WO2021216777A1 - Inhibiteurs d'erk pour thérapie anticancéreuse - Google Patents

Inhibiteurs d'erk pour thérapie anticancéreuse Download PDF

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WO2021216777A1
WO2021216777A1 PCT/US2021/028487 US2021028487W WO2021216777A1 WO 2021216777 A1 WO2021216777 A1 WO 2021216777A1 US 2021028487 W US2021028487 W US 2021028487W WO 2021216777 A1 WO2021216777 A1 WO 2021216777A1
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group
compound
methyl
hydroxy
formula
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PCT/US2021/028487
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English (en)
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Sunil Paliwal
Stephen CORNWELL
Michael Sabio
Sajedeh LOTFALIANSAREMI
Candice CASILLAS
William Windsor
Peter Tolias
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The Trustees Of The Stevens Institute Of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the mitogen-activated protein kinase (MAPK) signaling pathway (shown generally in FIG. 1) controls many essential cellular functions, such as cytoskeleton organization, aging and programmed cell death, calcium signaling, trafficking of vesicles, cellular proliferation, and cell division. Recent research suggests that this MAPK pathway plays a role in certain cancers. For example, cell proliferation has been found to be a critical component of the MAPK pathway because when perturbed it leads to many different types of solid tumors as well as blood cancers. Available FDA-approved drugs that function in the MAPK pathway generally target BRAF and MEK, and are estimated to exceed $10 billion per year with the right combination of drugs.
  • ERK is the last key protein involved in the signaling cascade in the MAPK pathway. And it is generally accepted that effective ERK therapy that is downstream will have an impact on curtailing cancer growth and improving patient survival. Flowever, despite more than three decades of intense research and pharmaceutical industry efforts, an FDA-approved, effective anti-cancer ERK inhibitor has yet to be developed. Such a drug against ERK would create a new effective first-line treatment for certain cancers, e.g., melanoma, colon, and pancreatic cancer, and would provide new hope for patients with BRAF and MEK resistant tumors.
  • a compound capable of inhibiting an ERK protein form is represented by Formula 1.
  • R 1 is hydrogen or methyl.
  • R 2 is hydrogen, an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen substituted hydroxy methyl group.
  • R 3 is a substituted or unsubstituted tert-butyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • Each R 4 is independently a halogen, an unsubstituted alkyl group, a haloalkyl group, an unsubstituted alkoxy group, or a haloalkoxy group.
  • n is 0 to 9.
  • R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, fluorine-substituted ethyl, tert- butyl, hydroxy-methyl, hydroxy-fluoromethyl, or hydroxy-difluoromethyl.
  • R 1 is methyl
  • R 2 is hydrogen
  • R 1 is hydrogen
  • R 2 is an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen-substituted hydroxy-methyl group.
  • R 1 is methyl
  • R 2 is an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen- substituted hydroxy-methyl group.
  • the compound represented by Formula 1 comprises one of Compounds 100-105, 107-109, 121 and 122.
  • the compound represented by Formula 1 comprises a compound represented by Formula 1A.
  • R 1 is hydrogen or methyl.
  • R 2 is hydrogen, an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen-substituted hydroxy methyl group.
  • each R 4 is independently a methyl group, or a halogen- substituted methyl group.
  • R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, fluorine-substituted ethyl, tert-butyl, hydroxy methyl, hydroxy-fluoromethyl, or hydroxy-difluoromethyl.
  • R 1 is methyl, and R 2 is hydrogen. And in some embodiments, in Formula 1A, R 1 is hydrogen, and R 2 is an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen- substituted hydroxy-methyl group. In some embodiments, in Formula 1A, R 1 is methyl, and R 2 is an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen-substituted hydroxy-methyl group.
  • the compound represented by Formula 1A comprises one of Compounds 104, 105 and 107.
  • the compound represented by Formula 1 comprises a compound represented by Formula 1 B.
  • R 1 is hydrogen or methyl.
