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WO2020167952A1 - Inhibiteurs de mat2a - Google Patents

Inhibiteurs de mat2a Download PDF

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Publication number
WO2020167952A1
WO2020167952A1 PCT/US2020/017934 US2020017934W WO2020167952A1 WO 2020167952 A1 WO2020167952 A1 WO 2020167952A1 US 2020017934 W US2020017934 W US 2020017934W WO 2020167952 A1 WO2020167952 A1 WO 2020167952A1
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Prior art keywords
methyl
imidazol
benzamide
trimethylphenyl
compound according
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Inventor
Thomas P. BOBINSKI
Matthew Arnold Marx
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Mirati Therapeutics Inc
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Mirati Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to compounds that inhibit Methionine Adenosyltransf erase 2 A (MAT2A).
  • MAT2A Methionine Adenosyltransf erase 2 A
  • the invention relates to compounds, pharmaceutical compositions comprising the compounds and methods for use therefor.
  • SAM S- adenosylmethionine
  • MAT adenosyltransferase
  • Mammals express three MAT genes, matla, mat2a and mat2b.
  • MAT1 A and MAT2A are catalytic subunits that catalyze the production of S-adenosylmethionine from methionine and ATP.
  • MAT1 A and MAT2A each form dimers with MAT2B, which acts as a regulatory subunit.
  • MTAP methylthioadenosine phosphorylase
  • MTA methylthioadenosine
  • PRMT5 methylthioadenosine
  • SAM SAM as a methyl donor substrate
  • MAT2A activity reduces intracellular SAM concentrations decreasing PRMT5 methylation activity selectively in MTAP deleted cells below the threshold level required for growth (e.g., see Marjon et al., (2016) Cell Reports 15:574-587).
  • the loss of MTAP activity reduces methylation activity of PRMT5 making the cells selectively dependent on PRMT5 activity.
  • MAT2a activity produces the SAM substrate for PRMT5
  • the inhibition of MAT2A activity results in synthetic lethality in MTAP-deleted cells through inhibition of PRMT5 activity and, thus, may provide therapeutic benefit for a wide range of cancers.
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 3 ;
  • R 2 is hydrogen, -L-SO2CI - C3 alkyl, -L-S02NR 5a R 5b , aralkyl, heteroarylalkyl or -O-heteroarylalkyl, wherein the aryl or heteroaryl portion of the aralkyl, heteroarylalkyl, or -O-heteroarylalkyl are each optionally substituted with one or more R 4 ;
  • each R 3 is independently cyano, acyl, halogen, hydroxyl, -Cl - C3 alkyl, -Cl - C3 alkoxy, or haloalkyl;
  • each R 4 is independently oxo, halogen, Cl - C3 alkyl, or -L-NR 5a R 5b ;
  • L is a bond or Cl - C3 alkylene;
  • R 5a and R 5b are each independently hydrogen or Cl - C3 alkyl
  • each R 6 is independently Cl - C3 alkyl or alkoxy; and [00018] m is 0, 1 or 2.
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 3 ;
  • R 2 is hydrogen, -L-SO2CI - C3 alkyl, -L-S02NR 5 R 5 , aralkyl, heteroarylalkyl or heteroarylalkyl-O-, wherein the aryl or heteroaryl portion of the aralkyl, heteroarylalkyl, or heteroarylalkyl-O- are each optionally substituted with one or more R 4 ;
  • each R 3 is independently acyl, halogen, hydroxyl, -Cl - C3 alkyl, -Cl - C3 alkoxy, or haloalkyl;
  • each R 4 is independently oxo, halogen, Cl - C3 alkyl, or -L-NR 5 R 5 ;
  • L is a bond or Cl - C3 alkylene
  • each R 5 is independently hydrogen or Cl - C3 alkyl
  • each R 6 is independently Cl - C3 alkyl or alkoxy; and [0018] m is 0, 1 or 2.
