EP4337216A1 - Multithérapies - Google Patents

Multithérapies

Info

Publication number
EP4337216A1
EP4337216A1 EP22725158.4A EP22725158A EP4337216A1 EP 4337216 A1 EP4337216 A1 EP 4337216A1 EP 22725158 A EP22725158 A EP 22725158A EP 4337216 A1 EP4337216 A1 EP 4337216A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
compound
group
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22725158.4A
Other languages
German (de)
English (en)
Inventor
Nikki DASKALAKIS
Christina Diane GUTTKE
Min Chul Kwon
Lucille Angela FERRANTE
Kathryn Elizabeth Packman
Eva Christine PIETSCH
Ulrike Philippar
Tinne Ann J VERHULST
Balpreet BHOGAL
Yu Sun
Wei Cai
Xuedong Dai
Olivier Alexis Georges Querolle
Johannes Wilhelmus J. Thuring
Yingtao LIU
Lianzhu LIU
Yanping Xu
Liqiang Fu
Ming Li
Lichao FANG
Xiangjun DENG
Alicia Tee Fuay Ng
Nicolas Freddy J DARVILLE
Vineet PANDE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of EP4337216A1 publication Critical patent/EP4337216A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to novel combinations comprising a therapeutically effective amount of a menin-mixed-lineage leukemia 1 (menin-MLL) inhibitor of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof; and a therapeutically effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor; and optionally, a therapeutically effective amount of at least one other antineoplastic agent; as well as to methods for treating a subject who has been diagnosed with a hematopoietic disorder.
  • menin-MLL menin-mixed-lineage leukemia 1
  • BCL-2 B-cell lymphoma 2
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALL acute lymphoblastic leukemia
  • AML is a common hematological malignancy whose incidence rises from 3: 100,000 in young adults to greater than 20: 100,000 in older adults.
  • OS overall survival
  • OS overall survival
  • the majority of newly diagnosed patients with AML are over the age of 60.
  • standard induction chemotherapy is often not an option due to increased treatment-related mortality as a result of age and co-morbidities.
  • Standard of care for AML patients unfit for combination chemotherapy is treatment with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine. Despite these frontline treatments, median OS is only about 10 months.
  • ALL is a hematologic malignancy propagated by impaired differentiation, proliferation, and accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites.
  • ALL represents 12%of all leukemia cases and is the most common childhood acute leukemia, with a worldwide incidence projected to be 1 to 4.75 per 100,000 people.
  • ALL represents about 20%of adult leukemias.
  • CR complete remission
  • Embodiments of the present invention relate to novel combinations of a menin-MLL inhibitor of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof; and a BCL-2 inhibitor; and optionally, at least one other antineoplastic agent.
  • Embodiments of the present invention relate to uses of such combinations for treating a subject who has been diagnosed with a hematopoietic disorder, including but not limited to, blood cancers, using a menin-MLL inhibitor described herein in combination with a BCL-2 inhibitor; and optionally, at least one other antineoplastic agent.
  • a hematopoietic disorder including but not limited to, blood cancers, using a menin-MLL inhibitor described herein in combination with a BCL-2 inhibitor; and optionally, at least one other antineoplastic agent.
  • Embodiments of the present invention relate to novel methods for treating a subject who has been diagnosed with a hematopoietic disorder using such combinations.
  • Embodiments of the novel methods comprise administering to the subject a therapeutically effective amount of a menin-MLL inhibitor as described herein; and a therapeutically effective amount of a BCL-2 inhibitor; and optionally, a therapeutically effective amount of at least one other antineoplastic agent; wherein the menin-MLL inhibitor is a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof.
  • Embodiments of the present invention relate to novel methods for treating a subject who has been diagnosed with a hematopoietic disorder using such combinations.
  • Embodiments of the novel methods comprise administering to the subject a therapeutically effective amount of a menin-MLL inhibitor as described herein; and a therapeutically effective amount of a BCL-2 inhibitor, and a therapeutically effective amount of at least one other antineoplastic agent; wherein the menin-MLL inhibitor is a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention is directed to methods for treating a subject who has been diagnosed with a hematopoietic disorder, the methods comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof; and a therapeutically effective amount of venetoclax, or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt or solvate thereof.
  • a menin-MLL inhibitor of Formula (I) or a pharmaceutically acceptable salt or a solvate thereof
  • venetoclax or a pharmaceutically acceptable salt or solvate thereof
  • azacitidine or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention is directed to methods for treating a subject who has been diagnosed with a hematopoietic disorder, the methods comprising administering to the subject a therapeutically effective amount of a menin-MLL inhibitor of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof; a therapeutically effective amount of venetoclax, or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt or solvate thereof; wherein the venetoclax, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject prior to, simultaneous with, or after the administration of the menin-MLL inhibitor; and wherein the azacitidine, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject prior to, simultaneous with, or after the administration of the menin-MLL inhibitor.
  • a menin-MLL inhibitor of Formula (I) or a pharmaceutically acceptable salt or a solvate thereof
  • the menin-MLL inhibitor of Formula (I) is:
  • Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
  • 5-or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 3-6 cycloalkyl and C 1-4 alkyl;
  • R xa and R xb are each independently selected from the group consisting of hydrogen, C 1- 4 alkyl and C 3-6 cycloalkyl;
  • R 1b represents F or Cl
  • Y 1 represents -CR 5a R 5b -, -O-or -NR 5c -;
  • R 2 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, -O-C 1-4 alkyl, and -NR 7a R 7b ;
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 5a , R 5b , R 5c , R 7a , and R 7b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a , and R 12b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide besylate salt (benzenesulfonate salt) :
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide besylate salt or hydrates thereof.
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt or solvates thereof.
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt or hydrates thereof.
  • the present invention is directed to (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt 0.5-2.0 equivalents hydrate.
  • the present invention is directed to (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt 2.0 equivalents hydrate.
  • the menin-MLL inhibitor of Formula (I) is a crystalline form A of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt hydrate.
  • the menin-MLL inhibitor of Formula (I) is a crystalline form A of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt 0.5-2.0 equivalents hydrate.
  • the present invention is directed to a crystalline form A of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt 2.0 equivalents hydrate.
  • FIG. 1 is an X-ray powder diffraction (XRPD) pattern of Compound A4: a crystalline form A of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt hydrate.
  • XRPD X-ray powder diffraction
  • FIG. 2 depicts a comparison of tumor volumes as a function of time for the control group and for the treatment groups treated with a regimen comprising various amounts of Compound A3.
  • FIG. 3 depicts a comparison of tumor percent survival as a function of time (e.g., Kaplan-Meier survival curves) for the control group and for the treatment groups treated with a regimen comprising various amounts of Compound A3.
