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  • 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
  • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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  • 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
  • C07D401/08—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 carbon chain containing alicyclic rings
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  • C07D401/14—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 three or more hetero rings
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • 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
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  • 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
  • C07D417/14—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 three or more hetero rings
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  • 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
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  • 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
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the groups of noncyclic radicals “alkyl”, “alkenyl”, “alkoxy”, “alkenyloxy”, “fluoroalkyl”, “fluoroalkoxy”, “alkylene”, “alkandiyl”, and the groups of radicals derived therefrom always include both unbranched and branched “alkyl”, “alkenyl”, “alkoxy”, “alkenyloxy”, “fluoroalkyl”, “fluoroalkoxy”, “alkylene” and “alkandiyl”, respectively.
• halogen designates in each case, fluorine, bromine, chlorine or iodine, specifically fluorine, chlorine or bromine
• Fluorinated cycloalkyl monocyclic, saturated hydrocarbon groups having three or more C atoms, e.g. 3, 4, 5, 6 or 7 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein at least one, e.g. 1, 2, 3, 4, 5 or 6 of the hydrogen atoms are replaced by fluorine atoms, examples including 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, etc.
• Fluoroalkoxy alkoxy as described above, in which the hydrogen atoms of these groups are partly or completely replaced by fluorine atoms, i.e. for example C 1 -C 4 -fluoroalkoxy, in particular C 1 -C 2 -fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3,3-trifluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 1-(fluoromethyl)-2-fluoroethoxy, specifically fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or
• Saturated or partially unsaturated 7 to 10-membered bicarbocyclic radicals include bicyclic carbocyclic radicals which ordinarily have from 7 to 10 carbon atoms as ring members and which are saturated or which have one or more, e.g. one or two C ⁇ C double bonds, or which include a monounsaturated carbocycle where the double bond is part of a fused benzene ring, e.g.
• Hetaryl a 5- or 6-membered aromatic heteromonocyclic radical (also termed 5- or 6-membered monocyclic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as ring members besides carbon atoms as ring members and a 8- to 10-membered aromatic heterobicyclic radical (also termed 8- to 10-membered bicyclic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as ring members besides carbon atoms as ring members: for example
• Hetarylalkyl a hetaryl radical as defined above which is linked via an alkylene group, in particular via a methylene, 1,1-ethylene or 1,2-ethylene group, to the remainder of the molecule.
• Het is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
• R x is preferably selected from halogen, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoralkoxy, phenyl, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
• Het are selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3
• Het has at least one imino-nitrogen as ring member, which is located in the position adjacent to the carbon atom which is bound to A and Het is selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents R x , in particular 0, 1 or 2 substituents R x .
• R x is preferably selected from halogen, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoralkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
• Het of this embodiment are 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals R x as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, me
• variable X 2 is C—R 7 .
• R 7 is as defined above and in particular H or Y 2 -Cyc 2 .
• X 1 is CH or preferably N.
• X 3 is preferably S or C(R 9 ) ⁇ C(R 8 ).
• X 3 is O, S, —X 4 ⁇ C(R 8 )—, where C(R 8 ) is bound to the carbon atom which carries R 2 .
• R 1 is Y 1 -Cyc 1 .
• X 1 is CH or preferably N and X 2 is preferably C—R 7 , where R 7 is as defined above and in particular H or Y 2 -Cyc 2 .
• R 7 is as defined above and in particular H or Y 2 -Cyc 2 .
• X 3 is S or X 3 is C(R 9 ) ⁇ C(R 8 ), where R 9 is preferably H or Y 3 -Cyc 3 , while R 8 is preferably hydrogen.
• Y 3 -Cyc 3 while R 8 is preferably hydrogen.
• Y 1 is preferably selected from O, NH and a chemical bond.
• Y 1 is a chemical bond.
• Y 2 is preferably selected from O, NH and a chemical bond.
• Y 2 is a chemical bond.
