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WO2019219805A1 - Polythérapie - Google Patents

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Publication number
WO2019219805A1
WO2019219805A1 PCT/EP2019/062610 EP2019062610W WO2019219805A1 WO 2019219805 A1 WO2019219805 A1 WO 2019219805A1 EP 2019062610 W EP2019062610 W EP 2019062610W WO 2019219805 A1 WO2019219805 A1 WO 2019219805A1
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Prior art keywords
compound according
optionally substituted
heteroaryl
group
phenyl
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Inventor
Rachel Allison ALTURA
Ian Werner KNEMEYER
Benjamin Nicholson
Ian Philip Street
David Curtis
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Ctxone Pty Ltd
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Ctxone Pty Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/7064—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 containing condensed or non-condensed pyrimidines
    • A61K31/7068—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 containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—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 containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to combination therapies for the treatment of hemoglobinopathies such as sickle cell disease (SSD) and b-thalassemia.
  • hemoglobinopathies such as sickle cell disease (SSD) and b-thalassemia.
  • Hemoglobin is a major protein in red blood cells and is essential for the transport of oxygen from the lungs to the tissues.
  • the most common hemoglobin type is a tetramer called hemoglobin A, consisting of two a and two b subunits.
  • hemoglobin A a tetramer
  • the hemoglobin molecule is made up of two a and two g chains. The gamma chains are gradually replaced by subunits as the infant grows.
  • the developmental switch in human b-like globin gene subtype from foetal (y) to adult (b) that begins at birth heralds the onset of the hemoglobinopathies b- thalassemia and sickle cell disease (SCD). In b-thalassemia the adult chains are not produced.
  • chemotherapeutic agents such as trichostatin A (histone deacetylase inhibitor), apicidin (histone deacetylase inhibitor), 5'-aza-cytidine (DNA methyltransferase inhibitor), hydroxyurea (ribonucleotide reductase inhibitor), butyrate and other short-chain fatty acids, have been demonstrated to stimulate fetal hemoglobin production.
  • trichostatin A histone deacetylase inhibitor
  • apicidin histone deacetylase inhibitor
  • 5'-aza-cytidine DNA methyltransferase inhibitor
  • hydroxyurea ribonucleotide reductase inhibitor
  • butyrate and other short-chain fatty acids have been demonstrated to stimulate fetal hemoglobin production.
  • Protein arginine N-methyltransferases catalyse the methylation of the guanidino nitrogen atoms of arginine residues through the transfer of a methyl group from S-adenosyl methionine (SAM).
  • SAM S-adenosyl methionine
  • a by-product of the enzymatic methylation step is S-adenosyl-L-homocysteine (AdoHcy), which is hydrolyzed to adenosine and homocysteine by AdoHcy hydrolase (Krause et al., 2007).
  • PRMT5 (aka JBP1 , SKB1 , IBP72, SKBI his and HRMTIL5) is a Type II arginine
  • PRMT5 plays a significant role in control and modulation of gene transcription.
  • PRMT5 is known to methylate histone H3 at Arg-8 (a site distinct from that methylated by PRMT4) and histone H4 at Arg-3 (the same site methylated by PRMT 1 ) as part of a complex with human SWI/SNF chromatin remodelling components BRG1 and BRM.
  • the enzyme's role in gene silencing is also mediated through the formation of multiprotein repressor complexes that include NuRD components, HDACs, MDB proteins and DNA methyltransferases, (Rank et al., 2010; Le Guezennec et al., 2006; Pal et al., 2003).
  • PRMT5 plays a critical role in triggering coordinated repressive epigenetic events that initiate with dimethylation of histone H4 Arginine 3 (H4R3me2s), and culminate in DNA methylation and transcriptional silencing of the g-genes (Rank et al., 2010). Integral to the synchronous establishment of the repressive markers is the assembly of a PRMT5-dependent complex containing the DNA methyltransferase DNMT3A, and other repressor proteins (Rank et al., 2010).
  • DNMT3A is directly recruited to bind to the PRMT5-induced H4R3me2s mark, and loss of this mark through shRNA-mediated knock-down of PRMT5, or enforced expression of a mutant form of PRMT5 lacking methyltransferase activity leads to marked upregulation of y- gene expression, and complete abrogation of DNA methylation at the g-promoter.
  • Treatment of human erythroid progenitors with non-specific methyltransferase inhibitors (Adox and MTA) also resulted in upregulation of g-gene expression (He Y, 2013).
  • Inhibitors of PRMT5 have thus been studied as potential therapeutics for hemoglobinopathies such as b-thalassemia and Sickle Cell Disease (SCD).
  • SCD Sickle Cell Disease
  • the present invention has been devised in light of the above considerations.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • the invention is based on the surprising finding that, while PRMT5 inhibitors are not effective as single agents in increasing g-globin, when combined with a DNA methyl transferase inhibitor, a synergistic increase in g-globin can be achieved.
  • the invention provides a method for treating a hemoglobinopathy in a patient in need thereof, the method comprising administering to the patient a combination of compounds, comprising compounds (a) and (b), in which (a) is a PRMT5 inhibitor; and (b) is a DNA methyl transferase inhibitor, wherein compounds (a) and (b) are administered to the patient simultaneously, or sequentially in either order.
  • the invention provides a combination of compounds for use in a method of treating a hemoglobinopathy in a patient in need of treatment, the method comprising administering to the patient the combination of compounds, comprising compounds (a) and (b), in which (a) is a PRMT5 inhibitor; and (b) is a DNA methyl transferase inhibitor, wherein compounds (a) and (b) are administered to the patient simultaneously, or sequentially in either order.
  • the invention provides a pharmaceutical composition comprising a
  • this invention provides the use of compounds (a) and (b), in the manufacture of a medicament for treating a hemoglobinopathy, in which (a) is a PRMT5 inhibitor; and (b) is a DNA methyl transferase inhibitor.
  • compound (a) is a compound selected from (i)-(x):
  • compound (x) compounds as described at page 6 line 32 to page 8 line 5 of WO 2017/153520.
  • compound (a) is a compound selected from (xi)-(xix):
  • compound (a) is a compound of formula lA or IB:
  • A is selected from optionally substituted monocyclic or bicyclic, saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from N , O and
  • X is selected from a bond, -0-, -N(R N )-, -CR 4A R 5A -, -0-CR 4A R 5A -, -N(R N )-CR 4A R 5A -, -O- CR 4A R 5A -0-, -N(R N )-CR 4A R 5A -0, -N(R N )-CR 4A R 5A -N(R n )-, -0-CR 4A R 5A -N(R n )-, -CR 4A R 5A -O-, - CR 4A R 5A -N(R N )-, -0-CR 4A R 5A -CR 6A R 7A -, -N(R N )-CR 4A R 5A -CR 6A R 7A -, -CR 6A R 7A -CR 4A R 5A -CR 6A R 7A -, -CR 6A
  • each R A is independently selected from H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R B is independently selected from H, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
  • Cy is an optionally substituted C 4-12 heterocyclic group or an optionally substituted Ce- 12 heterobicyclic group;
  • Y is selected from O and S;
  • R 4 and R Q7 are independently selected from H and Me;
  • R 6a , R 6b , R 3a and R 3b are independently selected from H, halogen and optionally substituted alkyl;
  • E is selected from optionally substituted 8 to 10-membered bicyclyl or heterobicyclyl; n is 1 or 2;
  • p is 0 or 1 ;
  • m is 0 or 1 .