  • X is a 5-membered partially saturated ring comprising one or two heteroatoms independently selected from O, N and S;
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 2 ;
  • each R 2 is independently acyl, halogen, Cl - C3 alkyl, or haloalkyl;
  • R 3a and R 3b are each independently hydrogen or Cl - C3 alkyl
  • each R 4 is independently oxo, halogen, Cl - C3 alkyl, or -L-NR 3a R 3b ;
  • L is a bond or Cl - C3 alkylene
  • n 0, 1 or 2
  • the compounds of the invention offer therapeutic benefit as inhibitors of MAT2A and areuseful for negatively modulating the activity of MAT2A in a cell, particularly a MTAP-deficient cell, and for treating various forms of MTAP-associated cancer.
  • compositions comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • methods for inhibiting MAT2A activity in a in a cell comprising contacting the cell with a compound of Formula (I) or Formula (II).
  • the contacting is in vitro.
  • the contacting is in vivo.
  • Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with MTAP double deletion (e.g., a MTAP-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • MTAP double deletion e.g., a MTAP-associated cancer
  • Also provided herein is a use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of MAT2A.
  • the invention relates to MAT2A inhibitors.
  • the invention relates to compounds that inhibit MAT2A activity, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor.
  • chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
  • an“alkyl” moiety generally refers to a monovalent radical (e.g. CH3-CH2-)
  • a bivalent linking moiety can be“alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term
  • alkylene (Similarly, in circumstances in which a divalent moiety is required and is stated as being“aryl,” those skilled in the art will understand that the term“aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
  • MAT2A refers to a mammalian methionine adenosyltransferase 2A (MAT2A) enzyme.
  • an“MAT2A inhibitor” refers to compounds of the invention that are represented by Formula (I) and Formula (II) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of the MAT2A.
  • MTAP refers to a mammalian methylthioadenosine phosphorylase (MTAP) enzyme.
  • An“MTAP-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a loss of MTAP activity resulting in sensitizing the disorder to selective inhibition of PRMT5 activity through the reduction in SAM levels by inhibition of MAT2A activity.
  • a non-limiting example of an MTAP- associated disease or disorder is a MTAP-associated cancer.
  • amino refers to -NFh.
  • acetyl refers to“-C(0)CH3.
  • acyl refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.
  • alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms.
  • “alkyl” encompasses Ci, C2, C3, C4, C5, C 6 , C7, Cs, C 9 , C10, C11 and C12 groups.
  • alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms.
  • “alkenyl” encompasses C2, C 3 , C4, C5, C 6 , C7, Cs, C 9 , C10, C11 and C12 groups.
  • alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • alkynyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms.
  • “alkynyl” encompasses C2, C 3 , C4, C5, C 6 , C7, Cs, C 9 , C10, C11 and C12 groups.
  • Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • alkylene is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
  • alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
  • alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
  • alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
  • alkoxy refers to -OC1 - C6 alkyl.
  • cycloalkyl as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons.
  • “cycloalkyl” includes C 3 , C4, C5, C 6 , C7, Cs, C 9 , C10, C11 and C12 cyclic hydrocarbon groups.
  • Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NR X , wherein R x is hydrogen or Cl - C3 alkyl.
  • heteroalkyl groups include methoxymethyl, methoxy ethyl and methoxypropyl.
  • An "aryl” group is a C6-C14 aromatic moiety comprising one to three aromatic rings.
  • “aryl” includes C 6 , Cio, C13, and Ci4 cyclic hydrocarbon groups.
  • An exemplary aryl group is a C6-C10 aryl group.
  • Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • An“aryl” group also includes fused multicyclic (e.g, bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.
  • An "aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety.
  • An exemplary aralkyl group is -(Cl - C6)alkyl(C6 - C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • a “heterocyclyl” or “heterocyclic” group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 4 , O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons.
  • heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4- piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
  • L-heterocyclyl refers to a heterocyclyl group covalently linked to another group via an alkylene linker
  • heteroaryl refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S.“Heteroaryl” also includes fused multicyclic (e.g, bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.
  • fused multicyclic e.g, bicyclic
  • heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][l,4]oxazin-3(4H)-one,
  • benztetrazolyl benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH- carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
  • pyridoimidazole pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
  • tetrahydroisoquinolinyl tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
  • A“L-heteroaryl”, “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroaryl group covalently linked to another group via an alkylene linker.
  • heteroalkyl groups comprise a Ci- Cr > alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
  • heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolyl ethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenyl ethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
  • arylene is an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
  • a moiety e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.