• Cyc 1 is selected from the groups of
• R C2 is preferably selected from the group consisting of phenyl, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2, or 3 methyl groups, fluorinated C 3 -C 6 -cycloalkyl, and 5- or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring members, which are selected from O, S and N, where phenyl the saturated heteromonocyclic radical is unsubstituted or carries 1, 2 or 3 radicals R C3 , which are preferably selected from fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 .
• Y 1 -Cyc 1 is e.g. selected from the group consisting of 1-piperidinyl, 4,4-difluoro-1-piperidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, morpholin-4-yl, 2-oxa-6-azaspiro-[3,4]octyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino, 1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino and especially from the group consisting of 1-piperidinyl, 4,4-difluoro-1-piperidinyl, 4-piperid
• Cyc 1 is phenyl or a 5- or 6 membered heteroaromatic radical, which has one heteroatom, selected from O, S and N as ring member and optionally one or two further heteroatoms as ring members, and which is in particular selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered heteroaromatic radical are unsubstituted or either carry, independently of each other, carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y′—R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R C1 , where R C1 , R C2 and Y′ are as defined herein and where Y′, if present, is preferably a chemical bond or O.
• a in formula I, and likewise in formulae I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 and I-10 is a bivalent radical A 1 .
• R 3 , R 4 are selected from hydrogen and fluorine and in particular to those compounds, where both R 3 and R 4 are hydrogen.
• R 5 and R 6 are, independently of each other, selected from the group consisting of hydrogen, fluorine and methyl, and in particular to those compounds, where both R 5 and R 6 are hydrogen.
• a in formula I and likewise in formulae I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 and I-10 is a bivalent radical A 4 , where A′ is O.
• Another particular preferred embodiment of the invention relates to the compounds of formula I-2.A, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
• a further particular preferred embodiment of the invention relates to the compounds of formula I-3.A, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
• R 1 , R 2 , R 3e , R 3f , R 7 , R 8 and R 9 are as defined here and in the claims and where R 3e and R 3f are in particular both hydrogen.
• R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are as defined here and in the claims.
• a further particular preferred embodiment of the invention relates to the compounds of formula I-5.C, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
• R 3b and R 3c are independently of each other in particular selected from the group consisting of hydrogen, fluorine and methyl or together form CH 2 CH 2 . Particular preference is given to compounds of the formulae I-7.B and I-8.B, where both R 3b and R 3c are hydrogen or fluorine.
• a particular preferred embodiment of the invention relates to the compounds of formula I-7.D, described below, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof:
• R 1 , R 2 , R 3b , R 3c , R 7 , and R 9 are as defined here and in the claims and where R 5 is in particular hydrogen.
• R 1 , R 2 , R 5 , R 7 , and R 9 are as defined here and in the claims and where R 5 is in particular hydrogen.
• Particular embodiments of the invention relate to compounds of the formulae I-9, I-10, I-9.A, I-10.A, I-9.B, I-10.B, I-9.C, I-10.C, I-9.D and I-10.D, described above, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof, where R 1 is a radical Y 1 -Cyc 1 and R 7 , and R 9 are as defined above and where R 7 is in particular selected from the group consisting of hydrogen, fluorine, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoroalkoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, fluorinated cyclopropyl and Y 2 -Cyc 2 , especially from the group consisting of hydrogen and Y 2 -
• R x is preferably selected from halogen, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 2 -fluoralkoxy, C 3 -C 6 -cycloalkyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated C 3 -C 6 -cycloalkyl.
• R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
• R x is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
• phenyl or a 5- or 6 membered hetaryl selected from pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R C1 or one radical Y′—R C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R C1 , where R C1 , R C2 and Y′ are as defined herein and where Y′, if present, is preferably a chemical bond or O.
