4C(S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N (ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq) Rq; -(CH2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(CH2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(CH2) 0-4
P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq)2; -(CH2)0 -4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq; and -(CH2)0-4C(O)O-N(Rq)2; or two R1, taken together with their intervening atoms, form a 3-12-membered
carbocyclyl, aryl, heterocyclyl or heteroaryl, wherein:
each Rq is independently selected from hydrogen,C1-6 aliphatic,
-CH2-carbocyclyl, -CH2-aryl, -CH2-heterocyclyl, -CH2-heteroaryl, -O(CH2)0-1 -carbocyclyl, -O (CH2)0-1-aryl, -O(CH2)0-1-heterocyclyl, -O(CH2)0-1-heteroaryl, carbocyclyl, aryl, heterocyclyl and heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, aryl, heterocyclyl or heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3 alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O- (unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3
alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted C1-C3 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)1-2(C1-C4 alkyl), optionally substituted heteroaryl and optionally substituted aryl;
Ra is hydrogen and Rb is selected from hydrogen, -C(O)-O-R3,
-C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)-N(R5)(R6), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)-C(O) -R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)-N(R7)- N(R7)-S(O)1-2-R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1-C4 alkyl), and heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-carbocyclyl, -(C0-C4
alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, and -(C0-C4 alkylene)-heteroaryl;
R5 and R6 are each independently selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; or
R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl;
each R7 and R9 are independently hydrogen or C1-C4 alkyl;
R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0- C4 alkylene)-heterocyclyl, -(C0-C4 alkylene)-heteroaryl;
Y is O or S; 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.
[00141] In a first aspect of compounds of structural formula I, each R7 is hydrogen. The values for the remaining variables are as defined with respect to structural formula I.
[00142] 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.
[00143] 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.
[00144] 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.
[00145] 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.
[00146] 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. [00147] 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 heterocyclyl; or
R2 is -C(O)-NH-NH(R6), and R6 is an optionally substituted heteroaryl; or
R2 is -C(O)-NH-NH-C(O)-R4, and R4 is selected from -NH-(C3-C6
cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-heterocyclyl and -(C0-C4 alkylene)-heteroaryl, each of which is optionally substituted; or
R2 is optionally substituted C5-C6 heteroaryl. The values for the remaining variables are as defined with respect to structural formula I, or first through sixth aspects thereof.
[00148] 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-1- yl, pyrrolidin-1-yl, or piperidin-1-yl; or
R2 is -C(O)-NH-NH(R6), and R6 is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or
R2 is -C(O)-NH-NH-C(O)-R4, and R4 is selected from -C(CH3)3, -NH-cyclopropyl, and optionally substituted -(CH2)0-1-pyrazinyl,
piperidinyl, -(CH2)0-1-morpholinyl, or pyrazolyl; 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.
[00149] 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 heteroaryl. The values for the remaining variables are as defined with respect to structural formula I, or first through eighth aspects thereof.
[00150] 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. [00151] 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.
[00152] 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 eleventh aspects thereof.
[00153] 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 twelfth aspects thereof.
[00154] In a fourteenth aspect of compounds of structural formula I, each R1 is
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 with respect to structural formula I, or first through thirteenth aspects thereof.
[00155] In a fifteenth aspect of compounds of structural formula I:
R2 is -C(O)-O-R3, and R3 is selected from unsubstituted C1-C4 alkyl, C1 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 -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 -C(O)-NH-NH-C(O)-R4, and R4 is selected from -NH-(C3-C6
cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-heterocyclyl and -(C0-C4 alkylene)-heteroaryl, each of which is optionally substituted; or
R2 is optionally substituted C5-C6 heteroaryl. The values for the remaining variables are as defined with respect to structural formula I, or first through fourteenth aspects thereof.
[00156] In one aspect, the compounds of structural formula I are represented by by structural formula (II):
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof. The values for the variables are as defined in the with respect to structural formula I, or any aspect thereof.
[00157] In another aspect, the compound of structural formula I are represented by structural formula (III):
Figure imgf000034_0002
or a pharmaceutically acceptable salt thereof, wherein:
R1a and R1b are each independently selected from halo;
haloalkyl; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O) OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-aryl, which is optionally substituted with R°; -(CH2)0-4-heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-heteroaryl, which is optionally substituted with
R°; -CH=CH-carbocyclyl, which is optionally substituted with
R°; -CH=CH-aryl, which is optionally substituted with
R°; -CH=CH-heterocyclyl, which is optionally substituted with
R°; -CH=CH-heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq;
-(CH2)0-4N(Rq)C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(Rq)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq) C(O)NRq2; -(CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O) (CH2)0-4SR°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2;
-(CH2)0-4C(S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N (ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq) Rq; -(CH2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(CH2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(CH2) 0-4
P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq)2; -(CH2)0 -4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq; and -(CH2)0-4C(O)O-N(Rq)2; or two R1, taken together with their intervening atoms, form a 3-12-membered carbocyclyl, aryl, heterocyclyl or heteroaryl, wherein:
each Rq is independently hydrogen, C1-6 aliphatic, -CH2-carbocyclyl, -CH2-aryl, -CH2-heterocyclyl, -CH2-heteroaryl, -O(CH2)0-1-carbocyclyl, -O
(CH2)0-1-aryl, -O(CH2)0-1-heterocyclyl, -O(CH2)0-1-heteroaryl, carbocyclyl, aryl, heterocyclyl or heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, aryl,
heterocyclyl or heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3 alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3
alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3
alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted C1-C3 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.
[00158] In a first aspect of the structural formula (III), R1a 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.
[00159] In a second aspect of the structural formula (III), R1b 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. [00160] 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.
[00161] 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.
[00162] In a fifth aspect of the structural formula (III), R1a and R1b 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 aspect thereof.
[00163] In a sixth aspect of the structural formula (III), R1a and R1b are each -CF3. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00164] In a seventh aspect of the structural formula (III):
R2 is -C(O)-O-R3, and R3 is selected from unsubstituted C1-C4 alkyl, C1 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 -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 -C(O)-NH-NH-C(O)-R4, and R4 is selected from -NH-(C3-C6
cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-heterocyclyl and -(C0-C4 alkylene)-heteroaryl, each of which are optionally substituted; or
R2 is optionally substituted C5-C6 heteroaryl. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00165] In another aspect of structural formula I, the compound is represented by structural formula (IIIA):
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rb is selected from -C(O)OH, -C(O)NH2, -C(O)-N(R7)-N(R5)(R6),
-C(O)-N(R7)-N(R7)-C(O)-R4 and -C(O)-N(R7)-N(R7)-S(O)1-2-R4; wherein:
R4 is selected from -N(H)(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-carbocyclyl, -(C0-C4
alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, and -(C0-C4 alkylene)-heteroaryl;
R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C2- C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; or R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl; and
each R7 is independently hydrogen or C1-C4 alkyl;
R2 is an optionally substituted C5-C15 heteroaryl, wherein:
unless otherwise designated, each alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, aryl, cycloalkyl, heterocyclyl and heteroaryl is optionally and independently substituted.
Alternative values for the variables in structural formula (IIIA) are as defined above for structural formula I or any aspect thereof.
[00166] In a first aspect of the structural formula (IIIA),
Rb is -C(O)OH; or -C(O)NH2; or -C(O)-NH-NH(R6), and R6 is an optionally substituted heteroaryl; or
Rb is or -C(O)-NH-NH-C(O)-R4 or -C(O)-NH-NH-S(O)1-2-R4, and R4 is selected from– N(H)(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-heterocyclyl and -(C0-C4 alkylene)-heteroaryl, each of which are optionally substituted. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00167] In a second aspect of the structural formula (IIIA), Rb is -C(O)NH2. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof. [00168] In a third aspect of the structural formula (IIIA), R2 is an optionally substituted 5-6- 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 structural formula I, or any aspect thereof.
[00169] In a fourth 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. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00170] In a fifth aspect of the structural formula (IIIA), 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 structural formula I, or any aspect thereof.
[00171] In a sixth 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. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00172] In a seventh aspect of the structural formula (IIIA), R2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00173] In an eighth aspect of the structural formula (IIIA), 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 structural formula I, or any aspect thereof.
[00174] In a ninth aspect of the structural formula (IIIA), R2 is optionally substituted with halogen, C1-C4 alkyl or C1-C4 alkoxy. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00175] In a tenth aspect of the structural formula (IIIA), Rb is -C(O)OH; or -C(O)NH2; or -C(O)-NH-NH(R6), and R6 is an optionally substituted C5-C6 heteroaryl;
