Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
  • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
  • C07D273/04—Six-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
• • 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
  • 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
  • C07D413/10—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 linked by a carbon chain containing aromatic rings
• • 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
  • C07D413/12—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 linked by a chain containing hetero atoms as chain links
• • 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
  • C07D417/10—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 linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • 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
  • C07D495/10—Spiro-condensed systems

Definitions

• the present invention provides dihydrooxadiazinone compounds of general formula (I) as described and defined herein, methods of preparing said compounds, pharmaceutical compositions and the use of said compounds for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases.
• Phenotypic screening identified some of the compounds known in the literature to be PDE3 inhibitors to be useful for the treatment of certain cancers. Co-expression of PDE3A and/or PDE3B and Schlafen 12 (SLFN12) polynucleotides or polypeptides are typically required for cells to be sensitive. PDE3A/B inhibitors which cause drug sensitivity have been found to stabiize the formation of a complex between PDE3A or PDE3B and SLFN12. PDE3A/B inhibitors which do not cause cell sensitivity typically do not stabilize the PDE3A- or PDE3B - SLFN12 complex.
• PDE-3 inhibitors such as milrinone, cilostazol, and levosimendan have been approved for clinical treatment of cardiovascular indications or thrombocythemia (anagrelide), but not for cancer indication.
• the most recent quality review of PDE inhibitors barely mentions cancer. From WO 2014/164704, WO2017/027854, and WO2017/134231 some PDE3 inhibitors are known.
• PDE-3 inhibitors may limit their therapeutic use when PDE3-inhibiting agents are used on a short- or/and long term basis, e.g. in cancer patients and a suitable therapeutic window is needed.
• the compounds of the present invention have surprisingly been found to inhibit tumor cell proliferation with IC 5 o values of ⁇ 100 nM in e.g. HeLa cells. Additionally, the compounds require higher concentrations for PDE3A and/or PDE3B inhibition where IC 5 o values for enzymatic PDE3A and/or PDE3B inhibition may be > 2.5 times higher than IC50 values for tumor cell proliferation.
• this distinction in inhibitory properties may be associated with PDE3A-SLFN12 complex induction and/or improved pharmacokinetic parameters in vitro or in vivo and/or improved physicochemical properties and/or improved safety pharmacological properties. With these advantageous properties, the compounds described herein may therefore be used for the treatment or prophylaxis of hyperproliferative diseases, such as cancer diseases.
• the present invention provides compounds of general formula (I) which modulate formation of a PDE3A- and/or PDE3B-SLFN12 complex, methods for their preparation, pharmaceutical composition and the use thereof and methods of treatment or prophylaxis of diseases, in particular of hyperproliferative diseases more particularly of cancer diseases.
• R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group , and a Ci -C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from,
• Ci -Ce-alkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a hydroxy group, a Ci-C 4 -alkoxy group, and a 3- to 7-membered heterocycloalkyi group,
• a C 2 -C 6 -alkenyl group which is optionally substituted with an Ci-C 4 -alkoxy group
• a C3-C9-cycloalkyl group which is optionally substituted with a hydroxy group
• a C 5 -C 9 -cycloalkenyl group which is optionally substituted with a hydroxy group
• a 3- to 9-membered heterocycloalkyi group comprising one, two or three heteroatoms which are independently selected from -0-, -S-, -S(O)-, S(0) 2 , and-NR 9 -
• said heterocycloalkyi group optionally further comprising a bridging group selected from -0-, -NR 9 -, -CH 2 -, -CH 2 -CH 2 -, -0-CH 2 -, -CH 2 -0-, -NR 9 -CH 2 -, and - CH 2 -NR 9 -;
• heterocycloalkyi group is optionally substituted with one, two or three substituents and each substituent is independently selected from
• Ci -C 3 -alkyl group which is optionally further substituted with a hydroxy group; a Ci -C 3 -haloalkyl group;
• an aryl group which is optionally substituted with one, two, three or four substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci-C3-alkyl group, a Ci-C3-haloalkyl group, a C1-C3- alkoxy group, a Ci-C 3 -haloalkoxy group, and a NR 5 R 6 group,
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci-C 3 -haloalkyl group, a Ci-C 3 -alkoxy group, a hydroxy group, and a NR 5 R 6 group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group;
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom, a Ci-Ce-alkyl group, a -C1-C5- alkylene-0-Ci-C 5 -alkyl group, a -Ci-Cs-alkylene-S-Ci-Cs-alkyl group, C 3 -C 6 -cycloalkyl group, and a C 3 -C 5 -heterocycloalkyl group;
• R 7 /R 8 are independently selected from
• halogen atom a cyano group, a hydoxy group, a C(0)NR 5 R 6 group, a NR 5 R 6 group,
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group or a bond
• the compounds are suitable for the treatment of a patient having a cancer that is sensitive to treatment with a phosphodiesterase 3A/B (PDE3A/B) modulator by detecting co-expression of PDE3A and / or PDE3B and Schlafen 12 (SLFN12) and / or SLFN12L mRNA, polynucleotides or polypeptides and/or a lack of decrease in expression of CREB3L 1 m RNA, polynucleotides or polypeptides in a cancer cell derived from such patients.
• PDE3A/B phosphodiesterase 3A/B
• Structures drawn include all permissible rotations about bonds.
• substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
• optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, in particular 1 , or 2.
• the term "one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means ⁇ , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".
• an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
• ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
• a composite substituent be composed of more than one parts, e.g. (Ci-C 4 -alkyl)-0-(Ci-C 4 -alkyl)-, a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should the composite substituent be substituted said substituted may be bound at any suitable carbon atom of the composite substitutent.
• a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent
• substituent it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
• halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
• Ci-C 6 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ferf-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl,
• said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ferf-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
• alkylene derives from the term “alkyl” as being a bivalent constituent named by addition of “ene” to the term “alkyl” e.g. "methyl” becomes “methylene” meaning a "-CH 2 -” constituent whereby the open bonds of branched constituents are located at the respective ends of the longest chain.
• Ci-C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
• Ci-C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl, more particularly trifluoromethyl or trifluoromethyl.
• Ci-C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-0-, in which the term "Ci-Ce-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
• Ci-C 6 -haloalkoxy means a linear or branched, saturated, monovalent Ci-Ce-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
• Said Ci-Ce-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
• C2-C6-alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 4 carbon atoms (“C2-C 4 -alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then it is possible for said double bonds to be isolated from, or conjugated with, each other.
• Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1 -yl (or “allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl,
• C2-C 6 -alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C3-alkynyl").
• Said C 2 -C 6 -alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl"), but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent
• alkynyl group is ethynyl, prop-1 -ynyl or prop-2-ynyl.
• Cs-Cg-cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms.
• Said C3-C 8 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, it also includes fused-, bridged- and spiro-cycloalkyl ring systems as e.g. a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl, bicyclo[2.2.1 ]heptyl or octahydropentalenyl as well as spirocycoalkyl systems as defined below.
