WO2015135094A1 - Composés thérapeutiques et leurs utilisations - Google Patents

Composés thérapeutiques et leurs utilisations Download PDF

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Publication number
WO2015135094A1
WO2015135094A1 PCT/CN2014/000261 CN2014000261W WO2015135094A1 WO 2015135094 A1 WO2015135094 A1 WO 2015135094A1 CN 2014000261 W CN2014000261 W CN 2014000261W WO 2015135094 A1 WO2015135094 A1 WO 2015135094A1
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Prior art keywords
pyrazol
phenyl
compound
oxo
aryl
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PCT/CN2014/000261
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English (en)
Inventor
Brian K. Albrecht
Victor S. Gehling
Jean-Christophe Harmange
Tommy Lai
Jun Liang
Peter Dragovich
Dan ORTWINE
Sharada Labadie
Birong Zhang
Jim KIEFER
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Genentech, Inc.
Constellation Pharmaceuticals, Inc.
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Application filed by Genentech, Inc., Constellation Pharmaceuticals, Inc. filed Critical Genentech, Inc.
Priority to PCT/CN2014/000261 priority Critical patent/WO2015135094A1/fr
Publication of WO2015135094A1 publication Critical patent/WO2015135094A1/fr

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • KDM5 histone demethylases
  • KDM5/JARID1 family of demethylases in humans contains four members, KDM5A, KDM5B, KDM5C and KDM5D.
  • KDM5 family members contain five conserved domains: JmjN, ARID, JmjC, PHD and a C 5 HC 2 zinc finger.
  • KDM5A, KDM5B, KDM5C and KDM5D are known and are publicly available, e.g., see UniProtKB/Swiss-Prot ⁇ see e.g., KDM5A ⁇ e.g., P29375-1 and P29375-2), KDM5B ⁇ e.g., Q9UGL1-1 and Q9UGL 1-2), KDM5C ⁇ e.g., P41229-1, P41229-2, P41229-3 and P41229-4) and KDM5D ⁇ e.g., Q9BY66-1, Q9BY66-2 and Q9BY66-3).
  • KDM5A ⁇ e.g., P29375-1 and P29375-2
  • KDM5B ⁇ e.g., Q9UGL1-1 and Q9UGL 1-2
  • KDM5C ⁇ e.g., P41229-1, P41229-2, P41229-3 and P41229-4)
  • One aspect provides a compound as described in any one of Examples 1-432 or a salt thereof.
  • Another aspect provides a compound of formula (I):
  • R 1 is H, Ci_ 6 alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 f f f
  • heterocyclyl 5-6 membered heteroaryl, halo, -OR , -SR , -N(R ) 2 , -CN, or -N0 2 , wherein said alkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci_3alkoxy and Ci_3alkyl;
  • R 2 is H, Ci_i 2 alkyl, C 2 _i 2 alkenyl, C 2 _i 2 alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR a , -SR a , -N(R a ) 2 , -CN, -N0 2 , -C(0)R a , -C0 2 R a , -C(0)N(R a ) 2 , -C(0)SR a , -C(0)C(0)R a , -C(0)CH 2 C(0)R a , -C(S)N(R a ) 2 , -C(S)OR a , -S(0)R a , -S0 2 R a , -S0 2 N(R a ) 2 , - N(R a )C(0)R a , -N(R a )C(0)N(R
  • R 3 is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more groups R x ;
  • C 3 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups R x ;
  • each R is independently selected from H, Ci_ 3 alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, or two R groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;
  • each R m is independently selected from H, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, carbocyclyl, Ci_ 6 alkanoyl, phenyl, and benzyl, wherein any Ci_ 6 alkyl,
  • C 2 _ 6 alkenyl, C 2 _ 6 alkynyl,Ci_ 6 haloalkyl, carbocyclyl, Ci_ 6 alkanoyl, phenyl, or benzyl is optionally substituted with one or more groups independently selected from halo, - CN, -N0 2 , -NR y R z , and -OR w ; or two R m groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;
  • each R v is independently hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl,wherein each Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, aryl, carbocyclyl, and Ci-C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R v are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci_ 3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
  • each R w is independently selected from H, C h alky 1, phenyl, benzyl, and phenethyl;
  • each R x is independently selected from oxo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0 2 , -N(R V ) 2 , -CN, -C(O)- N(R V ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -0-C(0)-0-R v , -C(O)- R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -0-C(0)-N(R v ) 2 , -N(R v
  • R v , -N(R v )-S(0) 2 -R v , and Ci_ 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;
  • each R y and R z is independently selected from H, Ci_ 4 alkyl, Ci_ 4 alkanoyl,
  • each R xa is independently selected from aryl, heteroaryl, heterocycle, and carbocycle, wherein any aryl, heteroaryl, heterocycle, and carbocycle is optionally substituted with one or more groups independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -F, -CI, -Br, -I, -N0 2 , -N(R V ) 2 , -CN, carbocycle, aryl, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S- R v , -0-C(0)-R v , -0-C(0)-0-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2
  • compositions comprising a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
  • Another aspect includes compounds and compositions for treating diseases, disorders or conditions associated with KDM5 activity.
  • diseases, disorders, or conditions include those described herein.
  • Another aspect includes a method of treating a disease associated with KDM5 activity, comprising administering a therapeutically effective amount of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Another aspect includes the use of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, in therapy.
  • Another aspect includes the use of a compound as described in any one of Examples
  • Another aspect includes the use of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with KDM5 activity.
  • Another aspect includes a method of increasing the efficacy of a cancer treatment comprising a cancer therapy agent, comprising administering to a patient (a) an effective amount of a compound as described in any one of Examples 1-432, or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.
  • Another aspect includes a method of treating an individual with cancer who has an increased likelihood of developing resistance to a cancer therapy agent comprising
  • Another aspect includes processes and synthetic intermediates that are useful for preparing a compound as described in any one of Examples 1-432, or a salt thereof.
  • compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
  • Another aspect includes a method of treating a disease associated with KDM5 activity, comprising administering an therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in therapy.
  • Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in treating a disease associated with KDM5 activity.
  • Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with KDM5 activity.
  • Another aspect includes a method of increasing the efficacy of a cancer treatment comprising a cancer therapy agent, comprising administering to a patient (a) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.
  • Another aspect includes a method of treating an individual with cancer who has an increased likelihood of developing resistance to a cancer therapy agent comprising administering to the individual (a) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) an effective amount of the cancer therapy agent.
  • Another aspect includes a processes and synthetic intermediates that are useful for preparing a compound of formula (I), or a salt thereof.
  • Another aspect includes compounds for the study of histone demethylases, such as KDM5, the study of intracellular signal transduction pathways mediated by such histone demethylases, and the comparative evaluation of modulators of these demethylases.
  • KDM5 histone demethylases
  • 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 included. Unless otherwise stated, all tautomeric forms of the compounds are included. 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.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are included. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.
  • a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched.”
  • “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer.
  • the compound is made up of at least about 95%, 98%>, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR + (as in N- substituted pyrrolidinyl)).
  • a "direct bond” or “covalent bond” refers to a single, double or triple bond. In certain embodiments, a “direct bond” or “covalent bond” refers to a single bond.
  • halo and "halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
  • aliphatic or "aliphatic group”, as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 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.
  • cycloaliphatic used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 10 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • the cycloalkyl has 3-6 carbons.
  • cycloaliphatic 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, where the radical or point of attachment is on an aliphatic ring.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • a cycloalkylene group is a 1,1 -cycloalkylene group (i.e., a spiro-fused
  • Exemplary 1,1 -cycloalkylene groups include In other embodiments, a cycloalkylene group is a 1 ,2-cycloalkylene group or a 1,3-cycloalkylene group. Exemplary
  • alkyl refers to a monovalent saturated, straight- or branched-chain hydrocarbon radical derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. In some embodiments, alkyl contains 1-5 carbon atoms. In another embodiment, alkyl contains 1-4 carbon atoms. In still other embodiments, alkyl contains 1-3 carbon atoms. In yet another embodiment, alkyl contains 1-2 carbons.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.
  • alkenyl denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. In certain embodiments, alkenyl contains 2-6 carbon atoms. In certain embodiments, alkenyl contains 2-5 carbon atoms. In some embodiments, alkenyl contains 2-4 carbon atoms. In another embodiment, alkenyl contains 2-3 carbon atoms. Alkenyl groups include, for example, ethenyl ("vinyl”), propenyl ("allyl”), butenyl, l-methyl-2-buten-l-yl, and the like.
  • alkynyl refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • alkynyl contains 2-6 carbon atoms.
  • alkynyl contains 2-5 carbon atoms.
  • alkynyl contains 2-4 carbon atoms.
  • alkynyl contains 2-3 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl ("propargyl”), 1-propynyl, and the like.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l ,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 4- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl), or (as in N- substituted pyrrolidinyl) .
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2- azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
  • heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • an inhibitor refers to a compound that binds to and inhibits a KDM5 enzyme with measurable affinity and activity.
  • an inhibitor has an IC 50 and/or binding constant of less about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, or less than about 10 nM.
  • measurable affinity and “measurably inhibit,” as used herein, refer to a measurable reduction in activity of a KDM5 enzyme between: (i) a sample comprising a compound a compound as described herein and such KDM5 enzyme, and (ii) an equivalent sample comprising such KDM5 enzyme, in the absence of said compound.
  • “Pharmaceutically acceptable salts” include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanes
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from
  • organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound or pharmaceutically acceptable salt thereof as described herein.
  • solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • “Therapeutically effective amount” refers to an amount of a a compound or pharmaceutically acceptable salt thereof as described herein that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma).
  • a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of drug tolerant or drug tolerant persisting cancer cells.
  • Treatment refers to clinical
  • Desirable effects of treatment include one or more of preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis.
  • a compound as described herein is used to delay development of a disease or disorder or to slow the progression of a disease or disorder.
  • Those individuals in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation or abberent expression of a gene or protein) or those in which the condition or disorder is to be prevented.
  • R 1 is H, Ci_ 6 alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 f f f
  • heterocyclyl 5-6 membered heteroaryl, halo, -OR , -SR , -N(R ) 2 , -CN, or -N0 2 , wherein said alkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halo, Ci_3alkoxy and Ci_3alkyl;
  • R 2 is H, Ci_i 2 alkyl, C 2 _i 2 alkenyl, C 2 _i 2 alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR a , -SR a , -N(R a ) 2 , -CN, -N0 2 , -C(0)R a , -C0 2 R a , -C(0)N(R a ) 2 , -C(0)SR a , -C(0)C(0)R a , -C(0)CH 2 C(0)R a , -C(S)N(R a ) 2 , -C(S)OR a , -S(0)R a , -S0 2 R a , -S0 2 N(R a ) 2 , - N(R a )C(0)R a , -N(R a )C(0)N(R
  • R 3 is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more groups R x ;
  • each R a is independently selected from H, Ci_6alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl, wherein each Ci_ 6 alkyl, C 3 _ 6 alkenyl,
  • C 3 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups R x ;
  • each R is independently selected from H, Ci_ 3 alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 membered heterocyclyl, and 5-6 membered heteroaryl, or two R groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;
  • each R m is independently selected from H, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _6alkynyl,
  • Ci_ 6 haloalkyl carbocyclyl, Ci_ 6 alkanoyl, phenyl, and benzyl, wherein any Ci_ 6 alkyl,
  • C 2 _ 6 alkenyl, C 2 _ 6 alkynyl,Ci_ 6 haloalkyl, carbocyclyl, Ci_ 6 alkanoyl, phenyl, or benzyl is optionally substituted with one or more groups independently selected from halo, - CN, -N0 2 , -NR y R z , and -OR w ; or two R m groups together with the nitrogen to which they are attached form a 3-6 membered heterocyle;
  • each R v is independently hydrogen, Ci_6alkyl, C 2 _6alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl,wherein each Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, aryl, carbocyclyl, and Ci-C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R v are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and Ci_ 3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each R
  • each R x is independently selected from oxo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0 2 , -N(R V ) 2 , -CN, -C(O)- N(R V ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -0-C(0)-0-R v , -C(O)- R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -0-C(0)-N(R v ) 2 , -N(R v
  • Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, and heterocycle is optionally substituted with one or more groups independently selected from R xa , oxo, halo, -N0 2 , -N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 - N(R V ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -C(0)-N(R v ) 2 ,
  • each R y and R z is independently selected from H, Ci_ 4 alkyl, Ci_ 4 alkanoyl,
  • each R xa is independently selected from aryl, heteroaryl, heterocycle, and carbocycle, wherein any aryl, heteroaryl, heterocycle, and carbocycle is optionally substituted with one or more groups independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, -F, -CI, -Br, -I, -N0 2 , -N(R V ) 2 , -CN, carbocycle, aryl, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S- R v , -0-C(0)-R v , -0-C(0)-0-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2
  • any C 2 _ 6 alkenyl, and C 2 _ 6 alkynyl is optionally substituted with one or more groups independently selected from oxo, halo, -N0 2 , -N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -O- C(0)-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -C(0)-N(R v ) 2 ,
  • R 1 is H, Ci_ 6 alkyl, trifluoromethyl, 3-6 membered carbocyclyl, 6 membered aryl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, halo, -OR , -
  • R 1 is H, methyl, or ethyl.