  • Kaplan-Meier survival curves e.g., Kaplan-Meier survival curves
  • FIG. 4A depicts a comparison of percent survival as a function of time of mice bearing established OCI-AML3 tumors following treatment with vehicle, monotherapy with either venetoclax, azacitidine or Compound A1, the doublet combination of either venetoclax and azacitidine, or Compound A1 and venetoclax, or the triplet combination of Compound A1, venetoclax and azacitidine.
  • FIG. 4B depicts a comparison of percent survival as a function of time of mice bearing established MOLM-13 tumors following treatment with vehicle, monotherapy with either venetoclax, azacitidine or Compound A1, the doublet combination of either venetoclax and azacitidine, or Compound A1 and venetoclax, or the triplet combination of Compound A1, venetoclax and azacitidine.
  • FIG. 5A is a contour plot for maxR which illustrates the effect of Compound A3 in combination with venetoclax on proliferation of MOLM-13 cells in vitro.
  • FIG. 5B is a contour plot for maxR which illustrates the effect of Compound A3 in combination with azacitidine and venetoclax on proliferation of MOLM-13 cells in vitro.
  • FIG. 6A is a contour plot for maxR which illustrates the effect of Compound A4 in combination with decitabine on proliferation of MOLM-13 cells in vitro.
  • FIG. 6B is a contour plot for maxR which illustrates the effect of Compound A4 in combination with decitabine and venetoclax on proliferation of MOLM-13 cells in vitro.
  • FIG. 7A is a contour plot for maxR which illustrates the effect of Compound A4 in combination with decitabine on proliferation of OCI-AML3 cells in vitro.
  • FIG. 7B is a contour plot for maxR which illustrates the effect of Compound A4 in combination with decitabine and venetoclax on proliferation of OCI-AML3 cells in vitro.
  • halo or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo.
  • C x-y refers to the number of carbon atoms in a given group.
  • a C 1-6 alkyl group contains from 1 to 6 carbon atoms, and so on.
  • C 1-4 alkyl as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
  • C 1-6 alkyl as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like.
  • C 3-6 cycloalkyl as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • An example of such a group is -CR 5a R 5b -.
  • Non-limiting examples of ‘monocyclic 5-or 6-membered aromatic rings containing one, two or three nitrogen atoms and optionally a carbonyl moiety’ include, but are not limited to pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1, 2-dihydro-2-oxo-4-pyridinyl.
  • a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and a carbonyl moiety includes, but is not limited to
  • each definition is independent.
  • substituted in general, whenever the term ‘substituted’ is used in the present invention, it is meant, unless otherwise indicated or clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using ‘substituted’ are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (isolation after a reaction e.g., purification by silica gel chromatography) .
  • the number of substituents is one.
  • Solid compound is in this context meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (isolation after a reaction e.g., purification by silica gel chromatography) .
  • substituents When two or more substituents are present on a moiety they may, where possible and unless otherwise indicated or clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.
  • saturated means ‘fully saturated’ , if not otherwise specified.
  • aromatic rings groups can be attached to the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked) .
  • aromatic rings groups may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to the embodiments.
  • subject refers to an animal, preferably a mammal (e.g., cat, dog, primate or human) , more preferably a human, who is or has been the object of treatment, observation or experiment.
  • a mammal e.g., cat, dog, primate or human
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product including the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • treatment and “treating, ” as used herein, are intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disorder, or amelioration of one or more symptoms thereof, but does not necessarily indicate a total elimination of all symptoms.
  • stereoisomers , “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
  • the invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • a 1: 1 mixture of a pair of enantiomers is a racemate or racemic mixture.
  • Atropisomers are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.
  • Diastereomers are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.
  • Substituents on bivalent cyclic saturated or partially saturated radicals may have either the cis-or trans-configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.
  • the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • stereoisomer is substantially free, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2%and most preferably less than 1%, of the other stereoisomers.
  • a compound of Formula (I) is for instance specified as (R)
  • a compound of Formula (I) is for instance specified as E
  • this means that the compound is substantially free of the Z isomer
  • a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate base or acid, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g., in vacuo, by freeze-drying or by filtration) .
  • Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • the pharmaceutically acceptable salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base salt forms which the compounds of Formula (I) and solvates thereof, are able to form.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e., ethanedioic) , malonic, succinic (i.e., butanedioic acid) , maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • said salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g., the lithium, sodium, potassium, cesium, magnesium, calcium salts and the like, salts with organic bases, e.g., primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, ly
  • prodrug includes any compound that, following oral or parenteral administration, in particular oral administration, is metabolised in vivo to a (more) active form in an experimentally-detectable amount, and within a predetermined time (e.g., within a dosing interval of between 0.5 and 24 hours, or e.g., within a dosing interval of between 6 and 24 hours (i.e., once to four times daily) ) .
  • parenteral administration includes all forms of administration other than oral administration, in particular intravenous (IV) , intramuscular (IM) , and subcutaneous (SC) injection.
  • Prodrugs may be prepared by modifying functional groups present on a compound in such a way that the modifications are cleaved in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • prodrugs include compounds wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g., in Bundegaard, H. “Design of Prodrugs” p. l-92, Elesevier, New York-Oxford (1985) .
  • solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form.
  • solvent addition forms are e.g., hydrates, alcoholates and the like.
  • the compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures.
  • a manner of separating the enantiomeric forms of the compounds of Formula (I) , and pharmaceutically acceptable salts, and solvates thereof involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • enantiomerically pure means that the product contains at least 80%by weight of one enantiomer and 20%by weight or less of the other enantiomer. Preferably the product contains at least 90%by weight of one enantiomer and 10%by weight or less of the other enantiomer. In the most preferred embodiment the term “enantiomerically pure” means that the composition contains at least 99%by weight of one enantiomer and 1%or less of the other enantiomer.
  • the present invention also embraces isotopically-labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature) .
  • isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the isotope is selected from the group of 2 H, 3 H, 11 C, 13 C and 18 F.
  • the isotope is selected from the group of 2 H, 3 H, 11 C and 18 F. More preferably, the isotope is 2 H, 3 H or 13 C. More preferably, the isotope is 2 H or 13 C. More preferably, the isotope is 2 H.