• spirocycloalkyi means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, or 9 carbon atoms, it being possible for said spirocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom.
• Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
• Cs-Ce-cycloalkenyl means a resulting a cyclopentenyl group, a cyclohexenyl group, a cyclopentadienyl group a cyclohexadienyl group
• the term means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7, 8 or 9 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C ⁇ Ce-cycloalkenyl").
• Said C 4 -C 8 -cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bridged ring system also a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1 ]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl, bicyclo[3.1 .0]hex-2-enyl.
• 3- to 9-membered heterocycloalkyl and “3- to 6-membered heterocycloalkyl” mean a saturated heterocycle with 3, 4, 5, 6, 7, 8 or 9 ring atoms respectively, 3, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms selected from from the series N, O, and S, said heterocycloalkyl group being attached to the rest of the molecule via any one of the carbon atoms or heteroatoms. It also includes bicyclic ring systems which are either fused- or bridged- or spiro-systems as defined below.
• heterocycloalkane refers to a compound consisting of a heterocycloalkyl group as defined herein, and a hydrogen atom to which said heterocycloalkyl group is bonded with its one valency.
• Said heterocycloalkyl group can be a 3- or 4- membered ring, such as azacyclopropyl, oxacyclopropyl, azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,1 -dioxidothiolanyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholin
• 4- to 6-membered heterocycloalkyl means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom or an oxygen atom or a sulfur atom and if it contains a nitrogen atom it may optionally contains one further ring heteroatom from the series: N, O, S.
• 5- or 6-membered heterocycloalkyi means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
• Said heterocycloalkyi group is being attached to the rest of the molecule via any carbon atom or where applicable via any nitrogen atom. Both of them may include bicyclic ring systems as mentioned above.
• a "partially unsaturated 3- to 9-membered heterocycloalkyi” means a monocyclic, unsaturated, non-aromatic heterocycle with 5, 6, 7, 8 or 9 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said partially unsaturated heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
• partially unsaturated heterocycloalkane refers to a compound consisting of a partially unsaturated heterocycloalkyi group as defined herein, and a hydrogen atom to which said partially unsaturated heterocycloalkyi group is bonded with its one valency.
• Said partially unsaturated heterocycloalkyi group is, for example, 4/-/-pyranyl, 2/-/-pyranyl, 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-2H-pyran-3-yl, tetrahydropyridinyl, e.g. 1 ,2,3,6-tetrahydropyridin-4-yl, dihydropyridinyl, e.g.
• fused heterocycloalkyi means a bicyclic, saturated heterocycle with 6, 7, 8, or 9 ring atoms in total, or respectively 5, 6 or 7 ring atoms in total, in which the two rings share two adjacent ring atoms, which "fused heterocycloalkyi" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
• Said fused heterocycloalkyi group is, for example, 3-azabicyclo[3.1 .0]hexan-3-yl, 3-azabicyclo[3.2.0]heptan-3-yl, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, or thiazabicyclo[4.3.0]nonyl.
• bridged heterocycloalkyi means a bicyclic, saturated heterocycle with 7, 8 or 9 ring atoms in total, or respectively 7 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which "bridged heterocycloalkyi" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
• Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1 ]heptyl, oxazabicyclo[2.2.1 ]heptyl, thiazabicyclo[2.2.1 ]heptyl, diazabicyclo[2.2.1 ]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1 ]octyl, diazabicyclo[3.2.1 ]octyl, oxazabicyclo[3.2.1 ]octyl, thiazabicyclo[3.2.1 ]octyl, azabicyclo[3.3.1 ]nonyl, diazabicyclo[3.3.1 ]nonyl, oxazabicyclo[3.3.1 ]
• heterospirocycloalkyi means a bicyclic, saturated heterocycle with 6,
• heterospirocycloalkyi contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
• Said heterospirocycloalkyi group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, 2lambda ⁇ sup>6 ⁇ /sup>-thia-6-azaspiro[3.3]heptane-2,2-dione, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[
• aryl refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (two or more fused rings) hydrocarbon ring system having 6 to 20 (e.g. 6 to 10 ring carbon atoms).
• Nonlimiting examples of aryl groups include phenyl, or napthyl ( e.g., 1 -napthyl, 2-napthyl, etc.).
• heteroaryl means a monovalent, monocyclic or bicyclic aromatic ring having 5, 6, 8, 9 or 10, ring atoms (a “5- to 10-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or a heteroatom to the rest of the molecule.
• heteroene refers to a compound consisting of a heteroaryl group as defined herein, and a hydrogen atom to which said heteroaryl group is bonded with its one valency.
• Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
• heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
• pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
• the heteroaryl group is a 2H-pyrrol-1 -yl group, a 1 H-pyrrazol-4-yl group, a 1 H-pyrrazol-5-yl group, which is optionally substituted with one or two methyl groups, a 1 ,2-thiazol-4-yl group, a 1 ,3-thiazol-5-yl group, a pyridin-3-yl, a pyridin-4-yl and a pyridin 5-yl group each group being optionally substituted with one or two substitutents and each substituent is independently selected from a halogen atom, a methyl group, a trifuoromethyl group, a methoxy group and a NH 2 group, a 1 H-indol-6-yl group, a 1 H- indazol-6-yl group, and a 1 H-benzimidazol-6-yl group, each group being optionally substituted with one or two substitutents and each substituent
• heteroaryl group is a:
• 2H-pyrrol-1 -yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a hydrogen atom, a cyano group and a methyl group,
• a 1 ,2-thiazol-4-yl group which is optionally substituted with one or two methyl groups
• a 1 ,3-thiazol-5-yl group which is optionally substituted with one or two methyl groups
• a pyridin-3-yl a pyridin 5-yl group
• each substituent is independently selected from a halogen atom, a methyl group, a trifuoromethyl group, a methoxy group and a NH 2 group
• heteroaryl group is a pyridinyl group which is optionally substituted with an amino group, or a pyrazolyl group which is optionally substituted with a difluoromethyl group or a trifluoromethyl group.
• Ci -Ce as used in the present text, e.g. in the context of the definition of "Ci -C 6 -alkyl", “Ci -C 6 -haloalkyl", “Ci -C 6 -alkoxy” or “Ci -C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
• C3-C 8 as used in the present text, e.g. in the context of the definition of "C3-C 8 -cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.