or -C(O)-NH-NH-C(O)-R4 or -C(O)-NH-NH-S(O)1-2-R4, and R4 is selected from optionally substituted–N(H)(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0- C4 alkylene)-(C3-C7)heterocyclyl and -(C0-C4 alkylene)-(C5-C6)heteroaryl. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof. [00176] In an eleventh 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, C1-C4 thioalkoxy, hydroxyl, amino, C1-C4 alkylamino, C1-C4 dialkylamino, sulfhydryl, cyano, C6 aryl and C5-C6 heteroaryl. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00177] In a twelfth 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 and cyano. The values for the remaining variables are as defined above for structural formula I, or any aspect thereof.
[00178] In another aspect, compounds of structural formual I are represented by structural formula (IIIB):
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof, wherein R2 is selected from optionally substituted heteroaryl and optionally substituted aryl.
[00179] In a first aspect of the structural formula (IIIB), R2 is optionally substituted C5-C15 heteroaryl.
[00180] In a second aspect of the structural formula (IIIB), R2 is an optionally substituted 5- 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
[00181] In a third aspect of the structural formula (IIIB), R2 is an optionally substituted 5- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
[00182] In a fourth aspect of the structural formula (IIIB), R2 is an optionally substituted pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl.
[00183] In a fifth aspect of the structural formula (IIIB), R2 is an optionally substituted 6- membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
[00184] In a sixth aspect of the structural formula (IIIB), R2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. [00185] In a seventh aspect of the structural formula (IIIB), R2 is 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, C6 aryl and C5-C6 heteroaryl.
[00186] In an eighth aspect of the structural formula (IIIB), R2 is optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, C1-C4 alkyl, -CF3, amino and cyano.
[00187] In another aspect of structural formula I, the compound is represented by structural formula (IV):
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl or pyridyl;
each of X1, X2, X3 and X4 is independently -N-, -N(H)-, -(C)- or -C(H)-, wherein at least one of X1, X2, X3 and X4 is -N- or -NH-;
each R1 is independently selected from halo; haloalkyl; -(CH2)1-4Rq; -(CH2)0-4ORq;
-O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O)OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -( CH2)0-4-carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-aryl, which is optionally substituted with R°; -(CH2)0-4-heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-heteroaryl, which is optionally substituted with R°; -CH=CH-carbocyclyl, which is optionally substituted with R°; -CH=CH-aryl, which is optionally substituted with R°; -CH=CH-heterocyclyl, which is optionally substituted with R°; -CH=CH-heteroaryl, which is optionally substituted with R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq)C(S)R q; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(Rq)C(O)ORq; -( CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)N(Rq) C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4C(O)ORq; -(CH2)0-4C(O)SR q; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O)(CH2)0-4SR°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC (O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C(S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC( O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O )Rq; -(CH2)0-4C(NORq)Rq; -(CH2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -( CH2)0-4OS(O)2Rq; -(CH2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2 ; -(CH2)0-4N(Rq)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2 Rq; -(CH2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq) 2; -(CH2)0-4-O -(CH2)1-4-N(Rq)2; -(CH2)1-4-O-(CH2)0-4-ORq;
and -(CH2)0-4C(O)O-N(Rq)2; or
two R1, taken together with their intervening atoms, form a 3-12-membered carbocyclyl, aryl, heterocyclyl or heteroaryl, wherein:
each Rq is independently
hydrogen,C1-6aliphatic, -CH2-carbocyclyl, -CH2-aryl,
-CH2-heterocyclyl, -CH2-heteroaryl, -O(CH2)0-1-carbocyclyl, -O(CH2)0-1-aryl, -O (CH2)0-1-heterocyclyl, -O(CH2)0-1-heteroaryl, carbocyclyl, aryl, heterocyclyl or heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, aryl, heterocyclyl or heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3 alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted C1-C3 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)1-2(C1-C4 alkyl), and heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl,
heterocyclyl and heteroaryl;
R4 is selected from -NH-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl),
-C1-C6 alkyl, -(C0-C4 alkylene)-carbocyclyl, -(C0-C4 alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, and -(C0-C4 alkylene)-heteroaryl;
R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl; or R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl;
each R7 is 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.
[00188] In a first aspect of structural formula (IV), the compound is represented by structural formula (V):
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof, wherein X4 is -N- or -C-. The values for the remaining variables are as defined above for the structural formula (IV).
[00189] In a second aspect of structural formula (IV), X4 is -C-. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00190] In a third aspect of structural formula (IV), one of X1, X2 and X3 is -N(H)-, and the remaining two are each -N-. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00191] In a fourth aspect of structural formula (IV), X1 is -N-, X2 is -N(H)-, X3 is -N-, and X4 is -C-. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00192] In a fifth aspect of structural formula (IV), X1 is -N-, X2 is -N-, X3 is -N(H)-, and X4 is -C-. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00193] In a sixth aspect of structural formula (IV), X4 is -N-. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof. [00194] In a seventh aspect of structural formula (IV), the ring represented by
Figure imgf000043_0001
structural formula (V) is selected from:
Figure imgf000043_0002
The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00195] In an eighth aspect of structural formula (IV), the ring represented by
Figure imgf000043_0003
in structural formula (IV) is selected from:
Figure imgf000043_0004
Figure imgf000043_0005
. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00196] In another aspect, the compound useful for practicing the methods defined herein is represented by structural formula (I), (II), (III), (IIIB), (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R2 is -C(O)OR3. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00197] For example, R3 is -CH(CH3)2. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00198] In another example, R3 is -CH2-(5-6 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur). The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00199] In another example, R3 is -CH2-(6 membered monocyclic heterocyclic ring having 1-3 nitrogen atoms). The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof. [00200] In another aspect, the compound of structural formula I is represented by structural formula (VI):
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof, wherein the values for R1, R3 and n are as defined above for structural formula I or any aspect thereof.
[00201] In another aspect of structural formula I, the compound is represented by structural formula (VII):
Figure imgf000044_0002
or a pharmaceutically acceptable salt thereof, wherein the values for R1a, R1b, m and R3 are as defined above for structural formula I or any aspect thereof.
[00202] In yet another aspect, the compound useful for practicing methods defined herein is represented by structural formula (I), (II), (III), (IIIA), (IIIB), (IV) or (V), or a
pharmaceutically acceptable salt thereof, wherein R2 is -C(O)-N(R5)(R6). The values for the remaining variables are as defined above for structural formula I or any aspect thereof.
[00203] For example, R5 and R6 are taken together with their intervening atoms to form an optionally substituted 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00204] In another example, R5 and R6 are taken together with their intervening atoms to form an optionally substituted 4-8 membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or two substituents independently selected from halo, (C1-C3)haloalkyl, (C1-C3)alkyl, -OH, pyridin-2-yl, -CH2-N(C1-C3
alkyl)2, -CH2-NH(C1-C3 alkyl), -CH2-NH2, -CN, -CO2H and -C(O)-O-(C1-C3 alkyl). The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00205] In another example, the 4-8 membered saturated heterocyclic ring formed by R5, R6 and their intervening atoms is an azetidin-1-yl ring optionally substituted at the 3-position with one or two substituents independently selected from halo, (C1-C3)haloalkyl, (C1- C3)alkyl, -OH, pyridin-2-yl, -CH2-N(C1-C3 alkyl)2, -CH2-NH(C1-C3
alkyl), -CH2-NH2, -CN, -CO2H and -C(O)-O-(C1-C3 alkyl). The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00206] In another example, the 4-8 membered saturated heterocyclic ring formed by R5, R6 and their intervening atoms is an azetidin-1-yl ring substituted at the 3-position with two fluoro substituents. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00207] In another example, R5 is hydrogen and R6 is selected
from -CH2-oxazol-5-yl, -CH2-pyrimidin-5-yl, -CH2-(1-methylpyrrolidin-3-yl),
Figure imgf000045_0001
or R5 and R6 are taken together with the nitrogen atom to which they are bound to form
Figure imgf000045_0002
, , , 4-hydroxypiperidin-1-yl, pyrrolidiny-1-yl, or azetidin-1-yl, wherein the pyrrolidiny-1-yl and azetidin-1-yl are each optionally and independently substituted at the 3-position with up to two substituents independently selected from fluoro, -CF3, -CH3, -OH, pyridin-2- yl, -CH2-N(CH3)2, -CH2-NH-CH3, -CH2-NH2, -CN and -C(O)-O-CH3. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00208] In another aspect of structural formula I, the compound is represented by structural formula (VIII):
Figure imgf000045_0003
or a pharmaceutically acceptable salt thereof, wherein the values for R1, R5, R6 and n are as defined above for structural formula I or any aspect thereof.
[00209] In another aspect of structural formula I, the compound is represented by structural formula (IX):
Figure imgf000046_0001
or a pharmaceutically acceptable salt thereof, wherein the values for R1a, R1b, R5, R6 and m are as defined above for structural formula I or any aspect thereof.
[00210] In one apsect, the compound useful for parcticing methods defined herein is represented by structural formula (I), (II), (III), (IIIB), (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein R2 is -C(O)-N(R7)-N(R5)(R6). The values for the remaining variables are as defined above for structural formula I or any aspect thereof.
[00211] For example, 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 structural formula I, or any aspect thereof.
[00212] In another example, 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 structural formula I, or any aspect thereof.
[00213] In another example, 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 structural formula I, or any aspect thereof. [00214] In yet another example, R2 is -C(O)-N(H)-N(R5)(R6) wherein R5 is methyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00215] In another example, 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 structural formula I, or any aspect thereof.
[00216] In another example, R2 is -C(O)-N(H)-N(R5)(R6), R5 is hydrogen, R6 is–C(=Y)-R8, and Y is O. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00217] In another example, R2 is
-C(O)-N(H)-N(R5)(R6), R5 is hydrogen, R6 is–C(=Y)-R8, and Y is S. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00218] In another examples, R2 is -C(O)-N(H)-N(R5)(R6) wherein R5 is H and R6 is– C(=Y)-R8