  • R 2 is hydrogen, an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen-substituted hydroxy methyl group.
  • An is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • Each R 4 is independently a halogen, an unsubstituted alkyl group, a haloalkyl group, an unsubstituted alkoxy group, or a haloalkoxy group.
  • n is 0 to 7.
  • R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, fluorine-substituted ethyl, tert-butyl, hydroxy methyl, hydroxy-fluoromethyl, or hydroxy-difluoromethyl.
  • R 1 is methyl, and R 2 is hydrogen.
  • R 1 is hydrogen
  • R 2 is an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen- substituted hydroxy-methyl group.
  • R 1 is methyl
  • R 2 is an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen-substituted hydroxy-methyl group.
  • the compound represented by Formula 1 B comprises one of Compounds 100-103, 108, 109, 121 and 122.
  • Compound 100 comprises one of Compounds 100-103, 108, 109, 121 and 122.
  • a pharmaceutical composition comprises at least one compound represented by Formula 1 , 1 A or 1 B, or a pharmaceutically acceptable salt or derivative thereof. And in some embodiments, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, additive, adjuvant or diluent.
  • a method of inhibiting an ERK protein form comprises contacting a cell in which inhibition is desired with at least one compound represented by Formula 1 , 1 A or 1 B, or a pharmaceutically acceptable salt or derivative thereof.
  • a method of inhibiting an ERK protein form comprises administering to a patient or subject a pharmaceutical composition comprising at least one compound represented by Formula 1, 1A or 1B.
  • a method of treating a disease or condition comprising administering to a patient or subject having the disease or condition at least one compound represented by Formula 1 , 1 A or 1 B, or a pharmaceutically acceptable salt or derivative thereof.
  • the method may comprise administering to the patient or subject having the disease or condition a pharmaceutical composition comprising the at least one compound represented by Formula 1 , 1 A or 1 B.
  • the disease or condition may be a cancer.
  • FIG. 1 is a schematic depicting the mitogen-activated protein kinase (MAPK) signaling pathway, reproduced from Nature Reviews
  • MAPK mitogen-activated protein kinase
  • compounds capable of inhibiting ERK protein forms include compounds represented by Formula 1 , and pharmaceutically acceptable salts thereof.
  • R 1 may be hydrogen or methyl.
  • R 2 in Formula 1 may be hydrogen, an unsubstituted alkyl group, a haloalkyl group, a hydroxy-methyl group, or a halogen-substituted hydroxy-methyl group.
  • halogen-substituted hydroxy-methyl and like terms refer to a hydroxy-methyl group (-CH2OH) in which one or more hydrogen atoms in the methylene chain have been replaced by a halogen atom, e.g., a F atom.
  • suitable halogen-substituted hydroxy-methyl groups include hydroxy-difluoromethyl (-CF2OH), and hydroxy-fluoromethyl (-CHFOH).
  • R 3 may be a substituted or unsubstituted tert-butyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • n may be 0 to 9. In some embodiments, n may be 0 to 7, n may be 0 to 6, n may be 0 to 3, or n may be 0 to 2.
  • R 3 when R 3 is a substituted or unsubstituted tert-butyl group, n may be 0 to 9 such that either none or any number of the hydrogen atoms of the tert-butyl group may be substituted as described herein.
  • n when R 3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, n may be 0 to 7, and in some embodiments, n may be 0 to 6, 0 to 3, or 0 to 2.
  • Each R 4 may independently be a halogen, an unsubstituted alkyl group, a haloalkyl group, an unsubstituted alkoxy group, or a haloalkoxy group.
  • each R 4 may a halogen, an unsubstituted alkyl group, a fluoroalkyl group, an unsubstituted alkoxy group, or a fluoroalkoxy group.
  • fluoroalkyl group and “fluoroalkoxy group” refer to a haloalkyl group or haloalkoxy group (as defined herein) in which the halogen atom(s) in the groups are F atoms.