  • deuterated compounds and 13 C-enriched compounds are intended to be included within the scope of the present invention. In particular, deuterated compounds are intended to be included within the scope of the present invention.
  • Certain isotopically-labeled compounds may be useful for example in substrate tissue distribution assays.
  • Tritiated ( 3 H) and carbon-l4 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies.
  • PET imaging in cancer finds utility in helping locate and identify tumors, stage the disease and determine suitable treatment.
  • Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets.
  • Radiolabelled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57 (37) , 4119-4127) .
  • target-specific PET radiotracers may be used as biomarkers to examine and evaluate pathology, by for example, measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016) , doi: 10.1016/j. canlet. 2016.05.008) .
  • Solid oral dosage forms such as, tablets or capsules, containing one or more compounds described herein may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • Additional oral forms in which the compounds described herein may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
  • one or more compounds described herein can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • inhalation intratracheal or intranasal
  • a suppository or pessary or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • An alternative means of administration includes transdermal administration by using a skin or transdermal patch.
  • compositions used in the methods of the present invention can also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally.
  • the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
  • compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
  • compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
  • compositions containing a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof, and a BCL-2 inhibitor and optionally, at least one other antineoplastic agent as an active ingredient can be prepared by mixing the compound (s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable diluent
  • diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc. ) .
  • suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations also may be optionally coated with substances such as, sugars, or be enterically coated so as to modulate the major site of absorption and disintegration.
  • the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives such as, solubilizers and preservatives.
  • methods using a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof, and a BCL-2 inhibitor and optionally, at least one other antineoplastic agent may comprise a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about (4x) per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof, and a BCL-2 inhibitor and optionally, at least one other antineoplastic agent, will vary as will the diseases, syndromes, conditions, and disorders being treated.
  • An embodiment of the present invention is directed to methods of using pharmaceutical compositions for oral administration, comprising a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof in an amount of from about 1 mg to about 500 mg.
  • a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and (4x) daily.
  • Optimal dosages of a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the hematopoietic disorder.
  • factors associated with the particular subject being treated including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect.
  • the above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof is administered to a subject in need thereof.
  • An embodiment of the present invention is directed to methods of using pharmaceutical compositions for intravenous or subcutaneous administration, comprising a BCL-2 inhibitor in an amount of from about 1 mg to about 500 mg.
  • a BCL-2 inhibitor may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and (4x) daily.
  • Optimal dosages of the BCL-2 inhibitor to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition or disorder.
  • factors associated with the particular subject being treated including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect.
  • the above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the BCL-2 inhibitor may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a BCL-2 inhibitor is administered to a subject in need thereof.
  • menin-MLL inhibitor refers to an inhibitor of the protein-protein interaction between menin and mixed-lineage leukemia 1 (MLL1) (also known as histone-lysine N-methyltransferase 2A (KMT2A) protein in the scientific field (UniProt Accession #Q03164) ) which inhibits or reduces menin-MLL 1 activity.
  • MML1 mixed-lineage leukemia 1
  • KMT2A histone-lysine N-methyltransferase 2A
  • Menin-MLL inhibitors described herein are disclosed in PCT/CN2020/137266 (which published as WO 2021/121327 on June 24, 2021) , which is incorporated by reference herein in its entirety, and which also discloses corresponding synthetic schemes and analytical characterizations.
  • BCL-2 inhibitor refers to an agent that inhibits or reduces BCL-2 activity.
  • anti-plastic agent refers to any agent that treats cancer.
  • hypomethylating agent refers to an agent that inhibits or reduces DNA methylation.
  • kinase inhibitor refers to an agent that inhibits or reduce the activity of at least one kinase (e.g., tyrosine and/or serine kinases such as fms-like receptor tyrosine kinase-3 (FLT3) , Bruton tyrosine kinase (BTK) , an Abelson tyrosine kinase 1 (ABL) , an Aurora serine/tyrosine kinase) .
  • tyrosine and/or serine kinases such as fms-like receptor tyrosine kinase-3 (FLT3) , Bruton tyrosine kinase (BTK) , an Abelson tyrosine kinase 1 (ABL) , an Aurora serine/tyrosine kinase
  • FLT-3 inhibitor refers to tyrosine kinase inhibitors (TKI) classified into first and next generation inhibitors based on their potency and specificity for fms-like receptor tyrosine kinase-3 (FLT3) and their associated downstream targets.
  • TKI tyrosine kinase inhibitors
  • CD20 inhibitor refers to any agent that reduces activity of CD20.
  • Isocitrate dehydrogenase (IDH) inhibitor refers to any agent that interferes with the conversion of isocitrate to ⁇ -ketoglutarate ( ⁇ -KG) in the tricarboxylic acid (TCA) cycle.
  • immunomodulatory antineoplastic agent refers to any agent that enhances antitumor immune cell activity.
  • PD-1 inhibitor refers to any agent that inhibits or reduces PD-1 activity.
  • DHODH dihydroorotate dehydrogenase inhibitor
  • the term “affect” or “affected” when referring to a disease, disorder, or medical condition that is affected by the inhibition or alteration of menin-MLL activity) includes a reduction in the frequency and/or severity of one or more symptoms or manifestations of said hematopoietic disorder; and/or includes the prevention of the development of one or more symptoms or manifestations of said hematopoietic disorder or the development of the hematopoietic disorder.
  • hematopoietic disorder refers to any disorder associated with the production of the cellular components of blood and blood plasma, including but not limited to blood cancers.
  • the invention provides combinations as described herein.
  • the invention provides combinations as described herein for use as a medicament.
  • the invention provides combinations as described herein for the manufacture of a medicament.
  • the invention provides combinations as described herein for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned herein.
  • the invention provides combinations as described herein for use in the prevention or treatment, in particular treatment, of diseases as described herein.
  • the invention provides combinations as described herein for use in the prevention or treatment, in particular treatment, of a hematopoietic disorder, including but not limited to blood cancers, including but not limited to lymphomas, myelomas and leukemias.
  • a hematopoietic disorder including but not limited to blood cancers, including but not limited to lymphomas, myelomas and leukemias.