• Ci -Ce encompasses Ci , C2, C3, C4, C5, Ce, C1 -C6, C1 -C5, C1 -C4, C1 -C3, C1 -C2, C2-C6, C2- C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
• C2-C6 encompasses C2, C3, C4, C5, Ce, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
• C3-C10 encompasses C3, C4, C5, Ce, C7, Ce, Cg, C10, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, Ce-Ce, C6-C7, C7-C10, C7-C9, C7-C8, Ce-Cio, Cs-Cg and
• C3-C8 encompasses C3, C4, C5, Ce, C7, Ce, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4- C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, Ce-Ce, C6-C7 and C7-C8;
• C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , C 3 -C 6 , C3-C5, C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
• C4-C8 encompasses C4, C5, Ce, C7, Ce, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7, C5-C6, Ce-Ce, C6-C7 and C7-C8;
• C4-C7 encompasses C 4 , C 5 , C 6 , C 7 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C5-C7, C 5 -C 6 and C 6 -C 7 ;
• C -C 6 encompasses C , C 5 , C 6 , C -C 6 , C -C 5 and C 5 -C 6 ;
• C5-C10 encompasses C5, Ce, C7, Cs, Cg, C10, C5-C10, Cs-Cg, Cs-Cs, C5-C7, C5-C6, C6-C10, Ce-Cg, Ce-Cs, C6-C7, C7-C10, C7-Cg, C7-C8, Cs-Cio, Cs-Cg and Cg-Cio;
• C6-C10 encompasses C6, C7, Cs, Cg, C10, C6-C10, C6-Cg, C6-Cs, C6-C7, C7-C10, C7-Cg, C7- Cs, Cs-Cio, Cs-Cg and Cg-Cio.
• the term "about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.1 %, 0.05%, or 0.01 % of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
• agent any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.
• ameliorate decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
• an analog is meant a molecule that is not identical, but has analogous functional or structural features.
• a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications that enhance the analog's function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding.
• An analog may include an unnatural amino acid.
• Detect refers to identifying the presence, absence or amount of the analyte to be detected.
• the analyte is a PDE3A or SLFN12 polypeptide.
• Disease is meant any condition or disease that damages or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include hyperproliferatiotive disorder, cancer types such as e.g., adenocarcinoma, breast cancer, cervical cancer, liver cancer, lung cancer and melanoma.
• an effective amount is meant the amount of a compound described herein required to ameliorate the symptoms of a disease relative to an untreated patient.
• the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amountln still other embodiments, the PDE3A modulator is a compound of formula (I).
• the term "leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
• a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphen
• modulator is meant any agent that binds to a polypeptide and alters a biological function or activity of the polypeptide.
• a modulator includes, without limitation, agents that reduce or eliminate a biological function or activity of a polypeptide (e.g., an "inhibitor”). For example, a modulator may inhibit a catalytic activity of a polypeptide.
• a modulator includes, without limitation, agents that increase or decrease binding of a polypeptide to another agent. For example, a modulator may promote binding of a polypeptide to another polypeptide.
• stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• prodrugs designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
• Derivatives of the compound 6 and the salts thereof which are converted into compound 6 or a salt thereof in a biological system are covered by the invention.
• Said biological system may be, for example, a mammalian organism, particularly a human subject.
• the bioprecursor is, for example, converted into a compound of formula (I) or a salt thereof by metabolic processes.
• pharmaceutically acceptable salt(s) of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. For example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.
• pharmaceutically acceptable salt refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein.
• pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
• a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50.
• reference is meant a standard or control condition.
• R 1 is selected from a hydrogen atom, a halogen atom , a cyano group, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group , and a Ci-C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from,
• Ci-Ce-alkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a hydroxy group, a Ci-C4-alkoxy group, and a 3- to 7-membered heterocycloalkyi group,
• a C 2 -C 6 -alkenyl group which is optionally substituted with an Ci-C 4 -alkoxy group
• a C3-C 9 -cycloalkyl group which is optionally substituted with a hydroxy group
• a C5-C9-cycloalkenyl group which is optionally substituted with a hydroxy group
• a 3- to 9-membered heterocycloalkyi group comprising one, two or three heteroatoms which are independently selected from -0-, -S-, -S(O)-, S(0) 2 , and-NR 9 -
• said heterocycloalkyi group optionally further comprising a bridging group selected from -0-, -NR 9 -, -CH 2 -, -CH 2 -CH 2 -, -O-CH2-, -CH2-O-, -NR 9 -CH 2 -, and - CH 2 -NR 9 -;
• heterocycloalkyi group is optionally substituted with one, two or three substituents and each substituent is independently selected from
• Ci-C 3 -alkyl group which is optionally further substituted with a hydroxy group; a Ci-C 3 -haloalkyl group;
• Ci-C 3 -haloalkoxy group a Ci-C 3 -haloalkoxy group
• an aryl group which is optionally substituted with one, two, three or four substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci-C3-alkyl group, a Ci-C3-haloalkyl group, a C1 -C3- alkoxy group, a Ci-C 3 -haloalkoxy group, and a NR 5 R 6 group,
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci-C 3 -haloalkyl group, a Ci-C 3 -alkoxy group, a hydroxy group, and a NR 5 R 6 group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group;
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom, a Ci-Ce-alkyl group, a -C1 -C5- alkylene-0-Ci-C 5 -alkyl group, a -Ci-Cs-alkylene-S-Ci-Cs-alkyl group, C 3 -C 6 -cycloalkyl group, and a C 3 -C 5 -heterocycloalkyl group;
• R 7 /R 8 are independently selected from
• halogen atom a cyano group, a hydoxy group, a C(0)NR 5 R 6 group, a NR 5 R 6 group,
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group or a bond
• the invention is further based at least in part on the discovery that the compounds of formula (I) are PDE3A- or PDE3B-SLFN12 complex modulators
• the invention further provides methods of selecting a subject as having a cancer that responds to a PDE3A- or PDE3B-SLFN12 complex modulator, especially a compound of formula (I), where the selection method involves detecting co-expression of PDE3A and/or PDE3B and Schlafen 12 (SLFN12) polypeptides or polynucleotides, in a cancer cell derived from such subjects.
• a PDE3A- or PDE3B-SLFN12 complex modulator especially a compound of formula (I)
• the selection method involves detecting co-expression of PDE3A and/or PDE3B and Schlafen 12 (SLFN12) polypeptides or polynucleotides, in a cancer cell derived from such subjects.
• the invention provides methods of determining that the expression of CREB3L1 or SLFN12 polynucleotide or polypeptide is reduced or is undetectable in a cancer cell that has acquired resistance to a PDE3A- and/or PDE3B- SLFN12 complex modulator in order to prevent ineffective treatment with a compound of formula (I).
• the invention provides methods comprising the steps of
• identifying subjects that have a malignancy that is likely to respond to PDE3A- and/or PDE3B-SLF12 complex modulator treatment especially a treatment with a compound of formula (I), based on the level of PDE3A and/or PDE3B and SLFN12 expression in a subject biological sample comprising a cancer cell
• the invention provides methods comprising the steps of
• identifying subjects that have a malignancy that is resistant to PDE3A- and/or PDE3B-SLF12 complex modulator treatment especially to the treatment of a compound of formula (I), based on a loss or reduction in the level of CREB3L1 or SLFN12 expression relative to a reference and - subsequently excluding them from an envisaged treatment schedule with a compound of formula (I).
• Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
• a salt for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein.
• Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
• a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein.
• Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
• prodrugs include Ci-e alkyl esters of carboxylic acid groups, which, upon administration to a subject, are capable of providing active compounds.
• a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
• suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyan
• an alkali metal salt for example a sodium or potassium salt
• an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
• salts are derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl) 4 + salts.
• alkali metal e.g., sodium
• alkaline earth metal e.g., magnesium
• ammonium e.g., sodium
• N-(alkyl) 4 + salts e.g., sodium
• the present invention also envisions the quaternization of any basic nitrogen- containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
• Salt forms of the compounds of any of the formulae herein can be amino acid salts of carboxyl groups (e.g., L-arginine, - lysine, -histidine salts).
• acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
• alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
• the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
• the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
• the present invention provides compounds which are in a prodrug form.
• Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the present invention.
• prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug.
• the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
• prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
• An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity.
• Additional examples include peptidyl derivatives of a compound of the present invention.
• the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio.
• polar solvents in particular water
• stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- , tetra-, penta- etc. solvates or hydrates, respectively, are possible.
• the present invention includes all such hydrates or solvates.
• the present invention also includes various hydrate and solvate forms of the compounds.
• the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 l) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention, particularly deuterium-containing compounds of formula (I).
• Formula (la) shows the positions D 1 , D 2 , D 3 and D 4 in which anyone of the hydrogen atoms may be exchanged by a deuterium atom. Additionally in residues R 1 -R 4 if these residues contain a heteroatom-H or carbon-H bond accessible for a chemical reaction such an exchange may be possible. Hydrogen atoms can be replaced by deuterium atoms using methods known to those with ordinary skill in the art to obtain a heteroatom- D or carbon-D bond.
• Race of R 1 , R 2 , or R 4 themselves can also be deuterium instead of hydrogen.
• one aspct of the invention are those compounds wherein independently anyone of R 1 , R 2 , or R 4 is deuterium and/or anyone of the hydrogen atoms as shown in formula (I) are replaced by a deuterium atom and or anyone of R 1 , R 2 , R 3 ,or R 4 bears a deuterium atom at a chemically accessible position or any combination of positions being deuterated at the same time.
• Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
• the term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
• the expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1 ), 217-235, 1998.
• isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 6 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 1, respectively.
• isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 6 CI, 82 Br, 123 l, 124 l, 125 l,
• the isotopic variant(s) of the compounds of general formula (I) may contain deuterium ("deuterium-containing compounds of general formula (I)").
• Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
• Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I).
• These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
• Deuterium-containing and 13 C- containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
• Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
• a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
• deuterium from D 2 0 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
• Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
• Catalytic deuteration of olefinic bonds and acetylenic bonds is a direct route for incorporation of deuterium.
• Metal catalysts i.e.
• deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
• deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
• the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
• the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641 ], lipophilicity [B. Testa et al. , Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed.
• physicochemical properties such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005,
• a compound of general formula (I) may have multiple potential sites of attack for metabolism.
• deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
• the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites
• the compounds of formula (I) may be isomers.
• “Isomers” are different compounds that have the same molecular formula.
• “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
• the term “isomer” includes any and all geometric isomers and stereoisomers.
• isomers include geometric double bond cis- and trans-isomers, also termed E- and Z- isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this invention
• the symbol denotes a bond that can be a single or a double bond as described herein.
• Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
• the arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.”
• the term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring.
• Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans.”
• the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired, which are e.g. carbon atoms having four different substituents. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres.
• the term "( ⁇ )" is used to designate a racemic mixture where appropriate. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
• stereochemistry at each chiral carbon can be specified by either (R) or (S).
• Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (S)-.
• the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures.
• Preferred compounds are those which produce the more desirable biological activity.
• Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
• the purification and the separation of such materials can be accomplished by standard techniques known in the art including chiral high pressure liquid chromatography (HPLC), the formation and crystallization of chiral salts, or prepared by asymmetric syntheses.
• HPLC high pressure liquid chromatography
• the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
• appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
• Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
• the optically active bases or acids are then liberated from the separated diastereomeric salts.
• a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
• Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
• Enzymatic separations, with or without derivatisation are also useful.
• the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
• the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Preferred is the stereoisomer which shows the desired effect.
• Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
• any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 3H tautomer, or even a mixture in any amount of the two tautomers, namely :
• the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
• the compounds of the present invention can potential exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
• the present invention includes all such chemically possible N-oxides.
• the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
• the present invention also includes prodrugs of the compounds according to the invention.
• prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
• the present invention includes prodrugs of the compounds of formula (I).
• the present invention includes stereoisomers, tautomes, an N-oxides, hydrates, solvates, or a salts, or a mixture of same of a compounds of formula (I).
• the present invention includes stereoisomers, tautomes, hydrates, solvates, or a salts, or a mixture of same of a compounds of formula (I). In a further embodiment the present invention includes stereoisomers, tautomes, solvates, or a salts, or a mixture of same of a compounds of formula (I).
• the present invention includes stereoisomers, tautomes, solvates, or a salts, or a mixture of same of a compounds of formula (I).
• the present invention includes stereoisomers, tautomes, or a salts, or a mixture of same of a compounds of formula (I).