• Cyc 1 if present in formulae I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-1.A, I-1.B, I-2.A, I-2.B, I-1.C, I-2.C, I-1.D, I-2.D, I-3.A, I-4.A, I-3.B, I-4.B, I-3.C, I-4.C, I-3.D, I-4.D, I-5.A, I-6.A, I-5.B, I-6.B, I-5.C, I-6.C, I-5.D, I-6.D, I-7.A, I-8.A, I-7.B, I-8.B, I-7.C, I-8.C, I-7.D, I-8.D, I-9.A, I-10.A, I-9.B, I-10.B, I-9.C, I-10.C, I-9.D and I-10.D, is selected from the group consisting of pheny
• Y 2 -Cyc 2 and Y 3 -Cyc 3 are, independently from each other, selected from the group consisting of phenyl and 5- or 6-membered hetaryl selected from the group consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3 radicals R C1 which are selected from the group consisting of fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH 2 .
• reaction of II with III′ is preferably carried out in an aprotic solvent, such as dimethylsulfoxide, acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethylacetamide, tetramethyl urea, or mixtures thereof or mixtures thereof with halogenated hydrocarbons such as dichloromethane.
• aprotic solvent such as dimethylsulfoxide, acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethylacetamide, tetramethyl urea, or mixtures thereof or mixtures thereof with halogenated hydrocarbons such as dichloromethane.
• the reaction is preferably carried out in the presence of a suitable base, e.g. an alkalimetal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate or an alkalimetal alkoxide.
• Y 1 -Cyc 1 , Y 2 -Cyc 2 or Y 3 -Cyc 3 is a N-bound radical
• Suitable palladium catalyst are for example tris-(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl 2 (dppf)) or palladium acetate (Pd(OAc) 2 ).
• X 1 , X 2 , X 3 , X 2a , X 3a , R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 and Het are as defined above.
• Compounds of the formulae V and Va, respectively, can be prepared in analogy to known methods, e.g. as described in Natl. Symposium Vacuum Technol., Chicago, (Trans.), 161-3; 1956, Journal of Organic Chemistry, 74(10), 3849-3855; 2009, or Journal of Heterocyclic Chemistry, 8(1), 57-60; 1971.
• compounds of the formula I (or likewise the compounds II), where Q is O and A is a radical A 1 can be prepared by hydrogenation of compounds of the formula I (or likewise the compounds II), where A is A 3 .
• compounds of the formula I (or likewise the compounds II), where Q is O and A is a radical A 4 with A′ being a CR 3b R 3c (R 3b and R 3c are as defined above) can be prepared by cyclopropanation of compounds of the formula I (or likewise the compounds II), where A is A 3 , in terms of a Simmon-Smith reaction.
• Compounds of the formula I (or likewise the compounds II), where Q is O and A is a radical A 4 with A′ being a O can be prepared by epoxidation of compounds of the formula I (or likewise the compounds II), where A is A 3 , using hydrogen peroxide.
• Compounds of the formula IIa can be prepared from compounds of the formula II by suitable metal-halogen exchange reactions.
• the reactions are usually performed in an organic solvent, including aprotic organic solvent, e.g. substituted amides, lactames and ureas; such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethyl urea, cyclic ethers; such as dioxane, tetrahydrofurane, halogenated hydrocarbons; such as dichloromethane, and mixtures thereof as well as mixtures thereof with C 1 -C 6 -alkanols and/or water.
• aprotic organic solvent e.g. substituted amides, lactames and ureas
• amides, lactames and ureas such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethyl urea, cyclic ethers
• dioxane tetrahydrofurane
• halogenated hydrocarbons such as dichloromethane, and
• the present invention also relates to a method for the treatment of a medical disorder, selected from neurological and psychiatric disorders which can be treated by inhibition of phosphodiesterase type 10A, said method comprising administering an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof, to a mammal in need thereof.
• a formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende füre [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
• a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and taking up the resulting mixture in soft or hard gelatin capsules.