  • the alkyl chain in the unsubstituted alkyl group, the haloalkyl (or fluoroalkyl) group, the unsubstituted alkoxy group, or the haloalkoxy (or fluoroalkoxy) group may be or include tert-butyl, but the present disclosure is not limited thereto.
  • the compound of Formula 1 may be represented by Formula 1A.
  • each R 4 is independently selected from methyl or halogen substituted methyl.
  • suitable R 4 groups include trifluoromethyl (-CF3), difluoromethyl (-CF2FI), and fluoromethyl (-CFI2F), and the terminal tert-butyl group may include any combination of different R 4 groups, without limitation.
  • all three of the R 4 groups may be methyl, all three of the R 4 groups may be trifluoromethyl, or only one of the R 4 groups may be methyl while the other two are trifluoromethyl, hydrogen, etc.
  • the compound of Formula 1 may be represented by Formula 1B.
  • an is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • an “aryl” group is an aromatic moiety having one or more aromatic rings, for example, from 1 to 2 aromatic rings. Each of the rings of the aryl group may optionally be substituted, as noted generally above. In some embodiments, the aryl group may have from 6 to 14 ring carbon atoms, for example, from 6 to 10 ring carbon atoms.
  • Suitable aryl groups include phenyl, naphthyl, dihydrobenzofuranyl, biphenyl, 1 ,2,3,4-tetrahydronaphthalenyl, IH-indenyl, 2,3-dihydro-IH-indenyl, and the like.
  • the aryl group may include a substituted or unsubstituted phenyl group.
  • the “heteroaryl” group is an aromatic moiety having one or more aromatic rings, in which at least one atom of at least one ring is a heteroatom.
  • at least one atom of at least one ring may be a heteroatom.
  • the heteroatom is not particularly limited, and may be any atom other than carbon.
  • the heteroatom may be selected from O, S, and N. Any of the ring atoms (including the heteroatoms) may also be substituted.
  • the size and configuration of the heteroaryl group is also not particularly limited, and the heteroaryl group may have any number of rings in any configuration.
  • the heteroaryl group may include from 1 to 2 rings, which may be arranged relative to each other in any way.
  • the rings of the heteroaryl group may be either bonded to each other or fused to each other, and in some embodiments, some rings of the group may be bonded while other rings may be fused.
  • the heteroaryl group may have from 5 to 10 ring atoms, for example 5, 6, 9, or 10 ring atoms, and/or 6, 10, or 14 electrons shared in a cyclic array.
  • heteroaryl groups include azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1 ,2- a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindddolinyl
  • the heteroaryl group may include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1 ,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, such as, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, ind
  • the heteroaryl group may be a pyridinyl group, a pyradizinyl group, a pyrimidinyl group, a pyrazinyl group, or a triazinyl group (e.g., a 1 ,2,4-triazinyl group, a 1,2,3-triazinyl group or a 1,3,5-triazinyl group).
  • R 1 and R 2 are as defined above in connection with Formulae 1 and 1A.
  • Each R 4 group in Formula 1 B may independently be selected from halogens, unsubstituted alkyl groups, haloalkyl groups, unsubstituted alkoxy groups, and haloalkoxy groups.
  • the halogen(s) may be any suitable halogen, without limitation, including, for example, Cl, Br, F and I.
  • the alkyl, haloalkyl, alkoxy and haloalkoxy groups are not particularly limited, and may be any such groups, as defined herein. In some embodiments, however, the alkyl chain in each of these groups may be a lower alkyl group, i.e., having between 1 and 8 carbon atoms, for example between 1 and 6, or between 1 and 4 carbon atoms.
  • the alkyl chain may include methyl, ethyl, isopropyl or tert-butyl.
  • each R 4 group in Formula 1B may independently be selected from halogens; unsubstituted methyl, ethyl, isopropyl or tert-butyl groups; halomethyl groups; haloethyl groups; halo-isopropyl groups; halo-tert-butyl groups; unsubstituted methoxy, ethoxy, isopropoxy or tert-butoxy groups; halomethoxy groups; haloethoxy groups; halo-isopropoxy groups; or halo-tert-butoxy groups.