  • R 1 is H.
  • R 2 is H.
  • R 2 is Ci_i 2 alkyl, C 2 _i 2 alkenyl, C 2 _i 2 alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, halo, -OR a , -SR a , -N(R a ) 2 , -CN, -
  • R 2 is H, Ci_6alkyl, C 2 _i 2 alkenyl, C 2 _i 2 alkynyl, carbocyclyl, aryl, heteroaryl, halo, -CN, -SR a , -N(R V ) 2 , and -C0 2 R a , wherein any Ci_6alkyl, carbocyclyl and aryl is optionally substituted with one or more groups independently selected from Ci_
  • R 2 is H, isopropyl, ethyl, iert-butyl, 2,2-difluoroethyl, cyclobutyl, 2-propyn-l-yl, bromo, chloro, 2-furyl, vinyl, phenyl, 2-chlorophenylthio, 2- fluoroethyl, 2-propenyl, 1-methylvinylcyclopropyl, 4-pyridyl, 2-buten-l-yl, iodo, l-methyl-2- propyn-l-yl, 1-methylprop-l-yl, l-(cyclopropyl)ethyl, methoxycarbonyl, 2-butynyl, 2- hydroxy-l-methylethyl, 4-(methylcarbonylamino)butyl, 3-(methylcarbonylamino)propyl, 4- aminobutyl, l-methyl-2-propenyl, 1-methylcyclobutyl, propyl, 2-me
  • R 3 is lH-pyrazol-4-yl, 1 -(cyclopropylmethyl)- lH-pyrazol-4- yl, l-(l-methylcyclopropyl)-lH-pyrazol-4-yl, 5-fluoro-lH-pyrazol-4-yl, l-(2-phenylpropan- 2-yl)-lH-pyrazol-4-yl, l-(pyridin-3-yl)-lH-pyrazol-4-yl, l-(pyridin-4-yl)-lH-pyrazol-4-yl, 1- (pyridin-2-yl)- 1 H-pyrazol-4-yl, 1 - [ 1 -(N-methylaminocarbonyl)- 1 , 1 -dimethylmethyl] - 1 H- pyrazol-4-yl, 5-fluoro- 1 -isopropyl- lH-pyrazol-4-yl, 1 -(
  • R 3 is pyrazol-4-yl, substituted with R x .
  • R 3 is phenyl, substituted with R x .
  • R x is Ci_ 6 alkyl, that is substituted with one or more groups independently selected from R xa , oxo, halo, -N0 2 , -N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -
  • R x is Ci_6alkyl that is substituted with R xa .
  • R x is C 2 _6alkenyl or C 2 _6alkynyl, wherein any C 2 _6alkenyl and C 2 _ 6 alkynyl is optionally substituted with one or more groups independently selected from R xa , oxo, halo, -N0 2 , -N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -O- C(0)-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -C(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -N(R
  • R x is selected from C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0 2 , -N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , - S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -0-C(0)-0-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , - S(0) 2 -R v , -0-C(0)-N(R v ) 2 , -N(R v )-C(0)-OR v , -N(R v
  • R 3 is heteroaryl that is substituted with oxo, Ci_6alkyl, C 2 _ 6 alkenyl, C 2 _6alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0 2 , - N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -O- C(0)-0-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -0-C(0)-N(R v ) 2 , -N(R v
  • R 3 is a 5-membered heteroaryl that is substituted with oxo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -F, -CI, -Br, -I, -N0 2 , -N(R V ) 2 , -CN, -C(0)-N(R v ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , - 0-C(0)-0-R v , -C(0)-R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -0-C(0)-N(R v ) 2
  • R v , -N(R v )-S(0) 2 -R v , and Ci_ 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo.
  • R 3 is phenyl that is substituted with oxo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, aryl, heteroaryl, heterocycle, -N(R V ) 2 , -CN, -C(O)- N(R V ) 2 , -S(0)-N(R v ) 2 , -S(0) 2 -N(R v ) 2 , -0-R v , -S-R v , -0-C(0)-R v , -0-C(0)-0-R v , -C(O)- R v , -C(0)-0-R v , -S(0)-R v , -S(0) 2 -R v , -0-C(0)-N(R v ) 2 , -N(R v )-C(0)-OR v , -N(R v ) 2
  • R 4 is H, methyl, ethyl, propyl, cyclopropylmethyl, 2- hydroxyethyl, 2-(dimethylmino)ethyl, phenyl, benzyl, or 2-methoxyethyl.
