WO2025043191A1 - Inhibiteurs de prc2 destinés à être utilisés dans le traitement de la drépanocytose - Google Patents

Inhibiteurs de prc2 destinés à être utilisés dans le traitement de la drépanocytose Download PDF

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WO2025043191A1
WO2025043191A1 PCT/US2024/043672 US2024043672W WO2025043191A1 WO 2025043191 A1 WO2025043191 A1 WO 2025043191A1 US 2024043672 W US2024043672 W US 2024043672W WO 2025043191 A1 WO2025043191 A1 WO 2025043191A1
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Lori S. Friedman
Pratik Sharad MULTANI
Edna Chow Maneval
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Oric Pharmaceuticals Inc
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Oric Pharmaceuticals Inc
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • 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
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C.
  • XRPD x-ray powder diffraction
  • Example 32 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6° ⁇ 0.2° 2-theta, 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2-theta, and 22.0° ⁇ 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • Example 32 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, and (b) exhibits less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • Example 32 exhibits less than about 10% degradation when the crystalline forms are stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • Example 32 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 8. 1° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • Example 32 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 9.6° ⁇ 0.2° 2-theta, 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2-theta, and 22.0° ⁇ 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • Example 32 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • Example 32 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, 13.7° ⁇ 0.2° 2-theta, and 19.2° ⁇ 0.2° 2- theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • compositions comprising a PRC2 inhibitor as disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent for use in the treatment of sickle cell disease in a subject.
  • Compounds of the disclosure may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • compounds disclosed herein are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.
  • compositions according to the disclosure may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
  • salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succin
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsul
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount without causing serious toxic effects in the subject treated.
  • a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0. 1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day.
  • a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • Embodiment 1 A method of treating sickle cell disease in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2), wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has: a. been administered hydroxyurea; and/or b. been administered a stable dose of one or more of voxelotor, crizanlizumab, and L- glutamine.
  • PRC2 polycomb repressive complex 2
  • Embodiment 2 The method of embodiment 1, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced: a. one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug-drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea; or b.
  • VOC vaso-occlusive crisis
  • ACS acute chest syndrome
  • voxelotor continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g/dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug -drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.
  • Embodiment 3 The method of embodiment 2, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug -drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea.
  • VOC vaso-occlusive crisis
  • ACS acute chest syndrome
  • Embodiment 4 The method of embodiment 2, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g/dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug -drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab,
  • Embodiment 6 The method of embodiment 5, wherein in the 6-month period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period; (b) episodes of acute chest syndrome (ACS); (c) an inability to tolerate continued administration of hydroxyurea; (d) unmanageable drug -drug interactions with the continued administration of hydroxyurea; and (e) the subject’s refusal to continue the further administration of hydroxyurea.
  • PRC2 inhibitor of polycomb repressive complex 2
  • VOC vaso-occlusive crisis
  • Embodiment 7 The method of embodiment 6, wherein the inability to tolerate continued administration of hydroxyurea is characterized by one or more of the following: (a) allergic reaction to the administration of hydroxyurea; (b) hematologic toxicity; (c) inability to tolerate gastrointestinal side effects; (d) intolerable fatigue; (e) intolerable dizziness; (f) intolerable headaches; (g) intolerable fever; (h) intolerable leg ulcers; and (i) intolerable skin changes.
  • Embodiment 8 The method of embodiment 7, wherein the hematologic toxicity is characterized by a decrease in one or more of red blood cells, white blood cells, and platelets.
  • Embodiment 9 The method of embodiment 7, wherein the gastrointestinal side effects are selected from one or more of nausea, vomiting, diarrhea, and abdominal pain.
  • Embodiment 10 The method of embodiment 1, wherein the subject has been administered one or more of voxelotor, crizanlizumab, and L-glutamine prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).
  • PRC2 poly comb repressive complex 2
  • Embodiment 11 The method of embodiment 10, wherein the subject has been administered voxelotor prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).
  • PRC2 poly comb repressive complex 2
  • Embodiment 12 The method of embodiment 11, wherein the subject has further exhibited one or more of (a) a failure to increase hemoglobin (Hb) by at least 1 g/dL, (b) an inability tolerate continued administration of voxelotor, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of voxelotor, and (d) the subject’s refusal to continue the further administration of voxelotor.
  • Embodiment 13 The method of embodiment 10, wherein the subject has been administered crizanlizumab prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2).
  • PRC2 polycomb repressive complex 2
  • Embodiment 14 The method of embodiment 13, wherein the subject has further exhibited one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period, (b) an inability tolerate continued administration of crizanlizumab, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of crizanlizumab, and (d) the subject’s refusal to continue the further administration of crizanlizumab.
  • VOC vaso-occlusive crisis
  • Embodiment 15 The method of embodiment 10, wherein the subject has been administered L- glutamine prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2).