• the present invention thus further relates to pharmaceutical compositions in which a plurality of active basic ingredients are present together, where at least one thereof is a compound of the invention.
• the compounds according to the invention are optionally mixed or diluted with one or more carriers.
• the compounds of the invention also include those compounds in which one or more atoms have been replaced by their stable, non-radioactive isotopes, for example, a hydrogen atom by deuterium.
• Stable isotopes are nonradioactive isotopes which contain one additional neutron than the normally abundant isotope of the respective atom.
• Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
• Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.
• Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction.
• Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to “kinetic isotope effect”.
• the weight percentage of hydrogen in a mammal indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakj a D M et al., Am. J. Physiol. 1961 201: 357).
• the hydrogens present on a particular organic compound have different capacities for exchange with deuterium.
• Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient.
• Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D 2 SO 4 /D 2 O.
• deuterium atoms may be incorporated in various combinations during the synthesis of compounds of the invention.
• Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention.
• Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
• 6-Fluoro-2-methylquinoline (1.00 g, 6.20 mmol) and sodium hydroxide were each added sequentially to the mixture of HCHO in water. Then 2 mL of EtOH were added to the mixture. The resulting solution was stirred at about 85° C. overnight. The organic layer was extracted with EA (3 ⁇ 10 mL), collected and dried with anhydrous Na 2 SO 4 , filtered and concentrated to afford a pink oil.
• the mixture was concentrated and purified on the ISCO Combiflash system using a 40 g C-18 column using the following gradient: A: Water (0.1% NH 4 HCO 3 ); B: Methanol; 30% B to 80% B over 20 min (160 mg, yield: 17.7%).
• the mixture was concentrated and was chromatographed on the ISCO Combiflash system using a 40 g Silicycle SiliaSep Silica gel column C-18 column using the following gradient: A: Water (0.1% NH 4 HCO 3 ); B: Methanol; 30% B to 80% B over 20 min (15 mg, 18.8%).
• N-tert-Butyl-2-chlorobenzamide (5.4 g, 25.6 mmol) was dissolved in THF (280 mL) and the solution was added with TMEDA (12.4 mL, 81.9 mmol) and then added with sec-butyllithium-hexane solution (1.0 molar, 82.7 mL, 81.9 mmol) dropwise at ⁇ 78° C. for 40 minutes under argon atmosphere, followed by stirring at the same temperature for 2.5 hours. Then. the mixture was added with DMF (4.36 mL, 56.3 mmol) and warmed from ⁇ 78° C. to room temperature over 2 hours.
• reaction mixture was added with water (200 mL), and extracted with ethyl acetate (100 ml,*3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by crystallization using diisopropyl ether to obtain product 3 (5.0 g, Yield: 81%).
• Examples 99 to 164 were prepared analogously to the method for Example 98.
• a reaction tube was charged with 8-chloro-2-(2-imidazo[1,2-a]pyridin-2-yl)ethyl]phthalazin-1(2H)-one (80 mg, 0.246 mmol) and a mixture of 1.5 mL of ethanol and 1.5 mL of toluene under argon.
• pyridin-3-ylboronic acid (30.3 mg, 0.246 mmol) and Na 2 CO 3 (39.2 mg, 0.369 mmol) were added.
• tetrakis(triphenylphoshine) palladium (28.5 mg, 0.025 mmol) was added.
• the reaction mixture was heated in a Biotage microwave at about 130° C. for about 30 min.
• a microwave reaction vial was charged with the 8-chloro-2-(2-imidazo[1,2-a]pyridin-2-yl)ethyl]phthalazin-1(2H)-one from Example 165.1 (100 mg, 0.31 mmol), Cs 2 CO 3 (201 mg, 0.62 mmol), Pd 2 (dba) 3 (5.64 mg, 6.16 ⁇ mol) and BINAP (11.50 mg, 0.018 mmol). The solids were purged with argon for 1 h. A separate flask was charged with toluene (993 ⁇ l) and morpholine (32.2 mg, 0.37 mmol), degas with argon for 1 h and then transferred to the microwave reaction vial under inert conditions.