  • R 3 is not phenyl, fluorophenyl, chlorophenyl, pyridyl, nitrophenyl, or propylisoxazole.
  • compositions are provided.
  • compositions comprising a a compound as described herein or a pharmaceutically acceptable salt thereof.
  • the composition further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the composition further comprises an amount of the compound effective to measurably inhibit KDM5.
  • the composition is
  • patient refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.
  • compositions of this invention refers to a nontoxic 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
  • compositions comprising a compound as described herein may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic,
  • the composition comprising a compound as described herein is formulated as a solid dosage form for oral administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the solid oral dosage form comprising a compound as described herein further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or sodium carbonate, (vi) solution retarding agents such as paraffin, (
  • the solid oral dosage form is formulated as capsules, tablets or pills.
  • the solid oral dosage form further comprises buffering agents.
  • such compositions for solid oral dosage forms may be formulated as fillers in soft and hard- filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.
  • compositions comprising a compound as described herein optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • a composition comprises micro-encapsulated compound as described herein, and optionally, further comprises one or more excipients.
  • compositions comprise liquid dosage formulations comprising a compound as described herein for oral administration, and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
  • liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.
  • adjuvant such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic 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, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the absorption of the compound may be desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound as described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.
  • Example dosage forms for topical or transdermal administration of a compound as described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the compound as described herein is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers.
  • Transdermal dosage forms can be made by dissolving or dispensing the compound as described herein in medium, for example ethanol or dimethylsulfoxide.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Nasal aerosol or inhalation formulations of a compound as described herein may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the amount of a compound as described herein in the composition will also depend upon the particular compound in the composition.
  • the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.
  • An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound as described herein, and further comprises about 95-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg
  • the process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound as described herein, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
  • Another aspect includes the use of a compound as described herein for the inhibition of KDM5.
  • Ccompounds as described herein may also be used to inhibit the removal of methyl marks on histone lysine residues, including inhibiting the removal of methyl marks from mono-, di- or tri-methylation of histones HI, H2A, H2B, H3 and H4, such as H3K4 (including for example the KDM5 substrate H3K4me3), thereby altering interactions of these histone proteins with DNA and/or other proteins, and altering certain subsequent genetic or protein expression.
  • Compounds as described herein may also be used to inhibit KDM5 and reduce drug-tolerant cells, thereby treating or preventing drug-resistant diseases, such as drug-resistant cancer.
  • the disease can be treated using a compound as described herein to prevent resistance from forming, for example before targets of chemotherapies become mutated to confer resistance to such chemotherapies.
  • the binding or inhibition activity of a compound as described herein may be determined by running a competition experiment where the is incubated with the KDM5 enzyme bound to known radioligands.
  • Detailed conditions for assaying a compound as an inhibitor of KDM5 or a mutant thereof are set forth in the Examples below.
  • detection of KDM5 activity is achieved with in vitro assays, which can be either direct binding (non-catalytic) or enzymatic (catalytic) asssays.
  • Types of substrates that are used in such assays may include: short synthetic peptides corresponding to a number of residues from the N-terminus of histone sequences comprising the target lysine residue, single recombinant histone polypeptides, histone octamers reconstituted with recombinant histone proteins, and reconstituted nucleosomes (using reconstituted octamers and specific recombinant DNA fragments).
  • the reconstituted nucleosomes may be mononucleosomes or oligonucleosomes.
  • Another aspect includes a method of treating or preventing a disease responsive to the inhibition of KDM5 activity in a patient.
  • the method includes administering a
  • Another aspect includes the use of a compound as described herein, in therapy.
  • Another aspect includes the use of a pharmaceutical composition comprising a compound as described herein, in therapy.
  • Another aspect includes the use of a compound as described herein, in treating a disease associated with KDM5 activity.
  • Another aspect includes the use of a pharmaceutical composition comprising a compound as described herein, in treating a disease associated with KDM5 activity.
  • Another aspect includes the use of a compound as described herein, in the
  • Another aspect includes the use of a pharmaceutical composition comprising a compound as described herein, in the manufacture of a medicament for the treatment of a disease associated with KDM5 activity.
  • the disease or condition is a hyperproliferative disease, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis,
  • treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • Another aspect includes a method for treating, ameliorating or preventing cancer, drug-resistant cancer or another proliferative disorder by administration of an effective amount of a compound as described herein to a mammal, for example a human, in need of such treatment.
  • the disease to be treated is cancer or drug resistant cancer.
  • cancers that may be treated using the compounds and methods described herein include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic
  • hemangioblastoma head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast
  • neurofibroma neuroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,
  • oligodendroglioma oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer,
  • paraganglioma pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor,
  • Another embodiment includes a method for the treatment of benign proliferative disorders.
  • benign proliferative disorders include, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic tumors, dermatofibroma, pilar cyst, pyogenic tumors, dermatofibroma, pilar cyst, pyogenic tumors, dermatofibroma, pilar cyst,
  • Another embodiment includes a therapeutic method useful for modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in diseases mentioned above, in particular cancer, comprising administering to a patient in need of such therapy a pharmacologically active and therapeutically effective amount of one or more of the compounds as described herein.
  • Another embodiment includes a method for regulating endogenous or heterologous promotor activity by contacting a cell with a compound as described herein.
  • Another embodiment includes the use of a compound as described herein for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis and/or amelioration of the diseases, disorders, illnesses and/or conditions as mentioned herein.
  • Another embodiment includes the use of a compound as described herein for the production of pharmaceutical compositions which are employed for the treatment and/or prophylaxis of diseases and/or disorders responsive or sensitive to the inhibition of histone demethylases, particularly those diseases mentioned above, such as e.g. cancer.
  • Compounds as described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder.
  • the exact amount required will vary from patient to patient, depending on the species, age, and general condition of the patient, for example the severity of the disorder, the particular compound, its mode of administration, and the like.
  • the total daily usage of a compound as described herein by a given patient will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • Another embodiment includes a method of inhibiting KDM5 activity in a biological sample comprising contacting said biological sample with a compound as described herein.