  • the invention provides combinations as described herein for use in the prevention or treatment, in particular treatment, of a hematopoietic disorder.
  • the hematopoietic disorder is selected from, but not limited to, lymphomas, myelomas, myelodysplasia and leukemias.
  • the hematopoietic disorder is a lymphoma selected from Hodgkin's disease lymphomas and Non-Hodgkin's lymphomas.
  • the lymphoma is a Non-Hodgkin’s disease that is Burkitt's lymphoma, anaplastic large cell lymphoma, splenic marginal zone lymphoma, hepatosplenic T-cell lymphoma or angioimmunoblastic T-cell lymphoma (AILT) .
  • a Non-Hodgkin’s disease that is Burkitt's lymphoma, anaplastic large cell lymphoma, splenic marginal zone lymphoma, hepatosplenic T-cell lymphoma or angioimmunoblastic T-cell lymphoma (AILT) .
  • the hematopoietic disorder is a myeloma. According to an embodiment, the hematopoietic disorder is a multiple myeloma, macroglobulinemia or plasmacytoma.
  • the hematopoietic disorder is a myelodysplasia including, but not limited to, myelodysplastic syndrome (MDS) .
  • MDS myelodysplastic syndrome
  • the hematopoietic disorder is a leukemia.
  • the hematopoietic disorder is a leukemia selected from acute leukemias and chronic leukemias.
  • the leukemia is an acute leukemia.
  • the leukemia is chronic leukemia.
  • the hematopoietic disorder is a myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, or lymphocytic leukemia
  • the hematopoietic disorder is a leukemia selected from, but not limited to, acute lymphocytic leukemia (ALL) , chronic lymphocytic leukemia (CLL) , small lymphocytic leukemia (SLL) , acute myeloid leukemia (AML) , chronic idiopathic myelofibrosis (MF) , chronic myelogenous leukemia (CML) , T-cell prolymphocytic leukemia (T-PLL) , B-cell prolymphocytic leukemia (B-PLL) , chronic neutrophilic leukemia (CNL) , Hairy cell leukemia (HCL) , T-cell large granular lymphocyte leukemia (T-LGL) and aggressive
  • ALL acute lymphocy
  • the leukemia is MDS, CLL, SLL, ALL or AML. According to an embodiment, the leukemia is CLL, SLL or AML. According to an embodiment, the leukemia is CLL or SLL. In some embodiments, the CLL or SLL is a CD20 expressing cancer. According to an embodiment, the leukemia is ALL or AML. According to an embodiment, the leukemia is ALL. According to an embodiment, the leukemia is AML. According to an embodiment, the hematopoietic disorder is macroglobulinemia.
  • the hematopoietic disorder is a MLL-rearranged leukemia, MLL-partial tandem duplication (PTD) leukemia, MLL amplified leukemia, MLL-positive leukemia, or leukemia exhibiting elevated HOX/MEIS1 gene expression signatures.
  • PTD MLL-partial tandem duplication
  • the leukemia is a MLL-rearranged leukemia &/or a nucleophosmin 1 (NPM1) -mutated leukemia.
  • the hematopoietic disorder is a MLL-rearranged leukemia.
  • the hematopoietic disorder is a nucleophosmin 1 (NPM1) -mutated leukemia (e.g., NPM1c) .
  • NPM1 nucleophosmin 1
  • the invention provides methods for treatment of a hematopoietic disorder that is myelodysplastic syndrome (MDS) , a myeloproliferative neoplasm (MPN) , acute lymphocytic leukemia (ALL) , acute myeloid leukemia (AML) , a small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof, and a BCL-2 inhibitor, and optionally, at least one other antineoplastic agent.
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasm
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • SLL small lymphocytic lymphoma
  • CLL chronic lymphocytic leukemia
  • the hematopoietic disorder is myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) .
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasm
  • the hematopoietic disorder is acute lymphocytic leukemia (ALL) .
  • ALL acute lymphocytic leukemia
  • the hematopoietic disorder is acute myeloid leukemia (AML) .
  • the hematopoietic disorder is a small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) .
  • SLL small lymphocytic lymphoma
  • CLL chronic lymphocytic leukemia
  • the hematopoietic disorder is a SLL or CLL where SLL or CLL is a CD20-expressing cancer.
  • the hematopoietic disorder is myelodysplastic syndrome (MDS) .
  • MDS myelodysplastic syndrome
  • the hematopoietic disorder is a myeloproliferative neoplasm (MPN) .
  • MPN myeloproliferative neoplasm
  • the hematopoietic disorder is a NPM1-mutated leukemia with a FLT3 mutation.
  • the hematopoietic disorder is a FLT3-dependent leukemia.
  • the hematopoietic disorder is a MEF2G-dependent leukemia.
  • the hematopoietic disorder harbours one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplification) and/or NPM1 mutations.
  • KMT2A MLL1
  • the hematopoietic disorder harbours (i) one or more MLL1 (KMT2A) gene rearrangements or alterations (e.g., duplications or amplification) and/or NPM1 mutations plus (ii) a FLT3 mutation.
  • KMT2A MLL1
  • alterations e.g., duplications or amplification
  • the hematopoietic disorder is an MLL-rearranged leukemia.
  • the hematopoietic disorder is acute myeloid leukemia (AML) .
  • the hematopoietic disorder is a small lymphocytic lymphoma (SLL) .
  • SLL small lymphocytic lymphoma
  • the hematopoietic disorder is a chronic lymphocytic leukemia (CLL) .
  • CLL chronic lymphocytic leukemia
  • the hematopoietic disorder is an acute leukemia, chronic leukemia, myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myelogeneous leukemia (AML) , chronic myelogenous leukemia (CML) , acute lymphoblastic leukemia (ALL) , chronic lymphocytic leukemia (CLL) , T cell prolymphocytic leukemias (T-PLL) , large granular lymphocytic leukemia, Hairy cell leukemia (HCL) , MLL-rearranged leukemia, MLL-PTD leukemia, MLL amplified leukemia, MLL-positive leukemia, or leukemia exhibiting elevated HOX/MEIS1 gene expression signatures.
  • AML acute myelogeneous leukemia
  • CML chronic myelogenous leukemia
  • ALL acute lymphoblastic leukemia
  • the hematopoietic disorder is AML, in particular nucleophosmin (NPM1) -mutated AML (i.e., NPM1 mut AML) , more in particular abstract NPM1-mutated AML.
  • NPM1 -mutated AML i.e., NPM1 mut AML
  • the hematopoietic disorder is a MLL-rearranged leukemia, in particular MLL-rearranged AML or ALL.
  • the hematopoietic disorder includes a MLL gene alteration, in particular the hematopoietic disorder is AML or ALL with MLL gene alteration (s) .
  • the MLL gene alteration is a duplication.
  • the MLL gene alteration is an amplification.
  • the hematopoietic disorder includes a NPM1 gene mutation and/or MLL1 (also known as KMT2A) gene mutation.
  • MLL1 gene mutations include, but are not limited to, MLL1 gene rearrangements, duplications or amplification.
  • the hematopoietic disorder is a mixed-lineage leukemia (MLL) , MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, leukemia associated with a MLL, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS) , or myeloproliferative neoplasms (MPN) .
  • MLL mixed-lineage leukemia
  • MLL-related leukemia MLL-associated leukemia
  • MLL-positive leukemia MLL-induced leukemia
  • leukemia associated with a MLL leukemia associated with a MLL
  • acute leukemia chronic leukemia
  • myelodysplastic syndrome MDS
  • MPN myeloproliferative neoplasms
  • All embodiments described herein for use in treating a hematopoietic disorder are also applicable for methods for treating said hematopoietic disorder.
  • the present invention relates to a novel combination comprising:
  • a therapeutically effective amount of a menin-MLL inhibitor of Formula (I) or a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or a solvate thereof;
  • ⁇ optionally, a therapeutically effective amount of at least one other antineoplastic agent.
  • compounds of Formula (I) are menin-MLL inhibitors having the structure:
  • Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
  • 5-or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 3-6 cycloalkyl and C 1-4 alkyl;
  • R xa and R xb are each independently selected from the group consisting of hydrogen, C 1- 4 alkyl and C 3-6 cycloalkyl;
  • R 1b represents F or Cl
  • Y 1 represents -CR 5a R 5b -, -O-or -NR 5c -;
  • R 2 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, -O-C 1-4 alkyl, and -NR 7a R 7b ;