, and R8 is selected from -N(R9)-(C3-C6 cycloalkyl), -C3-C6 alkyl, -(C0-C1 alkylene)-heterocyclyl, and -(C0-C1 alkylene)-heteroaryl, wherein any alkyl or alkylene portion of R2 is optionally substituted with -N(R7)2, wherein each R7 and R9 is
independently selected from hydrogen and C1-C4 alkyl; any heterocyclyl, and heteroaryl portion of R2 comprises at least one nitrogen atom in a ring; and any heterocyclyl, and heteroaryl portion of R2 is optionally substituted with C1-C4 alkyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00219] In another example, R2 is -C(O)-N(H)-N(R5)(R6) wherein R5 is H and R6 is– C(=Y)-R8
, and R8 is selected from -C(CH3)3,
-CH(NH2)-CH(CH3)2, -NH-cyclopropyl, -(CH2)0-1-pyrazinyl, piperidinyl,
hydroxypiperidinyl, N-methylpiperidinyl, -CH2-morpholin-4-yl, and methylpyrazolyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00220] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is selected
from -C(CH3)3, -CH(NH2)-CH(CH3)2, -NH-cyclopropyl, -(CH2)0-1-pyrazin-2-yl, piperidin- 3-yl, -CH2-morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00221] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is selected
from -C(CH3)3, -NH-cyclopropyl, -CH2-pyrazin-2-yl, -pyrazin-2-yl, -CH2-morpholin-4-yl, and 5-methyl-1-H-pyrazol-4-yl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00222] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is selected
from -N(R9)-(C3-C6 cycloalkyl), -C3-C6 alkyl, -(C0-C1 alkylene)
-heterocyclyl, and -(C0-C1 alkylene)-heteroaryl, wherein:
any alkyl or alkylene portion of R8 is optionally substituted with -N(R7)2;
any heterocyclyl or heteroaryl portion of R8 comprises at least one nitrogen
atom in a ring; and
any heterocyclyl or heteroaryl portion of R8 is optionally substituted with C1-C4 alkyl.
The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00223] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is selected
from -N(R9)-(C3-C6 cycloalkyl), -C3-C6 alkyl, -(C0-C1 alkylene)-heterocyclyl, and -(C0-C1 alkylene)-heteroaryl, wherein:
any alkyl or alkylene portion of any R8 is optionally and independently substituted with one or more substituents selected from oxo and -N(R7)2, wherein each R7 is independently selected from hydrogen and C1-C4 alkyl;
any heterocyclyl portion of R8 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from C1-C4 alkyl and oxo; and any heteroaryl portion of R8 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C1-C4 alkyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00224] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is -(C0- C1alkylene)-heterocyclyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00225] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is -(C0-C1
alkylene)-heterocyclyl, wherein the heterocyclyl is selected from pyrazinyl, piperidinyl, morpholinyl, and pyrazolyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00226] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8 is -(C0-C1
alkylene)-heterocyclyl, wherein the heterocyclyl is morpholinyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof. [00227] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8
is -(C1alkylene)-heterocyclyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00228] In another example, R5 is H and R6 is–C(=Y)-R8
, and R8
is -(C1alkylene)-morpholinyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00229] In another example, 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, 1,1-dioxotetrahydrothiophen-3-yl and cyclopropyl and is optionally substituted with one or more substituents independently selected from methyl and halogen; or R5 and R6 are taken together with their intervening atoms to form 4-hydroxypiperidin-1-yl, pyrrolidin-1- yl, azepan-1-yl, 4-benzylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 3-hydroxyazetidin-1-yl, or morpholin-4-yl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00230] 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; 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 structural formula I, or any aspect thereof.
[00231] In another aspect of structural formula I, the compound is represented by structural formula (X):
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof, wherein the values for R1, R5, R6 and n are as defined above for structural formula I or any aspect thereof.
[00232] In another aspect of structural formula I, the compound is represented by structural formula (XI):
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof, wherein the values for R1a, R1b, R5, R6 and m are as defined above for structural formula I or any aspect thereof.
[00233] In various embodiments, the compound useful for practicing methods defined herein is represented by structural formula (I), (II), (III), (IIIb), (IV) or (V), or a
pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00234] For example, R2 is an optionally substituted 5-6 membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00235] In another example, R2 is an optionally substituted 5-membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00236] In another example, R2 is an optionally substituted 6-membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00237] In another example, R2 is a heteroaryl (e.g., a C5-C6 heteroaryl or a 5-6 membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur) optionally substituted with one or more substituents selected from (C1-C3)alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, cyano, (C1-C3)haloalkyl, halogen, nitro, (C1-C3)haloalkoxy and (C1-C3)alkoxy. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00238] In various embodiments, the compound useful for practicing the methods defined herein is represented by structural formula (I), (II), (III), (IIIB), (IV) or (V), or a pharmaceutically acceptable salt thereof, wherein Rb is selected
from -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6),
-C(O)-N(R7)-N(R7)-C(O)-R4 and -C(O)-N(R7)-N(R7)-S(O)1-2-R4. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00239] For example, Rb is selected from
-C(O)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4 and -C(O)-N(R7)-N(R7)-S(O)1-2-R4. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00240] In another example, Rb is selected from -C(O)-OH; or-C(O)-NH2;
or -C(O)-NH-NH(R6), and R6 is an optionally substituted heteroaryl;
or -C(O)-NH-NH-C(O)-R4 or -C(O)-NH-NH-S(O)1-2-R4, and each R4 is independently selected from -N(H)(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-heterocyclyl and -(C0-C4 alkylene)-heteroaryl, each of which are optionally substituted. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00241] In another example, Rb is -C(O)NH2. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00242] In another example, R2 is an optionally substituted C5-C15 heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00243] In another example, R2 is an optionally substituted 5-6-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 structural formula I, or any aspect thereof.
[00244] In another example, 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 structural formula I, or any aspect thereof.
[00245] In another example, 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 structural formula I, or any aspect thereof. [00246] In another example, 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 structural formula I, or any aspect thereof.
[00247] In another example, R2 is an optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00248] In another example, 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 structural formula I, or any aspect thereof.
[00249] In another example, 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 structural formula I, or any aspect thereof.
[00250] In another example, X is -C(H)-. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00251] In another example, n is 0, 1 or 2. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00252] In another example, each R1 is 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), or is absent. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00253] In another example, 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 above for the structural formula I, or any aspect thereof.
[00254] In another example, Rb is -C(O)OH; or-C(O)NH2; or -C(O)-NH-NH(R6), and R6 is an optionally substituted C5-C6 heteroaryl; or -C(O)-NH-NH-C(O)-R4
or -C(O)-NH-NH-S(O)1-2-R4, and each R4 is selected from –N(H)(C3-C6
cycloalkyl), -N(C1-C4 alkyl)(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3- C7)heterocyclyl and -(C0-C4 alkylene)-(C5-C6)heteroaryl, each of which is optionally substituted. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00255] In another example, each R7 is hydrogen. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00256] In another example, R5 is selected from hydrogen and C1-C4 alkyl; and R6 is selected from C1-C4 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00257] In another example, R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a heterocyclyl or heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00258] In another example, R3 is selected from optionally substituted C1-C4 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00259] In another example, R4 is selected from -N(R7)(C3-C6 cycloalkyl), -C3-C6 alkyl, -(C0-C1 alkylene)-heterocyclyl, and -(C0-C1 alkylene)-heteroaryl, wherein R7 is hydrogen or -C1-C4 alkyl; any alkyl or alkylene portion of R4 is optionally and
independently substituted with one or more substituents selected from oxo and -N(R9)2, wherein each R9 is independently selected from hydrogen and C1-C4 alkyl; any heterocyclyl portion of R4 comprises at least one nitrogen atom in a ring, and is optionally substituted with one or more substituents selected from C1-C4 alkyl and oxo; and any heteroaryl portion of R4 comprises at least one nitrogen atom in a ring and is optionally substituted with one or more C1-C4 alkyl. The values for the remaining variables are as defined above for the structural formula I, or any aspect thereof.
[00260] In another example, R2 is 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, 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.
[00261] In another example, 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 structural formula I, or any aspect thereof. [00262] Exemplary compounds for use in the methods of the invention are set forth in Tables 1A-1F.
Methods of making compounds disclosed in Table 1A 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. Table 1A. Exemplary Compounds.
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000075_0002
[00263] In some embodiments, the compound is selected from
Figure imgf000075_0001
[00264] Methods of making the compounds of Table 1B 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. Table 1B. Exemplary Compounds.
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0002
[00265] In some embodiments, the compound
Figure imgf000086_0001
[00266] 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.
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0003
[00267] In some embodiments, the compound is selected from
Figure imgf000089_0001
[00268] Methods of making the compounds of Table 1D and compounds of formula (I) wherein R2 is heteroaryl are disclosed, for example, in International Application No. PCT/US2012/021406, the entire contents of which are incorporated herein by reference. Table 1D. Exemplary Compounds.
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0003
In some embodiments, the compound is selected from
Figure imgf000096_0001
.
[00269] Methods of making the compounds of Table 1E and compounds of formula (I) wherein R2 is -C(O)-N(R7)-N(R8)(R9) are disclosed, for example, in US Patent No. 9,096,543, the entire contents of which are incorporated herein by reference. Table 1E. Exemplary Compounds