  • PRC2 polycomb repressive complex 2
  • Embodiment 16 The method of embodiment 15, wherein the subject has further exhibited one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period, (b) an inability tolerate continued administration of L- glutamine, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of L-glutamine, and (d) the subject’s refusal to continue the further administration of L- glutamine.
  • VOC vaso-occlusive crisis
  • Embodiment 17 The method of any one of embodiments 1 to 16, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced one or more of: a. 4 or more vaso-occlusive crisis (VOC) events over the prior 12-month period; b. 2 or more vaso-occlusive crisis (VOC) events over the prior 6-month period; c. 2 or more vaso-occlusive crisis (VOC) events over the prior 12-month period and at least one of one or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism; d. 2 or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism over the prior 12-month period; e. pulmonary hypertension; and f. chronic kidney disease.
  • VOC vaso-occlusive crisis
  • VOC vaso-occlusive crisis
  • ACS acute chest syndrome
  • Embodiment 18 The method of embodiment 17, wherein the pulmonary hypertension is characterized by one or more of (a) tricuspid regurgitant jet velocity (TRV) of greater than or equal to 3.0 m/s; (b) TRV of greater than or equal to 2.5 m/s and N-terminal pro b-type natriuretic peptide (NT- proBNP) plasma level of greater than or equal to 160 pg/mL; and (c) documented ongoing pulmonary hypertension diagnosed from previous echocardiogram or right-sided heart catheterization with mean pulmonary artery pressure greater than 25 mm Hg.
  • TRV tricuspid regurgitant jet velocity
  • NT- proBNP N-terminal pro b-type natriuretic peptide
  • Embodiment 19 The method of embodiment 17, wherein the chronic kidney disease is characterized by measurement on two separate and consecutive occasions of one or more of (a) an estimated glomerular fdtration rate (eGFR) of greater than or equal to 30 mL/min/1.73 m 2 and less than 60 mL/min/1.73 m 2 ; and (b) proteinuria characterized by an albumin to creatinine ratio greater than 300 mg/g or protein to creatinine ratio greater than 30 mg/mmol.
  • eGFR estimated glomerular fdtration rate
  • Embodiment 20 The method of any one of embodiments 1 to 19, wherein the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and hydroxyurea, voxelotor, crizanlizumab, or L-glutamine.
  • Embodiment 21 The method of any one of embodiments 1 to 20, wherein in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered one or more of hydroxyurea, voxelotor, crizanlizumab, and L- glutamine.
  • Embodiment 22 The method of any one of embodiments 1 to 21, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject: a. has not undergone major surgery, serious illness, infection, fever, significant bleeding, cerebrovascular accident, or seizure within 14 days prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); b.
  • CYP cytochrome P450
  • PRC2 polycomb repressive complex 2
  • c. has not received a bone marrow transplant or human stem cell transplant or gene therapy
  • d. has not received a vaccination in the 7 days prior to administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2)
  • PRC2 polycomb repressive complex 2
  • alanine aminotransferase is not exhibiting alanine aminotransferase of equal to or greater than 3 times the upper limit of normal (ULN), albumin less than 2.0 mg/dL, direct (conjugated) bilirubin greater than 1.5mg/dL, or prothrombin time greater than 1.5 ULN; f. does not have severe renal disease defined as eGFR less than 30 mL/min/1.73 m 2 ; g. is not undergoing dialysis; h. does not have a history of human immunodeficiency virus (HIV) infection, a history of hepatitis B infection, or active hepatitis C infection; i. is not receiving regularly scheduled transfusions; j .
  • HIV human immunodeficiency virus
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • Embodiment 23 The method of any one of embodiments 1 to 22, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject is contraindicated for transfusions.
  • PRC2 poly comb repressive complex 2
  • Embodiment 24 The method of any one of embodiments 1 to 23, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is an inhibitor of embryonic ectoderm development protein (EED).
  • PRC2 polycomb repressive complex 2
  • EED embryonic ectoderm development protein
  • Embodiment 25 The method of embodiment 24, wherein the inhibitor of embryonic ectoderm development protein (EED) is MAK683, pociredir (FTX-6058), APG-5918 (EEDi-5273), HJM-353, or BR-002.