  • substituents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.
  • halogen or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine.
  • haloalkyl refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen.
  • exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chi orom ethyl, and fluorom ethyl.
  • hydroxyalkyl refers to -alkylene-OH.
  • an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of MAT2A enzyme.
  • a“therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of MAT2A. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • treatment means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.
  • “amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition” refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 3 ;
  • L is a bond or Cl - C3 alkylene
  • each R 6 is independently Cl - C3 alkyl or alkoxy; and [0080] m is 0, 1 or 2.
  • R 1 is cycloalkyl optionally substituted with one or more R 3 .
  • the cycloalkyl is cyclohexyl.
  • cycloalkyl is substituted with one or two R 3 , wherein R 3 is halogen.
  • the cycloalkyl is 4,4-difluoro-cyclohexyl.
  • the aryl is phenyl substituted with one, two or three R 3 .
  • the one, two or three R 3 are each
  • both the R 5a and the R 5b are methyl.
  • R 2 is heterocyclylalkyl, wherein the heterocyclyl portion is optionally substituted with one or more R 4 .
  • the heterocyclyl portion of the heterocyclylalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperdinyl or morpholinyl.
  • the heterocyclyl portion of the heterocyclylalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperdinyl or morpholinyl.
  • heterocyclyl portion of the heterocyclylalkyl is substituted with one R 4 , wherein the R 4 is oxo.
  • the oxo-substituted heterocyclyl portion of heterocyclylalkyl is azetidin-2-one, pyrrolidin-2-one, or imidazolidin-2-one.
  • the oxo-substituted heterocyclyl portion of heterocyclylalkyl is azetidin-2-one, pyrrolidin-2-one, or imidazolidin-2-one.
  • heterocyclyl portion is pyrrolidin-2-one.
  • the R 5a attached to the imidazole is C1-C3 alkyl and the R 5b attached to the amide nitrogen is hydrogen.
  • the R 5a is methyl.
  • both the R 5a and the R 5b are methyl.
  • R 2 is heterocyclylalkyl, wherein the heterocyclyl portion is substituted with two R 4 groups wherein the two R 4 groups are each oxo.
  • the dioxo-substituted heterocyclyl portion of heterocyclylalkyl is imidazolidin-2,5-dione, thiazolidin-2,5-dione or piperdin-2,5-dione.
  • the R 5a attached to the imidazole is C1-C3 alkyl and the R 5b attached to the amide nitrogen is hydrogen.
  • the R 5a is methyl.
  • both the R 5a and the R 5b are methyl.
  • R 2 is L-heteroaryl optionally substituted with one or more R 4 .
  • L is a bond.
  • L is Cl - C3 alkylene.
  • the Cl - C3 alkylene is methylene.
  • the heteroaryl is pyrolyl, pyrazolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridine-2-one or benzothiophenyl.
  • the heteroaryl is substituted with one R 3 group selected from the group consisting of oxo, Cl - C3 alkyl, halogen, haloalkyl and -L-NR5 a R5 b .
  • R 2 is -L-SO2CI - C3 alkyl.
  • L is methylene and the Cl - C3 alkyl is methyl or ethyl.
  • R 2 is -L-S02NR 5a R 5b .
  • L is methylene and R 5a and R 5b are each hydrogen.
  • L is methylene and R 5a and R 5b are each Cl - C3 alkyl.
  • R 2 is aralkyl optionally substituted with one or more R 4 .
  • the aralkyl is benzyl.
  • R 2 is hydrogen.
  • n is zero. In one embodiment, n equals one and R 4 is Cl - C3 alkyl or alkoxy. In certain embodiments, the Cl - C3 alkyl is methyl. In other embodiments, the alkoxy is methoxy.
  • R 5a is hydrogen. In one embodiment, R 5a is Cl - C3 alkyl. In certain embodiments, the Cl - C3 alkyl is methyl.
  • R 5b is hydrogen.
  • R 5a is Cl - C3 alkyl.
  • the Cl - C3 alkyl is methyl.