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 5a , R 5b , R 5c , R 7a , and R 7b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a , and R 12b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
  • 5-or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 3-6 cycloalkyl and C 1-4 alkyl;
  • R xa and R xb are each independently selected from the group consisting of hydrogen, C 1- 4 alkyl and C 3-6 cycloalkyl;
  • R 1b represents F or Cl
  • Y 1 represents -CR 5a R 5b -, -O-or -NR 5c -;
  • R 2 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, -O-C 1-4 alkyl, and -NR 7a R 7b ;
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 5a , R 5b , R 5c , R 7a , and R 7b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;
  • each of the C 1-4 alkyl or C 1-6 alkyl moieties in the R 3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo or -O-C 1-4 alkyl;
  • R 9a , R 9b , R 10a , R 10b , R 11 , R 12a , and R 12b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
  • 5-or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 3-6 cycloalkyl and C 1-4 alkyl;
  • R xa and R xb are each independently selected from the group consisting of hydrogen, C 1- 4 alkyl and C 3-6 cycloalkyl;
  • R 1b represents F or Cl
  • Y 1 represents -CR 5a R 5b -, -O-or -NR 5c -;
  • R 2 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, -O-C 1-4 alkyl, and -NR 7a R 7b ;
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 5a , R 5b , R 5c , R 7a , and R 7b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, OH, and -O-C 1-4 alkyl;
  • R 10a , R 10b , R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
  • 5-or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C 3-6 cycloalkyl and C 1-4 alkyl;
  • R xa and R xb are each independently selected from the group consisting of hydrogen, C 1- 4 alkyl and C 3-6 cycloalkyl;
  • R 1b represents F or Cl
  • Y 1 represents -CR 5a R 5b -, -O-or -NR 5c -;
  • R 2 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, -O-C 1-4 alkyl, and -NR 7a R 7b ;
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 5a , R 5b , R 5c , R 7a , and R 7b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-C 1-4 alkyl;
  • R 10a and R 10b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is substituted with one C 3-6 cycloalkyl;
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • each of the C 1-4 alkyl or C 1-6 alkyl moieties in the R 3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-C 1-4 alkyl;
  • R 9a , R 9b , R 10a , R 10b , R 10c , R 11 , R 12a , and R 12b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is substituted with one C 3-6 cycloalkyl;
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-C 1-4 alkyl;
  • R 10a , R 10b , and R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • U represents N or CH
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-C 1-4 alkyl;
  • R 10a , R 10b , and R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents pyrimidinyl substituted with one C 3-6 cycloalkyl
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one -OH;
  • R 10a , R 10b , and R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents pyrimidinyl substituted with one C 3-6 cycloalkyl
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n2 2;
  • n1, n3 and n4 are 1;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one -OH;
  • R 10a , R 10b , and R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n2 2;
  • n1, n3 and n4 are 1;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ;
  • R 10a , R 10b , and R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n2 2;
  • n1, n3 and n4 are 1;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b ;
  • R 10a , R 10b , and R 10c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ;
  • R 10a and R 10b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b ;
  • R 10a and R 10b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent hydrogen or C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b ;
  • R 10a and R 10b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent hydrogen or C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b ;
  • R 8a and R 8b are each independently selected from the group consisting of hydrogen; C 1- 6 alkyl; and C 1-6 alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and -O-C 1-4 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -C 1-6 alkyl-NR 8a R 8b ;
  • R 8a and R 8b are each independently selected from the group consisting of C 1-6 alkyl; and C 1-6 alkyl substituted with one -O-C 1-4 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 represents hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b ;
  • R 8a and R 8b are each independently selected from the group consisting of C 1-6 alkyl; and C 1-6 alkyl substituted with one -O-C 1-4 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein said 6-membered monocyclic aromatic ring is optionally substituted with one C 3- 6 cycloalkyl;
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 is hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 9a , R 9b , R 12a , and R 12b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • compounds of Formula (I) are as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R xa and R xb represent C 1-4 alkyl
  • R 1b represents F
  • Y 1 represents -O-
  • R 2 is hydrogen
  • n1, n2, n3 and n4 are each independently selected from 1 and 2;
  • X 1 represents CH, and X 2 represents N;
  • R 4 represents isopropyl
  • R 9a , R 9b , R 12a , and R 12b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 1b represents F.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 2 represents hydrogen.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y 1 represents -O-.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y 1 represents -O-; and U represents N.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y 1 represents -O-; U represents N; R 1b represents F; and R 2 represents hydrogen.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 5-or 6-membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 5-or 6-membered aromatic ring is substituted with one C 3-6 cycloalkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 5-or 6-membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 5-or 6-membered aromatic ring is substituted with one C 3-6 cycloalkyl; and R 1b represents F.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 6-membered aromatic ring containing one or two nitrogen atoms; wherein said monocyclic 6-membered aromatic ring is substituted with one C 3-6 cycloalkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a monocyclic 6-membered aromatic ring containing one or two nitrogen atoms; and wherein said monocyclic 6-membered aromatic ring is substituted with one C 3-6 cycloalkyl; and R 1b represents F.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-C 1-4 alkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -C 1-6 alkyl-NR 8a R 8b ; wherein the C 1-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-C 1-4 alkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -C 1-6 alkyl-NR 8a R 8b .
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -C 2-6 alkyl-NR 8a R 8b ; wherein the C 2-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo and -O-C 1-4 alkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -C 2-6 alkyl-NR 8a R 8b ; wherein the C 2-6 alkyl moiety in the R 3 definition may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, -OH, and -O-C 1-4 alkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -C 1-6 alkyl-NR 8a R 8b ; R 8a represents C 1-6 alkyl; and R 8b represents C 1-6 alkyl substituted with one -O-C 1-4 alkyl.
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b .
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 represents -CH 2 -CH 2 -CH 2 -NR 8a R 8b ; R 8a represents methyl; and R 8b represents -CH 2 -CH 2 -OCH 3 .
  • the present invention includes compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein C 1-6 alkyl in the R 3 definition -C 1-6 alkyl-NR 8a R 8b is limited to –CH 2 -CH 2 -CH 2 -.
  • the present invention includes compounds of Formula (I) or the pharmaceutically acceptable salts or the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (Ia) or Formula (Ib) :
  • R 1a , R 1b , R 3 , R 4 , R 5a , R 5b , X 1 , X 2 , n1, n2, n3, n4 and halo are as defined for the compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