  • EED embryonic ectoderm development protein
  • Embodiment 26 The method of embodiment 24, wherein the inhibitor of embryonic ectoderm development protein (EED) is a compound of Formula (I):
  • Z is O or S
  • X is O, CR 5 , CR 5 OH, or C(R 5 )2, wherein: when X is O, is a single bond; when X is C(R 5 )2, is a single bond; when X is CR 5 OH, is a single bond; or when X is CR 5 , is a double bond;
  • R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl and the cyclyl portion of the L-cycloalkyl, -N(R 5 )heterocyclyl, and L-heterocyclyl may be optionally substituted with one or more R 4 ;
  • R 2 is cyano, -COOR 5 or-C(O)N(R 5 )2, ;
  • R 3 is C1-C3 alkyl or halogen; each R 4 is independently oxo, cyano, halogen, -P(O)(OCi-C3)2, alkoxy, hydroxyl, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y’-heterocyclyl, -Y 2 -heterocyclyl, -L-N(R 5 )2, -O-L- N(R 5 ) 2 , -N(R 5 )CO(R 6 ), -O-L-OR 5 , -C(CF 3 )N(R 5 ) 2 , -Y
  • L is a bond or C1-C4 alkylene
  • Y 1 is a bond, -C(O)-, or -NHC(O)-;
  • Y 2 is a bond, -S-, -SO-, -SO2-, or -NR 5 SO2-, each R 5 is independently hydrogen or C1-C3 alkyl; or each R 5 taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R 6 ;
  • R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 7 is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R 5 )2, Ci-Ce alkyl or -Y’-heterocyclyl, wherein -Y’-heterocyclyl may be optionally substituted with one or more R 6 ; and n is 1 or 2.
  • Embodiment 27 The method of embodiment 26, wherein Z is O.
  • Embodiment 28 The method of embodiment 26, wherein Z is S.
  • Embodiment 29 The method according to any of embodiments 26 to 28, wherein n is 1.
  • Embodiment 30 The method according to any of embodiments 26 to 29, wherein R 2 is cyano.
  • Embodiment 31 The method according to any of embodiments 26 to 29, wherein R 2 is -
  • Embodiment 33 The method according to any of embodiments 26 to 32, wherein R 3 is halogen.
  • Embodiment 34 The method of embodiment 33, wherein the halogen is fluorine.
  • Embodiment 35 The method according to any of embodiments 26 to 33, wherein X is C(R 5 )2 and is a single bond.
  • Embodiment 36 The method according to any of embodiments 26 to 33, wherein X is CR 5 and is a double bond.
  • Embodiment 37 The method according to any of embodiments 26 to 33, wherein X is O and is a single bond.
  • Embodiment 38 The method according to any of embodiments 26 to 37, wherein R 1 is aryl optionally substituted with one or more R 4 .
  • Embodiment 39 The method of embodiment 38, wherein the aryl is phenyl optionally substituted with one or more R 4 .
  • Embodiment 40 The method of embodiment 39, wherein the phenyl is substituted with one, two or three R 4 .
  • Embodiment 41 The method of embodiment 40, wherein the one, two or three R 4 are each independently halogen, hydroxyl, haloalkyl, -COOR 5 , -Y’-Ci-Ce alkyl, Y 2 -Ci-Ce alkyl, -L-N(R 5 )2, -O-L- N(R 5 ) 2 , -C(CF3)N(R 5 )2, -Y’-N(R 5 )2, -Y 2 -N(R 5 )2,Y 2 -haloalkyl, -L-heterocyclyl, or -Y 1 -heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl or -Y 1 -heterocyclyl may be optionally substituted with one or more R 7 .
  • Embodiment 42 The method of embodiment 41, wherein R 4 is -Y'-Ci-Ce alkyl and Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl or pentyl.
  • Embodiment 43 The method of embodiment 41, wherein R 4 is -Y 2 -Ci-Ce alkyl and Y 2 is a - SO2- and the Ci-Ce alkyl is methyl.
  • Embodiment 44 The method of embodiment 41, wherein R 4 is -Y 2 -haloalkyl and Y 2 is -S- or - SO2- and the haloalkyl is trifluoromethyl.
  • Embodiment 45 The method of embodiment 41, wherein R 4 is -L-N(R 5 )2 and L is a bond and each R 5 is hydrogen, each R 5 is methyl, or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 46 The method of embodiment 41, wherein R 4 is -L-N(R 5 )2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl, or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 47 The method of embodiment 41, wherein R 4 is -Y'-N(R 5 )2, Y 1 is -C(O)- and each R 5 independently is hydrogen, each R 5 is independently methyl, or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 48 The method of embodiment 41, wherein R 4 is -Y 2 -N(R 5 ) 2 , Y 2 is -SO2- and each R 5 independently is hydrogen, each R 5 is methyl, or one R 5 is methyl and one R 5 is independently hydrogen.
  • Embodiment 49 The method of embodiment 41, wherein R 4 is -Y 1 -heterocyclyl and Y 1 is - C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.
  • Embodiment 50 The method of embodiment 41, wherein R 4 is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3X 2 -azabicyclo[3.1.0]hexanyl, each optionally substituted with one or more R 7 selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl and/or halogen.
  • Embodiment 51 The method of embodiment 41, wherein R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and/or halogen.
