WO2020157201A1 - Composés d'oxadiazinone pour le traitement de maladies hyperprolifératives - Google Patents
Composés d'oxadiazinone pour le traitement de maladies hyperprolifératives Download PDFInfo
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- WO2020157201A1 WO2020157201A1 PCT/EP2020/052295 EP2020052295W WO2020157201A1 WO 2020157201 A1 WO2020157201 A1 WO 2020157201A1 EP 2020052295 W EP2020052295 W EP 2020052295W WO 2020157201 A1 WO2020157201 A1 WO 2020157201A1
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- trifluoromethyl
- oxadiazin
- salt
- phenyl
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N C1CCNCC1 Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- ZDGSQIAVDXICTE-UHFFFAOYSA-N NCC1(CO)CCC1 Chemical compound NCC1(CO)CCC1 ZDGSQIAVDXICTE-UHFFFAOYSA-N 0.000 description 3
- HGWUUOXXAIISDB-UHFFFAOYSA-N C1C2C1CNC2 Chemical compound C1C2C1CNC2 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 description 2
- SNCMDWGNPFFORV-UHFFFAOYSA-N CC(C)N1CC(C2)C2C1 Chemical compound CC(C)N1CC(C2)C2C1 SNCMDWGNPFFORV-UHFFFAOYSA-N 0.000 description 1
- CHOCKQDOUJBEJP-UHFFFAOYSA-N CC(C)NCC1(CO)CCC1 Chemical compound CC(C)NCC1(CO)CCC1 CHOCKQDOUJBEJP-UHFFFAOYSA-N 0.000 description 1
- CJURQFZZQMCVPS-NSHDSACASA-N CC(C)[O+2]C[C@H](CC1)c2c1cccn2 Chemical compound CC(C)[O+2]C[C@H](CC1)c2c1cccn2 CJURQFZZQMCVPS-NSHDSACASA-N 0.000 description 1
- WBZQONLHGZSIQW-SNVBAGLBSA-N CC(C)[O+2][C@H](CC1)c2c1cccn2 Chemical compound CC(C)[O+2][C@H](CC1)c2c1cccn2 WBZQONLHGZSIQW-SNVBAGLBSA-N 0.000 description 1
- JRZZIDOUZVINEZ-UHFFFAOYSA-N CCC(CC1)(CCN1c(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O)O Chemical compound CCC(CC1)(CCN1c(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O)O JRZZIDOUZVINEZ-UHFFFAOYSA-N 0.000 description 1
- MCXSTGCHBXZVEP-UHFFFAOYSA-N CCOc(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O Chemical compound CCOc(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O MCXSTGCHBXZVEP-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N CN1CCCCC1 Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- BFNUIAJAKHBJBZ-UHFFFAOYSA-N COCCCc(c(F)c1)ccc1C(OC1)=NNC1=O Chemical compound COCCCc(c(F)c1)ccc1C(OC1)=NNC1=O BFNUIAJAKHBJBZ-UHFFFAOYSA-N 0.000 description 1
- XBJUMXIUTQOEIL-MRVPVSSYSA-N CO[C@H](CC1)c2c1cccn2 Chemical compound CO[C@H](CC1)c2c1cccn2 XBJUMXIUTQOEIL-MRVPVSSYSA-N 0.000 description 1
- SPLTZMWREVFSKY-AWEZNQCLSA-N C[C@](CC1)(CN1c(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O)O Chemical compound C[C@](CC1)(CN1c(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O)O SPLTZMWREVFSKY-AWEZNQCLSA-N 0.000 description 1