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a Ci-C3-alkyl group, a Ci-C 3 -haloalkyl group, and a Ci-C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from,
• Ci-Ce-alkyl group which is optionally substituted with a substituent which is selected from a hydroxy group, a Ci-C 4 -alkoxy group, and a a 3- to 7-membered heterocycloalkyl group,
• a C 2 -C 6 -alkenyl group which is optionally substituted with an Ci-C 4 -alkoxy group
• a C3-C 7 -cycloalkyl group which is optionally substituted with a hydroxy group
• a C 5 -C7-cycloalkenyl group which is optionally substituted with a hydroxy group a 3- to 7-membered-heterocycloalkyl group, comprising one, or two heteroatoms which are independently selected from -0-, S(0) 2 , and -NR 9 -,
• heterocycloalkyl group is optionallysubstituted with one, or two substituents and each substituent is independently selected from
• Ci -C 3 -alkyl group which is optionally further substituted with a hydroxy group; a Ci -C 3 -alkoxy group;
• a 5- to 7-membered-heterocycloalkyl group comprising a heteroatom which is selected from -0-, -S- and -NR 9 -, which is partially unsaturated and optionally substituted with a substituent which is selected from a Ci -C 3 -alkyl group a -C(0)R 5 R 6 group and a halogen atom, an aryl group which is optionally substituted with one, two, or three substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group, a C1-C3- alkoxy group, and a NR 5 R 6 group,
• a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci-C3-haloalkyl group, a Ci-C3-alkoxy group, and a NR 5 R 6 group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group;
• R 4 is selected from a hydrogen atom, and a Ci-C3-alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci-C 6 -alkyl group,
• R 7 /R 8 are independently selected from
• Ci-Ce-alkyl group which is optionally substituted with one, two, three or four substituents and said substituent is independently selected from
• halogen atom a cyano group, a hydroxy group, a C(0)NR 5 R 6 group, a
• a 3- to 7-membered heterocycloalkyl group comprising one, two or three heteroatoms which are independently selected from -O- and -NR 9 -, which is optionally further substituted with a Ci-C 3 -alkyl group,
• a 3- to 6-membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent independently selected from Ci-C 3 -alkyl group and a hydroxy group,
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group or a bond
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom, a Ci -C 3 -alkyl group, a C1-C3- haloalkyl group, and a Ci-C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from,
• Ci-Ce-alkyl group which is optionally substituted with a substituent which is selected from a hydroxy group, a Ci-C 4 -alkoxy group, and a a 3- to 7-membered heterocycloalkyl group,
• a C 2 -C 6 -alkenyl group which is optionally substituted with an Ci-C 4 -alkoxy group
• a C3-C 7 -cycloalkyl group which is optionally substituted with a hydroxy group
• a C 5 -C7-cycloalkenyl group
• a 3- to 7-membered heterocycloalkyl group comprising one, or two heteroatoms which are independently selected from -0-, and -NR 9 -,
• heterocycloalkyl group is optionallysubstituted with one, or two substituents and each substituent is independently selected from
• Ci -C 3 -alkyl group which is optionally further substituted with a hydroxy group; a Ci -C 3 -alkoxy group; and
• a 5- to 7-membered-heterocycloalkyl group comprising a heteroatom which is selected from -0-, and -NR 9 -, which is partially unsaturated and optionally substituted with a substituent which is selected from a Ci -C3-alkyl group and a halogen atom,
• an aryl group which is optionally substituted with one, two, or three substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci -C3-alkyl group, a Ci-C3-haloalkyl group, and a NR 5 R 6 group,
• a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, a Ci -C 3 -alkyl groupa Ci-C 3 -haloalkyl group, a Ci-C 3 -alkoxy group, and a NR 5 R 6 group; and a NR 7 R 8 group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group;
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci-C 6 -alkyl group,
• R 7 /R 8 are independently selected from
• Ci-Ce-alkyl group which is optionally substituted with one, two, three or four substituents and said substituent is independently selected from
• halogen atom a cyano group, a hydroxy group, , a NR 5 R 6 group, a Ci-C 3 -alkoxy group,
• a 3- to 7-membered heterocycloalkyl group comprising one, two or three heteroatoms which are independently selected from -O- and -NR 9 -, which is optionally further substituted with a Ci-C3-alkyl group,
• a 3- to 6-membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent independently selected from Ci-C 3 -alkyl group and a hydroxy group,
• R 9 is a hydrogen atom or a Ci-C3-alkyl group or a bond
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom , a Ci-C 3 -alkyl group, a C1-C3- haloalkyl group , and a Ci-C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from, a Ci -Ce-alkyl group which is optionally substituted with a substituent which is selected from a hydroxy group, a Ci -C4-alkoxy group, and a a 3- to 7-membered heterocycloalkyl group,
• a 3- to 6-membered heterocycloalkyl group comprising one, or two heteroatoms which are independently selected from -0-, and -NR 9 -,
• heterocycloalkyl group is optionallysubstituted with one, or two substituents and each substituent is independently selected from
• Ci -C 3 -alkyl group which is optionally further substituted with a hydroxy group
• a 5- to 6-membered-heterocycloalkyl group comprising a heteroatom which is selected from -0-, and -NR 9 -, which is partially unsaturated and optionally substituted with a substituent which is selected from a Ci -C3-alkyl group and a halogen atom
• an aryl group which is optionally substituted with one, or two, substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci -C3-alkyl group, a Ci -C3-haloalkyl group, and a NR 5 R 6 group, a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, a Ci -C 3 -alkyl groupa Ci -C 3 -haloalkyl group, a Ci -C 3 -alkoxy group, and a NR 5 R 6 group;
• R 4 is selected from a hydrogen atom, and a Ci -C3-alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci -C 6 -alkyl group
• R 7 /R 8 are independently selected from
• Ci -Ce-alkyl group which is optionally substituted with one, two, three or four substituents and said substituent is independently selected from
• Ci -C 3 -alkoxy group a C3-C 6 -cycloalkyl group which is optionally further substituted with one or two substituents and said substituents are independently selected from a Ci- C 3 -alkyl group and a Ci-C 3 -hydroxyalkyl group;
• a 4- to 6-membered heterocycloalkyl group comprising one, two or three heteroatoms which are independently selected from -O- and -NR 9 -, which is optionally further substituted with a Ci-C 3 -alkyl group,
• a 3- to 6-membered heterocycloalkyl group which is optionally substituted with one or two substituents, said substituent independently selected from Ci-C 3 -alkyl group and a hydroxy group, and