  • compound (a) is a compound of formula 1C:
  • A is selected from optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C 5-12 heteroaryl;
  • R 6a , R 6b , R 5 , R 4 , R 3a , R 3b and R Q7 are independently selected from H and Me;
  • E is selected from optionally substituted 8 to 10-membered bicyclyl or heterobicyclyl; n is 1 or 2;
  • p is 0 or 1 ;
  • m is 0 or 1 .
  • compound (a) is a compound of formula IIA:
  • n 1 or 2;
  • p is 0 or 1 ;
  • R 1 is optionally one or more halo or methyl groups
  • R 2a and R 2b are independently selected from the group consisting of:
  • R 2c and R 2d are independently selected from the group consisting of:
  • R 3a and R 3b are independently selected from H and Me;
  • R 4 is either H or Me
  • R 5 is either H or Me
  • R 6a and R 6b are independently selected from H and Me;
  • A is either
  • compound (iii) optionally substituted C 5-12 heteroaryl.
  • compound (a) is a compound of formula I IB:
  • compound (a) is a compound of formula III:
  • compound (a) is a compound of formula IV:
  • compound (b) is a DNMT3A inhibitor.
  • the DNMT3A inhibitor may be a cytidine analogue.
  • the DNMT3A inhibitor may be decitabine or azacitidine.
  • the patient is a human patient.
  • the hemoglobinopathy is sickle cell disease (SCD). In other embodiments of this invention, the hemoglobinopathy is b-thalassemia.
  • compounds (a) and (b) are administered in combination with a cytidine deaminase inhibitor.
  • the cytidine deaminase inhibitor is tetrahydrouridine (THU).
  • the treatment reduces expression of one or more HbF transcriptional repressors.
  • the HbF transcriptional repressor is selected from the group consisting of GATA2, KLF1 and BCL11A.
  • the present disclosure provides combinations of compounds that induce y globin and can produce beneficial therapeutic effects.
  • compounds and compositions described herein are used to treat hemoglobinopathies such as sickle cell disease (SCD; also known as sickle cell anemia) or b-thalassemia.
  • SCD sickle cell disease
  • b-thalassemia a hemoglobinopathies such as sickle cell disease (SCD; also known as sickle cell anemia) or b-thalassemia.
  • a provided combination of compounds is used to treat SCD.
  • SCD is the most common single gene disease in the world, affecting 20-25 million people globally and causing considerable morbidity and mortality.
  • the gene defect is a single nucleotide polymorphism that results in a glutamic acid residue being substituted by a valine residue at position 6 in the b-globin polypeptide.
  • a provided combination of compounds is used to treat a b-thalassemia.
  • b-thalassemias are caused by reduced or absent synthesis of the hemoglobin b-chain.
  • the treatments of the present invention are combination therapies utilizing at least two agents.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually (independently) varying dose schedules and via different routes.
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent and needs of the patient.
  • composition of the invention may be administered alone or in combination with further treatments, either simultaneously or sequentially dependent upon the needs of the patient.
  • agents i.e., the combination of compound as described here, optionally together with one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • suitable doses of supplements such as folic acid and/or suitable doses of pain relief drugs such as non-steroidal anti-inflammatory drugs (e.g. aspirin, paracetamol, ibuprofen or ketoprofen) or opiates such as morphine, or antiemetics.
  • pain relief drugs such as non-steroidal anti-inflammatory drugs (e.g. aspirin, paracetamol, ibuprofen or ketoprofen) or opiates such as morphine, or antiemetics.
  • C5-12 heteroaryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic structure having from 5 to 12 rings atoms, of which from 1 to 3 are ring heteroatoms.
  • aromatic structure is used to denote a single ring or fused ring systems having aromatic properties
  • ring heteroatom refers to a nitrogen, oxygen or sulphur atom.
  • the prefixes denote the number of atoms making up the aromatic structure, or range of number of atoms making up the aromatic structure, whether carbon atoms or heteroatoms.
  • Examples of C 5 -12 heteroaryl structures include, but are not limited to, those derived from:
  • Ni pyrrole (azole) (C5), pyridine (azine) ⁇ Ce) ' , pyridone ⁇ Ce) ' , indole (C9); quinoline (C10);
  • N1O1 oxazole (C5), isoxazole (C5), isoxazine ⁇ Ce) ' ,
  • N1S1 thiazole (C5), isothiazole (C5);
  • N 2 imidazole (1 ,3-diazole) (C 5 ), pyrazole (1 ,2-diazole) (C 5 ), pyridazine (1 ,2-diazine) ⁇ Ce), pyrimidine (1 ,3-diazine) ⁇ Ce) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) ⁇ Ce) ' , benzimidazole (C 9 )
  • N3 triazole (C5), triazine ⁇ Ce).
  • the optional substituents for the phenyl, naphthyl and C 5 -12 heteroaryl groups in A may be selected from the following groups.
  • C1-4 alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 4 carbon atoms.
  • saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), and butyl (C4).
  • saturated linear alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C 3 ), and n-butyl (C4).
  • saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C4), sec-butyl (C4) and tert-butyl (C4).
  • C1-4 fluoroalkyl refers to a C1-4 alkyl group as defined above where one of more of the hydrogen atoms is replaced by a fluoro.
  • Examples of C1-4 fluoroalkyl include, but are not limited to, -CF 3 , CF 2 H, -C2F 5 , and -C2F4H.
  • C3-6 cycloalkyl the term‘C3-6 cycloalkyl’ as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic core having 3, 4, 5 or 6 atom in the cyclic core all of which are carbon atoms.
  • Examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclohexyl and cyclopentyl.
  • C5-6 heteroaryl the term C5-6 heteroaryl as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of an aromatic structure having between one and three atoms that are not carbon forming part of said ring. Wherein, those atoms that are not carbon can be chosen independently from the list nitrogen, oxygen and sulphur. The group may be substituted by one or more C1-4 alkyl groups.
  • C5-6 heteroaryl groups include, but are not limited to, groups derived from:
  • Ni pyridine (Ce);
  • N1O1 oxazole (C5), isoxazole (C5);
  • N2O1 oxadiazole (furazan) (C5);
  • N2 imidazole (1 ,3-diazole) (C5), pyrazole (1 ,2-diazole) (C5), pyridazine (1 ,2-diazine) ⁇ Ce), pyrimidine (1 ,3-diazine) ⁇ Ce) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) ⁇ Ce),
  • N3 triazole (C5).