  • alkyl refers to straight and branched chain aliphatic groups.
  • the length of the alkyl group is not particularly limited, but in some embodiments, the alkyl group may have from 1 to 12 carbon atoms.
  • the alkyl group may be a lower alkyl group, i.e. , a straight or branched chain aliphatic group having from 1 to 8 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and fe/f-butyl
  • the alkyl group may include methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl, but the present disclosure is not limited thereto.
  • haloalkyl refers to an alkyl chain in which one or more hydrogen atoms have been replaced by a F atom.
  • suitable haloalkyl groups include methyl, ethyl, propyl, iso-propyl, butyl and tert-butyl groups substituted with at least one (or one or more) F atom, or perfluorinated methyl, ethyl, propyl and butyl groups (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, -CFHCHs, -CF2CH3, -CH2CFH2, -CH2CF2H, -CH2CF3, - CF2CF3, etc.).
  • the haloalkyl group may include methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl substituted with one or more F atoms, but the present disclosure is not limited thereto.
  • haloalkoxy refers to a haloalkyl group bonded to an oxygen atom.
  • the oxygen atom is bonded to the relevant position of Formula 1 or 1B.
  • the haloalkoxy group has the formula *-0-haloalkyl, where * represents the binding site to Formula 1 or 1B.
  • the haloalkoxy group may include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, or tert-butoxy substituted with one or more F atoms, but the present disclosure is not limited thereto.
  • alkoxy refers to an alkyl group bonded to an oxygen atom.
  • the oxygen atom is bonded to the relevant position of Formula 1 or 1B.
  • the alkoxy group has the formula *-0-alkyl, where * represents the binding site to Formula 1 or 1B.
  • the alkoxy group may include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, or tert-butoxy, but the present disclosure is not limited thereto.
  • Formulae 1A may include up to 9 R 4 substituents
  • Formulae 1B limits the number of R 4 substituents to a maximum of 7.
  • R 3 of Formula 1 when R 3 of Formula 1 is a substituted or unsubstituted tert-butyl group, the number of R 4 s may be 0 to 9, while when R 3 of Formula 1 is a substituted or unsubstituted aryl or heteroaryl group, the number of R 4 s may be 0 to 7.
  • Some non-limiting examples of compounds satisfying Formula 1, 1A and 1B include compounds 100 to 122, and stereoisomers thereof.
  • the compound represented by Formula 1, 1A or 1B may be or include at least one of 100-105, 107-109, 121 and 122. And in some embodiments, the compound represented by Formula 1 may be or include at least one of compounds 100-103, 108, 109, 121 or 122.
  • a pharmaceutical composition may include one or more of the compounds described herein (or pharmaceutically acceptable salts or derivatives thereof) in a therapeutically effective amount.
  • the pharmaceutical composition may include one or more compounds represented by Formula 1, 1A and 1B (or pharmaceutically acceptable salts thereof), as well as one or more pharmaceutically acceptable carriers, excipients, adjuvants or diluents. Acceptable carriers, excipients and diluents are well known in the art and can be selected with regard to the intended route of administration and standard practice.
  • Some non-limiting examples include binders, lubricants, suspending agents, coating agents, solubilizing agents, preserving agents, wetting agents, emulsifiers, surfactants, sweeteners, colorants, flavoring agents, odorants, buffers, antioxidants, stabilizing agents and/or salts.
  • Compounds according to embodiments of this 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 according to embodiments of the present disclosure are administered intravenously in a hospital setting.
  • administration may be by the oral route.
  • compositions according to embodiments of this disclosure may contain (in addition to the inhibitor compound(s) of Formula 1, 1A or 1B) 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, Mack Publishing Company, Easton, Pa., 18th edition, 1990.