- CQJVKDILNKWBRT-UHFFFAOYSA-N Cc(cc(cc1)F)c1-c(cc1)ccc1C(OC1)=NNC1=O Chemical compound Cc(cc(cc1)F)c1-c(cc1)ccc1C(OC1)=NNC1=O CQJVKDILNKWBRT-UHFFFAOYSA-N 0.000 description 1
- UBDGDDQLCWUCSY-UHFFFAOYSA-N NNC(c(cc1)cc(C(F)(F)F)c1Cl)=O Chemical compound NNC(c(cc1)cc(C(F)(F)F)c1Cl)=O UBDGDDQLCWUCSY-UHFFFAOYSA-N 0.000 description 1
- ILZMPXWYANDHDC-UHFFFAOYSA-N NNC(c(cc1)cc(F)c1F)=O Chemical compound NNC(c(cc1)cc(F)c1F)=O ILZMPXWYANDHDC-UHFFFAOYSA-N 0.000 description 1
- NECVLZHRAMSVGN-UHFFFAOYSA-N O=C(CCl)NNC(c(cc1)cc(C(F)(F)F)c1Br)=O Chemical compound O=C(CCl)NNC(c(cc1)cc(C(F)(F)F)c1Br)=O NECVLZHRAMSVGN-UHFFFAOYSA-N 0.000 description 1
- OWQPSMYXFCDDBP-UHFFFAOYSA-N O=C(CCl)NNC(c(cc1)cc(F)c1Cl)=O Chemical compound O=C(CCl)NNC(c(cc1)cc(F)c1Cl)=O OWQPSMYXFCDDBP-UHFFFAOYSA-N 0.000 description 1
- OBSRSEIQVKVBNI-UHFFFAOYSA-N O=C1NN=C(c(cc2)cc(C(F)(F)F)c2Br)OC1 Chemical compound O=C1NN=C(c(cc2)cc(C(F)(F)F)c2Br)OC1 OBSRSEIQVKVBNI-UHFFFAOYSA-N 0.000 description 1
- JNGNDZOIKIWCMK-UHFFFAOYSA-N O=C1NN=C(c(cc2)cc(C(F)(F)F)c2F)OC1 Chemical compound O=C1NN=C(c(cc2)cc(C(F)(F)F)c2F)OC1 JNGNDZOIKIWCMK-UHFFFAOYSA-N 0.000 description 1
- GZMCJJUZEZXZRX-UHFFFAOYSA-N O=C1NN=C(c(cc2)cc(F)c2N2CCOCC2)OC1 Chemical compound O=C1NN=C(c(cc2)cc(F)c2N2CCOCC2)OC1 GZMCJJUZEZXZRX-UHFFFAOYSA-N 0.000 description 1
- YAQFSORVNQBZND-UHFFFAOYSA-N O=C1NN=C(c(cc2)ccc2-c2c(C(F)(F)F)cccc2)OC1 Chemical compound O=C1NN=C(c(cc2)ccc2-c2c(C(F)(F)F)cccc2)OC1 YAQFSORVNQBZND-UHFFFAOYSA-N 0.000 description 1
- IOPBECDXBGVYBF-UHFFFAOYSA-N O=C1NN=C(c(cc2F)cnc2Br)OC1 Chemical compound O=C1NN=C(c(cc2F)cnc2Br)OC1 IOPBECDXBGVYBF-UHFFFAOYSA-N 0.000 description 1
- ABWYQENGECPYHL-UHFFFAOYSA-N O=C1NN=C(c(cn2)cc(C(F)(F)F)c2Cl)OC1 Chemical compound O=C1NN=C(c(cn2)cc(C(F)(F)F)c2Cl)OC1 ABWYQENGECPYHL-UHFFFAOYSA-N 0.000 description 1
- KUAPOELGODPUPR-UHFFFAOYSA-N O=C1NN=C(c2ccc(-c(ccc(F)c3)c3F)c(F)c2)OC1 Chemical compound O=C1NN=C(c2ccc(-c(ccc(F)c3)c3F)c(F)c2)OC1 KUAPOELGODPUPR-UHFFFAOYSA-N 0.000 description 1
- 0 OC(C(F)(F)F)=*NC(c(cc1)cc(C(F)(F)F)c1Br)=O Chemical compound OC(C(F)(F)F)=*NC(c(cc1)cc(C(F)(F)F)c1Br)=O 0.000 description 1
- IBSWPRGAYKRADG-VIFPVBQESA-N OC[C@H](CC1)N1c(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O Chemical compound OC[C@H](CC1)N1c(cc1)c(C(F)(F)F)cc1C(OC1)=NNC1=O IBSWPRGAYKRADG-VIFPVBQESA-N 0.000 description 1
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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
Definitions
- the present invention includes oxadiazinone compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases, as a sole agent or in combination with other active ingredients.