  • C5-6 heteroaryl methyl -CH2-(C5-6 heteroaryl), wheren C5-6 heteroaryl is as defined above.
  • C4-6 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a monocyclic heterocyclic compound, which moiety has from 4 to 6 ring atoms; of which from 1 to 2 atoms are
  • heteroatoms chosen from oxygen or nitrogen.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C4-6 heterocyclyl groups include, but are not limited to, those derived from:
  • Ni azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline,
  • N2 diazetidine (C4), imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine ⁇ Ce) ' ,
  • N 1 O 1 tetrahydrooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahydroisoxazole (C 5 ), dihydroisoxazole (C5), morpholine ⁇ Ce), tetrahydrooxazine ⁇ Ce), dihydrooxazine ⁇ Ce), oxazine ⁇ Ce).
  • C 4-6 heterocyclyl methyl -CH 2 -(C 4-6 heterocyclyl), wherein C 4-6 heterocyclyl is as defined above.
  • Phenyl -C 6 H 5 , wherein the phenyl may itself be optionally substituted by one or more Ci -4 alkyl groups, one or more Ci -4 fluoroalkyl groups, one or more Ci -4 alkoxy groups, one or more halo substituents and one or more cyano substituents.
  • Benzyl -Chh-Phenyl, wherein phenyl is as defined above.
  • Halo refers to a group selected from fluoro, chloro, bromo and iodo.
  • the cyclic amido groups may also be bridged by a further group selected from (-CH2-) ni and -(CH2) mi -X-(CH2)pi-, where n1 is 1-3 and ml and p1 are 1-3.
  • the cyclic amido groups may also be further substituted by one, two or more hydroxy, oxo, C1-2 alkyl, C1-2 alkyl-Ci-2 alkoxy, C1-2 alkyl-hydroxy and C1-2 alkoxy groups or one spiro C 4-6 heteroaryl or spiro C 4-6 cycloalkyl group or be fused to an C5-7 aromatic ring.
  • amidomethyl -CH2-amido, where amido is as defined above,
  • acylamidomethyl -CFh-acylamido, where acylamido is as defined above,
  • Ci- 4 alkyl ester methyl -CH2-(CI -4 alkyl ester), where Ci -4 alkyl ester is as defined above.
  • Ci -4 alkyl carbamoyl methyl -CH2-(CI -4 alkyl carbamoyl), where Ci -4 alkyl carbamoyl is as defined above.
  • Examples of Ci -4 alkyl carbamoyl methyl include, but are not limited to,
  • Ci- 4 alkylacyl methyl -CH2-(CI -4 alkylacyl), where Ci -4 alkylacyl is as defined above.
  • Carboxy (carboxylic acid): -C( 0)0H.
  • Ether -OP, wherein P is chosen from one of the following substituents: Ci -4 alkyl, benzyl, phenyl, Ci -4 fluoroalkyl, C 5-6 heteroaryl, -CH2-C 5-6 heteroaryl, C 4-6 heterocyclyl, and -CH2-C 4-6 heterocyclyl as defined above.
  • Examples of an ether include, but are not limited to, -OPh, -OBn, -OCFs, -OCH2CF3, -OCH(CH 3 ) 2 , -OCFh-cyclopropyl,
  • -0-(N-acetyl)azetidinyl e.g. -0-(N-acetyl)piperidinyl, e.g. -O-oxetanyl, e.g.;
  • Piperidyloxy e.g -0-(N- -O-tetrahydropyranyl, e.g.;
  • -NPP amino acid-N(H)pyridazinyl
  • P and P’ are independently chosen from H, Ci -4 alkyl, C 4-6 heterocyclyl, phenyl and C5-6 heteroaryl as defined above.
  • Examples of an amine include, but are not limited to, -NH2,-N(H)pyridazinyl,
  • -NH-(N-acetyl)azetidinyl e.g. -NH-(N-acetyl)piperidinyl, -NH-oxetanyl, e.g.;
  • Aminomethyl -CH 2 -Amino, where amino is as defined above.
  • Examples of aminomethyl include, but are not limited to, -CH 2 -NH 2 and -CH 2 -N(H)pyridazinyl.
  • Sulfonamido -SO 2 NRR’ wherein R and R’ are independently selected from H, C 1-4 alkyl, phenyl and C 5-6 heteroaryl as defined above.
  • R and R’ are independently selected from H, C 1-4 alkyl, phenyl and C 5-6 heteroaryl as defined above.
  • Examples of sulfonamido groups include, but are not limited to, -SC>2N(Me)2 and -SC>2NPhMe.
  • Sulfonamino -NHSO 2 R wherein R is selected from Ci -4 alkyl, phenyl and C 5-6 heteroaryl as defined above.
  • R is selected from Ci -4 alkyl, phenyl and C 5-6 heteroaryl as defined above.
  • Examples of sulfonamino groups include, but are not limited, to -NHSC> 2 Me and -NHS0 2 Ph.
  • Sulfone -SO 2 R, wherein R is selected from Ci -4 alkyl and Ci -4 fluoroalkyl as defined above.
  • R is selected from Ci -4 alkyl and Ci -4 fluoroalkyl as defined above.
  • Example of sulfone groups includes but is not limited to SO 2 CF 3 .
  • Sulfoxide -SOR, wherein R is selected from Ci -4 alkyl and Ci -4 fluoroalkyl as defined above.
  • Example of sulfoxide groups includes but is not limited to SOCF 3 .
  • Nitrilemethyl -CH 2 -CN Fused N-heterocyclic ring: where A is phenyl, it may have a C 5-6 Ni-containing heterocyclic ring fused to it as a substituent group.
  • the C 5-6 Ni-containing heterocyclic ring may in particular be selected from:
  • N ring atom which may be fused in any orientation, and wherein the N ring atom may be optionally substituted, for example by a Ci -4 alkylacyl group.
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 ), a salt or solvate thereof, as well as conventional protected forms.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as AG 3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e. NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + , NhbfV, NHR 3 + , NFV).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
  • glucheptonic, gluconic, glutamic glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, trifluoroacetic acid and valeric.
  • suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • Certain compounds of the invention may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; o and b-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as“isomers” (or“isomeric forms”).
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms“racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the compounds of the invention can be prepared using procedures described in detail in the documents set out under points (i)-(xix) above, in particular WO 2016/034673.
  • the reaction conditions referred to are illustrative and non-limiting, for example one skilled in the art may use a diverse range of synthetic methods to synthesise the desired compounds such as but not limited to methods described in additional literature (for example but not limited to March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition or Larock’s Comprehensive Organic Transformations: Comprehensive Organic Transformations: A Guide to Functional Group Preparations).
  • compositions according to the present disclosure may comprise, in addition to the active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such a gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the therapeutic agent is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • other pharmaceutically acceptable ingredients such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • the DNA methyl transferase (DNMT) family of enzymes catalyse the transfer of a methyl group to DNA.
  • exemplary members of the DNMT family include DNMT 1 , DNMT3A and DNMT3B.