  • the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the compounds and exhibit minimal or no undesired toxicological effects.
  • suitable such pharmaceutically acceptable salts include 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, e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic 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, e.g., acetic acid
  • quaternary ammonium salts represented by -N(R)2- , wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion (non-limiting examples of which include chloride, bromide, iodide, O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (non-limiting examples of which include benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • the compound(s) described herein may be present in the pharmaceutical compositions together with the pharmaceutically acceptable carrier or diluent in any suitable amount.
  • the compound(s) may be present in an amount sufficient to deliver a therapeutically effective amount of the compound(s) to a patient or subject without causing (or minimizing the risk of) serious toxic effects in the patient or subject.
  • the active compound i.e.
  • the compound(s) of Formula 1, 1A or 1B) may be administered by any route in a dose of about 0.01 to 300 mg/kg per day, for example about 0.1 to 100 mg/kg per day, or about 0.5 to about 25 mg/kg per day.
  • the active compound may be administered via a topical route in a dose of about 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of pharmaceutically acceptable derivatives or salts can be calculated based on the weight of the parent compound to be delivered. And if the derivative or salt exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by any other means known to those of ordinary skill in the art.
  • a method of inhibiting ERK protein forms includes contacting a cell in which inhibition is desired with an effective amount of one or more compounds represented by Formula 1, 1A or 1 B (or one or more pharmaceutically acceptable salts or derivatives thereof).
  • the method of inhibiting ERK protein forms may include administering a pharmaceutical composition as described herein to a patient or subject in need of ERK protein form inhibition. Contacting the cell with the compound(s), salt(s) or derivative(s) thereof, or the pharmaceutical composition may occur in vivo or in vitro. The contacting (or administration) may be accomplished in a single dose or over multiple doses.
  • a method of treating a condition or disease includes administering to a patient or subject having the disease or condition a therapeutically effective amount of one or more compounds represented by Formula 1, 1A or 1B (or one or more pharmaceutically acceptable salts or derivatives thereof).
  • the method may include administering a pharmaceutical composition as described herein to a patient or subject having the disease or condition.
  • the disease or condition treated using these methods is not particularly limited, and may be any disease or condition. In some embodiments, however, the disease or condition treated is one that is (or has become) resistant to other drugs (such as BRAF and MEK inhibitors), including various solid and blood cancers.
  • Some non-limiting examples of cancers to be treated using methods according to embodiments of the present disclosure include lung, pancreatic, ovarian, colon, gastric, thyroid, and melanoma cancers.
  • the concentration, treatment protocol, and administration route will vary depending on the particular patient and type of cancer to be treated.
  • the compounds described herein, pharmaceutically acceptable salts or derivatives thereof, and pharmaceutical compositions described herein may be co-administered with other therapies (e.g., anti-neoplastic compounds, such as chemotherapy agents), or administered in combination with other treatments (such as radiation or surgical intervention).
  • other therapies e.g., anti-neoplastic compounds, such as chemotherapy agents
  • other treatments such as radiation or surgical intervention
  • the compounds and pharmaceutical compositions described herein may be used either as an adjuvant prior to surgery or may be used post-operatively.
  • Reaction scheme 1 depicts the synthesis of
  • TEA 13.70 g, 135.40 mmol, 18.85 ml_, 2.5 eq
  • ethyl 2- aminoacetate 8.32 g, 59.57 mmol, 1.1 eq, HCI
  • EDCI 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • AIBN (1.01 g, 6.14 mmol, 0.2 eq) was added in one portion at 20 °C under N2 to a mixture of compound 3 (9.4 g, 30.70 mmol, 1 eq) and NBS (7.10 g, 39.91 mmol, 1.3 eq) in CHCh (94 ml_).
  • the mixture was heated to 70 °C and stirred for 12 hrs.