  • biological sample includes, without limitation, a cell, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • the compound as described herein may be employed alone or in combination with other agents for treatment.
  • the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound as described herein such that they do not adversely affect each other.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately.
  • a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.
  • co-administering refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are
  • the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • any agent that has activity against a disease or condition being treated may be co-administered.
  • agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.
  • the treatment method includes the co-administration of a compound as described herein and at least one cytotoxic agent.
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive . , , . ,21 1 ⁇ 131 ⁇ 125 ⁇ 90 D 186 D 188 c 153 radical radical.212 ⁇ 32 ⁇ , 212 , , .
  • isotopes e.g., At , I , I , ⁇ , Re , Re , Sm , ⁇ , ⁇ , Pb and radioactive isotopes of Lu
  • chemotherapeutic agents e.g., At , I , I , ⁇ , Re , Re , Sm , ⁇ , ⁇ , Pb and radioactive isotopes of Lu
  • chemotherapeutic agents e.g., At , I , I , ⁇ , Re , Re , Sm , ⁇ , ⁇ , Pb and radioactive isotopes of Lu
  • growth inhibitory agents e.g., enzymes and fragments thereof such as nucleolytic enzymes
  • toxins such as small molecule toxins or
  • enzymatically active toxins of bacterial, fungal, plant or animal origin including fragments and/or variants thereof.
  • Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, nhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
  • “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA ® , Genentech/OSI Pharm.), bortezomib (VELCADE ® , Millennium Pharm.), disulfiram , epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ® , AstraZeneca), sunitib (SUTENT ® , Pfizer/Sugen), letrozole (FEMARA ® , Novartis), imatinib mesylate (GLEEVEC ® ., Novartis), finasunate (VATALANIB ® , Novartis), oxaliplatin (ELOXATIN ® , Sanofi), 5-FU (5-
  • alkylating agents such as thiotepa and CYTOXAN ® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine;
  • acetogenins especially bullatacin and bullatacinone
  • a camptothecin including topotecan and irinotecan
  • bryostatin callystatin
  • CC-1065 including its adozelesin, carzelesin and bizelesin synthetic analogs
  • cryptophycins particularly cryptophycin 1 and cryptophycin 8
  • adrenocorticosteroids including prednisone and prednisolone
  • cyproterone acetate 5a- reductases including finasteride and dutasteride
  • vorinostat romidepsin, panobinostat, valproic acid, mocetinostat dolastatin
  • aldesleukin, talc duocarmycin including the synthetic analogs, KW-2189 and CB1-TM1
  • pancratistatin a sarcodictyin
  • spongistatin nitrogen mustards such as chloride
  • novembichin novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin ⁇ and calicheamicin coll (Angew Chem. Intl. Ed. Engl. 1994 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as
  • neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puro
  • methotrexate, pteropterin, trimetrexate purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti- adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;
  • amsacrine bestrabucil
  • bisantrene edatraxate
  • defofamine demecolcine
  • diaziquone diaziquone
  • elfomithine elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
  • lentinan lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK ® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine;
  • NAVELBINE ® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA ® ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
  • DMFO difluoromethylornithine
  • retinoids such as retinoic acid
  • pharmaceutically acceptable salts, acids and derivatives of any of the above DMFO
  • DMFO difluoromethylornithine
  • Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ® ;
  • SERMs selective estrogen receptor modulators
  • aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE ® (megestrol acetate), AROMASIN ® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR ® (vorozole), FEMARA ® (letrozole; Novartis), and ARIMIDEX ® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, le
  • troxacitabine a 1,3-dioxolane nucleoside cytosine analog
  • protein kinase inhibitors kinase inhibitors
  • lipid kinase inhibitors antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras
  • ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME ® ) and HER2 expression inhibitors
  • vaccines such as gene therapy vaccines, for example, ALLOVECTIN ® , LEUVECTIN ® , and VAXID ® ; PROLEUKIN ® , rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN ® ; ABARELIX ® rmR
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen poutuzumab
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, n
  • Chemotherapeutic agent also includes "EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al) and variants thereof, such as chimerized 225 (C225 or Cetuximab;
  • ERBUTIX ® reshaped human 225
  • H225 human 225
  • IMC-11F8 a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900
  • EMD7200 a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding
  • human EGFR antibody HuMax-EGFR (GenMab)
  • Fully human antibodies known as El .l, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem. 279(29):30375-30384 (2004)).
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g.,
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451,
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA ® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fiuorophenyl)amino]-7-[3-(4- morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD 1839, gefitinib (IRES S A®) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (CP-358774, erlotinib, TARCEVA ® Genentech/OSI Pharmaceuticals
  • Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the
  • EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan- HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non- HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®,
  • PTK787/ZK222584 available from Novartis/Schering AG
  • MAPK extracellular regulated kinase I inhibitor CI-1040 available from Pharmacia
  • quinazolines such as PD 153035,4- (3-chloroanilino) quinazoline
  • pyridopyrimidines such as PD 153035,4- (3-chloroanilino) quinazoline
  • pyridopyrimidines such as pyrimidopyrimidines
  • pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706
  • pyrazolopyrimidines 4-(phenylamino)-7H- pyrrolo[2,3-d] pyrimidines
  • curcumin diiferuloyl methane, 4,5-bis (4- fluoroanilino)phthalimide
  • tyrphostines containing nitrothiophene moieties PD-018380
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone- 17-valerate,
  • betamethasone valerate betamethasone dipropionate
  • ImSAIDs immune selective anti-inflammatory peptides
  • FEG phenylalanine-glutamine-glycine
  • feG D-isomeric form
  • anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, lefiunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNF ) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia
  • Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal/p2 blockers such as Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341 , phenylbutyrate, ET-18- OCH 3 , or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate
  • Targetedron® bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate
  • SKELID® or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifarnib (Rl 1577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone;
  • COX-2 inhibitor e.g. celecoxib or etoricoxib
  • proteosome inhibitor e.g. PS341
  • CCI-779 e.g. tipifarnib (Rl 1577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone;
  • farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and
  • CHOP an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • Chemotherapeutic agents also include non-steroidal anti-inflammatory drugswith analgesic, antipyretic and anti-inflammatory effects.