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0002
[00270] In some embodiments, the compound is selected from
,
Figure imgf000098_0001
[00271] Methods of making the compounds of Table 1F 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. Table 1F. Exemplary Compounds
Figure imgf000098_0003
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
[00272] In some embodiments, the compound is selected from
Figure imgf000106_0002
[00273] In some embodiments, the compound
Figure imgf000107_0001
Pharmaceutically Acceptable Compositions
[00274] Provided herein are compositions comprising a compound of this invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that it is effective to measurably inhibit CRM1 in a biological sample or in a subject. In certain embodiments, a composition of this invention is formulated for administration to a subject in need of such composition.
[00275] The term“pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Other pharmaceutically acceptable carriers, adjuvants or vehicles include water, saline and dimethylsulfoxide, as well as other hydrophobic or hydrophilic solvents.
[00276] Compositions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and/or intraperitonally. Preferably, the compounds and compositions described herein are administered orally or parenterally. [00277] The term“parenteral,” as used herein, includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00278] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained/delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A compound disclosed herein can also be in micro-encapsulated form.
[00279] The amount of a compound of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the subject being treated and the particular mode of administration. In one embodiment, provided compositions should be formulated so that a dosage of between about 0.01– about 100 mg/kg body weight/day of the compound can be administered to a subject receiving these compositions. In another embodiment, the dosage is from about 0.5 to about 100 mg/kg of body weight, or between about 1 mg and about 1000 mg/dose, about every 4 to 120 hours, or according to the requirements of the particular drug. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day.
[00280] In some embodiments, the compound is formulated for oral administration at a dosage of approximately 5 mg/kg to approximately 10 mg/kg, preferably at a dosage of approximately 7.5 mg/kg.
[00281] Alternatively, the compound can be formulated for oral administration at a dosage from about 60mg to about 100mg per dose (e.g., an 80 mg dose orally). The dose can be administered daily, every other day, once per week, twice per week etc. for as long as needed. For example, the compound can be dosed orally at about 80 mg twice weekly for four weeks. Four weeks can be considered a cycle and multiple cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) can be administered as needed.
[00282] In some embodiments, the compound is formulated for topical administration at a concentration of approximately 0.3 mM to approximately 10 mM.
[00283] It should also be understood that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
[00284] Upon improvement of a subject’s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. Methods
[00285] Specific proteins and RNAs are carried into and out of the nucleus by specialized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus. Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters. Chromosomal Region Maintenance 1 (CRM1), which is also called exportin-1 or Xpo1, is a major exportin. Inhibition of CRM1 blocks the exodus of proteins and/or growth regulators such as p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27, E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or forkhead proteins (e.g. FOXO3a) from the nucleus that are associated with gene expression, cell proliferation, angiogenesis, neurological disorders, and epigenetics.
[00286] Compounds and compositions described herein are generally useful for the inhibition of CRM1 and are therefore useful for treating one or more disorders associated with activity of CRM1, such as hematological cancer. Thus, in certain embodiments, the present invention provides a method for treating a hematological cancer comprising the step of administering to a subject in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. In some embodiments, the hematological cancer is myeloma. The compounds and compositions described herein can also be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of hematological cancers, including those described herein.
[00287] The activity of a compound utilized in this invention as an inhibitor of CRM1 may be assayed in vitro, in vivo or in a cell line. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of CRM1 are set forth in US Patent No.9,096,543, and International Application Nos. PCT/US2011/027328; PCT/US2012/048368;
PCT/US2012/048319; PCT/US2012/021406; and PCT/2014/04479. The activity of many of the compounds in Tables 1A-1F in assays designed to measure CRM1 inhibitory activity can also be found in US Patent No.9,096,543, and International Application Nos.
PCT/US2011/027328; PCT/US2012/048368; PCT/US2012/048319; PCT/US2012/021406; and PCT/2014/04479.
[00288] Compounds of the invention, and pharmaceutically acceptable salts thereof, are also useful in the manufacture of a medicament for the treatment of hematological cancer Also provided herein are disclosed compounds and compositions for use in the treatment of hematological cancer. Combination Therapies
[00289] In some embodiments, a compound described herein is administered together with one or more additional,“second,” therapeutic agent, active pharmaceutical ingredient (API), or treatment. The choice of the second therapeutic agent may be made from any agent that is typically used to treat hematological cancer. As used herein, the term “administered together” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a therapeutically effective amount of a compound of the present invention may be administered with a therapeutically effective amount of another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a
pharmaceutically acceptable carrier, adjuvant, or vehicle.
[00290] In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the therapeutically effective amount of the compound of this invention is less than its therapeutically effective amount would be where the second therapeutic agent is not administered. In another embodiment, the therapeutically effective amount of the second therapeutic agent is less than its therapeutically effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
[00291] The amount of both a compound of the invention and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between about 0.01 – about 100 mg/kg body weight/day of a compound of the invention can be administered. In certain embodiments, a therapeutically effective amount of a compound described herein may be administered alone or in combination with therapeutically effective amounts of other compounds useful for treating hematological cancer. [00292] Examples of a second agent that can be used in combination with the compounds described herein include, but are not limited to immunomodulators and/or check-point modulators.
[00293] In an example embodiment, the immunomodulators are immunomodulatory imide drugs (IMiD) such as thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast). Other examples include azathioprine and 6-mercaptopurine (6-MP) and their analogs. Still further examples include cyclosporine A, tacrolimus, and methotrexate.
[00294] Examples of check-point modulators include PD-1 inhibitors (Pembrolizumab, Nivolumab), PD-L1 inhibitors (Atezolizumab), and CTLA-4 modulator Ipilimumab.
[00295] In yet another example embodiment, compounds described herein are co- administered with dexamethasone. EXEMPLIFICATION
[00296] The structural formula of compound C-3, also known as Selinexor, is reproduced below:
Figure imgf000112_0001
[00298] The STORM (Selinexor Treatment of Refractory Myeloma) trial is a clinical trial in which the combination of Selinexor™ (compound C-3) and dexamethasone in multiple myeloma patients refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide (quad-refractory), or in addition, to daratumumab (penta-refractory), was tested. The protocol and experimental procedures are described in Vogl et al.,“Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory Multiple Myeloma (MM): STORM Study” Blood 2016128:491, the entire teachings of which arfe incorporated herein by reference.
[00299] The objective of the experiments described below was to identify biomarkers for selection of patients at higher likelihood of clinical benefit from Selinexor.
[00300] Example 1: International Myeloma Working Group Response Criteria
[00301] Table A, below, lists International Myeloma Working Group Response Criteria, Myeloma (see Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 2014; 32(6):587-600. )
Table A
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
[00302] Abbreviations: CR = complete response; FLC = free light chain; hr = hour; MR = minimal response; PD = progressive disease; PR = partial response; sCR = stringent complete response; SD = stable disease; VGPR = very good partial response.
[00303] Clinical and laboratory methods for evaluating the indicators listed in Table A are well within the purview of a person of ordinary skill in the arts.
[00304] Example 2: Differentiatl Expression Analysis of Refractory Multiple Myeloma Patients
[00305] Transcriptional differences of selected genes were analyzed in 32 patients enrolled in the STORM study by using RNA sequencing in CD138+ cells collected from bone marrow aspirates obtained prior to treatment. The raw data (nucleotide sequences in the “fastq” format) was mapped by using the Spliced Transcripts Alignment to a Reference (STAR) tool, available at https://www.ncbi.nlm.nih.gov/pubmed/23104886. The sequences were gene-level annotated by FEATURECOUNTS, a tool for assigning sequence reads to genomic features, available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages. [00306] Patients were split in two groups based on their progression-free survival (PFS) following treatment with compound C-3. Differential expression analysis was performed using the“DESeq2” tool for differential gene expression analysis, available under the General Public License at the URL https://github.com/mikelove/DESeq2. DESeq2 enables a quantitative analysis of comparative RNA-seq data using shrinkage estimators for dispersion and fold change.
[00307] The results, presented in FIG.1, revealed significant up-regulation of the E2F1 gene in patients with PFS < 120 days (n = 21, p < 0.05) versus patients with PFS > 120 days (n=11). [00308] Example 3: Validation of the E2F1 expression in Refrcatory Multiple Myeloma Patients as a Biomarker of Responsivness to Compound C-3
[00309] The expression of E2F1 gene as a biomarker of responsiveness to the compound C- 3 was further confirmed in an independent cohort of 26 MM patients enrolled in the STORM study. The pre-dose E2F1 expression level in these patients was analyzed by Affymetrix® U133 gene expression microarrays, available from Affimetrix® at the URL https://www.affymetrix.com/products_services/arrays/specific/hgu133_array_strip.affx.
[00310] Data was analyzed using the Signal Space Transformation (SST)-Robust Multi- Chip Analysis (RMA) algorithm. Patients with PFS < 120 days (n = 19) exhibited significant upregulation of E2F1 (p < 0.05) (Fig.2).
[00311] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.
[00312] While this invention has been 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