  • DNMT3A, and DNMT3B symmetrically methylate cytosines in the dinucleotide Cytosine- phosphate-Guanine (CpG) on both strands of unmethylated DNA.
  • the combinations of compounds of this invention includes at least one compound that is a DNMT inhibitor.
  • the DNMT inhibitor exhibits selectivity for one or more DNMT enzymes.
  • the DNMT inhibitor exhibits selectivity for DNMT3, more preferably DNMT3A.
  • the DNMT inhibitor used in this invention may be a cytidine analogue such as decitabine or azacitidine.
  • a given compound acts as a DNMT inhibitor using standard techniques and assays known in the art, e.g. by using decitabine or azacitidine as a reference (comparator) control agent.
  • a given compound can be identified as a DNMT inhibitor by demonstrating reduced DNA methylation in the nucleus of cells treated with the compound using bisulphite sequencing of DNA from the treated cells.
  • Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the subject.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of primary human bone marrow CD34+ cells or in non-human primate models.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Based on such pilot experiments, useful doses and routes for administration in humans can be determined.
  • a therapeutically effective dose refers to that amount of active ingredient, for example a nucleic acid or a protein of the invention or an antibody, which is sufficient for treating a specific condition.
  • Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as LD50/ED50.
  • Pharmaceutical compositions, which exhibit large therapeutic indices, are preferred.
  • the dosage is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage employed, sensitivity of the patient, and the route of administration. The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect.
  • Factors which may be taken into account, include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week or once every two weeks depending on half-life and clearance rate of the particular formulation. Normal dosage amounts may vary from 0.1 to 100,000 micrograms, up to a total dose of about 1 g, depending upon the route of
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • Medicaments and pharmaceutical compositions according to aspects of the present invention may be formulated for administration by a number of routes, including but not limited to, parenteral, intravenous, intra-arterial, intramuscular, intratumoural, oral and nasal.
  • the medicaments and compositions may be formulated in fluid or solid form.
  • Fluid formulations may be formulated as aqueous solutions for administration by injection to a selected region of the human or animal body.
  • the patient to be treated may be any animal or human.
  • the subject is preferably mammalian, more preferably a placental mammal and most preferably a human.
  • the subject may be a non- human mammal, but is more preferably human.
  • the subject may be male or female.
  • the subject may be a patient.
  • Therapeutic uses may be in human or animals (veterinary use).
  • Figure 1 FACS analysis showing percentage fetal hemoglobin expression in human bone marrow derived CD34+ cells treated with DMSO; a PRMT5i of the invention, Compound 1 , denoted‘PRMTi’; Decitabine; and a combination of Compound 1 and Decitabine, denoted ‘PRMT5i and Decitabine’, which combination is an exemplary combination of this invention.
  • FIG. 1 DNA methylation analysis of CpG sites at positions -160, -51 , -48, +5, +16 and +49 relative to the transcriptional start site of the g-globin promoter, following treatment with DMSO (vehicle), a PRMT5i of the invention, Compound 1 , denoted‘PRMTi’, Decitabine and a combination of Compound 1 and Decitabine, denoted‘PRMT5i + Decitabine’.
  • Figure 3 FACS analysis showing percentage cell viability (panel A) and percentage of cells expressing fetal hemoglobin (panel B) in human bone marrow derived CD34+ cells treated with the PRMT5i inhibitor Compound 1 at 30 nM and 100 nM (labelled C1 / 30 and C1 / 100) or its enantiomer Compound 2 at 100 nM (labelled as C2 / 100), alone or in combination with
  • Figure 4 Fold-increase in globin RNA expression levels in in human bone marrow derived CD34+ cells treated with the PRMT5i inhibitor Compound 1 at 30 nM and 100 nM (labelled‘30’ and ⁇ 00’) or its enantiomer Compound 2 at 100 nM (labelled as‘Enatnt’), alone or in combination with Decitabine at 10 nM and 30 nM.
  • Upper panel shows a-globin RNA levels
  • center panel shows b-globin RNA levels
  • lower panel shows g-globin RNA levels.
  • Panel A Percentage of HbF positive cells,‘F-cells’; and percentage of HbF as a percentage of total hemoglobin at time points from day 1 to day 64, in animals that had been treated with decitabine only at days 14 and 22 (gray plot), or with decitabine at day 14 followed by decitabine and a PRMT5i at day 22 (black plot).
  • Panel B Ratio of hemoglobin-g to total hemoglobin (i.e. hemoglobin-g and b) mRNA levels following PRMT5i treatment alone, decitabine treatment alone, or a combination of decitabine and PRMT5L
  • Panel A Percentage of HbF positive cells,‘F-cells’; and percentage of HbF as a percentage of total hemoglobin at time points from day 1 to day 78, in animals that had been treated with a combination of decitabine and tetrahydrouridine (THU) at days 14 and 22 (gray plot), or with decitabine and THU at day 14 followed by decitabine, THU and a PRMT5i at day 22 (black plot).
  • Panel B Ratio of hemoglobin-g to total hemoglobin (i.e. hemoglobin-g and b) mRNA levels following treatment with vehicle, with a combination of decitabine and THU, or with a combination of decitabine, THU and PRMT5L
  • Figure 7 shows the raw data of the percentage of F-cells from each animal from the first and second cohorts. Dashed and solid lines represent animals treated with combinations of the invention (decitabine and a PRMT5i). X-axis denotes treatment day; Y-axis denotes
  • Figure 8 shows the methylation patterns of the g-globin promoter in baboon bone marrow- derived mononuclear cells.
  • Key regions of the g-globin promoter denoted CpG+49, CpG+16 and CpG+5, each have eight cytosine residues, which can be methylated (5mC) shown as light gray squares, or demethylated (cytosine) shown as black squares.
  • Figure 9 shows an aggregation of the methylation data of Figure 8.
  • the percentage mCpG of the cells treated with decitabine alone (3 rd bar) is not significantly different from the percentage mCpG of the cells treated with a combination of decitabine and the PRMT5i L-1353 (4 th bar).
  • Panel A is a 2D PCA plot of the data from three repeated gene expression analyses on human erythroblasts treated with the PRMT5i L-1353 (positioned at the centre-left of the plot), the enantiomer compound (positioned at lower part of the plot), decitabine (centre-right of the plot) and with a combination of decitabine and L-1353 (at the top of the plot).
  • Panel B presents Venn diagrams respectively showing the number of genes in which expression is increased (left hand diagram) and decreased (right hand diagram) in human erythroblasts treated with decitabine, with the PRMT5i L-1353, and with a combination of decitabine and the PRMT5i L-1353.
  • FIG 11 The upper panel shows a schematic of erythroid cell subtype development.
  • the lower panel shows how erythroid cell subtype development can proceed following treatment with the PRMT5i L-1353, its enantiomer compound, decitabine, or a combination of decitabine and L-1353.
  • the hematopoietic stem cell count starts near 100 in each plot before falling away on day 3 and 5 (light gray).