  • Embodiment 52 The method of embodiment 41, wherein R 4 is -Y 1 -heterocyclyl and Y 1 is - C(O)- and the heterocyclyl portion of the Y 1 -heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
  • Embodiment 53 The method of embodiment 41, wherein R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
  • Embodiment 54 The method of embodiment 53, wherein the -L-heteroaryl is tetrazolyl.
  • Embodiment 55 The method of embodiment 26, wherein R 4 is -POsCCi-Cs alkyl)2.
  • Embodiment 56 The method of embodiment 41, wherein R 4 is -COOR 5 .
  • Embodiment 57 The method of embodiment 26, wherein R 4 is hydroxyalkyl.
  • Embodiment 58 The method of embodiment 41, wherein R 4 is -O-L-N(R 5 )2.
  • Embodiment 59 The method of embodiment 26, wherein R 4 is aralkyl.
  • Embodiment 61 The method of embodiment 60, wherein the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H- pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R 4 .
  • Embodiment 62 The method of embodiment 61, wherein the heteroaryl is substituted with one or more R 4 ; wherein each R 4 is independently cyano, halogen, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R 5 )2, -Y’-N(R 5 )2, -L-heteroaryl, -L- heterocyclyl, or -Y 1 -heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y 1 -heterocyclyl may be optionally substituted with one or more R 7 .
  • Embodiment 63 The method of embodiment 62, wherein the heteroaryl is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl may be optionally substituted with one or more R 7 .
  • R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl may be optionally substituted with one or more R 7
  • Embodiment 64 The method of embodiment 63, wherein R 4 is -L-heteroaryl and L is methylene where the heteroaryl is pyridyl optional substituted with one or more R 7 .
  • Embodiment 65 The method of embodiment 63, wherein R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl.
  • Embodiment 66 The method of embodiment 63, wherein R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl.
  • Embodiment 67 The method of embodiment 63, wherein R 4 is -L-N(R 5 )2 where L is methylene and each R 5 is independently hydrogen, each R 5 is independently C1-C3 alkyl, or one R 5 is Ci- C3 alkyl and one R 5 is hydrogen.
  • Embodiment 68 The method of embodiment 63, wherein R 4 is -Y'-Ci-Ce alkyl where Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl or isopropyl.
  • Embodiment 69 The method of embodiment 63, wherein the heteroaryl is pyrazolyl optionally substituted with two R 4 groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y’-Ci-Ce alkyl.
  • Embodiment 70 The method of embodiment 63, wherein the heteroaryl is pyridyl optionally substituted with one R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, -Y’-N(R 5 )2, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or more R 7 .
  • R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, -Y’-N(R 5 )2, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or more R 7 .
  • Embodiment 71 The method according to any of embodiments 26 to 37, wherein R 1 is -L- cycloalkyl optionally substituted with one or more R 4 .
  • Embodiment 72 The method according to any of embodiments 26 to 37, wherein R 1 is -L- heterocyclyl optionally substituted with one or more R 4 .
  • Embodiment 73 The method of embodiment 72, wherein L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.
  • Embodiment 74 The method according to any of embodiments 26 to 28, wherein n is two.
  • Embodiment 75 The method of any one of embodiments 1 to 24, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is a compound selected from a compound disclosed herein.
  • Embodiment 76 The method according to any one of embodiments 1 to 75, wherein the method results in induction of fetal hemoglobin expression in erythroid cells.
  • Embodiment 77 The method according to any one of embodiments 1 to 75, wherein the method results in upregulation of mRNA levels of fetal hemoglobin protein in the subject.
  • Embodiment 78 The method according to any one of embodiments 1 to 75, wherein the method results in increased levels of fetal hemoglobin protein in the subject.
  • a method of treating sickle cell disease in a subject comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2) as disclosed herein.
  • PRC2 polycomb repressive complex 2
  • any of the methods disclosed herein wherein the method results in induction of fetal hemoglobin expression in erythroid cells.
  • any of the methods disclosed herein wherein the method results in upregulation of mRNA levels of fetal hemoglobin protein.
  • any of the methods disclosed herein wherein the method results in increased levels of fetal hemoglobin protein in the subject.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • other anti-neoplastic compounds e.g., chemotherapy
  • other treatments such as radiation or surgical intervention
  • the degree of mono- and dimethylation of histone H3K27 may be monitored in the subject using well known methods, including those described in Example A below, to access the effectiveness of treatment, along with other prognostic or biological factors, and dosages may be adjusted accordingly by the attending medical practitioner.
  • Inhibitors of polycomb repressive complex 2 are known to those of ordinary skill in the art or may be prepared by methods known to those having ordinary skill in the art.
  • the compounds of Formula (I) disclosed herein may be prepared using methods described in United States Patent No. 11,091,495, the contents of which are incorporated by reference herein for that purpose.