What is claimed is: 1. A method for treating a cancer in a subject in need thereof,
wherein the subject has been determined to have a pre-dose level of a E2F1 gene product less than or equal to a control value,
the method comprising administering to the subject an effective amount of a compound represented by structural formula I:
Figure imgf000117_0001
,
or a pharmaceutically acceptable salt thereof,
wherein:
ring A is phenyl or pyridyl;
X is -C(H)- or -N-;
each R1 is independently selected from haloalkyl;
halo; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O) OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-(C3-C12) carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-(C6-C12) aryl, which is optionally substituted with R°; -(CH2)0-4-(4-12 member) heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-(5-12 member) heteroaryl, which is optionally substituted with R°; -CH=CH-(C3-C12) carbocyclyl, which is optionally substituted with R°; -CH=CH-(C6-C12)aryl, which is optionally substituted with R°; -CH=CH-(4-12-member)heterocyclyl, which is optionally substituted with R°; -CH=CH-(4-12-member)heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq )C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(R q)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; - (CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4 C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O)(CH2)0-4S R°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C( S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq)Rq; -(C H2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(C H2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(C H2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq) 2; -(CH2)0-4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq;
and -(CH2)0-4C(O)O-N(Rq)2; or
two R1, taken together with their intervening atoms, form a 3-12- membered carbocyclyl, (C6-C12)aryl, (4-12-member)heterocyclyl or (5-12- member)heteroaryl, wherein:
each Rq is independently selected from
hydrogen,C1-6 aliphatic, -CH2-(C3-C12)carbocyclyl, -CH2-(C6- C12)aryl, -CH2-(4-12 member)heterocyclyl, -CH2-(5-12- member)heteroaryl, -O(CH2)0-1–(C3-C12)carbocyclyl, -O-(CH2)0-1-(C6 C12)aryl, -O(CH2)0-1-(4-12 member)heterocyclyl, -O(CH2)0-1-(5-12- member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12 member)heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and
independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3
alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3
alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted 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 (5-12
member)heteroaryl and optionally substituted (C6-C12)aryl;
Ra is hydrogen;
Rb is selected from hydrogen, -C(O)-O-R3,
-C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)-N(R5)(R6 ), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)- C(O)-R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)- N(R7)-N(R7)-S(O)1-2-R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1- C4 alkyl), and (5-12-member)heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3- C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3-C12)carbocyclyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)-(C6-C12)aryl, and -(C0-C4 alkylene)- (5-12-member)heteroaryl;
R5 is selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl and (5-12-member)heteroaryl;
R6 is selected from (5-12-member)heteroaryl, hydrogen,–C(=Y)-R8, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, and (4-12 member)heterocyclyl; or
R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12- member)heteroaryl;
each R7 and R9 are independently hydrogen or C1-C4 alkyl;
R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)- (5- 12-member)heteroaryl;
Y is O or S; 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. 2. A method for treating a cancer in a subject in need thereof, the method comprising steps of:
receiving information related to a pre-dose level of E2F1 gene product in a subject suffering from the cancer; and
administering to the subject an effective amount of a compound represented by structural formula I:
Figure imgf000120_0001
,
or a pharmaceutically acceptable salt thereof, wherein the information indicates that the pre-dose level of E2F1 gene product is less than or equal to a control value,
wherein:
ring A is phenyl or pyridyl;
X is -C(H)- or -N- ;
each R1 is independently selected from haloalkyl;
halo; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O) OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-(C3-C12) carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-(C6-C12) aryl, which is optionally substituted with R°; -(CH2)0-4-(4-12 member) heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-(5-12 member) heteroaryl, which is optionally substituted with R°; -CH=CH-(C3-C12) carbocyclyl, which is optionally substituted with R°; -CH=CH-(C6-C12)aryl, which is optionally substituted with R°; -CH=CH-(4-12-member)heterocyclyl, which is optionally substituted with R°; -CH=CH-(4-12-member)heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq )C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(R q)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; - (CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4 C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O)(CH2)0-4S R°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C( S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq)Rq; -(C H2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(C H2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(C H2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq) 2; -(CH2)0-4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq;
and -(CH2)0-4C(O)O-N(Rq)2; or
two R1, taken together with their intervening atoms, form a 3-12- membered carbocyclyl, (C6-C12)aryl, (4-12-member)heterocyclyl or (5-12- member)heteroaryl, wherein:
each Rq is independently selected from
hydrogen,C1-6 aliphatic, -CH2-(C3-C12)carbocyclyl, -CH2-(C6- C12)aryl, -CH2-(4-12 member)heterocyclyl, -CH2-(5-12- member)heteroaryl, -O(CH2)0-1–(C3-C12)carbocyclyl, -O-(CH2)0-1-(C6 C12)aryl, -O(CH2)0-1-(4-12 member)heterocyclyl, -O(CH2)0-1-(5-12- member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12 member)heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and
independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3
alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted C1-C3 alkyl);
R2 is
selectedfrom -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 (5-12
member)heteroaryl and optionally substituted (C6-C12)aryl;
Ra is hydrogen and Rb is selected from hydrogen, -C(O)-O-R3, -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)-N(R5)(R6 ), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)- C(O)-R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)- N(R7)-N(R7)-S(O)1-2-R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1- C4 alkyl), and (5-12-member)heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3- C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3-C12)carbocyclyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)-(C6-C12)aryl, and -(C0-C4 alkylene)- (5-12-member)heteroaryl;
R5 is selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl and (5-12-member)heteroaryl;
R6 is selected from (5-12-member)heteroaryl, hydrogen,–C(=Y)-R8, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, and (4-12 member)heterocyclyl; or
R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12- member)heteroaryl;
each R7 and R9 are independently hydrogen or C1-C4 alkyl;
R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)- (5- 12-member)heteroaryl;
Y is O or S; 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. 3. A method of treating a subject suffering from a cancer, comprising the steps of:
obtaining a sample comprising a cell from the subject;
determining a pre-dose level of an E2F1 gene product in the sample; and administering an effective amount of a compound to the subject, wherein the pre-dose level of the E2F1 gene product in the sample is determined to be less than or equal to a control value,