- BACKGROUND Cancer kills over 550,000 people in the United States and over 8 million people world-wide each year. New agents, including small molecules, molecules that impact tissue-specific growth requirements, and immunomodulatory agents, have been shown to benefit a subset of patients whose cancers have unique genomic mutations or other characteristics. Unfortunately, many cancer patients are still left without effective therapeutic options.
- 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 stabilze the formation of a complex between PDE3A and/or PDE3B and SLFN12. PDE3A and/or B inhibitors which do not cause inhibition of tumor cell proliferation typically do not stabilize the PDE3A- and/or PDE3B-SLFN12 complex.
- Some oxadiazinones are known from EP080296 and EP0085227 having cardiotonic and/or anti hypertensive activity.
- the compounds of the present invention have surprisingly been found to inhibit tumor cell proliferation with IC 50 values of ⁇ 100 nM in e.g. HeLa cells. Additionally, the compounds do not inhibit enzymatic PDE3A and/or PDE3B at the concentration at which they inhibit tumor cell proliferation but at concentrations where IC 50 values for enzymatic PDE3A and/or PDE3B inhibition may be > 10 times higher than IC 50 values for tumor cell proliferation.
- this distinction in inhibitory properties may be associated with PDE3A- and/or PDE3B- SLFN12 complex induction and/or improved pharmacokinetic parameters in vitro or in vivo and/or improved physicochemical properties and/or improved safety
- 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-SLFN12 complex 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.
- the present invention includes compounds of general formula (I):
- R 1 is a hydrogen atom, a halogen atom, a Ci-C 3 -alkyl group, or a Ci-C 3 -haloalkyl group
- Y is N, or CR 2 , where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- Ci-C 6 -alkyl group which is optionally substituted with a group independently selected from
- a C 2 -C 6 -alkenyl group which is optionally substituted with a CrC 3 -alkoxy group
- a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded; a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a Ci-C 3 -haloalkyl group;
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C 3 -alkyl group, Ci-C 3 -alkoxy group, a C 1 -C 3 - haloalkoxy group and a Ci-C 3 -haloalkyl group;
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a Ci-C 3 -alkyl group, a Ci-C 3 -hydroxyalkyl group and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C 3 -alkyl group and a Ci-C 3 -haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a cyano group, a halogen atom, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC 4 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a 4- to 6-membered heterocycloalkyl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 3 -C 6 -cycloalkyl, whereby said cycloalkyl group is optionally substituted with a Ci-C 3 -hydroxyalkyl group,
- the present invention includes compounds of general formula (I): wherein
- R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
- Y is N, or CR 2 , where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- Ci-C 6 -alkenyl group which is optionally substituted with a Ci-C 3 -alkoxy group
- Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from
- Ci-C 3 -haloalkyl group a Ci-C 3 -haloalkyl group
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C3-alkyl group, Ci-C3-alkoxy group, a C1-C3- haloalkoxy group and a Ci-C3-haloalkyl group;
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a Ci-C3-alkyl group, a Ci-C3-hydroxyalkyl group and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C3-alkyl group and a Ci-C3-haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a cyano group, a halogen atom, a Ci-C3-alkyl group, a Ci-C3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC4-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a 4- to 6-membered heterocycloalkyl group, a CrC3-alkoxy group, a hydroxy group, a CrC3-haloalkyl group, and a C3-C6-cycloalkyl,
- cycloalkyl group is optionally substituted with a CrC3-hydroxyalkyl group
- a hyperproliferative disease particularly cancer, more particularly cervix cancer or melanoma.
- 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, or 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“1 , 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.
- Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to a sulfur atom.
- 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-C4-alkoxy)-(Ci-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the Ci-C4-alkoxy part can be attached to any carbon atom of the Ci-C4-alkyl part of said (Ci-C4-alkoxy)-(Ci-C4-alkyl)- group.
- 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.
- 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.
- any item is referred to as“supra” within the description it indicates any of the respective disclosures made within the specification in any of the preceding pages, or above on the same page. If within the present text any item is referred to as“infra” within the description it indicates any of the respective disclosures made within the specification in any of the subsequent pages, or below on the same page.
- halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, or chlorine atom except where halogen is intended to be a leaving group.