  • the R 5a attached to the imidazole is C1-C3 alkyl and the R 5b attached to the amide nitrogen is hydrogen. In certain embodiments, the R 5a is methyl. In certain embodiments, both the R 5a and the R 5b are methyl.
  • the compound of Formula (I) is:
  • X is a 5-membered partially saturated ring comprising one or two heteroatoms independently selected from O, N and S;
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 2 ;
  • each R 2 is independently cyano, acyl, halogen, Cl - C3 alkyl, or haloalkyl;
  • R 3a and R 3b are each independently hydrogen or Cl - C3 alkyl
  • each R 4 is independently oxo, halogen, Cl - C3 alkyl, or -L-NR 3a R 3b ;
  • L is a bond or Cl - C3 alkylene
  • n 0, 1 or 2.
  • R 1 is aryl optionally substituted with one or more R 2 .
  • the aryl is indenyl or phenyl.
  • the aryl is 5-methyl-2,3-dihydro-lH-indenyl.
  • the aryl is phenyl substituted with one, two or three R 2 .
  • the one, two or three R 2 are each
  • halogen is chloro, fluoro or bromo.
  • Cl - C3 alkyl is methyl or ethyl.
  • haloalkyl is trifluorom ethyl.
  • R 1 is phenyl substituted with two or three Cl - C3 alkyl. In other embodiments, the Cl - C3 alkyl is methyl or ethyl. In one embodiment for the compounds of Formula (I), R 1 is phenyl substituted with halogen and two Cl - C3 alkyl. In certain embodiments, the halogen is chloro, fluoro or bromo and the two Cl - C3 alkyl are each independently methyl or ethyl.
  • R 1 is phenyl substituted with hydroxyl. In one embodiment for the compounds of Formula (II), R 1 is phenyl substituted with -Cl- C3 alkoxy. In one embodiment for the compounds of Formula (II), the alkoxy is methoxy. In one embodiment for the compounds of Formula (II), R 1 is phenyl substituted with one -Cl - C3 alkoxy and one or two -Cl - C3 alkyl.
  • R 3a is hydrogen. In one embodiment, R 3a is Cl - C3 alkyl. In certain embodiments, the Cl - C3 alkyl is methyl.
  • R 3b is hydrogen.
  • R 3a is Cl - C3 alkyl.
  • the Cl - C3 alkyl is methyl.
  • the compound of Formula (II) is:
  • the invention provides pharmaceutical compositions comprising a MAT2A inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Compounds of the invention 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 of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.
  • compositions according to the invention 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.
  • the term“pharmaceutically acceptable 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, naphthalenesulfonic 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
  • 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, methyl sulfonate, 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, methyl s
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient 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.
  • compositions comprising compounds of the invention may be used in the methods described herein.
  • the invention provides for methods for inhibiting MAT2A activity in a cell, comprising contacting the cell in which inhibition of MAT2A activity is desired in vitro with an effective amount of a compound of Formula (I) or Formula (II), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
  • compositions and methods provided herein are particularly deemed useful for inhibiting MAT2A activity in a cell.
  • a cell in which inhibition of MAT2A activity is desired is contacted in vivo with a therapeutically effective amount of a compound of Formula (I) or Formula (II) to negatively modulate the activity of MAT2A.
  • a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I) or Formula (II) may be used.
  • the cell is a MTAP-deficient cell.
  • the methods are designed to reduce intracellular SAM substrate concentrations to further inhibit PRMT5 activity to block cellular proliferation.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to affect the desired negative modulation of MAT2A.
  • the degree intracellular SAM depletion may be monitored in the cell using well known methods, including those described in Example B below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
  • methods of treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I) or Formula (II), pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.
  • a compound of Formula (I) or Formula (II) pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.
  • the cancer is a MTAP-associated cancer.
  • the compositions and methods provided herein may be used for the treatment of a wide variety of cancer including tumors such as prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • kidney adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,
  • the cancer is a MTAP-associated cancer selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • 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.
  • the compounds of the invention may be prepared using 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.
  • Compounds of Formula (I) of the invention may be prepared following General Reaction Scheme I.
  • An R'-aryl or heteroaryl substituted methyl ketone is brominated in Step A to the a-bromoketone, by nucleophilic addition to an electrophilic bromine equivalent, such as NBS.