  • the compounds disclosed herein may also be prepared using methods known to those having ordinary skill in the art and commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art.
  • Halogenated Intermediate C containing a suitable R 2 reactant, e.g., an ester, in the presence of a suitable base is converted to acid intermediate by saponification, then treated with NH4CI in the presence of HATU to form the amide which is subsequently dehydrated to form nitrile Intermediate H.
  • R 1 is coupled to Intermediate H via a Suzuki reaction using boronic acid derivative (Y) in the presence of base.
  • Y boronic acid derivative
  • the nitrile group of R1 -containing Intermediate G is hydrolyzed in the presence of acid and water to afford title compound amide F.
  • An exemplary Intermediate A, Intermediate A-l may be used to synthesize compounds of formula (I).
  • a mixture of 6-amino-5 -bromo- lH-pyrimidin-2 -one (2.00 g, 10.5 mmol, 1.00 equiv) and ethyl 3-bromo-2-oxo-propanoate (3.12 g, 16.0 mmol, 2.00 m , 1.52 equiv) in DMF (20.0 m ) was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo to give a residue.
  • a second exemplary Intermediate A, Intermediate A-2 also may be used to synthesize compounds of formula (I).
  • ethyl 8-bromo-5-oxo-6H-imidazo[ 1 ,2-c]pyrimidine-2- carboxylate (3.00 g, 10.2 mmol, 1.00 equiv) in MeOH (60.0 mb) was added NaOH (1 M, 30.5 mb, 3.00 equiv).
  • the resultant mixture was stirred at 60 °C for 1 h. Subsequently, the reaction mixture was concentrated and the pH was adjusted to 4 with IM aq HC1 at which time a precipitate formed.
  • Intermediate A-2 may be prepared on a large scale as follows:
  • An exemplary Intermediate B, Intermediate B-l may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, and is a single bond.
  • reaction mixture was diluted with petroleum ether (100 mL) and washed with brine (50.0 mL x 4). dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue.
  • the crude material was purified by column chromatography (petroleum ether) to afford l-bromo-3-(2,2- diethoxyethoxy)benzene (17.0 g, 48.2 mmol, 83.4% yield, 82.0% purity) as a light yellow oil.
  • a second exemplary Intermediate B, Intermediate B-2 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR 5 , is a double bond and one R 3 is fluorine.
  • a third exemplary Intermediate B, Intermediate B-3 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond and one R 3 is chlorine.
  • the vessel was evacuated and purged with hydrogen several times. The mixture was stirred at 25 °C for 12 h under hydrogen (50.0 psi).
  • a fourth exemplary Intermediate B, Intermediate B-4 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • Z is O
  • n is one
  • X is C(R 5 )2
  • R 3 is fluorine.
  • the reaction mixture was diluted with ethyl acetate (500 mL), washed with brine (500 ml 5), and concentrated at reduced pressure to provide a residue.
  • Intermediate A-2 may be prepared on a large scale as follows:
  • a fifth exemplary Intermediate B, Intermediate B-5 may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • a sixth exemplary Intermediate B, Intermediate B-6 may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • An exemplary Intermediate C, Intermediate C-l may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • a second exemplary Intermediate C, Intermediate C-2 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR 5 , is a double bond and one R 3 is fluorine.
  • a mixture of 8-bromo-5-chloro-imidazo[I,2-c]pyrimidine-2-carboxylate 160 mg, 525 pmol.
  • a third exemplary Intermediate C, Intermediate C-3 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, and is a single bond.
  • ethyl 8-bromo- 5-chloro-imidazo[I,2-c] pyrimidine -2 -carboxylate 103 mg, 328 pmol, 1.00 equiv
  • l,3-benzodioxol-4- ylmethanamine 54.6 mg, 361 pmol, 1.10 equiv
  • DMF 2.00 mb
  • DIEA 42.4 mg, 328 pmol, 57.2 pL, 1.00 equiv.
  • a fourth exemplary Intermediate C, Intermediate C-4 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond and one R 3 is chlorine.
  • ethyl 8-bromo-5-chloro-imidazo[l,2-c]pyrimidine-2 -carboxylate 230 mg, 755 pmol, 1.00 equiv
  • (5-chloro-2,3-dihydrobenzofuran-4-yl)methanamine 118 mg, 642 pmol, 0.850 equiv
  • DIEA 195 mg, 1.51 mmol, 263 pL, 2.00 equiv
  • Another Intermediate C may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R 5 )2, and is a single bond.
  • DIPEA 207 mg, 1.60 mmol, 279 pL, 2.00 eq.
  • chroman-5-ylmethanamine 170 mg, 1.04 mmol, 1.30 eq.
  • Intermediate C-4B may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • a fifth exemplary Intermediate C, Intermediate C-5 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • Intermediate C-5 may be prepared as follows:
  • a sixth exemplary Intermediate C, Intermediate C-6 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond and one R 3 is fluorine.