  • the BFU-E/early CFU-E count rises from about zero on day 0 in each plot and rises to approximately 40 on day 3 before falling away (dark gray).
  • the pro- erythroblast count starts from just above zero on day 0 in each plot before rising to a peak on day 7 for the enantiomer and L-1353 and on day 5 for the decitabine and combination-treated cells (dark gray).
  • the basophilic erythroblast count starts at about zero on day 0 in each plot and rises gradually to peak at day 12 or 14 at around 30-40 for enantiomer and L-1353 treated cells, and around 70-80 for the decitabine and combination-treated cells (light-medium gray).
  • the orthochromatic erythroblast count starts from about zero on day 0 in each plot and does not begin to rise until about day 10 or day 12 in each plot (dark-medium gray).
  • the F-cell count starts at zero in each plot and rises to the top portion of each plot on day 14 or 17 (black).
  • Figure 12 shows expression of HbF transcriptional repressors GATA2, GATA1, KLF1 and BCL11A in basophilic erythroblasts (upper plots) and pro-erythroblasts (lower plots)
  • Figure 13 shows expression of HbF transcriptional repressors GATA2, GATA1, KLF1 and BCL11A in bone marrow cells from baboons treated with the PRMT5i L-1353, its enantiomer compound, decitabine, or a combination of decitabine and L-1353.
  • the expression levels of GATA2, KLF1 and BCL11A are reduced in animals treated with the combination of decitabine and L-1353, relative to animals treated with either decitabine or L-1353 alone.
  • PRMT5 inhibitors are a component of the combination therapies according to this invention.
  • Suitable PRMT5i compounds have been described previously, for instance in the International patent (PCT) applications listed above as (i)-(xix), the contents of which are incorporated in its entirety, which describe synthesis methods for PRMT5i compounds.
  • PRMT5i activity can be assessed by methods known in the art, for instance by using the PRMT5 biomarker and biochemical assays disclosed in the PCT applications listed as (i)-(xix).
  • n is 1. In some embodiments, n is 2.
  • p is 0. In some embodiments, p is 1.
  • R 1 represents one to four Me or halo groups, preferably one to three Me or halo groups and more preferably one or two Me or halo groups. In some of these embodiments, R 1 may represent F. In others of these embodiments, R 1 may represent Me groups.
  • R 2a , R 2b , R 2c and R 2d are independently selected from H, F, CH 2 OH and Me. In some of these embodiments, R 2a , R 2b , R 2c and R 2d are independently selected from H, Me and CH 2 OH. In further of these embodiments, R 2a , R 2b , R 2c and R 2d are independently selected from H and Me.
  • R 2a , R 2b , R 2c and R 2d are all H.
  • R 2a , R 2b , R 2c and R 2d are comprised of three H and one Me or CH 2 OH group. It may be preferred in these embodiments that R 2a is Me and R 2b , R 2c and R 2d are H. It may be preferred in these embodiments that R 2c is Me or CH 2 OH and R 2a , R 2b and R 2d are H.
  • R 2a , R 2b , R 2c and R 2d are comprised of two H and two Me groups. It may be preferred in these embodiments that R 2a and R 2c are Me and R 2b and R 2d are H. It may be preferred in these embodiments that R 2a and R 2b are Me and R 2c and R 2d are H. It may also be preferred in these embodiments that R 2c and R 2d are Me and R 2a and R 2b are H.
  • R 3a and R 3b are independently selected from H and Me. In some embodiments R 3a is H and R 3b is Me. In some embodiments R 3a and R 3b are both H. In some embodiments R 3a and R 3b are both Me.
  • R 4 is H. In some embodiments R 4 is Me.
  • R 5 is H. In some embodiments R 5 is Me.
  • R 6a and R 6b are independently selected from H and Me. In some embodiments R 6a is H and R 6b is Me. In some embodiments R 6a and R 6b are both H. In some embodiments R 6a and R 6b are both Me.
  • the carbon to which R 4 is attached is a chiral centre.
  • the compound is a mixture of stereoisomers at this centre.
  • the compound is a single stereoisomer.
  • the compound is the (RJ-stereoisomer.
  • the compound is the (SJ- stereoisomer.
  • the compound may also include further chiral centres.
  • the carbon in the THIQ moiety is chiral.
  • the compound is a mixture of stereoisomers at this centre.
  • the compound is a single stereoisomer at this centre.
  • the compound is the (R)- stereoisomer at this center.
  • the compound is the (S,)- stereoisomer at this centre.
  • the compound may be a single diastereomer or a mixture of diastereomers.
  • the compounds may have one of the following stereochemistries:
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 , R 5 , R 6a and R 6b are all H, n is 1 and P is 0, and thus the compound of formula IIA is of formula V:
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 , R 5 , R 6a and R 6b are all H, n is 1 and p is 1 , and thus the compound of formula IIA is of formula VI:
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 , R 5 , R 6a are all H, n is 1 and p is 0, and R 6b is Me and thus the compound of formula IIA is of formula VII:
  • the optional substituent on A is Ci -4 alkyl, it may be preferably selected from methyl, ethyl, / ' - Pr, f-Bu.
  • the optional substituent on A is Ci -4 fluoroalkyl, it may preferably be selected from -CF3 and -CF2H .
  • the optional substituent on A is C5-6 heteroaryl, it may be substituted by one or more Ci -4 alkyl groups. These groups may preferably be on one or more of the nitrogen ring atoms (if present). These groups may also preferably be methyl.
  • the optional substituent on A is C5-6 heteroaryl, it may preferably be selected from pyridizinyl, pyrimidinyl, pyridinyl, pyrazolyl, pyrazinyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, benzimidazolyl and thiadiazolyl.
  • the optional substituent on A is C5-6 heteroaryl methyl, it may preferably be selected from -CFh-imidazolyl and -CFh-triazolyl.
  • the optional substituent on A is C5-6 heterocyclyl, it may preferably be morpholino.
  • the optional substituent on A is C5-6 heterocyclyl methyl, it may preferably be selected from -CFh-morpholino and -CFh-piperazinyl.
  • the optional substituent on A is phenyl, it may be substituted by one or more Ci -4 alkyl groups. These groups may preferably be methyl.
  • the optional substituent on A is phenyl, it may be substituted by one or more Ci -4 fluoroalkyl groups. These groups may preferably be trifluoromethyl.
  • the optional substituent on A When the optional substituent on A is phenyl, it may be substituted by one or more Ci -4 alkoxy groups. These groups may preferably be methoxy. When the optional substituent on A is phenyl, it may be substituted by one or more halo substituents. These groups may preferably be fluoro or chloro, more preferably fluoro.
  • the optional substituent on A is phenyl, it may be substituted by one or more cyano groups. It may be preferred that there is a single cyano substituent.
  • the optional substituent on A is halo, it may preferably be selected from F, Cl and Br.