  • Pd(PPh3)4 (189.96 mg, 164.39 umol, 0.05 eq) was added in one portion at 20°C under N2 to a mixture of compound 5 (1 g, 3.29 mmol, 1 eq) and hexamethylditin (1.62 g, 4.93 mmol, 1.02 ml_, 1.5 eq) in dioxane (7 ml_).
  • the mixture was heated to 120 °C and stirred for 4 hrs.
  • Pd(PPh3)4 (190.57 mg, 164.92 umol, 0.05 eq) was added in one portion at 20 °C under N2 to a mixture of compound 6 (1.28 g, 3.30 mmol, 1 eq) and 2,4,5- trichloropyrimidine (968.00 mg, 5.28 mmol, 1.6 eq) in toluene (12.8 ml_).
  • the mixture was heated to 110 °C and stirred for 4 hrs.
  • N,N-Diisopropylethylamine (DIEA) (364.58 mg, 2.82 mmol, 491.34 uL, 2.5 eq) was added in one portion at 20 °C under N2 to a mixture of compound 7 (0.42 g, 1.13 mmol, 1 eq) and tetrahydropyran-4-amine (228.26 mg, 2.26 mmol, 2 eq) in dioxane (4.2 ml_). The mixture was heated to 90 °C and stirred for 16 hrs. Liquid chromatography-mass spectrometry (LCMS) showed that the starting material was consumed completely.
  • LCMS Liquid chromatography-mass spectrometry
  • Example 1 i.e. , through synthesis of compound 9 ( ) Compound 9 was then used synthesize according to the following reaction.
  • the compound 9 precursor in the above reaction schemes can be used to synthesize the compounds disclosed herein by selecting appropriate additional reactants and reaction parameters. Such a selection of reactants and parameters is within the skill of the ordinary artisan in this field based on the desired end product. For example, to synthesize any compound of Formula 1 , the below general reaction scheme could be used.
  • Table 1 below shows the ICso values for inhibition of ERK2 and HT29 cell proliferation achieved by Examples 1 and 2.
  • the ERK2 assay was performed using FRET-based Z’-LYTE ® Kinase Assay (from Invitrogen ® Corporation, cat. #PV3176) at room temperature (kinase reaction for 2 hours, and development for 1 hour).
  • the HT29 cell proliferation assay was conducted using a resazurin reduction cell proliferation assay (conducted over 4 days at 37°C).
  • Table 1 Biochemical Assay Data
  • Example 1 and 2 compounds achieved 50% ERK2 inhibition at concentrations under 2 nM (or 0.002 mM), and achieved 50% HT29 cell proliferation inhibition at concentrations 300 nM (or 0.3 mM) or below. And the Example 2 compound achieved 50% HT29 cell proliferation at a concentration of 40 nm (or 0.04 pM).
  • a pharmaceutical composition may consist essentially of a compound represented by Formula 1 and one or more excipients, adjuvants or carriers.
  • “consisting essentially of” means that any additional components will not materially affect the chemical, physical, therapeutic or pharmaceutical properties of the pharmaceutical composition.

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Abstract

La présente invention concerne des composés utiles dans le traitement de divers cancers et dans l'inhibition de formes de protéines ERK qui sont représentés par la formule 1 : (I) Dans la formule 1, R1 représente un hydrogène ou un méthyle. R2 représente un hydrogène, un groupe alkyle non substitué, un groupe halogénoalkyle, un groupe hydroxy-méthyle ou un groupe hydroxy-méthyle substitué par un halogène. R3 représente un groupe tert-butyle substitué ou non substitué, un groupe aryle substitué ou non substitué ou un groupe hétéroaryle substitué ou non substitué. Chaque R4 représente indépendamment un halogène, un groupe alkyle non substitué, un groupe halogénoalkyle, un groupe alcoxy non substitué ou un groupe halogénoalcoxy. Et n va de 0 à 9.
PCT/US2021/028487 2020-04-21 2021-04-21 Inhibiteurs d'erk pour thérapie anticancéreuse WO2021216777A1 (fr)

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Citations (4)

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