  • the a-bromoketone is cyclized in the presence of methyl-aminopyrimidine in Step B to R ⁇ R 5a -substituted 1 -methyl -///-i mi dazol -2-amine.
  • M ethyl -///-i mi dazol -2-amine is coupled in Step C to R 2 and R 6 substituted benzoic acid in the presence of a suitable coupling agent, e.g., HATU, to provide R 1 , R 2 , R 5a , R 5b R 6 -substituted amide compounds of Formula (I).
  • a suitable coupling agent e.g., HATU
  • Compounds of Formula (II) of the invention may be prepared following General Reaction Scheme IF To a mixture of fused aryl or heteroaryl-carboxylic acid in suitable polar solvent is added an appropriate coupling agent, e.g., HATU, and base, e.g., a Lewis base, and the reaction mixture is stirred. An appropriately substituted 2-aminoimidazole is added to the mixture, and the reaction mixture is stirred until completion to provide the appropriately R 1 , ( ⁇ -substituted amide compounds of Formula (II).
  • General Reaction Scheme III General Reaction Scheme III
  • Compounds of Formula (I) of the invention wherein R 2 is -L-SO2CI - C3 alkyl and R 5b is hydrogen, may be prepared following General Reaction Scheme III.
  • a solution of a compound of Formula (I) wherein R 2 is -L-SC1 - C3 alkyl in polar protic solvent is added a solution of appropriate oxidant, e.g., Oxone, in polar protic solvent, e.g., methanol.
  • polar protic solvent e.g., methanol
  • Compounds of Formula (I) of the invention wherein R 2 is -L-heterocyclyl, may be prepared following General Reaction Scheme IV.
  • a secondary heterocyclic- amine and appropriately substituted compound of Formula (I) wherein R 2 initially is -CFhBr in polar aprotic solvent, e.g., DMF is added K2CO3 and 18-crown-6.
  • the mixture is stirred until completion, to provide benzylamine product of Formula (I), wherein R 2 is -L- heterocyclyl and L is methylene.
  • An exemplary intermediate, Intermediate A may be used to synthesize compounds of Formula (I) and Formula (II).
  • pyrrolidin-2-one (10.6 g, 124 mmol, 9.53 mL, 1.36 eq) dropwise at 0 °C.
  • the mixture was stirred at this temperature for 0.5 hour, and then methyl 3-(bromomethyl) benzoate (21.0 g, 91.7 mmol, 1.0 eq) was added at 0 °C.
  • the resulting mixture was stirred at 60 °C for 11.5 hours.
  • An exemplary intermediate, Intermediate B may be used to synthesize compounds of Formula (I) and Formula (II).
  • l-(w-tolyl)ethanone 700 mg, 5.22 mmol, 693 pL, 1.0 eq
  • THF 15.0 mL
  • TFA 595 mg, 5.22 mmol, 386 pL, 1.0 eq
  • pyridinium tribromide 2.0 g, 6.26 mmol, 1.20 eq
  • reaction mixture was diluted with H2O (5.0 mL) and extracted with ethyl acetate (3 ⁇ 10 mL). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue.
  • Example 88 Following the teachings of General Reaction Scheme IV and the procedure described for the preparation of Example 88, the following compounds of Formula (I), Examples 88-95, shown in Table 3 were prepared:
  • Example 97 Following the teachings of General Reaction Scheme V and the procedure described for the preparation of Example 97, the following compounds of Formula (I), Examples 98- 100, shown in Table 4 were prepared:
  • reaction mixture was added H2O (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was washed with saturated brine (2 c 30 mL), dried over NaiSCri, filtered and concentrated under reduced pressure to give a residue.
  • Example 101 Following the teachings of General Reaction Scheme VI and the procedure described for the preparation of Example 101, the following compound of Formula (I), Example 102, shown in Table 5 was prepared:
  • Ten-point dose-response curves for compounds of the invention were determined using a MAT2A Inhibitor Assay Kit (BPS Biosciences Catalog #71402).
  • the assay uses purified human, MAT2A enzyme to covert L-Methionine and ATP to S-adenosylmethionine (SAM).