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group or a bond
• the present invention provides compounds of general formula (I :
• R 1 is selected from a hydrogen atom, a halogen atom, a cyano group, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group, and a Ci-C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from a halogen atom
• a C 3 -C 7 -heterocycloalkyl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom and a Ci-C 3 -alkyl group, a hydroxy group, NR 5 R 6 group, a Ci-C 3 -haloalkyl group and a Ci-C3-haloalkoxy group,
• an aryl group which is optionally substituted with one, two, three or four substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group, a Ci-C 3 - alkoxy group, a Ci-C 3 -haloalkoxy group, and a NR 5 R 6 group,
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci-C 3 -haloalkyl group, a Ci-C 3 -alkoxy group, a hydroxy group, and a NR 5 R 6 group;
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom, a Ci-Ce-alkyl group, a -C1-C5- alkylene-0-Ci-C 5 -alkyl group, a -Ci-Cs-alkylene-S-Ci-Cs-alkyl group, C 3 -C 6 -cycloalkyl group, and a C 3 -C 5 -heterocycloalkyl group,
• R 7 /R 8 is independently selected from a hydrogen atom, and a Ci-C 6 -alkyl group, a -Ci- C5-alkylene-0-Ci-C5-alkyl group, a -Ci-Cs-alkylene-S-Ci-Cs-alkyl group, a -C1-C5- alkylene-NR 5 -Ci-C 5 -alkyl group, a C 3 -C 6 -cycloalkyl group, a C 3 -C 5 -heterocycloalkyl group,
• R 7 and R 8 together form a 5-, 6- or 7-membered ring, said ring can optionally contain a bridging group selected from -0-, -NR 9 -, -CH 2 -, -CH2-CH2-, -O-CH2-,- NR 9 -CH 2 -;
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom, a Ci -C 3 -alkyl group, a C1-C3- haloalkyl group, a Ci-C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom, and a halogen atom
• R 3 is selected from a halogen atom
• a C3-C 6 -heterocycloalkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom and a Ci-C 3 -alkyl group;
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a Ci-C3-alkyl group, a cyano group, a Ci -C3-haloalkyl group, a Ci-C 3 -alkoxy group, and a NR 5 R 6 group;
• R 4 is selected from a hydrogen atom, and a Ci -C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom, a Ci-Ce-alkyl group, a -C1 -C3- alkylene-0-Ci -C 3 -alkyl group, a -Ci -C 3 -alkylene-S-Ci -C 3 -alkyl group, and a C3-C5- heterocycloalkyl group,
• R 7 /R 8 is independently selected from a hydrogen atom, and a Ci-C 6 -alkyl group, a -Ci- C 3 -alkylene-0-Ci -C 3 -alkyl group, a -Ci -C 3 -alkylene-S-Ci-C 3 -alkyl group, a -Ci -C 3 - alkylene-NR 5 -Ci-C 3 -alkyl group, a C 3 -C 6 -cycloalkyl group, a C 3 -C 5 -heterocycloalkyl group, or R 7 and R 8 together form a 3-, 4-, 5-, 6- or 7-membered ring optionally containing one or two additional heteroatoms selected from the group consisting of - 0-, -S- and-NR 9 -,
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group
• R 1 is selected from a halogen atom, a Ci-C3-alkyl group and a Ci -C3-haloalkyl group
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from a halogen atom
• a C3-C 6 -heterocycloalkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom and a Ci-C3-alkyl group;
• an phenyl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a Ci-C 3 -alkyl group, a Ci -C 3 -haloalkyl group, and a NR 5 R 6 group;
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci -C 3 -haloalkyl group, a Ci-C 3 -alkoxy group, and a NR 5 R 6 group;
• R 4 is selected from a hydrogen atom, and a methyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci-C3-alkyl group; and R 7 /R 8 is independently selected from a hydrogen atom, a C3-C 5 -cycloalkyl group, and a Ci -Ce-alkyl group;
• R 7 and R 8 together form a 4-, 5-, or 6-membered ring optionally containing one additional oxygen atom
• the present invention provides compounds of general formula (I):
• R 1 is selected from CF 3 , -CH 3 , -OCF 3 and a fluorine atom
• R 2 is selected from a hydrogen atom
• R 3 is selected from a halogen atom
• a C3-C 6 -heterocycloalkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom and a Ci-C3-alkyl group;
• an phenyl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group, and a NR 5 R 6 group;
• a mono- or bicyclic heteroaryl group which is optionally substituted with one, two or three substituents and each substituent is independently selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci-C 3 -haloalkyl group, a Ci-C 3 -alkoxy group, and a NR 5 R 6 group;
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci-C 3 -alkyl group
• R 7 /R 8 is independently selected from a hydrogen atom and a Ci-C 6 -alkyl group
• R 7 and R 8 together form a 4-, 5-, or 6-membered ring optionally containing one additional oxygen atom
• the present invention provides compounds of general formula (I):
• R 1 is selected from CF 3 , -CH 3 , -OCF 3 and a fluorine atom
• R 2 is selected from a hydrogen atom
• R 3 is selected from a halogen atom
• a prop-1 -en-1 -yl group which is optionally substituted with a methyl group
• a piperidin-1 -yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a fluorine atom and a methyl group
• a morpholin-4-yl group which is optionally substituted with one or two methyl groups
• a pyrrolidin-1 -yl group which is optionally substituted with with one or two halogen atoms
• a 6-OXO-1 ,6-dihydropyridin-3-yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a hydrogen atom and a methyl group,
• a phenyl group which is optionally substituted with one, two or three substitutents and each substituent is independently selected from from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF 3 , CF 2 H group, a methoxy group, a CF 3 0 group, a NH 2 group and a NHCH 3 group,
• a 2H-pyrrol-1 -yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a hydrogen atom, a cyano group and a methyl group,
• a 1 H-pyrrazol-4-yl group which is optionally substituted with with one or two substitutents and each substituent is independently selected from a methyl group, an ethyl group or a CF 3 group,
• 1 ,2-oxazol-4-yl which is optionally substituted with with one or two methyl groups
• a 1 ,2-thiazol-4-yl group which is optionally substituted with a methyl group
• a 1 ,3-thiazol-5-yl group which is optionally substituted with a methyl group
• a pyridin-3-yl a pyridin-4-yl and a pyridin 5-yl group
• each substituent is independently selected from a halogen atom, a methyl group, a CF 3 group, a methoxy group and a NH 2 group
• a 1 H-indol-6-yl group a 1 H-indazol-6-yl group which is optionally substituted with a methyl group
• a 1 H-benzimidazol-6-yl group which is optionally substituted with a methyl group
• a NH(C 2 H 5 ) group a NH(C 3 H 7 ) group
• a NH(C 4 H 9 ) group a NCH 3 (C 4 H 9 ) group
• a NH(C 5 Hi i ) group a NH(cyclopentyl) group, a NCH 3 (cyclopentyl) group
• a 1 H-indol-6-yl group a 1 H-indazol-6-yl group which is optionally substituted with a methyl group
• a 1 H-benzimidazol-6-yl group which is optionally substituted with a methyl group
• a NH(C 2 H 5 ) group a NH(C
• R 4 is selected from a hydrogen atom, and a Ci -C 3 -alkyl group