  • Further cyclic amido groups include:
  • Further cyclic amidomethyl groups include:
  • Ci -4 alkylacyl it may preferably be selected from
  • the optional substituent on A is ether, it may preferably be selected from methoxy, ethoxy, -OBn, -OPh, -OCF3,-OCF 2 H, -0-(C 6 H )-CN, -O-oxanyl, -OCH 2 pyridinyl,
  • the amino substituent may be a C5-6 heteroaryl group, in which case the amino group may preferably be selected from -NH-pyrazinyl, -NH- pyrimidine.
  • the amino substituent may be a C 4-6 heterocyclyl group, such as optionally N-substituted azetidinyl, optionally N-substituted piperidinyl and oxetanyl.
  • a further amino group may be:
  • the optional substituent on A is aminomethyl, it may preferably be -CH 2 NH 2 .
  • the amino substituent may be as defined above
  • the optional substituent on A is sulfonamido it may preferably be selected from -S0 2 NMePh, -S0 2 NMe 2 , and -S0 2 NHEt.
  • the optional substituent on A is sulfonamino, it may preferably be selected from
  • the optional substituent on A is sulfone, it may preferably be -S0 2 CF 3 .
  • A may be an optionally substituted phenyl.
  • A is unsubstituted phenyl.
  • the phenyl of A has 1 , 2, 3, 4 or 5 substituents.
  • the phenyl of A has 1 or 2 substituents.
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 and R 5 are all hydrogen and n is 1 .
  • p may be 0 or 1.
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 and R 5 is not hydrogen.
  • both R 6a and R 6b may be H.
  • R 1 6 and n and p are such that the compound is of formula V, VI or VII.
  • the optional substituents are independently selected from the following: Ci -4 alkyl; Ci -4 fluoroalkyl; C3-6 cycloalkyl; C5-6 heteroaryl; C5-6 heteroaryl methyl; C 4-6 heterocyclyl; C 4-6 heterocyclyl methyl; phenyl; benzyl; halo; amido;
  • the optional substituent is a C5-6 heteroaryl group
  • the heteroaryl ring itself is substituted with one or more Ci -4 alkyl groups.
  • Halo and methoxy (including CF 3 0) substituents may be preferred in the ortho position of the phenyl group.
  • Ethoxy and alkyl (e.g. methyl, CF 2 H and CF 3 ) substituents may also be preferred in the ortho position of the phenyl group.
  • Alkyl and C5-6 heteroaryl may be preferred in the meta position of the phenyl group.
  • Amido and amidomethyl substituents may be preferred in the para position of the phenyl group.
  • Particular favoured groups in the ortho position are ethoxy, methoxy, Cl, F and CF 2 H.
  • the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group.
  • the phenyl group bears an amino substituent in the meta position.
  • A may have a core structure selected from: Particular A groups of interest include:
  • A When A is naphthyl, it may be in any orientation, e.g. naphth-1 -yl, naphth-2-yl.
  • A may be optionally substituted naphthyl. In some of these embodiments, A is unsubstituted naphthyl.
  • the naphthyl ring of A has 1 , 2, 3, 4 or 5 substituents.
  • the naphthyl ring of A has 1 or 2 substituents.
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 and R 5 are all hydrogen and n is 1 .
  • p may be 0 or 1.
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 and R 5 is not hydrogen.
  • both R 6a and R 6b may be H.
  • R 1 6 and n and p are such that the compound is of formula V, VI or VII.
  • Ci -4 alkyl independently selected from the following: Ci -4 alkyl; Ci -4 fluoroalkyl; C 3-6 cycloalkyl; C 5-6 heteroaryl; C 5-6 heteroaryl methyl; C 4-6 heterocyclyl; C 4-6 heterocyclyl methyl; phenyl; benzyl; halo; amido; amidomethyl; acylamido; acylamidomethyl; C 1-4 alkyl ester; C 1-4 alkyl ester methyl; C 1-4 alkyl carbamoyl; C 1-4 alkyl carbamoyl methyl; C 1-4 alkylacyl; C 1-4 alkyl acyl methyl; phenylcarbonyl; carboxy; carboxymethyl; ether; amino; aminomethyl; sulfonamido; sulfonamino; sulfone; nitrile; and nitrilemethyl.
  • A may be an optionally substituted C5-12 heteroaryl group.
  • A is unsubstituted C5-12 heteroaryl group.
  • the C5-12 heteroaryl of A has 1 , 2, 3, 4 or 5 substituents.
  • the C5-12 heteroaryl of A has 1 or 2 substituents.
  • the C5-12 heteroaryl ring is selected from one of the following: pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridonyl, imidazolyl, benzimidazolyl, imidazopyridinyl and quinolinyl.
  • the heteroatoms may be in any location in the ring, which may be joined to the remainder of the molecule via a ring carbon atom. It may be further preferred that the C5-12 heteroaryl ring is either pyridinyl or pyrimidinyl. It may also be further preferred that the C5-12 heteroaryl is selected from pyridyl, pyrimidinyl, oxazolyl, oxadiazolyl, pyrazolyl and thiazolyl and in particular:
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 and R 5 are all hydrogen and n is 1 .
  • p may be 0 or 1.
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4 and R 5 is not hydrogen.
  • both R 6a and R 6b may be H.
  • R 1 6 and n and p are such that the compound is of formula V, VI or VII.
  • the optional substituents are independently selected from the following: Ci -4 alkyl; Ci -4 fluoroalkyl; C3-6 cycloalkyl; C5-6 heteroaryl; C5-6 heteroaryl methyl; C 4-6 heterocyclyl; C 4-6 heterocyclyl methyl; phenyl; benzyl; halo; amido;
  • Ci -4 alkyl Ci -4 fluoroalkyl; C5-6 heteroaryl, C 4-6 heterocyclyl; phenyl; halo; and ether.
  • Halo and methoxy substituents may be preferred in the ortho position of a Ce heteroaryl group, or a-position of C5 and C7-12 heteroaryl group.
  • Amido and amidomethyl substituents may be preferred in the para position of a C 6 heteroaryl group, or g-position of C5 and C7-12 heteroaryl group.
  • a C 6 heteroaryl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position.
  • a C 6 heteroaryl group bears an amino substituent in the meta position.
  • a C5 or C7-12 heteroaryl group bears an amino substituent in the b- position.
  • C 6 heteroaryl group is 4-pyridyl
  • it may bear an ether substituent, for example in the
  • the ether substituent may be -O-C4-6 heterocyclyl, wherein the C4-6 heterocyclyl may itself bear an ester group (e.g. methoxy ester).
  • the C 6 heteroaryl group is 2-pyridyl, it may bear an amido substituent, for example in the
  • the C 6 heteroaryl group is 4-pyrimidinyl
  • it may bear an amino substituent, for example in the 3-position.
  • A is a C 5 heteroaryl group (e.g. oxazolyl, oxadiazolyl, pyrazolyl and thiazolyl), it may bear an amino, phenyl or C 6 heteroaryl substituent in the b-position.