  • the compounds of Formula (I) , or the pharmaceutically acceptable salts or the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments are restricted to compounds of Formula (Ia) , or the pharmaceutically acceptable salts or the solvates thereof.
  • the compounds of Formula (I) , or the pharmaceutically acceptable salts or the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments are restricted to compounds of Formula (Ib) , or the pharmaceutically acceptable salts or the solvates thereof.
  • the present invention includes compounds of Formula (I) , or the pharmaceutically acceptable salts or the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to compounds of Formula (I-y) :
  • R 3 is as defined for the compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
  • n1 is 1, n2 is 2, n3 is 1, and n4 is 1.
  • the compound of Formula (I) is Compound A:
  • the compound of Formula (I) is Compound A1:
  • the compound of Formula (I) is Compound A2:
  • the compound of Formula (I) is Compound A3:
  • the compound of Formula (I) is Compound A4-a:
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide besylate salt or a hydrate thereof.
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt or a solvate thereof.
  • the menin-MLL inhibitor of Formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt (Compound A4-b) or a hydrate thereof.
  • the menin-MLL inhibitor of Formula (I) is Compound A4: crystalline form A of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt hydrate.
  • the menin-MLL inhibitor of Formula (I) is a crystalline form A of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide bis-besylate salt 0.5-2.0 equivalents hydrate.
  • the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.
  • the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds, tautomers and stereoisomeric forms thereof, and the free bases, any pharmaceutically acceptable salts, and the solvates thereof.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a combination as described in any of the other embodiments.
  • a combination therapy comprising a menin-MLL inhibitor of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof, a BCL-2 inhibitor and optionally, at least one other antineoplastic agent.
  • the menin-MLL inhibitor is a compound of Formula (I) , or a pharmaceutically acceptable salt or a solvate thereof.
  • the menin-MLL inhibitor is Compound A or a pharmaceutically acceptable salt or solvate thereof.
  • the menin-MLL inhibitor is Compound A1.
  • the menin-MLL inhibitor is Compound A2.
  • the menin-MLL inhibitor is Compound A3.
  • the menin-MLL inhibitor is Compound A4-a or a solvate thereof.
  • the menin-MLL inhibitor is Compound A4-b or a hydrate thereof.
  • the menin-MLL inhibitor is Compound A4.
  • the menin-MLL inhibitor may have improved metabolic stability properties.
  • the menin-MLL inhibitor may have extended in vivo half-life (T1/2) .
  • the menin-MLL inhibitor may have improved oral bioavailability.
  • the menin-MLL inhibitor may reduce tumor growth e.g., tumors harbouring MLL (KMT2A) gene rearrangements/alterations and/or NPM1 mutations.
  • KMT2A MLL
  • the menin-MLL inhibitor may have improved PD properties in vivo during a prolonged period of time, e.g. inhibition of target gene expression such as MEIS1 and upregulation of differentiation marker over a period of at least 16 hours.
  • the menin-MLL inhibitor may have an improved safety profile (e.g., reduced hERG inhibition; improved cardiovascular safety) .
  • the menin-MLL inhibitor may be suitable for Q.D. dosing (once daily) .
  • the BCL-2 inhibitor is selected from obatoclax, HA14-1, navitoclax, ABT-737, TW-37, AT101, sabutoclax, gamgogic acid and venetoclax, or pharmaceutically acceptable salts or solvates thereof.
  • the BCL-2 inhibitor is venetoclax, or a pharmaceutically acceptable salt or solvate thereof.
  • At least one other antineoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, immunomodulatory antineoplastic agent or a DHODH inhibitor.
  • At least one other antineoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase (IDH) inhibitor.
  • the hypomethylating agent includes, but is not limited to, azacitidine, decitabine, or pharmaceutically acceptable salts or solvates thereof.
  • the DNA intercalating agent includes, but is not limited to, an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin) .
  • an anthracycline e.g., daunorubicin, doxorubicin, idarubicin
  • the DNA intercalating agent is daunorubicin.
  • the DNA intercalating agent is doxorubicin.
  • the DNA intercalating agent is idarubicin.
  • the pyrimidine analog includes, but is not limited to, cytarabine (ARA-C) .
  • the purine analog is fludarabine.
  • the kinase inhibitor is a FLT-3 inhibitor, a BTK inhibitor, an ABL inhibitor, an Aurora inhibitor or a multi-kinase inhibitor of two or more kinase inhibitors thereof.
  • the kinase inhibitor is a multi-kinase inhibitor of FLT-3 inhibitor, ABL inhibitor, and Aurora inhibitor.
  • such multi-kinase inhibitor includes, but is not limited to KW-2449.
  • the kinase inhibitor is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is a FLT-3 inhibitor or a BTK inhibitor.
  • the FLT3 inhibitor includes, but is not limited to, sorafenib, sunitinib, midostaurin (PKC412) , lestaurtinib (CEP-701) , tandutinib (MLN518) , quizartinib (AC220) , gilteritinib (ASP2215) , and KW-2449.
  • the BTK inhibitor includes, but is not limited to, ibrutinib.
  • the CD20 inhibitor includes, but is not limited to, an anti-CD20 antibody (e.g., obinutuzumab (GA101) ) .
  • an anti-CD20 antibody e.g., obinutuzumab (GA101) .
  • the IDH inhibitor includes, but is not limited to, ivosidenib and enasidenib.
  • the isocitrate dehydrogenase-1 inhibitor includes, but is not limited to, ivosidenib.
  • the isocitrate dehydrogenase-2 inhibitor includes, but is not limited to, enasidenib.
  • the immunomodulatory antineoplastic agent includes, but is not limited to, PD-1 inhibitors (e.g., nivolumab, atezolizumab and pembrolizumab) , thalidomide, lenalidomide, pomalidomide, Bacillus Calmette–Guérin (BCG) and levamisole.
  • PD-1 inhibitors e.g., nivolumab, atezolizumab and pembrolizumab
  • thalidomide e.g., lenalidomide, pomalidomide, Bacillus Calmette–Guérin (BCG) and levamisole.
  • the PD-1 inhibitor includes, but is not limited to, nivolumab, atezolizumab and pembrolizumab.
  • the DHODH inhibitor includes, but is not limited to, a compound having the structure of Formula (Z) :
  • X is CH or N
  • Y is CH or N
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 2- 6 haloalkenyl; N (CH 3 ) 2 ; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with C 1-6 alkyl; and phenyl;
  • R 2 is wherein
  • R a is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
  • R b is C 1-6 alkyl or C 1-6 alkyl substituted with a member selected from the group consisting of: OH, halo, CN, OC 1-6 alkyl, OC 1-6 haloalkyl and OC 3-6 cycloalkyl;
  • R 3 is selected from the group consisting of: H, halo, CH 3 and OCH 3 ;
  • R 4 is selected from the group consisting of:
  • each R c is independently selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; NO 2 ; OH; O-CH 2 CH 2 OH; and OC 1-6 alkyl;
  • R d is selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; CN; and OC 1-6 alkyl;
  • R g is selected from the group consisting of: H; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1- 6 haloalkyl; and C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and
  • n 1, or 2;
  • the DHODH inhibitor includes, but is not limited to, a compound having the structure of Formula (Z) :
  • X is CH or N
  • Y is CH or N
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 2- 6 haloalkenyl; N (CH 3 ) 2 ; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with C 1-6 alkyl; and phenyl;
  • R 2 is wherein
  • R a is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
  • R b is C 1-6 alkyl or C 1-6 alkyl substituted with a member selected from the group consisting of: OH, halo, CN, OC 1-6 alkyl, OC 1-6 haloalkyl and OC 3-6 cycloalkyl;
  • R 3 is selected from the group consisting of: H, halo, CH 3 and OCH 3 ;
  • R 4 is selected from the group consisting of:
  • each R c is independently selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; NO 2 ; OH; O-CH 2 CH 2 OH; and OC 1-6 alkyl;
  • R d is selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; CN; and OC 1-6 alkyl;
  • R g is selected from the group consisting of: H; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1- 6 haloalkyl; and C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and
  • n 1, or 2;
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. ) .
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2-6 for straight chain, C 3-6 for branched chain) .
  • haloalkyl refers to a straight-or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain optionally substituting hydrogens with halogens.
  • C 1- 6 haloalkyl refers to a straight-or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain, optionally substituting hydrogens with halogens.
  • C 1-4 haloalkyl refers to a straight-or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally substituting hydrogens with halogens.
  • haloalkyl groups include trifluoromethyl (CF 3 ) , difluoromethyl (CF 2 H) , monofluoromethyl (CH 2 F) , pentafluoroethyl (CF 2 CF 3 ) , tetrafluoroethyl (CHFCF 3 ) , monofluoroethyl (CH 2 CH 2 F) , trifluoroethyl (CH 2 CF 3 ) , tetrafluorotrifluoromethylethyl (CF (CF 3 ) 2 ) , and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • haloalkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond and having from 1 to 6 carbon atoms in the chain optionally substituting hydrogens with halogens.
  • aryl refers to a monocyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 atoms per ring. (Carbon atoms in the aryl groups are sp2 hybridized. )
  • heteroaryl refers to a monocyclic or fused bicyclic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 9 ring atoms per heterocycle.
  • heteroaryl groups include the following entities, in the form of properly bonded moieties:
  • variable point of attachment means that a group is allowed to be attached at more than one alternative position in a structure.
  • the attachment will always replace a hydrogen atom on one of the ring atoms.
  • all permutations of bonding are represented by the single diagram, as shown in the illustrations below.
  • the DHODH inhibitor is a compound of Formula (Z) wherein X is CH.
  • the DHODH inhibitor is a compound of Formula (Z) wherein X is N.
  • the DHODH inhibitor is a compound of Formula (Z) wherein Y is CH.
  • the DHODH inhibitor is a compound of Formula (Z) wherein Y is N.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 1 is C 1-4 alkyl; C 1-4 alkyl substituted with OH, or OCH 3 ; C 2-4 alkenyl; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with OH, or OCH 3 ; C 2-4 haloalkenyl; N (CH 3 ) 2 ; cyclopropyl; cyclopropyl substituted with C 1-4 alkyl; or phenyl.
  • R 1 is C 1-4 alkyl; C 1-4 alkyl substituted with OH, or OCH 3 ; C 2-4 alkenyl; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with OH, or OCH 3 ; C 2-4 haloalkenyl; N (CH 3 ) 2 ; cyclopropyl; cyclopropyl substituted with C 1-4 alkyl; or phenyl.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 1 is CH 3 , CH 2 CH 3 ,
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 1 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • R 2 is wherein R b is C 1-4 alkyl substituted with OH, halo, CN, OC 1-4 alkyl, OC 1-4 haloalkyl or OC 3-6 cycloalkyl; and
  • R a is C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 2 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 3 is H.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 3 is F.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 3 is CH 3 .
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 3 is OCH 3 .
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 4 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • R 4 is wherein
  • each R c is independently selected from the group consisting of: H; halo; C 1-4 alkyl; C 1- alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and NO 2 ;
  • R d is selected from the group consisting of: H; halo; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH 3 , SCH 3 , or OCF 3 ; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with OH, or OCH 3 ; or OC 1-4 alkyl; CN; and OC 1-6 alkyl; and
  • n 1, or 2.
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • each R c is independently selected from the group consisting of: H, halo, C 1-4 alkyl, C 1-4 haloalkyl, NO 2 , O-CH 2 CH 2 OH, and OC 1-4 alkyl;
  • R d is selected from the group consisting of: H, halo, C 1-4 alkyl, CN, and OC 1-6 alkyl; and n is 1, or 2.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 4 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 4 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • each R c is independently selected from the group consisting of: H; halo; C 1-4 alkyl; C 1- alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and R d is selected from the group consisting of: halo; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH 3 , SCH 3 , or OCF 3 ; C 1-4 haloalkyl; C 1- 4 haloalkyl substituted with OH, or OCH 3 ; or OC 1-4 alkyl; CN; and OC 1-6 alkyl.
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • R 4 is wherein
  • each R c is independently selected from the group consisting of: H, halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, and OH;
  • R d is selected from the group consisting of: halo, C 1-4 alkyl, and OC 1-4 alkyl; and n is 1, or 2.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 4 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 4 is
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • R 4 is wherein
  • R c is H; halo; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH 3 , SCH 3 , or OCF 3 ; C 1-4 haloalkyl; C 1-4 haloalkyl substituted with OH, or OCH 3 ; or OC 1-4 alkyl;
  • R d is halo; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH 3 , SCH 3 , or OCF 3 ; C 1-4 haloalkyl; or C 1-4 haloalkyl substituted with OH, or OCH 3 ; and
  • R g is H; C 1-4 alkyl; C 1-4 alkyl substituted with OH, OCH 3 , SCH 3 , or OCF 3 ; C 1-4 haloalkyl; or C 1-4 haloalkyl substituted with OH, or OCH 3 .
  • the DHODH inhibitor is a compound of Formula (Z) wherein
  • R 4 is wherein
  • R c is H or halo
  • R d is C 1-4 alkyl
  • R g is H.
  • the DHODH inhibitor is a compound of Formula (Z) wherein R 4 is
  • the DHODH inhibitor is a compound of Formula (Z) selected from the group consisting of:
  • the DHODH inhibitor is a compound of Formula (Z) selected from the group consisting of:
  • the DHODH inhibitor is a compound of Formula (Z) selected from the group consisting of:
  • the DHODH inhibitor is a compound of Formula (Z) having the Formula (Za) :
  • Y is CH or N
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 2-6 haloalkenyl; N (CH 3 ) 2 ; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with C 1-6 alkyl; and phenyl;
  • R 3 is selected from the group consisting of: H, halo, CH 3 and OCH 3 ;
  • R 4 is selected from the group consisting of:
  • C 1-6 alkyl C 1-6 alkyl; C 1-6 alkyl substituted with one or two OCH 3 ; C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with CH 3 , or OCH 3 ; CH 2 -C 3-6 cycloalkyl; and
  • each R c is independently selected from the group consisting of: H; halo; C 1-6 alkyl; C 1- 6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; NO 2 ; OH; O-CH 2 CH 2 OH; and OC 1- 6 alkyl;
  • R d is selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; CN; and OC 1-6 alkyl;
  • R g is selected from the group consisting of: H; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1- 6 haloalkyl; and C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and
  • n 1, or 2;
  • the DHODH inhibitor is a compound of Formula (Z) having the Formula (Zb) :
  • Y is CH or N:
  • R 1 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkenyl;
  • R 3 is selected from the group consisting of: H, halo and OCH 3 ;
  • R 4 is selected from the group consisting of:
  • R c is selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and NO 2 ;
  • R d is selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; CN; and OC 1-6 alkyl;
  • R g is selected from the group consisting of: H; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; C 1- 6 haloalkyl; and C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and
  • n 1;