- CrCs-alkyl- means a linear or branched, saturated hydrocarbon group having 1 , 2, 3, 4, 5, or 6, carbon atoms, such as, for example, a methyl-, ethyl-, propyl-, iso propyl ⁇ , n-butyl-, iso- butyl-, sec-butyl-, tert- butyl-, n- pentyl-, iso- pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1 ,2-dimethylpropyl-, neo-pentyl-, 1 , 1-dimethylpropyl-, n- hexyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-,
- said group has 1 , 2, 3 or 4 carbon atoms (“CrC4-alkyl-”), e.g., a methyl-, ethyl-, n-propyl-, /so-propyl-, n-butyl-, iso- butyl-, sec-butyl- or a tert- butyl- group, 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl-”), e.g., a methyl-, ethyl-, n-propyl- or a /so-propyl group, or 1 or 2 carbon atoms (“Ci-C3-alkyl-”), e.g., a methyl-, ethyl-, n-propyl- or a /so-propyl group, or 1 or 2 carbon atoms (“Ci
- alkyl group be placed within a chain as a bivalent“Ci-C 6 -alkylene” moiety. All names as mentioned above then will bear an“ene” added to the end, thus e.g., a“pentyl” becomes a bivalent“pentylene” group.
- a“pentyl” becomes a bivalent“pentylene” group.
- the term“Ci-C 6 -heteroalkyl” refers to a CrC 6 -alkyl group in which one or more of the carbon atoms have been replaced with an atom selected from N, O, S, or P, which are substituted as mentioned herein to satisfy atom valency requirements.
- CrC 6 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“CrC 6 -alkyl” is defined supra, and in which 1 , 2 or 3 hydrogen atoms are replaced with a hydroxy group, such as, for example, a hydroxymethyl-, 1-hydroxyethyl-, 2-hydroxyethyl-, 1 ,2-dihydroxyethyl-, 3-hydroxypropyl-,
- CrC 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“CrC 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.
- Said CrC 6 -haloalkyl group is, for example, a fluoromethyl-, difluoromethyl-, trifluoromethyl-, 2-fluoroethyl-, 2.2-difluoroethyl-, 2,2,2-trifluoroethyl-, pentafluoroethyl-, 3,3,3-trifluoropropyl- or a
- haloalkyl is trifluoromethyl or difluoromethyl.
- the term“CrC 6 -alkoxy” means a linear or branched, saturated, monovalent group of formula (CrC 6 -alkyl)-0-, in which the term“CrC 6 -alkyl” is as defined supra, such as, for example, a methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, sec-butoxy-, isobutoxy-, tert- butoxy-, pentyloxy-, isopentyloxy or a n-hexyloxy group, or an isomer thereof.
- CrC 6 -haloalkoxy means a linear or branched, saturated, monovalent CrC 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
- said halogen atom is a fluorine atom.
- Said CrC 6 -haloalkoxy group is, for example, a fluoromethoxy-, difluoromethoxy-, trifluoromethoxy-, 2,2,2-trifluoroethoxy- or a pentafluoroethoxy group.
- cycloalkoxy means a cycloalkyl group as defined below which is attached to the rest of the molecule via an oxygen atom, e.g. a cyclopropyl-O- , a cyclobutyl-O- , a cyclopentyl-O- or a cyclohexyl-O- group.
- Heterocycloalkoxy groups are heterocycloalkyl groups as defined herein attached to the rest of the molecule via an oxygen atom, e.g., a azetidinyloxy-, a oxetanyloxy- or a thietanyloxy-, a tetrahydrofuranyloxy-, a 1 ,3-dioxolanyloxy-, a thiolanyloxy-, a pyrrolidinyloxy-, a imidazolidinyloxy-, a pyrazolidinyloxy-, a 1 , 1-dioxidothiolanyloxy-, a 1 ,2-oxazolidinyloxy-, a 1 ,3-oxazolidinyloxy- or a 1 ,3-thiazolidinyloxy-, a tetrahydropyranyloxy-, a tetrahydrothiopyranyloxy-,
- 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 3 carbon atoms (“C2-C3-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-, prop-2-enyl-, (£)-prop-1-enyl-, (Z)-prop-1-enyl-, /so-propenyl-, but-3-enyl-, (£)-but-2-enyl-, (Z)-but-2-enyl-, (£)-but-1-enyl-, (Z)-but-1-enyl-,
- alkenyl group be placed within a chain as a bivalent“CrC 6 -alkenylene” moiety. All names as mentioned above then will bear a “ene” added to their end, thus e.g., a“pentenyl” becomes a bivalent“pentenylene” group.