  • a seventh exemplary Intermediate C, Intermediate C-7 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond, one R 3 is fluorine and R 1 is heteroaryl which may then be further substituted with one or more R 4 .
  • An eighth exemplary Intermediate C, Intermediate C-8 may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R 5 )2, is a single bond, one R 3 is fluorine and R 1 is heteroaryl which is substituted two R 4 groups, one of which serves as an intermediate to generate various R 4 groups, e.g., L-N(R 5 )2.
  • reaction mixture was diluted with water (10.0 mb) and extracted with ethyl acetate (10.0 mb x 3). The combined organic layer was washed with brine (20.0 mb), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue.
  • the resultant residue was diluted with dichloromethane (6 mb) and the combined organic layer was washed with brine (3 mb x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-TLC (ethyl acetate) to afford 8-(2-cyano-4-formylphenyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (30.0 mg, 50.2% yield, 90.0% purity) as a yellow solid.
  • reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layer was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue.
  • the mixture was stirred at 25 °C for 1 h and was subsequently diluted with water (20.0 mb).
  • the suspension was filtered and the solid was dried under reduced pressure to give the crude product.
  • the crude product diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mb* 2).
  • reaction was quenched with saturated aqueous potassium fluoride (20.0 mb) and extracted with ethyl acetate (20.0 mLx2). The combined organic phase was washed with brine (20.0 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide a residue.
  • the aqueous phase was extracted with ethyl acetate (3.00 m x 2).
  • the combined organic phase was washed with brine (3.00 mb x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluorobenzo[d][l,3]dioxol-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (50.0 mg, 128 pmol, 82.5% yield) as a yellow solid.
  • An exemplary Intermediate D, Intermediate D-l may be used to synthesize compounds of formula I wherein R 1 is a disubstituted heteroaryl.
  • the reaction mixture was fdtered and concentrated under reduced pressure to provide a residue.
  • the crude material was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 3 / 1) to afford a mixture of l-isopropyl-3- methyl-4- (4, 4, 5, 5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) and l-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) as a light yellow oil.
  • a second exemplary Intermediate D, Intermediate D-2 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
  • a third exemplary Intermediate D, Intermediate D-3 may be used to synthesize compounds of formula I or formula II wherein R 1 is heteroaryl substituted with two R 4 substituents.
  • a fourth exemplary Intermediate D, Intermediate D-4 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
  • a mixture of sodium (111 mg, 4.82 mmol, 1.00 equiv) in methanol (772 mg, 24.1 mmol, 975. pL, 5.00 equiv) was stirred at 25 °C for 0.5 h.
  • To this solution was added 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) and the mixture was stirred at 25 °C for 2 h.
  • the reaction was quenched upon the addition of water (5 mL).
  • a fifth exemplary Intermediate D, Intermediate D-5 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
  • R 1 is heteroaryl substituted with two R 4 substituents.
  • a sixth exemplary Intermediate D, Intermediate D-6 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with two R 4 substituents.
  • R 1 is aryl substituted with two R 4 substituents.
  • NaSMe 869 mg, 5.29 mmol, 1.00 equiv.
  • the reaction mixture was stirred at 50 °C for 12 h.
  • the reaction mixture was diluted with ethyl acetate (50.0 mL) and the organic layer was washed with brine (40.0 mb x 3).
  • a seventh exemplary Intermediate D, Intermediate D-7 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with an R 4 substituent.
  • R 1 is aryl substituted with an R 4 substituent.
  • pyrrolidine (1.79 g, 25.1 mmol, 2.10 mL, 5.00 equiv) in methanol (16.0 mL) was added NaBHsCN (347 mg, 5.53 mmol, 1.10 equiv). The mixture was stirred at 20 °C for 24 h.
  • An eighth exemplary Intermediate D, Intermediate D-8 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
  • R 1 is heteroaryl substituted with two R 4 substituents.
  • n- butyllithium (2.50 M, 1.80 m , 1.00 equiv) was added dropwise over one min to z-PrMgCl (2.00 M, 1.12 mb, 0.500 equiv) in THF (12 mL) at 0 °C under a nitrogen atmosphere.
  • a ninth exemplary Intermediate D, Intermediate D-9 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with three R 4 substituents.
  • a tenth exemplary Intermediate D, Intermediate D-10 may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with two R 4 substituents.
  • a mixture of 3-bromo-6- fIuoro-2-methyl-pyridine (1.00 g, 5.26 mmol, 1.00 equiv) and A-mcthylpipcrazinc (685 mg, 6.84 mmol, 759 pL, 1.30 equiv) was stirred at 110 °C for 12 h. The mixture was diluted with ethyl acetate (50.0 mL), washed with brine (20.0 mL x 3).