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumirac
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to- moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to- moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
  • agents for treating multiple sclerosis such as beta interferon (e.g., Avonex ® and Rebif ® ), glatiramer acetate, and mitoxantrone
  • treatments for asthma such as albuterol and montelukast sodium
  • agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol
  • anti-inflammatory agents such as
  • corticosteroids corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine
  • immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine
  • neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and antiparkinsonian agents
  • agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins
  • agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents
  • chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.
  • compositions of this invention are formulated such that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive can be administered.
  • the additional therapeutic agent and the compound as described herein may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or there may be fewer side effects for the patient given that a lower dose is used. In certain embodiments, in such compositions a dosage of between 0.01 - 1 ,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • a method of treating or preventing drug resistant cancer in a patient comprises administering a therapeutically effective amount of a compound as described herein to the patient alone or in combination with a cytotoxic agent.
  • the individual is selected for treatment with a cytotoxic agent (e.g. , targeted therapies, chemotherapies, and/or radiotherapies).
  • the individual starts treatment comprising administration of a compound as described herein prior to treatment with the cytotoxic agent.
  • the individual concurrently receives treatment comprising the compound as described herein and the cytotoxic agent.
  • the compound as described herein increases the period of cancer sensitivity and/or delays development of cancer resistance.
  • a compound as described herein comprising administering to the individual (a) a compound as described herein and (b) a cytotoxic agent (e.g. , targeted therapy, chemotherapy, and/or radiotherapy).
  • a cytotoxic agent e.g. , targeted therapy, chemotherapy, and/or radiotherapy.
  • the respective amounts of the compound as described herein and the cytotoxic agent are effective to increase the period of cancer sensitivity and/or delay the development of cancer cell resistance to the cancer therapy agent.
  • the respective amounts of the compound as described herein and the cytotoxic agent are effective to increase efficacy of a cancer treatment comprising the cancer therapy agent.
  • the respective amounts of the compound as described herein and the cytotoxic agent are effective to increase efficacy compared to a treatment (e.g., standard of care treatment) (e.g., standard of care treatment) comprising administering an effective amount of the cancer therapy agent without (in the absence of) the compound as described herein.
  • a treatment e.g., standard of care treatment
  • the respective amounts of the compound as described herein and cytotoxic agent agent are effective to increase response (e.g., complete response) compared to a treatment (e.g., standard of care treatment) comprising administering an effective amount of cytotoxic agent without (in the absence of) the compound as described herein.
  • cancer treatment comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of a cytotoxic agent, wherein the cancer treatment has increased efficacy compared to a treatment (e.g., standard of care treatment) comprising administering an effective amount of cytotoxic agent without (in the absence of) the compound as described herein.
  • a treatment e.g., standard of care treatment
  • kits for delaying and/or preventing development of cancer resistant to a cancer therapy agent in an individual comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.
  • kits for increasing sensitivity to a cancer therapy agent in an individual with cancer comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.
  • kits for extending the period of a cancer therapy agent sensitivity in an individual with cancer comprising administering to the individual (a) an effective amount of a compound as described herein and (b) an effective amount of the cytotoxic agent.
  • cytotoxic agent is a targeted therapy.
  • the targeted therapy is one or more of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.
  • the targeted therapy is an EGFR antagonist.
  • the EGFR antagonist is N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or a pharmaceutical acceptable salt thereof.
  • the EGFR antagonist is N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)-4-quinazolinamine.
  • the EGFR antagonist is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2- (methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4- methylbenzenesulfonate or a pharmaceutically acceptable salt thereof (e.g. , lapatinib).
  • targeted therapy is a RAF inhibitor.
  • the RAF inhibitor is a BRAF inhibitor.
  • the RAF inhibitor is a CRAF inhibitor.
  • the BRAF inhibitor is
  • the RAF inhibitor is 3-(2-cyanopropan-2-yl)-N-(4- methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide or a pharmaceutically acceptable salt thereof (e.g. , AZ628 (CAS# 878739-06-1)).
  • the targeted therapy is a PI3K inhibitor.
  • the cytotoxic agent is chemotherapy.
  • the chemotherapy is a taxane.
  • the taxane is paclitaxel.
  • the taxane is docetaxel.
  • the cytotoxic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments of any of the methods, the cytotoxic agent is a taxane and a platinum agent. In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is docetaxel. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin.
  • the cytotoxic agent is a vinca alkyloid. In certain embodiments, the vinca alkyloid is vinorelbine. In certain embodiments of any of the methods, the chemotherapy is a nucleoside analog. In certain embodiments, the
  • nucleoside analog is gemcitabine.
  • the cytotoxic agent is radiotherapy.
  • the compound as described herein is concomitantly administered with the cytotoxic agent (e.g. , targeted therapy, chemotherapy, and/or radiotherapy).
  • the compound as described herein is
  • cytotoxic agent e.g. , targeted therapy, chemotherapy, and/or radiotherapy.
  • the cancer is lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and/or melanoma.
  • the cancer is lung.
  • the lung cancer is NSCLC.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds, the following general methods, and other methods known to one of ordinary skill in the art, can typically be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • chloride 5 could also be coupled with an amine to give compound 11.
  • the chloride in compound 5 could be further transformed to bromide 12, in the presence of TMSBr. Subsequent coupling reaction of bromide 12 with an alcohol provided compound 13.
  • Example 3 In a similar procedure as shown in Example 1 , the title compound was prepared in 36% yield from 5-amino-lH-pyrazole-4-carbonitrile and diethyl 2-ethylmalonate.