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La divulgation concerne des combinaisons comprenant une quantité thérapeutiquement efficace d'un inhibiteur de ménine-MLL de formule (I) ou d'un sel pharmaceutiquement acceptable ou d'un solvate de celui-ci; et une quantité thérapeutiquement efficace d'un inhibiteur de BCL-2; et éventuellement, une quantité thérapeutiquement efficace d'au moins un autre agent antinéoplasique. La divulgation concerne également des méthodes pour traiter un sujet qui a été diagnostiqué avec un trouble hématopoïétique en utilisant de telles combinaisons. Les composés sont représentés par la formule (I) comme suit : R 1a, R 1b, R 2, R 3, R 4, U, Y 1, X 1, X 2, n1, n2, n3 et n4 étant définis ici.
EP22725158.4A 2021-05-11 2022-05-09 Multithérapies Pending EP4337216A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2021093036 2021-05-11
CN2021100523 2021-06-17
CN2022086004 2022-04-11
PCT/CN2022/091679 WO2022237720A1 (fr) 2021-05-11 2022-05-09 Multithérapies

Publications (1)

Publication Number Publication Date
EP4337216A1 true EP4337216A1 (fr) 2024-03-20

Family

ID=81753154

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22725158.4A Pending EP4337216A1 (fr) 2021-05-11 2022-05-09 Multithérapies

Country Status (16)

Country Link
EP (1) EP4337216A1 (fr)
JP (1) JP2024518497A (fr)
KR (1) KR20240006631A (fr)
CN (2) CN117460513A (fr)
AU (1) AU2022274071A1 (fr)
CA (1) CA3215313A1 (fr)
CL (2) CL2023003239A1 (fr)
CO (1) CO2023014322A2 (fr)
DO (1) DOP2023000246A (fr)
IL (1) IL308335A (fr)
MX (1) MX2023013410A (fr)
PE (1) PE20240593A1 (fr)
PH (1) PH12023552974A1 (fr)
TW (1) TW202308643A (fr)
UY (1) UY39761A (fr)
WO (1) WO2022237720A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202525813A (zh) 2019-12-19 2025-07-01 比利時商健生藥品公司 經取代之直鏈螺環接衍生物
EP4626426A1 (fr) * 2022-11-30 2025-10-08 JANSSEN Pharmaceutica NV Associations comprenant un inhibiteur de ménine-mll et au moins un autre agent thérapeutique
WO2024114666A1 (fr) * 2022-11-30 2024-06-06 Janssen Pharmaceutica Nv Combinaisons comprenant un inhibiteur de ménine-mll et un inhibiteur de bcl-2
EP4698182A1 (fr) * 2023-04-17 2026-02-25 Janssen Pharmaceutica NV Combinaison d'un inhibiteur ménine-ll1, d'un agent intercalant de l'adn et d'un analogue de pyrimidine pour traiter un trouble hématopoïétique
WO2025082444A2 (fr) * 2023-10-20 2025-04-24 Janssen Pharmaceutica Nv (r)-n-éthyl-5-fluoro-n-isopropyl-2-((5-(2-(6-((2-méthoxyéthyl)(méthyl)amino)-2-méthylhexan-3-yl)-2, 6-diazaspiro[3,4]octan-6-yl)-1, 2, 4-triazin-6-yl)oxy)benzamide, formulations et schémas posologiques de celui-ci, destinés à être utilisés pour le traitement du cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017112768A1 (fr) * 2015-12-22 2017-06-29 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2017214367A1 (fr) * 2016-06-10 2017-12-14 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TN2017000080A1 (en) 2014-12-18 2018-07-04 Takeda Pharmaceuticals Co Solid state forms of fused heteroaromatic pyrrolidinones
TW202104207A (zh) 2019-04-17 2021-02-01 美商健生生物科技公司 二氫乳清酸脫氫酶抑制劑
TW202525813A (zh) 2019-12-19 2025-07-01 比利時商健生藥品公司 經取代之直鏈螺環接衍生物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017112768A1 (fr) * 2015-12-22 2017-06-29 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2017214367A1 (fr) * 2016-06-10 2017-12-14 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2022237720A1 *

Also Published As

Publication number Publication date
AU2022274071A1 (en) 2024-01-04
MX2023013410A (es) 2023-12-06
JP2024518497A (ja) 2024-05-01
CO2023014322A2 (es) 2023-11-20
DOP2023000246A (es) 2024-04-30
IL308335A (en) 2024-01-01
CL2024002832A1 (es) 2025-02-14
CA3215313A1 (fr) 2022-11-17
PH12023552974A1 (en) 2024-03-11
CL2023003239A1 (es) 2024-06-07
PE20240593A1 (es) 2024-03-21
TW202308643A (zh) 2023-03-01
CN118845787A (zh) 2024-10-29
UY39761A (es) 2022-11-30
CN117460513A (zh) 2024-01-26
WO2022237720A1 (fr) 2022-11-17
KR20240006631A (ko) 2024-01-15

Similar Documents

Publication Publication Date Title
WO2022237720A1 (fr) Multithérapies
US12473295B2 (en) Substituted straight chain spiro derivatives
WO2022237719A1 (fr) Polythérapies
WO2024114666A1 (fr) Combinaisons comprenant un inhibiteur de ménine-mll et un inhibiteur de bcl-2
WO2024114664A1 (fr) Associations comprenant un inhibiteur de ménine-mll et au moins un autre agent thérapeutique
US20250302840A1 (en) Combination therapies
EA051809B1 (ru) Комбинированные терапии
US20260125387A1 (en) (r)-n-ethyl-5-fluoro-n-isopropyl-2-((5-(2-(6-((2-methoxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide besylate salt
HK40117870A (zh) 组合疗法
EA051795B1 (ru) Комбинированные терапии
HK40100348A (zh) 组合疗法
HK40118806A (zh) 组合疗法
HK40098242A (zh) 组合疗法

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20231211

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40109226

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20250916