  • A is selected from one of the following groups:
  • A is selected from one of the following groups:
  • the A group may be selected from:
  • heterocyclic group - in these groups the pyridyl N may be in the meta position; these groups may also have (in some embodiments) an ortho-ethoxy group; and
  • R N , R 1 , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 4b , R 5 , R 6a and R 6b are all hydrogen and that R 4a is OH and n is 1.
  • p may be 0 or 1.
  • Bone marrow samples were obtained from healthy human volunteers.
  • CD34+ cells were isolated from the bone marrow samples and stored at -80 ° C in freeze media composed of RPMI (50%) FBS (10%) and DMSO.
  • RPMI 50%) FBS (10%)
  • DMSO DMSO
  • the isolated CD34+ cells were thawed and seeded into a 6-well plate containing 3 ml. of Erythroid Growth and Differentiation Medium (EGDM), prepared according to Table I.
  • EGDM Erythroid Growth and Differentiation Medium
  • the CD34+ cells were incubated in EGDM for 3 days at 37 ° C and 10% CO2.
  • Human bone marrow derived CD34+ cells originating from three donors, were prepared according to Example 1 and were then treated for 7 days with EGDM supplemented with the following compounds:
  • the CD34+cells were passaged on day 2 and day 4 (split to a cell concentration of 2x10 5 cells/mL); and were harvested by centrifugation on day 7. Some of the harvested cells were analyzed by FACS, as described below. FACS staining was performed as follows.
  • Permeabilization The washed/pelleted cells are resuspended and vortexed in 0.5 ml. 0.1 % Triton-X100® (Polyoxyethylene octyl phenyl ether). Incubate for 10 minutes at room temperature.
  • Triton-X100® Polyoxyethylene octyl phenyl ether
  • the stained cells were resuspended in PBS/2 mM EDTA/pH 7.4 and analyzed on a FACS Canto II.
  • Live/Dead stain Harvested cell pellets are resuspended in LIVE/DEADTM Fixable Violet Dead Cell Stain Kit, for 405 nm excitation (Thermo Scientific, #L34955) at 1 :500 dilution in 1 xPBS; incubate for 30 min in the dark at room temperature
  • Figure 1 shows the percentage of cells stained by Pharmingen #560041 (HbF+ cells) in each treatment group, as analyzed by FACS.
  • the combination of the PRMT5i, Compound 1 plus Decitabine achieves a synergistic induction of HbF (39% +/- 8.8%) compared with 6% +/-1 .0% for Compound 1 alone and 17% +/- 1 .2% for Decitabine alone.
  • Genomic DNA was extracted using the DNeasy® Blood & Tissue kit from Qiagen according to the manufacturer’s instructions.
  • 1x10 6 CD34 + cells were resuspended in 200 pl_ 1 xPBS.
  • 20 mI_ Proteinase K and 200 mI_ Buffer AL were added to the cells, mixed thoroughly and incubated at 56 ° C for 10 min.
  • 200 mI_ of 96-100 % Ethanol were added and the mixture loaded onto a Mini spin column. The column was spun, and the bound DNA washed twice with 500 mI_ of Buffer AW1 and AW2.
  • the DNA was eluted with 200 mI_ Buffer AE.
  • Human bone marrow derived CD34+ cells obtained from a healthy donor according to the methods in Example 1 ) were treated for 7 days with EGDM supplemented with the following compounds:
  • the CD34+ cells were passaged on day 2 and day 4 (split to a cell concentration of 2x10 5 cells/mL); and were harvested by centrifugation on day 7. Some of the harvested cells were analyzed by FACS. The FACS staining method was as described above in Example 2. A separate portion of the harvested cells was resuspended in Trizol for RNA extraction.
  • Figure 3 shows the results of the FACS experiment.
  • RNA which was extracted from the cell portion that was resuspended in Trizol, was used for cDNA synthesis, as follows: 250 ng RNA was and 1 mI_ anchored/oligo(dT)i 8 primer were mixed in water to total volume of 13 pL (template-primer mix). The template-primer mixture was denatured by heating the tube for 10 min at 65 ° C in thermal block (Biorad) before cooling to 4 ° C. Transcriptor reverse transcriptase (Roche #04379012001 ) was used according to manufacturer instructions with provided buffers and deoxynucleotide mix (1 hour at 50 ° C).
  • RT-qPCR was performed on the cDNA using the following primers:
  • Human alpha globin F: tcaagctcctaagccactgc
  • Human beta globin F: acgtggatgaagttggtggt
  • Human gamma globin F: ctgcatgtggatcctgagaa
  • RNA5-8S5 F gtaacccgttgaaccccatt
  • hHPRTI F gaaaaggaccccacgaagtgt
  • Figure 4 shows the results of the PCR study of mRNA expression levels. Expression of y- globin mRNA is shown in the lower panel. Treatment with the PRMT5i compounds in combination with 30 nM Decitabine causes a dramatic increase in g-globin mRNA, compared to g-globin RNA levels following treatment with the PRMT5i compounds when administered alone. The observed combination benefit in a-globin and b-globin mRNA levels was unexpected and may provide further clinical benefit.
  • Baboons were used for this study because they are higher primates, which switch from fetal hemoglobin in a similar manner to humans.
  • the inventors firstly compared a combination of the invention (decitabine plus the PRMT5 inhibitor L-1353) with decitabine alone.
  • the inventors compared a triple combination of the invention (decitabine plus the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) and L-1353) with decitabine plus THU.
  • CDA cytidine deaminase
  • THU tetrahydrouridine
  • the CDA inhibitor THU was used because decitabine is rapidly metabolized in liver and intestine due to the activity of CDA resulting in a half-life of less than 15 min; therefore THU potentiates the action of decitabine and reduces the doses needed to achieve a strong effect. High concentrations of decitabine have been shown to result in off-target effects including cellular cytotoxicity, which are particularly pronounced in CDA-low tissues such as the bone marrow.
  • a cohort of two animals was dosed with decitabine and THU at day 14 followed by decitabine, THU and a PRMT5i at day 22, while a control cohort received a combination of decitabine and THU at day 14 and day 22.
  • the effect of these treatments on the percentage of cells expressing fetal hemoglobin (F-cells) and on the percentage of fetal hemoglobin is shown in Figure 6.
  • F-cells were detected in peripheral blood using the following FACS staining protocols:
  • Anti-Human Fetal Hemoglobin PE (BD Pharmingen #560041 ) at 1 :500 dilution.
  • the Alfred Pathology Service performs Hemoglobin Variant screening on the Primus Ultra2 HPLC (Trinity Biotech), utilizing the principles of ion exchange chromatography and high performance liquid chromatography (HPLC).
  • the analytical column contains an ion-exchange resin bound to a silica gel support. Separation of hemoglobin species is accomplished through the use of a gradient between two mobile phases with differences in salt concentration and pH. Hemoglobin species migrate through the column at rates determined by their individual physical properties, and spectrophotometrically detected at 413 nm. See also Clin Biochem Rev. 2010 Nov; 31 (4): S7-S52.