- C3-C6-cycloalkyl- means a saturated monocyclic or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6, carbon atoms (“C3-C6-cycloalkyl-”).
- Said C3-C6-cycloalkyl- group may be, for example, a monocyclic hydrocarbon ring, such as, for example, a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- cycloheptyl ring- a cyclooctyl or a cyclononyl ring, or a bicyclic hydrocarbon ring, such as decalinyl ring.
- said hydrocarbon ring is monocyclic and contains 5, or 6 carbon atoms (“Cs-Ce-cycloalkyl-”), such as, for example, cyclopentyl-, or a cyclohexyl ring.
- Cs-Ce-cycloalkyl- such as, for example, cyclopentyl-, or a cyclohexyl ring.
- a cycloalkyl group may be optionally substituted as defined at the respective part wherein such term is used.
- C4-C6-cycloalkenyl means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, or 6carbon atoms and one double bond
- Said C4-C6-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, such as , for example, a cyclobutenyl-, cyclopentenyl-, or a cyclohexenyl-, group.
- the cycloalkenyl group is a Cs-Ce-cycloalkenyl group.
- Said heterocycloalkyl group can be a 4-membered ring, such as, for example, a azetidinyl-, oxetanyl- or thietanyl group; or a 5-membered ring, such as a tetrahydrofuranyl-, 1 ,3-dioxolanyl-, thiolanyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, 1 , 1-dioxidothiolanyl-, 1 ,2-oxazolidinyl-, 1 ,3-oxazolidinyl- or a 4-membered ring, such as, for example, a azetidinyl-, oxetanyl- or thietanyl group; or a 5-membered ring, such as a tetrahydrofuranyl-, 1 ,3-dioxolanyl
- 1.3-thiazolidinyl group for example; or a 6-membered ring, such as, for example, a tetrahydropyranyl-, tetrahydrothiopyranyl-, piperidinyl-, morpholinyl-, dithianyl-, thiomorpholinyl-, piperazinyl-, 1 ,3-dioxanyl-, 1 ,4-dioxanyl- or a 1 ,2-oxazinanyl group, for example, or a 7-membered ring, such as an azepanyl-, 1 ,4-diazepanyl- or a
- a “partially unsaturated 3- to 9-membered heterocycloalkyl” 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 heterocycloalkyl 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 heterocycloalkyl group as defined herein, and a hydrogen atom to which said partially unsaturated heterocycloalkyl group is bonded with its one valency.
- Said partially unsaturated heterocycloalkyl group is, for example, 4/-/-pyranyl, 2/-/-pyranyl,
- aryl means a phenyl-, naphthyl-, 5,6-dihydronaphthyl-, 7,8-dihydronaphthyl-, 5,6,7,8-tetrahydronaphthyl-, an indanyl-, or an indenyl group, which is unsubstituted or substituted with one, two, three, four or five substituents, each substituent independently selected from a halogen atom, a cyano group, a CrC3-alkyl group, aCrC3-haloalkyl group, a CrC3-alkoxy group, a CrC3-thioalkyl group, a CrC3-haloalkoxy group, a C1-C3- halothioalkyl group, a Cs-Cs-cycloalkyl group, particularly a halogen atom, a CrC3-alkyl group, a CrC3-halo
- heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a“5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, more particularly 5 or 6 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 optionally via a ring nitrogen atom (if allowed by valency).
- Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, a thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl- or a tetrazolyl group; or a 6-membered heteroaryl group, such as, for example, a pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or a triazinyl group; or a benzo-fused 5-membered heteroaryl- group, such as, for example, a benzofuranyl-, benzothienyl-, benzoxazolyl-, benzisoxazolyl-, benzimidazolyl
- heteroaryl or heteroarylene groups include all possible isomeric forms thereof, for example: 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.
- C 2 -C 6 as used throughout this text, e.g., in the context of the definitions of“C 2 -C 6 -alkenyl-” and“C 2 -C 6 -alkynyl-”, is to be understood as meaning an alkenyl- group or an alkynyl group having a whole number of carbon atoms from 2 to 6, i.e., 2, 3, 4, 5 or 6 carbon atoms.