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom , a Ci-C 3 -alkyl group, and a Ci-C 3 - haloalkyl group ,;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from,
• Ci -Ce-alkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a hydroxy group, a Ci-C 4 -alkoxy group, and a 3- to 7-membered heterocycloalkyl group,
• a C 2 -C 6 -alkenyl group which is optionally substituted with an Ci-C 3 -alkoxy group
• a C 3 -C7-cycloalkyl group which is optionally substituted with a hydroxy group
• a C 5 -C 6 -cycloalkenyl group which is optionally substituted with a hydroxy group a 3- to 6-membered heterocycloalkyl group, comprising one, two or three heteroatoms which are independently selected from -O- and-NR 9 -,
• heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from
• Ci -C 3 -alkyl group which is optionally substituted with a hydroxy group
• a 5- to 7-membered heterocycloalkyl group which is partially unsaturated and optionally substituted with one or two substituents and each substituent is independently selected from a Ci-C 3 -alkyl group and a halogen atom, an aryl group which is optionally substituted with one, two, three or four substituents and each substituent is independently selected from a halogen atom, a hydroxy group, a cyano group, a Ci -C 3 -alkyl group, a Ci -C 3 -haloalkyl group, a Ci -C 3 - alkoxy group, a Ci-C 3 -haloalkoxy group, and a NR 5 R 6 group, a mono- or bicyclic heteroaryl group which is optionally substituted with one or two substituents and each substituent is independently selected from a halogen atom, a Ci-C 3 -alkyl group, a cyano group, a Ci-C 3 -halo
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci-Ce-alkyl group,
• R 7 /R 8 are independently selected from
• a C3-C 7 -cycloalkyl group which is optionally substituted with one or two substitutents and said subtituents are independently selected from a Ci- C 3 -alkyl group, a hydroxy group, and a Ci-C 3 -hydroxyalkyl group;
• R 9 is a hydrogen atom or a Ci-C 3 -alkyl group or a bond
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom , a Ci-C 3 -alkyl group, and a Ci-C 3 - haloalkyl group ;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from, a 3- to 6-membered heterocycloalkyi group, comprising one, or two heteroatoms which are independently selected from -0-, and -NR 9 -,
• heterocycloalkyi group is optionallysubstituted with one, or two substituents and each substituent is independently selected from
• Ci-C 3 -alkyl group which is optionally further substituted with a hydroxy group; an aryl group which is optionally substituted with one, or two, substituents and each substituent is independently selected from a halogen atom, a hydroxy group, and a Ci-C 3 -haloalkyl group,
• a mono- or bicyclic heteroaryl group which is optionally substituted with a substituent which is selected from a halogen atom, a Ci-C 3 -alkyl groupa Ci-C 3 -haloalkyl group and a NR 5 R 6 group, with the proviso that said monocyclic heteroaryl group is not a pyridin-4-yl group;
• R 4 is selected from a hydrogen atom, and a Ci-C 3 -alkyl group
• R 5 /R 6 is independently selected from a hydrogen atom and a Ci-C 3 -alkyl group
• R 7 /R 8 are independently selected from
• Ci-Ce-alkyl group which is optionally substituted with one or two, three or four substituents and said substituent is independently selected from
• a 5- to 6-membered heterocycloalkyi group comprising one, or two heteroatoms which are independently selected from -O- and -NR 9 -, which is optionally further substituted with a Ci-C 3 -alkyl group,
• a 4- to 5-membered heterocycloalkyi group which is optionally substituted with one or two substituents, said substituent independently selected from Ci-C 3 -alkyl group and a hydroxy group, and R 9 is a hydrogen atom or a Ci-C 3 -alkyl group or a bond;
• the present invention provides compounds of general formula (I):
• R 1 is selected from CF 3 and a fluorine atom
• R 2 is a hydrogen atom
• R 3 is selected from
• Ci-C 3 -haloalkyl group and NR 5 R 6 group Ci-C 3 -haloalkyl group and NR 5 R 6 group
• R 4 is selected from a hydrogen atom and a methyl group
• R 5 /R 6 is a hydrogen atom or a methyl group
• R 7 /R 8 are independently selected from
• Ci-C 3 -alkyl group which is optionally substituted with onetwo or four substituents and said substituent is independently selected from
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a fluorine atom, a cyano group , a methyl group a
• R 2 is selected from a hydrogen atom, or a fluorine atom
• R 3 is selected from
• Ci -Ce-akyl group which is optionally substituted with a substitutent said substitutent is selected from a 2-hydroxy group, a methoxy group and a morpholino group;
• a cyclohexyl group which is optionally substituted with a hydroxy group
• a C5-C7-cycloalkenyl group a 3-6-membered heterocycloalkyi group which is optionally substituted with one or two substitutents said substitutents are independently selected from a fluorine atom, a -C(0)NH2 group, a hydroxy group a methyl group, an ethyl group, a hydroxymethyl group, a cyano group, and a amino group;
• a phenyl group which is optionally substituted with one, two or three substitutents said substitutents are independently selected from a methyl group, an ethyl group, a fluorine atom, a chlorine atom, an amino group, a hydroxy group, a methoxy group, a cyano group, a difluoromethyl group, a trifluoromethyl group and a methylamino group;
• a 5-membered heteroaryl group which is optionally substituted with one or two substitutents said substitutents are independently selected from a methyl group, an ethyl group, a trifluoromethyl group, a difluoromethyl group, and a cyano group
• a 6-membered heteroaryl group which is optionally substituted with one or two substitutents said substitutents are independently selected from a methyl group, a fluorine atom, a chlorine atom, a trifluoromethyl group, a amino group, and a methoxy group
• R 7 R 8 are independently selected from a hydrogen atom
• Ci-C 6 alkyl group which is otionally substituted with one or two substitutents said substitutents are independently selected from a amino group, a methoxy group, a ethoxy group, a cyano group, a hydroxy group, a trifluoromethyl group, a cyclopropyl group, a 2,2-dimethylcyclopropyl group, a 1 -hydroxycyclobutyl group, a
• 3-hydroxycyclobutyl group methyloxetanyl group, an oxolanyl group, an oxanyl group, a methyloxanyl group, a tetrahydrofuranyl group, oxopyrrolidinyl group, a oxopiperidinyl gruop, a methyl-1 H-imidazolyl group, a 1 H-pyrazolyl group, 1 H- imidazolyl group, a 1 -methyl-1 H-pyrazolyl group, a pyrazinyl group, a pyridinyl group, a pyrimidinyl group,
• a C5-C7-cycloalkyl group which is optionally substituted with a hydroxy group
• a 4-6- membered heterocycloalkyi group which isoptionally substituted with a methyl group
• R 4 is a hydrogen atom or a methyl group
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a fluorine atom, a cyano group , a CH 3 group a OCF 3 group, a CHF 2 group and a CF 3 group,
• R 2 is selected from a hydrogen atom(many examples), or a fluorine atom
• R 3 is selected from