wherein the compound is represented by structural formula I:
Figure imgf000123_0001
,
or a pharmaceutically acceptable salt thereof,
wherein:
ring A is phenyl or pyridyl;
X is -C(H)- or -N- ;
each R1 is independently selected from haloalkyl;
halo; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O) OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-(C3-C12) carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-(C6-C12) aryl, which is optionally substituted with R°; -(CH2)0-4-(4-12 member) heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-(5-12 member) heteroaryl, which is optionally substituted with R°; -CH=CH-(C3-C12) carbocyclyl, which is optionally substituted with R°; -CH=CH-(C6-C12)aryl, which is optionally substituted with R°; -CH=CH-(4-12-member)heterocyclyl, which is optionally substituted with R°; -CH=CH-(4-12-member)heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq )C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(R q)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; - (CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4 C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O)(CH2)0-4S R°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C( S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq)Rq; -(C H2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(C H2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(C H2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq) 2; -(CH2)0-4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq;
and -(CH2)0-4C(O)O-N(Rq)2; or
two R1, taken together with their intervening atoms, form a 3-12- membered carbocyclyl, (C6-C12)aryl, (4-12-member)heterocyclyl or (5-12- member)heteroaryl, wherein:
each Rq is independently selected from
hydrogen,C1-6 aliphatic, -CH2-(C3-C12)carbocyclyl, -CH2-(C6- C12)aryl, -CH2-(4-12 member)heterocyclyl, -CH2-(5-12- member)heteroaryl, -O(CH2)0-1–(C3-C12)carbocyclyl, -O-(CH2)0-1-(C6 C12)aryl, -O(CH2)0-1-(4-12 member)heterocyclyl, -O(CH2)0-1-(5-12- member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12 member)heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and
independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3
alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted 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 (5-12
member)heteroaryl and optionally substituted (C6-C12)aryl;
Ra is hydrogen and Rb is selected from hydrogen, -C(O)-O-R3, -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)-N(R5)(R6 ), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)- C(O)-R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)- N(R7)-N(R7)-S(O)1-2-R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1- C4 alkyl), and (5-12-member)heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3- C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3-C12)carbocyclyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)-(C6-C12)aryl, and -(C0-C4 alkylene)- (5-12-member)heteroaryl;
R5 is selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl and (5-12-member)heteroaryl;
R6 is selected from (5-12-member)heteroaryl, hydrogen,–C(=Y)-R8, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, and (4-12 member)heterocyclyl;; or
R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12- member)heteroaryl;
each R7 and R9 are independently hydrogen or C1-C4 alkyl;
R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)- (5- 12-member)heteroaryl;
Y is O or S; 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. 4. A method for treating a cancer in a subject in need thereof, the method comprising:
selecting the subject on the basis of an E2F1 gene product; and administering to the selected subject an effective amount of a compound represented by structural formula I:
Figure imgf000126_0001
,
or a pharmaceutically acceptable salt thereof,
wherein:
ring A is phenyl or pyridyl;
X is -C(H)- or -N- ;
each R1 is independently selected from haloalkyl;
halo; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O) OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-(C3-C12) carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-(C6-C12) aryl, which is optionally substituted with R°; -(CH2)0-4-(4-12 member) heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-(5-12 member) heteroaryl, which is optionally substituted with R°; -CH=CH-(C3-C12) carbocyclyl, which is optionally substituted with R°; -CH=CH-(C6-C12)aryl, which is optionally substituted with R°; -CH=CH-(4-12-member)heterocyclyl, which is optionally substituted with R°; -CH=CH-(4-12-member)heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq )C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(R q)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; - (CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4 C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O)(CH2)0-4S R°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C( S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq)Rq; -(C H2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(C H2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(C H2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq) 2; -(CH2)0-4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq;
and -(CH2)0-4C(O)O-N(Rq)2; or
two R1, taken together with their intervening atoms, form a 3-12- membered carbocyclyl, (C6-C12)aryl, (4-12-member)heterocyclyl or (5-12- member)heteroaryl, wherein:
each Rq is independently selected from
hydrogen,C1-6 aliphatic, -CH2-(C3-C12)carbocyclyl, -CH2-(C6- C12)aryl, -CH2-(4-12 member)heterocyclyl, -CH2-(5-12- member)heteroaryl, -O(CH2)0-1–(C3-C12)carbocyclyl, -O-(CH2)0-1-(C6 C12)aryl, -O(CH2)0-1-(4-12 member)heterocyclyl, -O(CH2)0-1-(5-12- member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12 member)heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and
independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3
alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3
alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted 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 (5-12
member)heteroaryl and optionally substituted (C6-C12)aryl;
Ra is hydrogen and Rb is selected from hydrogen, -C(O)-O-R3, -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)-N(R5)(R6 ), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)- C(O)-R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)- N(R7)-N(R7)-S(O)1-2-R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1- C4 alkyl), and (5-12-member)heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3- C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3-C12)carbocyclyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)-(C6-C12)aryl, and -(C0-C4 alkylene)- (5-12-member)heteroaryl;
R5 is selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl and (5-12-member)heteroaryl;
R6 is selected from (5-12-member)heteroaryl, hydrogen,–C(=Y)-R8, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, and (4-12 member)heterocyclyl; or
R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12- member)heteroaryl;
each R7 and R9 are independently hydrogen or C1-C4 alkyl;
R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)- (5- 12-member)heteroaryl;
Y is O or S; 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.
5. The method of Claim 4, wherein selecting the subject includes receiving
information related to a pre-dose level of an E2F1 gene product in the subject.
6. A method of treating a cancer in a subject in need thereof, the method comprising:
administering an effective amount of a compound of formula I
Figure imgf000129_0001
or a pharmaceutically acceptable salt thereof to the subject,
wherein a sample collected from the subject is determined to have a pre-dose level of an E2F1 gene product that is less than or equal to a control value,
wherein:
ring A is phenyl or pyridyl;
X is -C(H)- or -N- ;
each R1 is independently selected from haloalkyl;