  • An eleventh exemplary Intermediate D, Intermediate D-l l may be used to synthesize compounds of formula I, wherein R 1 is heteroaryl substituted with three R 4 substituents.
  • R 1 is heteroaryl substituted with three R 4 substituents.
  • (2S)-2 -methyloxirane (392 mg, 6.75 mmol, 473 pL, 15.0 equiv) was added cesium carbonate (29.3 mg, 90.1 pmol, 0.20 equiv).
  • a twelfth exemplary Intermediate D, Intermediate D-12 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with two R 4 substituents.
  • R 1 is aryl substituted with two R 4 substituents.
  • DIEA 490 mg, 3.79 mmol, 660 pL, 3.00 equiv
  • AA'-dimcthylaminc 2.00 M in THF, 1.27 m , 2.00 equiv
  • DMF 3.00 m
  • HATU 727 mg, 1.91 mmol, 1.50 equiv.
  • a thirteenth exemplary Intermediate D, Intermediate D-13 may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with two R 4 substituents.
  • a fourteenth exemplary Intermediate D, Intermediate D-14, may be used to synthesize compounds of formula I, wherein R 1 is aryl substituted with one R 4 substituent.
  • R 1 is aryl substituted with one R 4 substituent.
  • ammonia 7 N in MeOH, 224 pL, 1.57 mmol, 2.00 equiv.
  • the reaction mixture was stirred at 25 °C for 30 min.
  • the mixture was concentrated in vacuo to provide a residue that was poured into water (10.0 m ).
  • reaction mixture was fdtered and concentrated under reduced pressure to give a residue.
  • Tributyl(chloro)stannane (602 mg, 1.85 mmol, 498 pL, 1.00 equiv) was added drop-wise and the reaction was stirred at -78 °C for another 30 min.
  • the reaction mixture was partitioned between ethyl acetate (5.00 mL) and saturated ammonium chloride (5.00 mL).
  • the organic phase was separated, washed with brine (5.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tributyl-(2-cyclopropylpyrazol-3-yl)stannane (1.00 g, crude) as a colorless oil which used for the next step without further purification.
  • the precipitate was filtered to provide the crude material (80 mg) as a brown solid.
  • the crude material was purified by prep- HPLC(column: Phenomenex Synergi C18 150x25x 10 pm; mobile phase:[water (0.1 %TFA) - ACN]; B%: 12% - 42%, 10 min) to afford 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (10.0 mg, 99.7 % purity) as a gray solid.
  • EXAMPEES 5 -10 were prepared following the procedure set forth in Example 4 and using the general reactions schemes and intermediates described herein.
  • reaction mixture was diluted with ethyl acetate (10.0 mL) and washed with water (10.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure to give a residue.
  • the mixture was subsequently stirred at 25 °C for 1 h.
  • the reaction mixture was diluted with ethyl acetate (10.0 mL), the pH was adjusted to ⁇ 7 with TFA, and the organic layer was washed with brine (5.00 mL x 3). Concentration in vacuo provided the crude material.
  • EXAMPLES 88 -136 were prepared following the procedure set forth in Example 87 and using the general reactions schemes and intermediates described herein.
  • the vessel was purged with nitrogen, stirred at 105 °C for 1 h and subsequently concentrated in vacuo to provide a residue.
  • the residue was purified by Prep- TLC (SiC>2, petroleum ether/ethyl acetate, 1/1) to afford ethyl 8-(3,6-dihydro-2H-pyran-4-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[ l,2-c]pyrimidine-2 -carboxylate (81.0 mg, 77.7% yield, 96.6% purity) as a white solid.
  • the resultant mixture was stirred at 0 - 30 °C for 1 h and was subsequently fdtered and concentrated to provide the crude residue.
  • the residue was purified by prep-HPEC (column: Gemini 150x25 5 u; mobile phase: [water (0.04 %NHsH2O) - ACN]; B %: 35.0 % - 65.0 %, 10 min) to afford 5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro-2H-pyran-4-yl)imidazo[l,2- c]pyrimidine-2 -carbonitrile (26.0 mg, 63.1 pmol, 92.7% yield, 95.5% purity) as a yellow solid.
  • reaction mixture was cooled to rt and quenched with sat aq potassium fluoride (2.00 mL).
  • the mixture was extracted with ethyl acetate (2.00 mL x 3) and the combined organic layer was washed with brine (2.00 mL x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue.
  • EXAMPLES 143 -146 were prepared following the procedure set forth in Example 142 and using the general reactions schemes and intermediates described herein.
  • EXAMPLES 150 -152 were prepared following the procedure set forth in Example 149 and using the general reactions schemes and intermediates described herein. TABLE 6
  • EXAMPLE 154 was prepared following the procedure set forth in Example 153 and using the general reactions schemes and intermediates described herein.