• the resulting reaction mixture was heated on microwave at 100° C. for 20 h.
• the reaction mixture was poured into water and extracted with DCM. The solids were removed.
• the organic layer was washed with water, dried over MgSO 4 , filtered and concentrated in vacuo.
• the residue was purified on a silica column (eluent: DCM/methanol) and then recrystallized from EA to afford the title product (11 mg, 9.52%).
• Example 192.1 The compound from Example 192.1 (1 g, 4.4 mmol) was suspended in 5 mL acetic acid under nitrogen. The resulting thick slurry was heated to 90° C. At approximately 80° C., a homogeneous solution was obtained. Hydrazine monohydrate (64%, 0.66 mL, 13.2 mmol) was added dropwise (exotherm), keeping the internal temperature between 90 and 93° C. over approximately 4 h. The resulting suspension was continued to stir at 90° C. as the conversion of starting material was monitored by LC ( ⁇ 1%). Water (10 mL) preheated to 80° C. was added, maintaining the mixture at 80-90° C. followed by cooling down to 20° C. over approximately 2 h time. At this point, the resulting suspension was transferred onto a filter. The filter cake was rinsed with water (10 mL*3). The wet product was air-dried overnight to afford the title product (570 mg, Yield: 58%).
• a reaction tube was charged with a solution of 3-bromo-5-[2-(quinolin-2-yl)ethyl]thieno[3,2-c]pyridin-4(5H)-on (100 mg, 0.260 mmol) in 1.5 mL of ethanol and 1.5 mL of toluene under argon.
• 3-methoxypyridin-4-ylboronic acid 39.7 mg, 0.260 mmol
• a 2M solution of Na 2 CO 3 (41.3 mg, 0.389 mmol) were added.
• tetrakis(triphenylphoshine)palladium 30.0 mg, 0.026 mmol
• Example 204 to 210 were prepared in analogy to the method described above.
• a reaction tube was charged with 8-chloro-2-(2-(imidazo[1,2-a]pyridin-2-yl)ethyl)phthalazin-1(2H)-one (155 mg, 0.48 mmol), BINAP (17.83 mg, 0.029 mmol), tris(dibenzylideneacetone)dipalladium(0) (8.74 mg, 9.55 ⁇ mol) and cesium carbonate (311 mg, 0.955 mmol) in 1591 ⁇ l of toluene. The mixture was stirred for 1 h under argon. To this mixture, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (89 mg, 0.477 mmol) was added.
• 3-Bromothieno[3,2-c]pyridin-4(5H)-one 1000 mg, 4.35 mmol
• Example 202.3 3-Bromothieno[3,2-c]pyridin-4(5H)-one (1000 mg, 4.35 mmol) from Example 202.3 was suspended in 2 mL of toluene and 2 mL of ethanol under argon. Then, an aqueous solution of sodium carbonate (691 mg, 6.52 mmol, 2 M) was added. To the suspension, pyridin-4-boronic acid (534 mg, 4.35 mmol) and then tetrakis(triphenyl phosphine)palladium(0) (502 mg, 0.435 mmol) were added. The reaction mixture was heated in a Biotage microwave at 130° C. for 30 min Water and EA were added.
• a reaction tube was charged with 3-bromofuro[3,2-c]pyridin-4(5H)-one (1000 mg, 4.67 mmol) and a mixture of 1 mL of ethanol and 1 mL of toluene under argon.
• pyridin-4-ylboronic acid 574 mg, 4.67 mmol
• a 2 M solution of Na 2 CO 3 743 mg, 7.01 mmol
• tetrakis(triphenylphoshine)palladium 540 mg, 0.467 mmol.
• the reaction mixture was heated in a Cem microwave at about 130° C. for about 30 min
• EA was added followed by the addition of 2 N HCl.

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