  • Example 3 Example 3
  • reaction mixture was heated at 110 °C for 30 min under microwave condition. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 50-100% EtOAc in hexanes to give crude product which was further purified by rpHPLC (Gemini C 18 150 x 25 mm x 10 urn, 35-65% MeCN/H 2 0) to give the desired product (62 mg, 30% yield) as a white solid.
  • reaction mixture was heated at 1 10 °C for 30 min under microwave condiction. After being cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-3% MeOH in DCM to provide the desired prouct (220 mg crude) as a brown solid.
  • LCMS m/z 417.0 [M+H] + .
  • 6-Isopropyl-7-oxo-5-(l-(pyridin-2-yl)-lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l,5- o]pyrimidine-3-carbonitrile To a solution of 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l ,5- fl]pyrimidine-3-carbonitrile (200 mg, 0.75 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 90 mg, 2.25 mmol) in DMF (5 mL) at 0 °C under N 2 .
  • reaction mixture was heated at 110 °C for 16 hours. After being cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-3% MeOH in DCM to provide the crude product which was re-crystallizated from TBME/MeOH (5/1, 20 mL) to give the desired product (760 mg, 44% yield) as a brown solid.
  • Example 3 In a similar procedure as shown in Example 3, the title compound was prepared in 14% yield from 6-isopropyl-7-oxo-5-(lH-pyrazol-4-yl)-4,7-dihydropyrazolo[l ,5-a]pyrimidine-3- carbonitrile and 5-fluoro- 1 -isopropyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ⁇ - pyrazole as an off white solid.
  • 6-isopro yl-7-oxo-5-phenethyl-4,7-dihydro yrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 2-isopropyl-3-oxo-5-phenylpentanoate (700 mg, 2.67 mmol) and 3- amino-lH-pyrazole-4-carbonitrile (433 mg, 4 mmol) in toluene (7 mL) was added titanium tetrachloride (0.2 mL, 1.6 mmol) via syringe under N 2 atmosphere and then heated to 80 °C for 16 hours.
  • 6-ethyl-5-(lH-imidazol-2-yl)-7-oxo-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile To the suspension of 6-ethyl-5-formyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (54 mg, 0.25 mmol,), NH 4 OH (28 % in water, 228 mg, 3.75 mmol) and water (0.25 mL) was added glyoxal (40 % in water, 181 mg, 1.25 mmol). The mixture was stirred at room temperature for 16 hours.
  • 6-Cyclobutyl-7-oxo-5-phenyl-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile To a solution of ethyl 3-oxo-3-phenyl-propanoate (1.00 g, 5.2 mmol) and cyclobutanone (0.44 g, 6.2 mmol) in 2-MeTHF (50 mL) was added titanium(IV) chloride (11.0 mL 1M in DCM, 11 mmol), followed by pyridine (2.1 mL, 26 mmol). The resulting suspension was stirred at room temperature for 20 hours.
  • 6-isopropyl-7-oxo-5-(phenylamino)-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile The mixture of 5-chloro-6-isopropyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (60 mg, 0.253 mmol), aniline (71 mg, 0.76 mmol), BrettPhos (14 mg, 0.025 mmol), BrettPhos Pre-catalyst (20 mg, 0.025 mmol), and iBuONa (75 mg, 0.76 mmol) in 1,4-dioxane (2 mL) was purged with N 2 for 2 min, then heated at 140 °C in a microwave reactor for 20 min.
  • 6-isopropyl-7-oxo-5-phenoxy-4,7-dihydropyrazolo[l,5-a]pyrimidine-3-carbonitrile The mixture of 5-bromo-6-isopropyl-7-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carbonitrile (80 mg, 0.28 mmol), phenol (81 mg, 0.85 mmol), Cul (5 mg, 0.028 mmol), trans-N,N'- dimethylcyclohexane-l,2-diamine (8 mg, 0.056 mmol), and K 3 PO 4 (187 mg, 0.85 mmol) in DMSO (2 mL) was purged with N 2 for 2 min, then heated at 150 °C in a microwave reactor for 20 min.
  • KDM5A demethylase assay (MassSpec assay - A)
  • Full length recombinant Flag tagged KDM5A protein is purified from Sf9 insect cells.
  • the demethylation reaction buffer containes 50 mM TrisCl pH 7.4, 0.01% Triton X-100, 0.025 mg/mL BSA, 1 mM ascorbate (Cat# A4034, Sigma Aldrich), 2 mM TCEP (Cat# D9779, Sigma Aldrich), 2.0 ⁇ ⁇ -ketoglutarate (# K2010, Sigma Aldrich) and 50 ⁇ Fe 2 (NH 4 ) 2 (S0 4 ) 2 (Cat# F1543, Sigma Aldrich).
  • H3K9mel peptide (1-21 aa) , and Fe 2 (NH 4 ) 2 (S0 4 ) 2 are added to initiate the reaction. (All reagent concentrations are final reagent concentrations.) Reactions are incubated for 30 minutes at room temperature, and then quenched by addition of an equal volume of 1% formic acid. After termination, plates are sealed and frozen at -80 °C for analysis.
  • Full length recombinant Flag tagged KDM5A protein is purified from Sf9 insect cells.
  • the demethylation reaction buffer containes 50 mM TrisCl pH 7.4, 0.01% Triton X-100, 0.025 mg/mL BSA, 1 mM ascorbate, 2 mM TCEP, 3.0 ⁇ ⁇ -ketoglutarate, and 50 ⁇
  • Reactions are incubated for 25 minutes at room temperature, and then quenched by addition of 5 uL of detection reagents (buffer as above with addition of 0.3 mM EDTA, 150 mM NaCl, 150 uM SA-SurelightAPC and 1.5 uM Eu(W1024)-K3K4Mel/2 antibody (TR-FRET reagents both Perkin-Elmer)). After a one hour incubation assays are read on a Perkin-Elmer Envision equipped with a laser source and appropriate filters. IC50S are calculated using standard dose-response equations and relative to a Max (no inhibition) and Min (no enzyme or quenched enzyme) controls.