  • EXAMPLE 155 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile
  • the filtrate was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL x 3). The combined organic phase was washed with aqueous sodium sulfite solution (2.00 mL), brine (2.00 mL), dried over anh sod sulfate, filtered, and concentrated to provide the crude material.
  • EXAMPLES 157 -184 were prepared following the procedure set forth in EXAMPLE 87 and using the general reactions schemes and intermediates described herein.
  • EXAMPLES 193 and 194 were prepared following the procedure set forth in EXAMPLE 142 and using the general reactions schemes and intermediates described herein.
  • EXAMPLE 217 8-(3-(2-(dimethylamino)ethyl)phenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile
  • EXAMPLES 219 -228 were prepared following the procedure set forth in Example 87 and using the general reactions schemes and intermediates described herein.
  • the reaction was stirred at 25 °C for 1 h and was subsequently quenched by the addition of water (30.0 mL) at 25 °C.
  • the aqueous layer was diluted with ethyl acetate (50.0 mL), at which time a white precipitate formed.
  • the compounds of the present disclosure may have one or more chiral center and, if so, are synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space.
  • the compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma- Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions, as well as methods described herein, e.g., EXAMPLES 213 and 214.
  • Example 32 illustrates that treatment of bone marrow derived CD34+ cells from two healthy human donors with compound Example 32 (8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5- fluoro-2,3-dihydrobenzofuran-2-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile) increases fetal hemoglobin levels in the cells.
  • STEMdiffTM Erythroid Supplement E2 10X was added to each well on Day 2, 4, 9 and 11 during differentiation. On day 7, cells were passaged and replated at a density of 167,000 cells/well in a 12-well plate. Flow cytometry was performed every 7 days to assess the stages of differentiation using anti -human CD71 and anti-human glycophorin A (CD235a) antibody (StemCell #60106AZ; #60152FI).
  • RNA extraction and RT-qPCR analysis The cell pellets harvested for mRNA analysis were first washed once with PBS and then resuspended in 600 pL of RLT lysis buffer (from the Qiagen kit) supplemented with 1% of beta-mercaptoethanol (Sigma- Aldrich #M6250). RNA was extracted by QIAcube (Qiagen #9001292, software vl.0.1) using the RNeasy Mini QIAcube kit (Qiagen #74116) according to manufacturer’s instructions. The extracted RNA was then quantified using a NanoDropTM 8000 Spectrophotometer (ThermoFisher #ND8000-GL, software version 2.3.2).
  • RT qPCR reactions were set up using 3 pL of 3 ng of RNA in 7 pL of pre-mixed SensiFASTTM SYBR No-ROX One-Step Kit reagents (BIOLINE, Cat# BIO-98005) and RT-qPCR was run on a Bio-Rad CFX384 Real-Time PCR System.
  • HBG1 and HBG2 mRNA levels were normalized to housekeeping gene RPL27 and are plotted relative to mRNA levels in vehicle treated cells.

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Abstract

La présente divulgation concerne des méthodes de traitement d'un sujet atteint d'une drépanocytose, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un inhibiteur du complexe répressif polycomb 2 (PRC2). Dans certains modes de réalisation des méthodes divulguées, avant l'administration au sujet de l'inhibiteur du complexe répressif polycomb 2 (PRC2), (a) une hydroxyurée est administrée au sujet ; et/ou (b) une dose stable d'un ou de plusieurs du voxelotor, du crizanlizumab et de la L-glutamine est administrée.
PCT/US2024/043672 2023-08-24 2024-08-23 Inhibiteurs de prc2 destinés à être utilisés dans le traitement de la drépanocytose Pending WO2025043191A1 (fr)

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Citations (2)

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WO2023049723A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins
WO2023049724A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins

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WO2023049723A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins
WO2023049724A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins

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BRANDOW A. M., LIEM R. I.: "Advances in the diagnosis and treatment of sickle cell disease", JOURNAL OF HEMATOLOGY & ONCOLOGY, BIOMED CENTRAL LTD, LONDON UK, vol. 15, no. 1, London UK , XP093284029, ISSN: 1756-8722, DOI: 10.1186/s13045-022-01237-z *
BRUNO PAUL, KANTER JULIE, ZIEGLER JOHN, STUART BILLY, AHN JAE, DUNN JUDY, ALLEN GEOFF, MORABITO CHRISTOPHER: "P1472 INTERIM RESULTS OF SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS FROM AN ONGOING OPEN-LABEL STUDY INVESTIGATING FTX-6058 IN ADULTS LIVING WITH SICKLE CELL DISEASE ", HEMASPHERE, WOLTERS KLUWER HEALTH, US, vol. 6, 1 June 2022 (2022-06-01), US , pages 2581, XP093284025, ISSN: 2572-9241, DOI: 10.1097/01.HS9.0000848744.04551.56 *
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