- C 2 -C 6 is to be interpreted as disclosing any sub-range comprised therein, e.g., C 2 -C 6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; particularly C2-C3.
- the term“C 3 -C 7 ”, as used throughout this text, e.g., in the context of the definition of“C 3 -C 7 -cycloalkyl-”, is to be understood as meaning a cycloalkyl- group having a whole number of carbon atoms of 3 to 7, i.e., 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term“C 3 -C 7 ” is to be interpreted as disclosing any sub range comprised therein, e.g., C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C7 ; particularly C3- C 6 .
- 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 a chloro-, bromo- or iodo group, a (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-, [(trifluoromethyl)sulfonyl]oxy-, [(nonafluorobutyl)sulfonyl]oxy-, [(4- bromophenyl)sulfonyl]oxy-, [(4-nitrophenyl)sulfonyl]oxy-, [(2-nitrophenyl)sulfonyl]oxy-, [(4-isopropylphenyl)sulfonyl]oxy-,
- the term“protective group” is a protective group attached to an oxygen or nitrogen atom in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g., by chemical modification of the respective hydroxy or amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for hydroxy and amino groups are descibed for example in T.W. Greene and P.G.M.
- protective groups for amino groups can be selected from substituted sulfonyl groups, such as a mesyl-, tosyl- or a phenylsulfonyl group, acyl groups such as a benzoyl-, acetyl- or a tetrahydropyranoyl group, or carbamate based groups, such as a te/f-butoxycarbonyl group (Boc).
- substituted sulfonyl groups such as a mesyl-, tosyl- or a phenylsulfonyl group
- acyl groups such as a benzoyl-, acetyl- or a tetrahydropyranoyl group
- carbamate based groups such as a te/f-butoxycarbonyl group (Boc).
- Protective groups for hydroxy groups can be selected from acyl groups such as a benzoyl-, acetyl, pivaloyl- or a tetrahydropyranoyl group, or can include silicon, as in e.g., a tert-butyldimethylsilyl-, tert- butyldiphenylsilyl-, triethylsilyl- or a triisopropylsilyl group.
- acyl groups such as a benzoyl-, acetyl, pivaloyl- or a tetrahydropyranoyl group
- silicon as in e.g., a tert-butyldimethylsilyl-, tert- butyldiphenylsilyl-, triethylsilyl- or a triisopropylsilyl group.
- substituted refers to a group “substituted” on, e.g., an alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group, replacing one or more hydrogen atoms therein.
- the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent.
- a substituent may itself be substituted with any one of the above substituents.
- optionalally substituted means unsubstituted (e.g., substituted with an H) or substituted.
- subject is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, rodent, or feline.
- An“oxo” substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond.
- the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
- 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.
- 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 examples 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, 36 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, 36 CI, 82 Br, 123 l, 124 l, 125 l
- the isotopic variant(s) of the compounds of general formula (I) particularly contain deuterium (“deuterium-containing compounds of general formula (I)”).
- 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 (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131) 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, particularly for a deuterium-containing reagent.
- a reagent for an isotopic variant of said reagent particularly 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 (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052).
- Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
- 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. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al. , J. Org. Chem. 55, 3992-3997, 1990; R. P.
- 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%, particularly higher than 90%, 95%, 96% or 97%, even more particularly 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; A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85, 2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641 ; C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L.
- deuterium-containing compound of general formula (I) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I).
- deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
- the major effect of deuteration is to reduce the rate of systemic clearance.
- Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
- 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 of attack for metabolizing enzymes such as e.g. cytochrome P450.
- 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.
- the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. 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. 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.
- 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.
- Preferred isomers are those which produce the more desirable biological activity should they be different for the isomers.
- These separated, pure or partially purified isomers or racemic mixtures of the compounds of this 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.
- 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.
- Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention can be 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 pyrazol moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H 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 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 possible N-oxides.
- the present invention also includes useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co- precipitates.
- 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 compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
- 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.
- pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
- 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 hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid, and nitric acid or with an organic acid, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, sal
- A“pharmaceutically acceptable anion” refers to the deprotonated form of a conventional acid, such as, for example, a hydroxide, a carboxylate, a sulfate, a halide, a phosphate, or a nitrate.
- Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, such as, by way of example and by preference, alkali metal salts (for example lithium, sodium and potassium salts), alkaline earth metal salts (for example calcium, strontium and magnesium salts) or an aluminium salt or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as by way of example and by preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, N- methylpiperidine
- the compounds according to the invention may form salts with a quaternary ammonium ion obtainable, e.g., by quaternisation of a basic nitrogen-containing group with agents such as lower alkylhalides, such as alkylchlorides, e.g. methylchloride, ethylchloride, propylchloride and butylchloride; such as alkylbromides, e.g. methylbromide, ethylbromide, propylbromide and butylbromide; and such as alkyliodides;e.g.
- dialkylsulfates such as dimethylsulfate, diethylsulfate, dibutylsulfate and diamylsulfates, long chain halides such as e.g.
- decylchloride laurylchloride, myristylchloride and stearylchloride
- decylbromide laurylbromide
- myristylbromide and stearylbromide decyliodide
- lauryliodide myristyliodide and stearyliodide
- aralkylhalides such as benzylchloride, benzylbromide, benzyliodide and phenethylbromides and others.
- quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra(n- propyl)ammonium, tetra (n-butyl)ammonium, or /V-benzyl-/V,/V,/V-trimethylammonium.
- 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.
- Solvates and hydrates of disclosed intermediates or example compounds, or salts thereof, which have been obtained, by the preparation and/or purification processes described herein, may be formed in any ratio.
- 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 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.
- a prodrug may be in the form of an in vivo hydrolysable ester of the specified compound.
- Derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) 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 the compound of formula (I) or a salt thereof by metabolic processes.
- the present invention includes compounds of general formula (I), supra,
- R 1 is a hydrogen atom, a halogen atom, a CrC3-alkyl group, or a CrC3-haloalkyl group
- Y is N, or CR 2 , where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C 2 -C 6 -alkenyl group which is optionally substituted with a CrC 3 -alkoxy group
- a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded; a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a CrC 3 -haloalkyl group;
- a C 5 -C 6 -cycloalkenyl group a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C 3 -alkyl group, Ci-C 3 -alkoxy group, a C 1 -C 3 - haloalkoxy group and a Ci-C 3 -haloalkyl group;
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a C 1 -C 3 - alkyl group and a CrC 3 -haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a cyano group, a halogen atom, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C 4 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a 4- to 6-membered heterocycloalkyl group, a Ci-C 3 -alkoxy group, a hydroxy group, a Ci-C 3 -haloalkyl group, and a C 3 -C 6 -cycloalkyl,
- cycloalkyl group is optionally substituted with a Ci-C 3 -hydroxyalkyl group
- a C(0)-(Ci-Ce-alkyl) group or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, wherein
- R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
- Y is N, or CR 2 , where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C 2 -C 6 -alkenyl group which is optionally substituted with a CrC 3 -alkoxy group
- a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted CrC 4 -alkyl group or an unsubstituted CrC 4 -alkoxy group is excluded;
- a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a C 1 -C 3 - haloalkyl group;
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, CrC 3 -alkoxy group, a C 1 -C 3 - haloalkoxy group and a CrC 3 -haloalkyl group;
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a Ci-C 3 -alkyl group, a Ci-C 3 -hydroxyalkyl group and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a C 1 -C 3 - alkyl group and a Ci-C 3 -haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a cyano group, a halogen atom, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C 4 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a 4- to 6-membered heterocycloalkyl group, a CrC 3 -alkoxy group, a hydroxy group, a CrC 3 -haloalkyl group, and a C 3 -C 6 -cycloalkyl,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a halogen atom, a Ci-C3-alkyl group, or a Ci-C3-haloalkyl group
- Y is N, or CR 2 , where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- Ci-C3-alkoxy group a Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from
- Ci-C3-alkyl group which itself can be substituted with a Ci-C3-alkyl group
- a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a Ci-C3-alkyl group
- a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a C 1 -C 3 - haloalkyl group,
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, Ci-C 3 -alkyl group, Ci-C 3 -alkoxy group, a C 1 -C 3 - haloalkoxy group and a CrC 3 -haloalkyl group,
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a cyano group,
- a group, a group, a group, a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C 3 -alkyl group and a Ci-C 3 -haloalkyl group
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a cyano group, a halogen atom, a CrC 3 -alkyl group, a CrC 3 -haloalkyl group, and
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a 4- to 6-membered heterocycloalkyl group, a Ci-C 3 -alkoxy group, a hydroxy group, a Ci-C 3 -haloalkyl group, and a C 3 -C 6 -cycloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