  • SAM S-adenosylmethionine
  • the transfer of the adenosyl group from ATP to L-Methionine generates free phosphate, which is quantitated spectrophotometrically to determine the activity of MAT2A enzyme in the presence and absence of compound.
  • compounds of the invention were solubilized in 100% DMSO at a highest concentration of 30 mM.
  • a series of intermediate compound dilutions were made for each compound in 100% DMSO and then diluted 20-fold in assay buffer (50 MM Tris-HCl, pH 8.0, 15 mM MgCh, 50 mM KC1, 80 mM L-Methionine (Sigma Aldrich Catalog #64319), 100 pM ATP (Sigma Aldrich Catalog A6419) and 0.5 mg/ml BSA) for an intermediate concentration of 5% DMSO. All of the compounds were initially tested at a final concentration of 10 mM and the percent inhibition was calculated as reported below in Table 7.
  • the initial starting concentration for the serial dilutions of each compound was 300 mM.
  • Control samples lacking compound, MAT2A enzyme or various reaction components also were prepared and processed in parallel with compound test samples.
  • Compound MHC03177 was used as a positive control for assay validation.
  • Bioscience Catalog # 71401 was preincubated with test compound in assay buffer lacking Methionine and ATP for 60 minutes at room tempaerture.
  • the enzymatic reaction was initiated by adding Methionine and ATP at the final concentrations above to duplicate samples (25 m ⁇ total volume, 1% DMSO) and the samples were incubated for 1 hr at room temperature. After 1 hr, a 50 m ⁇ aliquot of a colorimetric detection reagent (BPS Bioscience Catalog # 74001) was added to each well and the samples were incubated for an additional 20 minutes at room temperature. Absorbance was measured at 630 nM for each sample using a Tecan Infinite M1000 microplate reader.
  • ICso value for each compound was determined from each 10-point dose-response curve using GraphPad Prism software and the results for exemplary compounds of Formula (I) and Formula (II) are shown in Table 7.
  • This Example illustrates that exemplary compounds of the invention are capable of reducing intracellular SAM levels via the inhibition of MAT2A activity.
  • HCT116 cells (ATCC CCL-247) were plated in 10cm dishes. The following day, cells were treated with DMSO vehicle control or MAT2A inhibitor, at 3 mM or 10 pM, for 6 hours. Cell lysates were prepared on ice using non-ionic NP-40 lysis buffer and total protein concentration was determined using a Bradford assay. Total protein concentrations were normalized across samples and stored at -80C.
  • Calibrator lysates were prepared by transferring 5 pi of each respective sub-stock into Eppendorf tubes containing 95 pi of control cell lysate. Calibration standards and study samples were diluted 10-fold into water (20pl sample into 180pl of water) containing candidate internal standards, including 250 ng/ml oxymorphone-D6 and hydromorphone-D4. Samples were analyzed using a LC-MS-MS instrument according to the manufacturer’s instructions and SAM concentrations in cell lysates were calculated against the standard curve.
  • Example 101 is capabale of depleting intracellular SAM concentrations by about 72% and 88% at 10 mM and 30 pM, respectively.

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Abstract

L'invention concerne des composés de formule (I), qui inhibent l'activité de la méthionine adénosyltransférase 2A (MAT2A). En particulier, l'invention concerne des composés, des compositions pharmaceutiques et des procédés d'utilisation, tels que des procédés de traitement du cancer à l'aide des composés et des compositions pharmaceutiques de l'invention.
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Cited By (2)

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CN116239541A (zh) * 2023-05-11 2023-06-09 英矽智能科技(上海)有限公司 N-苯基-2-氧代喹唑啉类化合物及其应用
WO2023194708A1 (fr) 2022-04-04 2023-10-12 Cambridge Enterprise Limited Inhibiteur de mat2a et inhibiteur de tsg101 pour un usage en thérapie antivirale

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023194708A1 (fr) 2022-04-04 2023-10-12 Cambridge Enterprise Limited Inhibiteur de mat2a et inhibiteur de tsg101 pour un usage en thérapie antivirale
CN116239541A (zh) * 2023-05-11 2023-06-09 英矽智能科技(上海)有限公司 N-苯基-2-氧代喹唑啉类化合物及其应用

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