  • the hematocrit levels changed only marginally and are back on the normal range with the exeption of animal 03.
  • the platelet counts decreased to baseline levels.
  • the levels of reticulocytes were comparable to baseline.
  • the percentage of fetal globin expressing red blood cells showed a small upwards trend.
  • Four weeks of wash-out did not result in F-cell numbers returning to baseline, suggesting that the drug-mediated effects are retained despite cessation of the drug treatment.
  • the levels of reticulocytes remained low except animal 05 which surprisingly showed a spike to 3%.
  • the percentage of fetal globin expressing red blood cells (F-cells) slightly decreased in all animals except 08 which showed a small increase.
  • Mononuclear cells were isolated from baboon bone marrow as follows:
  • Genomic DNA was extracted using the DNeasy® Blood & Tissue kit from Qiagen according to the manufacturer’s instructions. Samples a) to c) were isolated on the 09/12/2016. The gDNA was used for Bisulfide-conversion using the EpiTect Fast DNA Bisulfite Kit from Qiagen #59824 according to the manufacturer’s instructions. The cycling conditions were as follows. Denaturation (95°C / 5 min); incubation (60°C / 10 min); denaturation (95°C / 5 min);
  • DNA methylation state of CpG’s were assessed by bisulfite conversion, PCR and sequencing.
  • a total of 1 pL from both amplicons were pooled into one PCR tube for library preparation using the Nextera XT indexing kit (lllumina #47403 496) with GoTaq Polymerase. After PCR amplifcation, the samples were purified with the MinElute PCR Purification kit from Qiagen # 28004 according to the manufacturer's instructions. Global DNA methylation levels could be summarized. Data from bismark could be then used in visualization software such as methpat. A multiqc report was generated after alignment to the hg19 human reference genome using Bismark.
  • PRMT5 plays a critical role in triggering coordinated repressive epigenetic events that culminate in DNA methylation and transcriptional silencing of the g-genes (Rank et al., 2010).
  • the inventors had expected to find an additive effect of the global methyl transferase inhibition caused by the decitabine and the specific inhibition of the methylation of the g-globin promoter caused by the PRMT5L The inventors were surprised to find no such effect.
  • CD34+ cells isolated from the bone marrow of healthy human volunteers were thawed, seeded into a 6-well plate containing 3 ml. of Erythroid Growth and Differentiation Medium and incubated at 37C, 10% CO2 for three days. Cells were then treated with 100 nM of the PRMT5i L-1353, or 100 nM of its enantiomer compound, or 30 nM decitabine, or a combination of 100 nM L-1353 and 30 nM decitabine, for seven days in the same media under the same conditions. Samples were then prepared for ATACseq analysis as follows:
  • sequencing reads were aligned to the human genome hg19 and analysed on the
  • FIG. 10B The Venn diagram of Figure 10B shows that the six different treatment conditions share some ATAC-Seq peaks while most also have unique peaks that would indicate drug-specific peaks. Due to the wide spread of the data sets within the biological replicates and heterogeneity of the samples within the different treatment groups, it was not possible to make a definitive
  • CD34+ cells isolated from the bone marrow of healthy human volunteers were thawed and seeded into a 6-well plate containing 3 mL of Erythroid Growth and Differentiation Medium and incubated at 37C and 10% CO2 for 3 days.
  • the cells were then treated with 100 nM of the PRMT5i L-1353, or 100 nM of its enantiomer compound, or 30 nM decitabine, or a combination of 100 nM L-1353 and 30 nM decitabine for 14 days.
  • Cell types were determined by FACS using anti-human CD34-APC at 1/100 dilution (BD Pharmingen #561209); anti-human CD36- FITC at 1/200 dilution (BD Pharmingen #561820); and anti-human CD235a-PeCy7 at 1/200 dilution (BD Pharmingen #563666). The results are shown in Figure 11.
  • a fourth part of this investigation aimed to determine the trancript levels of known globin regulators (negative and positive) in pro-erythroblasts and basophilic erythroblasts differentiated in vitro from human bone marrow-derived CD34+ cells, sorted via FACS and treated with L- 1353 and/or decitabine, or in bone marrow cells taken from the treated baboons.
  • the human bone marrow-derived pro-erythroblast and basophilic erythroblast cells were treated for 7 days with 100 nM of the PRMT5i L-1353, or 100 nM of its enantiomer compound, or 30 nM decitabine, or a combination of 100 nM L-1353 and 30 nM decitabine.
  • transcript levels were determined via RT-qPCR. The results are shown in Figure 12 and Figure 13. These results indicate that the expression of HbF transcriptional repressors GATA2, KLF1 and BCL11A is repressed by combining decitabine with L1353.

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Abstract

La présente invention concerne une méthode de traitement des hémoglobinopathies telles que la drépanocytose et la β-thalassémie grâce à l'administration au patient d'une combinaison de composés. L'invention concerne également des compositions comprenant la combinaison de composés pour utilisation dans lesdites méthodes.
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CN113493438A (zh) * 2020-03-20 2021-10-12 江苏先声药业有限公司 四氢异喹啉类化合物
WO2022002142A1 (fr) * 2020-06-30 2022-01-06 江苏先声药业有限公司 Composés de tétrahydroisoquinoline et leur utilisation
US11492350B2 (en) 2020-07-31 2022-11-08 Tango Therapeutics, Inc. Compounds and methods of use
WO2023125947A1 (fr) * 2021-12-30 2023-07-06 江苏先声药业有限公司 Sel pharmaceutiquement acceptable de composé tétrahydroisoquinoléine, forme cristalline et utilisation associée
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US11986471B2 (en) 2018-07-18 2024-05-21 Tango Therapeutics, Inc. Compounds and methods of use
US12403137B2 (en) 2019-10-28 2025-09-02 Tango Therapeutics, Inc. Compounds and methods of use
CN113493438A (zh) * 2020-03-20 2021-10-12 江苏先声药业有限公司 四氢异喹啉类化合物
CN113493438B (zh) * 2020-03-20 2023-10-20 南京再明医药有限公司 四氢异喹啉类化合物
WO2022002142A1 (fr) * 2020-06-30 2022-01-06 江苏先声药业有限公司 Composés de tétrahydroisoquinoline et leur utilisation
US11492350B2 (en) 2020-07-31 2022-11-08 Tango Therapeutics, Inc. Compounds and methods of use
US11999727B2 (en) 2020-07-31 2024-06-04 Tango Therapeutics, Inc. Compounds and methods of use
US12264154B2 (en) 2020-07-31 2025-04-01 Tango Therapeutics, Inc. Compounds and methods of use
US12304907B2 (en) 2020-07-31 2025-05-20 Tango Therapeutics, Inc. Compounds and methods of use
WO2023125947A1 (fr) * 2021-12-30 2023-07-06 江苏先声药业有限公司 Sel pharmaceutiquement acceptable de composé tétrahydroisoquinoléine, forme cristalline et utilisation associée

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