  • the demethylation reaction buffer contained 50 mM HEPES pH 7.0, 0.01% Triton X-100, 0.5 mM ascorbate, 2 mM DTT, 1 ⁇ ⁇ -ketoglutarate, and 100 ⁇ Fe2(NH 4 )2(S0 4 )2.
  • Reactions are incubated for 30 minutes at room temperature, and then quenched by addition of 5uL stop buffer (3mM EDTA, 50 mM TrisCl pH 7.5, 0.01% Triton X-100, 0.01 mg/mL BSA) followed by addition of 5 uL of detection reagents (buffer as above without EDTA but with addition of 200 nM SA-XL665 (CisBio) and 2 nM Eu(W1024)-anti-H3K4Mel-2 antibody (PerkinElmer)). After a 30 minute incubation assays are read on a Perkin-Elmer Envision equipped with appropriate filters. IC50S are calculated using standard dose-response equations and relative to a Max (no inhibition) and Min (no enzyme or quenched enzyme) controls.
  • 5uL stop buffer 3mM EDTA, 50 mM TrisCl pH 7.5, 0.01% Triton X-100, 0.01 mg/mL BSA
  • Biotin-H3 4me3 peptide was purchased from New England Biolabs.
  • HTRF reagents containing Eu-labeied H3 4mel-2 antibody, and streptavidin-XL665) were purchased from Cis-Bio International. Plates were read on an Envision multi-label plate reader (Perkin Elmer).
  • the HTRF assay mixture contained 2 nM full length KDM5A enzyme, 100 nM H3K4Me3 peptide substrate, 1 uM 2-OG, 100 uM Fe 2+ , 500 uM ascorbate. 50 mM HEPES pH 7.0 buffer, 0.01% Triton - X 100, 2 mM DTT, 0.25 % DMSO at a final volume of 10 uL.
  • the enzyme reaction was earned out at room temperature in black Proxiplate 384-Plus plate (Corning, Costar) within 30 minutes, in the presence of varying concentration of a test compound.
  • PC9 cells were seeded in a 384 well plate (2000 cells/well) with a test compound and incubated for 120 hours at 37 °C. H3K4Me3 mark level was assessed using A lpha ! .ISA reagents from Perkin Elmer. Briefly, cells were lysed in 5 xL of Histone cell lysis buffer for 30 min on ice. Then histories were extracted by addition of 10 ⁇ of Histone extraction buffer to each well for 20 minutes. 10 ⁇ , of acceptor beads and 10 ⁇ , of donor beads were added sequentially one hour apart, and the mixture was incubated at 26 °C for 30 minutes. Assay plate was read subsequently on Envision (Perkin Elmer), Each compound was mn in duplicate. Data were normalized to DMSO treated wells as the low response and ECso's were calculate using a four-parameter fit. Data for the compounds of Examples 1-432 from the assays described in Examples 434 and 435 is provided in the following table.

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Abstract

La présente invention concerne des composés utiles en tant qu'inhibiteurs d'une ou de plusieurs histones déméthylases, tel que KDM5. L'invention concerne également des compositions pharmaceutiquement acceptables comprenant les composés de la présente invention, ainsi que des méthodes d'utilisation desdites compositions dans le traitement de divers troubles.
PCT/CN2014/000261 2014-03-13 2014-03-13 Composés thérapeutiques et leurs utilisations WO2015135094A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3525786A4 (fr) * 2016-10-12 2020-03-18 Merck Sharp & Dohme Corp. Inhibiteurs de kdm5
EP3525785A4 (fr) * 2016-10-12 2020-03-25 Merck Sharp & Dohme Corp. Inhibiteurs de kdm5
US10738056B2 (en) 2017-09-15 2020-08-11 Aduro Biotech Inc. Pyrazolopyrimidinone compounds and uses thereof
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11512097B2 (en) 2019-11-25 2022-11-29 Amgen Inc. Heterocyclic compounds as Delta-5 desaturase inhibitors and methods of use
WO2024100236A1 (fr) 2022-11-11 2024-05-16 Astrazeneca Ab Polythérapies pour le traitement du cancer

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005008581A (ja) * 2003-06-20 2005-01-13 Kissei Pharmaceut Co Ltd 新規なピラゾロ［１，５−ａ］ピリミジン誘導体、それを含有する医薬組成物およびそれらの用途
WO2007044410A1 (fr) * 2005-10-06 2007-04-19 Schering Corporation Pyrazolo[1,5-a]pyrimidines servant d'inhibiteurs de protéines kinases
WO2014066795A1 (fr) * 2012-10-25 2014-05-01 Bioenergenix Composés hétérocycliques pour l'inhibition de pask

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005008581A (ja) * 2003-06-20 2005-01-13 Kissei Pharmaceut Co Ltd 新規なピラゾロ［１，５−ａ］ピリミジン誘導体、それを含有する医薬組成物およびそれらの用途
WO2007044410A1 (fr) * 2005-10-06 2007-04-19 Schering Corporation Pyrazolo[1,5-a]pyrimidines servant d'inhibiteurs de protéines kinases
WO2014066795A1 (fr) * 2012-10-25 2014-05-01 Bioenergenix Composés hétérocycliques pour l'inhibition de pask

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3525786A4 (fr) * 2016-10-12 2020-03-18 Merck Sharp & Dohme Corp. Inhibiteurs de kdm5
EP3525785A4 (fr) * 2016-10-12 2020-03-25 Merck Sharp & Dohme Corp. Inhibiteurs de kdm5
US10975084B2 (en) 2016-10-12 2021-04-13 Merck Sharp & Dohme Corp. KDM5 inhibitors
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US10738056B2 (en) 2017-09-15 2020-08-11 Aduro Biotech Inc. Pyrazolopyrimidinone compounds and uses thereof
US11512097B2 (en) 2019-11-25 2022-11-29 Amgen Inc. Heterocyclic compounds as Delta-5 desaturase inhibitors and methods of use
WO2024100236A1 (fr) 2022-11-11 2024-05-16 Astrazeneca Ab Polythérapies pour le traitement du cancer

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