• a methyl group a propan-2-yl group, a 2-methylpropyl group, a 2-hydroxypropan-2-yl group, a 3,3-dimethylbutyl group, a 3-methoxypropyl group,
• a prop-1 -en-2-yl group a 2-methylprop-1 -en-1 -yl group, a 3,3-dimethylbut-1 -en-1 -yl group, a 3-methoxyprop-1 -en-1 -yl group,
• a oxan-3-yl group a 3,3-dif luoroazetidin-1 -yl group, azetidin-3-carbocxamide, a 2- hydroxyazetidin-1 -yl group, a 3-hydroxy-3-methylazetidin-1 -yl group, a 2- (hydroxymethyl)azetidin-l -yl group, a 3-cyano-3-methylazetidin-1 -yl group, a 2,4- dimethylazetidin-1 -yl group, a -2lambda ⁇ sup>6 ⁇ /sup>-thia-6-azaspiro[3.3]heptane-2,2- dione group, a 3-hydroxypyrrolidin-1 -yl group, a 3,3-dif luoropyrrolidin-1 -yl group, a 3- azabicyclo[3.1 .0]hexan-3-yl group, a 1 -amino
• a 2,5-dihydrofuran-3-yl group a 5,6-dihydro-2H-pyran-3-yl group, a 3,6-dihydro-2H- pyran-4-yl group, a 1 ,2,3,6-tetrahydropyridin-4-yl group, a 1 -methyl-1 ,2,3,6- tetrahydropyridin-4-yl group, a 6-oxo-1 ,6-dihydropyridin-3-yl group,
• a phenyl group 2-methylphenyl group, 2-ethylphenyl group, a 2-fluorophenyl group, a 2- aminophenyl group, a 2-hydroxyphenyl group, a 2-methoxyphenyl group, a 2,4- dimethylphenyl group, a 2-fluoro-4-methylphenyl group, a 2-fluoro-4-aminophenyl group, a 4-cyano-2-methylphenyl group, a 2-chloro-4-fluorophenyl group, a 2,3-difluorophenyl group, a 2-fluoro-3-aminophenyl group, a 2,5-difluorophenyl group, a 2,6-difluorophenyl group, a 4-fluoro-6-methylphenyl group, a (2-difluoromethyl)phenyl group, a 2- cyanophenyl group, a 2,4-difluorophenyl group, a
• a 1 H-pyrazol-4-yl group a 1 -methyl-1 H-pyrazol-4-yl group, a 1 -ethyl-a 3-(trifluoromethyl)- 1 H-pyrazol-1 -y group, 1 H-pyrazol-4-yl group, a 1 -(propan-2-yl)-1 H-pyrazol-4-yl group, a 1 -(difluoromethyl)-1 H-pyrazol-4-yl group, a 1 -methyl-1 H-pyrazol-5-yl group, a 3-methyl- 1 H-pyrazol-4-yl group, a 1 ,3-dimethyl-1 H-pyrazol-4-yl group, a 3,5-dimethyl-1 H-pyrazol-
• a pyridin-2-yl group a 5-methyl-pyridin-2-yl group, a 5-chloro-pyridin-2-yl group, a 5- fluoro-pyridin-2-yl group, a pyridin-3-yl group, a 4-methylpyridin-3-yl group, a 2- methylpyridin-3-yl group, a 6-fluoropyridin-3-yl group, a 6-methylpyridin-3-yl group, a 6- (trifuoromethyl)pyridin-3-yl group, a 6-aminopyridin-3-yl group, a 6-methoxypyridin-3-yl group, a 5-fluoro-6-methylpyridin-3-yl group, a 2-methoxy-6-methylpyridin-3-yl group, a pyridin-4-yl group, a 2-methylpyridin-4-yl group, a 2-methoxypyridin-4-yl group, a 2- amino
• a 1 -benzothiophen-2-yl group an imidazo[1 ,2-a]pyridin-6-yl group, a 1 -methyl-1 H- benzimidazol-6-yl group, a 1 -methyl-1 H-indazol-6-yl group, a 1 H-indazol-6-yl group, a 1 H-indol-6-yl group, a 1 H-indol-5-yl group,
• R 4 is a hydrogen atom or a methyl group
• the present invention provides compounds of general formula (I):
• R 1 is selected from CF 3 , and a fluorine atom
• R 2 is selected from a hydrogen atom
• R 3 is selected from
• a prop-1 -en-1 -yl group which is optionally substituted with a methyl group
• a piperidin-1 -yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a fluorine atom and a methyl group
• a morpholin-4-yl group which is optionally substituted with one or two methyl groups
• a pyrrolidin-1 -yl group which is optionally substituted with with one or two halogen atoms
• a 6-OXO-1 ,6-dihydropyridin-3-yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a hydrogen atom and a methyl group,
• a phenyl group which is optionally substituted with one, two or three substitutents and each substituent is independently selected from from a halogen atom, a hydroxy group, a methyl group, an ethyl group, a CF 3 , CF 2 H group, a methoxy group, a CF 3 0 group, a NH 2 group and a NHCH 3 group,
• a 2H-pyrrol-1 -yl group which is optionally substituted with one or two substitutents and each substituent is independently selected from a hydrogen atom, a cyano group and a methyl group,
• a 1 H-pyrrazol-4-yl group which is optionally substituted with with one or two substitutents and each substituent is independently selected from a methyl group, an ethyl group or a CF 3 group,
• 1 ,2-oxazol-4-yl which is optionally substituted with with one or two methyl groups
• a 1 ,2-thiazol-4-yl group which is optionally substituted with a methyl group
• a 1 ,3-thiazol-5-yl group which is optionally substituted with a methyl group
• a pyridin-3-yl a pyridin-4-yl and a pyridin 5-yl group
• each substituent is independently selected from a halogen atom, a methyl group, a CF 3 group, a methoxy group and a NH 2 group
• a 1 H-indazol-6-yl group which is optionally substituted with a methyl group a 1 H-benzimidazol-6-yl group which is optionally substituted with a methyl group, a NH(C 2 H 5 ) group, a NH(C 3 H 7 ) group, a NH(C 4 H 9 ) group, a ⁇ 3 (0 4 ⁇ 9 ) group, a NH(C5Hi i ) group, a NH(cyclopentyl) group, a NCH3(cyclopentyl) group;
• R 4 is selected from a hydrogen atom and a methyl group;
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I): wherein the compound is selected from the group
• the present invention provides compounds of general formula (I): wherein the compound is selected from the group
• the present invention provides compounds of general formula (I): wherein the compound is selected from the group
• the present invention provides compounds of general formula (I): wherein the compound is selected from the group
• the present invention provides compounds of general formula (I): wherein the compound is selected from the group
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides compounds of general formula (I):
• the present invention provides the compounds as specifically exemplified in the experimental section or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
• the present invention provides compounds of general formula (I):
• R 1 is selected from a hydrogen atom, a halogen atom , a cyano group, a Ci -C 3 -alkyl group, a Ci-C 3 -haloalkyl group , and a Ci -C 3 -haloalkoxy group;
• R 2 is selected from a hydrogen atom and a halogen atom
• R 3 is selected from,
• Ci -Ce-alkyl group which is optionally substituted with one or two substituents and each substituent is independently selected from a hydroxy group, a Ci-C 4 -alkoxy group, and a 3- to 7-membered heterocycloalkyl group,
• a C2-C6-alkenyl group which is optionally substituted with an Ci-C4-alkoxy group
• a C3-C 9 -cycloalkyl group which is optionally substituted with a hydroxy group
• a C 5 -C 9 -cycloalkenyl group which is optionally substituted with a hydroxy group
• a 3- to 9-membered heterocycloalkyl group comprising one, two or three heteroatoms which are independently selected from -0-, -S-, -S(O)-, S(0)2, and-NR 9 -
• said heterocycloalkyl group optionally further comprising a bridging group selected from -0-, -NR 9 -, -CH 2 -, -CH 2 -CH 2 -, -O-CH2-, -CH2-O-, -NR 9 -CH 2 -, and - CH 2 -NR 9 -;
• heterocycloalkyl group is optionally substituted with one, two or three substituents and each substituent is independently selected from
• Ci -C3-alkyl group which is optionally substituted with a hydroxy group
• Ci -C 3 -haloalkyl group a Ci -C 3 -haloalkyl group

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