halo; -(CH2)1-4Rq; -(CH2)0-4ORq; -O-(CH2)0-4C(O)OR°; -O-(CH=CH)-C(O) OR°; -(CH2)0-4CH(ORq)2; -(CH2)0-4SRq; -(CH2)0-4-(C3-C12) carbocyclyl, which is optionally substituted with R°; -(CH2)0-4-(C6-C12) aryl, which is optionally substituted with R°; -(CH2)0-4-(4-12 member) heterocyclyl, which is optionally substituted with R°; -(CH2)0-4-(5-12 member) heteroaryl, which is optionally substituted with R°; -CH=CH-(C3-C12) carbocyclyl, which is optionally substituted with R°; -CH=CH-(C6-C12)aryl, which is optionally substituted with R°; -CH=CH-(4-12-member)heterocyclyl, which is optionally substituted with R°; -CH=CH-(4-12-member)heteroaryl, which is optionally substituted with
R°; -NO2; -CN; -N3; -(CH2)0-4N(Rq)2; -(CH2)0-4N(Rq)C(O)Rq; -(CH2)0-4N(Rq )C(S)Rq; -(CH2)0-4N(Rq)C(O)NRq2; -(CH2)0-4N(Rq)C(S)NRq2; -(CH2)0-4N(R q)C(O)ORq; -(CH2)0-4N(Rq)N(Rq)C(O)Rq; -(CH2)0-4N(Rq)N(Rq)C(O)NRq2; - (CH2)0-4N(Rq)N(Rq)C(O)ORq; -(CH2)0-4C(O)Rq; -(CH2)0-4C(S)Rq; -(CH2)0-4 C(O)ORq; -(CH2)0-4C(O)SRq; -(CH2)0-4OC(O)Rq; -(CH2)0-4OC(O)(CH2)0-4S R°, -(CH2)0-4SC(S)SR°; -(CH2)0-4SC(O)Rq; -(CH2)0-4C(O)NRq2; -(CH2)0-4C( S)NRq2; -(CH2)0-4C(S)SR°; -(CH2)0-4OC(O)NRq2; -(CH2)0-4C(O)N(ORq)Rq; -(CH2)0-4C(O)C(O)Rq; -(CH2)0-4C(O)CH2C(O)Rq; -(CH2)0-4C(NORq)Rq; -(C H2)0-4SSRq; -(CH2)0-4S(O)2Rq; -(CH2)0-4S(O)2ORq; -(CH2)0-4OS(O)2Rq; -(C H2)0-4S(O)2NRq2; -(CH2)0-4S(O)Rq; -(CH2)0-4N(Rq)S(O)2NRq2; -(CH2)0-4N(R q)S(O)2Rq; -(CH2)0-4N(ORq)Rq; -(CH2)0-4C(NH)NRq2; -(CH2)0-4P(O)2Rq; -(C H2)0-4P(O)Rq2; -(CH2)0-4OP(O)Rq2; -(CH2)0-4OP(O)(ORq)2; -(CH2)0-4ON(Rq) 2; -(CH2)0-4-O-(CH2)1-4-N(Rq)2; -(CH2)0-4-O-(CH2)1-4-ORq;
and -(CH2)0-4C(O)O-N(Rq)2; or
two R1, taken together with their intervening atoms, form a 3-12- membered carbocyclyl, (C6-C12)aryl, (4-12-member)heterocyclyl or (5-12- member)heteroaryl, wherein:
each Rq is independently selected from
hydrogen,C1-6 aliphatic, -CH2-(C3-C12)carbocyclyl, -CH2-(C6- C12)aryl, -CH2-(4-12 member)heterocyclyl, -CH2-(5-12- member)heteroaryl, -O(CH2)0-1–(C3-C12)carbocyclyl, -O-(CH2)0-1-(C6 C12)aryl, -O(CH2)0-1-(4-12 member)heterocyclyl, -O(CH2)0-1-(5-12- member)heteroaryl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl, (5-12 member)heteroaryl, or two independent occurrences of Rq, taken together with their intervening atom(s), form a 3-12-membered carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl or (5-12 member)heteroaryl; and
each Rq and each ring formed from two independent occurrences of Rq, taken together with their intervening atom(s), are optionally and
independently substituted with one or more substituents selected from halo, CN, OH, unsubstituted C1-C3 alkyl, halo-C1-C3
alkyl, -NH2, -NO2, -NH(unsubstituted C1-C3 alkyl), -N(unsubstituted C1-C3 alkyl)2, -O-C1-C3 alkyl, -C(O)OH, -C(O)O-(unsubstituted C1-C3 alkyl), -C(O)-(unsubstituted C1-C3 alkyl), -O-(unsubstituted C1-C3 alkyl), and -S-(unsubstituted 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 (5-12
member)heteroaryl and optionally substituted (C6-C12)aryl;
Ra is hydrogen and Rb is selected from hydrogen, -C(O)-O-R3, -C(O)-N(R5)(R6), -C(O)-N(R7)-N(R5)(R6), -CN, -C(S)-O-R3, -C(S)-N(R5)(R6 ), -C(S)-N(R7)-N(R5)(R6), -C(O)-N(R7)-N(R7)-C(O)-R4, -C(S)-N(R7)-N(R7)- C(O)-R4, -C(O)-N(R7)-N(R7)-C(S)-R4, -C(S)-N(R7)-N(R7)-C(S)-R4, -C(O)- N(R7)-N(R7)-S(O)1-2-R4, -C(S)-N(R7)-N(R7)-S(O)1-2-R4
, -CF3, -S(O)1-2(C1- C4 alkyl), and (5-12-member)heteroaryl, wherein:
R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3- C12)carbocyclyl, (C6-C12)aryl, (4-12 member)heterocyclyl and (5-12- member)heteroaryl;
R4 is selected from–NR7-(C3-C6 cycloalkyl), -N(C1-C4 alkyl)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(C3-C12)carbocyclyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)-(C6-C12)aryl, and -(C0-C4 alkylene)- (5-12-member)heteroaryl;
R5 is selected from hydrogen,–C(=Y)-R8, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, (4-12
member)heterocyclyl and (5-12-member)heteroaryl;
R6 is selected from (5-12-member)heteroaryl, hydrogen,–C(=Y)-R8, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C12)carbocyclyl, (C6-C12)aryl, and (4-12 member)heterocyclyl; or
R5 and R6 are taken together with the nitrogen atom to which they are commonly attached to form a (4-12 member)heterocyclyl or (5-12- member)heteroaryl;
each R7 and R9 are independently hydrogen or C1-C4 alkyl;
R8 is selected from–N(R9)2, -N(R9)-(C3-C6 cycloalkyl), -C1-C6 alkyl, -(C0-C4 alkylene)-(4-12 member)heterocyclyl, -(C0-C4 alkylene)- (5- 12-member)heteroaryl;
Y is O or S; 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.
7. The method of any one of Claims 1-6, wherein the E2F1 gene product is an E2F1 mRNA.
8. The method of any one of Claims 1-7, wherein the control value is from 150% to 100% of the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
9. The method of any one of Claims 1-7, wherein the control value is equal to the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
10. The method of any one of Claims 1-7, wherein the control value is equal to 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110%, or 105% of the median value of log2-normalized level of E2F1 mRNA expression in a population of subjects suffering from the same cancer.
11. The method of any one of Claims 1-7, wherein the cancer is a solid tumor.
12. The method of any one of Claims 1-7, wherein the cancer is a hematological cancer.
13. The method of Claim 12, wherein the hematological cancer is selected from
leukemia, lymphoma and myeloma.
14. The method of Claim 13 wherein the hematological cancer is multiple myeloma.
15. The method of Claim 14, wherein the multiple myeloma is a refractory multiple myeloma.
16. The method of any one of Claims 1-15, wherein the level of the E2F1 gene product has been determined in a CD138+ cell. 17. The method of any one of claims 1-16, wherein the compound is represented by formula (IIIA):
Figure imgf000133_0001
or a pharmaceutically acceptable salt thereof, wherein:
Rb is -C(O)-NH2, and
R2 is an optionally substituted 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The method of any one of claims 1-16, wherein R2 is -C(O)-N(H)-N(R5)(R6).
19. The method of claim 18, 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.
20. The method of any one of claims 1-16, wherein the compound is selected from compounds C-1 to C-26 in Table 1C.
21. The method of any one of Claims 1-16, wherein the compound is selected from
Figure imgf000134_0001
22. The method of any one of claims 1-19, wherein the compound is represented by the following structural formula:
Figure imgf000134_0002
,
where the exocyclic double bond is in a cis configuration.
23. The method of any one of Claims 1-16, wherein
R5 is H;
R6 is–C(=Y)-R8
; and
R8 is selected from -N(R9)-(C3-C6 cycloalkyl), -C3-C6 alkyl, -(C0-C1 alkylene)- (4-12 member)heterocyclyl, and -(C0-C1 alkylene)- (5-12- member)heteroaryl, wherein
any alkyl or alkylene portion of R2 is optionally substituted with -N(R7)2; each R7 and R9 is independently selected from hydrogen and C1-C4 alkyl; any heterocyclyl or heteroaryl portion of R2 comprises at least one nitrogen atom in a ring; and
any heterocyclyl or heteroaryl portion of R2 is optionally substituted with C1-C4 alkyl.
24. The method of any one of claims 1-16, wherein the compound is selected from
compounds E-1 to E-15 in Table 1E.
25. The method of any one of Claims 1-17, wherein the compound is selected from
Figure imgf000135_0001
26. The method of any one of claims 1-16, wherein R2 is optionally substituted
heteroaryl.
27. The method of claim 26, wherein R2 is an optionally substituted 5-6 membered heteroaryl ring having at least one nitrogen atom and, optionally, 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur, where the optional substituents are selected from (C1-C3)alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, cyano, (C1-C3)haloalkyl, halogen, nitro, (C1-C3)haloalkoxy and (C1-C3)alkoxy.
28. The method of any one of claims 1-16, wherein the compound is represented by the following structural formula:
Figure imgf000136_0001
or a pharmaceutically acceptable salt thereof.
PCT/US2019/059483 2018-11-01 2019-11-01 E2f1 as a biomarker for treatments using xpo1 inhibitors WO2020092965A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862754343P 2018-11-01 2018-11-01
US62/754,343 2018-11-01

Publications (1)

Publication Number Publication Date
WO2020092965A1 true WO2020092965A1 (en) 2020-05-07

Family

ID=68655730

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/059483 WO2020092965A1 (en) 2018-11-01 2019-11-01 E2f1 as a biomarker for treatments using xpo1 inhibitors

Country Status (1)

Country Link
WO (1) WO2020092965A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112057450A (en) * 2020-09-28 2020-12-11 深圳市人民医院 Nuclear export protein inhibitor KPT-335 and application of composition thereof in antitumor drugs
WO2022232417A1 (en) * 2021-04-28 2022-11-03 Karyopharm Therapeutics Inc. Biomarkers for response to exportin-1 inhibitors in multiple myeloma patients
WO2022246065A1 (en) * 2021-05-19 2022-11-24 Karyopharm Therapeutics Inc. Calb1 biomarker in the treatment of de-differentiated liposarcoma using xpo1 inhibitors, such as selinexor
WO2023072248A1 (en) * 2021-10-29 2023-05-04 正大天晴药业集团股份有限公司 Pyridyl-containing compound

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070060615A1 (en) * 2003-02-18 2007-03-15 University Of South Florida Method of Modulating Apoptosis Through Modulation of E2F1
US20130317031A1 (en) * 2012-05-09 2013-11-28 Karyopharm Therapeutics Inc. Nuclear Transport Modulators And Uses Thereof
WO2014004479A2 (en) 2012-06-25 2014-01-03 Massachusetts Institute Of Technology Porous film
US20140364408A1 (en) * 2011-07-29 2014-12-11 Karyopharm Therapeutics Inc. Hydrazide Containing Nuclear Transport Modulators And Uses Thereof
US20160152596A1 (en) * 2013-06-21 2016-06-02 Karyopharm Therapeutics Inc. Nuclear Transport Modulators and Uses Thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070060615A1 (en) * 2003-02-18 2007-03-15 University Of South Florida Method of Modulating Apoptosis Through Modulation of E2F1
US20140364408A1 (en) * 2011-07-29 2014-12-11 Karyopharm Therapeutics Inc. Hydrazide Containing Nuclear Transport Modulators And Uses Thereof
US20130317031A1 (en) * 2012-05-09 2013-11-28 Karyopharm Therapeutics Inc. Nuclear Transport Modulators And Uses Thereof
US9096543B2 (en) 2012-05-09 2015-08-04 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
WO2014004479A2 (en) 2012-06-25 2014-01-03 Massachusetts Institute Of Technology Porous film
US20160152596A1 (en) * 2013-06-21 2016-06-02 Karyopharm Therapeutics Inc. Nuclear Transport Modulators and Uses Thereof

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
"Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H", 1979, PERGAMON PRESS
A. LAGANA, ET AL.: "E2F1 is a biomarker of selinexor resistance in relapsed/refractory multiple myeloma patients", BLOOD, vol. 132, Supplement 1, 29 November 2018 (2018-11-29), American Society of Hematology, Washington, DC, US, pages 3216, XP055666265, ISSN: 0006-4971, DOI: 10.1182/blood-2018-99-116500 *
BATZER ET AL., NUCLEIC ACID RES., vol. 19, 1991, pages 5081
CASSOL ET AL., MOL. CELL. PROBES, vol. 6, 1992, pages 327 - 331
D.T. VOGL, ET AL.: "Selinexor and low-dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM Study", BLOOD, vol. 128, no. 22, 2 December 2016 (2016-12-02), American Society of Hematology, Washington, DC, US, pages 491, XP055666309, DOI: 10.1182/blood.V128.22.491.491 *
J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
OHTSUKA ET AL., J. BIOL. CHEM., vol. 260, 1985, pages 2605 - 2608
PALUMBO ARAJKUMAR SVSAN MIGUEL JF ET AL.: "International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation", J CLIN ONCOL, vol. 32, no. 6, 2014, pages 587 - 600
ROSSOLINI ET AL., MOL. CELL. PROBES, vol. 8, 1994, pages 1119 - 1190
THOMAS SORRELL: "Handbook of Chemistry and Physics", 1999, UNIVERSITY SCIENCE BOOKS
VOGL ET AL.: "Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory Multiple Myeloma (MM): STORM Study", BLOOD, vol. 128, 2016, pages 491

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112057450A (en) * 2020-09-28 2020-12-11 深圳市人民医院 Nuclear export protein inhibitor KPT-335 and application of composition thereof in antitumor drugs
CN112057450B (en) * 2020-09-28 2022-04-19 深圳市人民医院 Nuclear export protein inhibitor KPT-335 and application of composition thereof in antitumor drugs
WO2022232417A1 (en) * 2021-04-28 2022-11-03 Karyopharm Therapeutics Inc. Biomarkers for response to exportin-1 inhibitors in multiple myeloma patients
WO2022246065A1 (en) * 2021-05-19 2022-11-24 Karyopharm Therapeutics Inc. Calb1 biomarker in the treatment of de-differentiated liposarcoma using xpo1 inhibitors, such as selinexor
WO2023072248A1 (en) * 2021-10-29 2023-05-04 正大天晴药业集团股份有限公司 Pyridyl-containing compound

Similar Documents

Publication Publication Date Title
ES2751902T3 (en) 6,7,8,9-Tetrahydro-3H-pyrazolo [4,3-f] isoquinoline derivative useful in cancer treatment
WO2020092965A1 (en) E2f1 as a biomarker for treatments using xpo1 inhibitors
TWI585088B (en) Imidazo[1,2-b]pyridazine analogues as kinase inhibitors
EP3204379B1 (en) Pyrrolidine amide compounds as histone demethylase inhibitors
RU2654857C2 (en) New compounds
RU2743360C2 (en) Heteroaryl compounds as irak inhibitors and use thereof
RU2701517C2 (en) Quinazolinone derivatives applicable as modulators of fgfr kinase
RU2625303C2 (en) Quinolines as fgfr kinase modulators
KR102086871B1 (en) Anticancer benzopyrazines via the inhibition of fgfr kinases
CN104936954B (en) Compound and its application method
RU2629194C2 (en) Derivatives of 1,5- and 1,7-naphthyridine useful in treatment of fgfr-mediated diseases
EP3286188B1 (en) Isoxazolyl substituted imidazopyridines
JP2021524838A (en) How to use KRAS G12C inhibitor and the same
TW202130645A (en) Small molecule inhibitors of kras g12c mutant
EA029497B1 (en) Benzimidazolone derivatives as bromodomain inhibitors
AU2008224657B2 (en) Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
KR20130044382A (en) Compounds and therapeutic uses thereof
JP7200120B2 (en) Heteroaryl compounds useful as MK2 inhibitors
JP6898919B2 (en) New compound
JP2020511468A (en) Deuterated analogs of MK2 inhibitors and uses thereof
EP4165035A1 (en) Heteroaryl alkylene substituted 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors
EP4181920A1 (en) Kat6 inhibitor methods and combinations for cancer treatment
US20230322853A1 (en) Compounds and compositions for the treatment of proliferative diseases and disorders
CN115785071B (en) 3-ethynyl-5- (1H-1, 2, 3-triazole-4-yl) -1H-indazole compound and application thereof
KR20180052631A (en) Non-heteroaryl substituted 1,4-benzodiazepines and their use for the treatment of cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19809317

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19809317

Country of ref document: EP

Kind code of ref document: A1