- Y is CR or N, where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C 2 -C 4 -alkenyl group which is optionally substituted with a CrC 3 -alkoxy group
- a CrC 4 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded; a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a CrC 3 -haloalkyl group,
- a C 5 -C 6 -cycloalkenyl group a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, CrC 3 -alkoxy group, a C 1 -C 3 - haloalkoxy group and a CrC 3 -haloalkyl group,
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a cyano group,
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a cyano group, a CrC 3 -alkyl group, a CrC 3 -haloalkyl group, and
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC 4 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, and a CrC 3 -haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group
- Y is CR or N, where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C 2 -C 4 -alkenyl group which is optionally substituted with a CrC 3 -alkoxy group
- a CrC 4 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted CrC 4 -alkyl group or an unsubstituted CrC 4 -alkoxy group is excluded;
- R 3 as an unsubstituted methyl group is excluded; a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a CrC 3 -haloalkyl group,
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC 3 -alkyl group, CrC 3 -alkoxy group, a C 1 -C 3 - haloalkoxy group and a CrC 3 -haloalkyl group,
- a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC 3 -alkyl group, a CrC 3 -hydroxyalkyl group and a cyano group,
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a cyano group, a CrC 3 -alkyl group, a CrC 3 -haloalkyl group, and
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC 4 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC 3 -alkoxy group, a hydroxy group, and a CrC 3 -haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group;
- Y is CR 2 , where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a CrC 3 -alkyl group
- a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group which itself can be substituted with a CrC 3 -alkyl group, a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a CrC 3 -alkyl group, and a 5- to 6-membered heteroaryl group;
- a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more times with a group independently selected from a halogen atom, and a C 1 -C 3 - haloalkyl group;
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a CrC 3 -haloalkyl group;
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC 3 -alkyl group, and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C3-alkyl group and a CrC3-haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a halogen atom, and a CrC3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, a CrC3-haloalkyl group, and a C3-C6-cycloalkyl,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a halogen atom, a CrC3-alkyl group, or a CrC3-haloalkyl group;
- Y is CR 2 or N, where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a CrC3-alkyl group; a C2-C4-alkenyl group, which is optionally substituted with a Ci-C3-alkoxy group, a Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded; a 4- to 6-membered heterocycloalkoxy group;
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a Ci-C3-haloalkyl group;
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a Ci-C3-alkyl group, and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C3-alkyl group and a CrC3-haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a CrC3-alkyl group, a halogen atom, and a CrC3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a Ci-C3-alkoxy group, a hydroxy group, and a Ci-C3-haloalkyl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a halogen atom, a CrC3-alkyl group, or a CrC3-haloalkyl group
- Y is CR 2 or N, where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C2-C4-alkenyl group which is optionally substituted with a CrC3-alkoxy group, a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a CrC3-haloalkyl group;
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, and a cyano group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a CrC3-alkyl group, a halogen atom, and a CrC3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, and a CrC3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a halogen atom, a CrC3-alkyl group, or a CrC3-haloalkyl group;
- Y is CR 2 , where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C2-C4-alkenyl group which is optionally substituted with a CrC3-alkoxy group, a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from
- a CrC3-alkoxy group a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a CrC3-alkyl group,
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a CrC3-haloalkyl group;
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a C1-C3- alkyl group and a Ci-C3-haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a Ci-C3-alkyl group, a halogen atom, and a Ci-C3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, and a CrC3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a Ci-C3-alkyl group, or a Ci-C3-haloalkyl group
- Y is CR 2 , where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- Ci-C 6 -alkyl group which is optionally substituted with a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a Ci-C3-alkyl group, a Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from
- a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more timew with a group independently selected from a halogen atom, and a C1-C3- haloalkyl group,
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a Ci-C3-haloalkyl group,
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a Ci-C3-alkyl group, and a cyano group,
- a *Oo group a group, a group, a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a halogen atom, a Ci-C3-haloalkyl group,
- R 5 is a hydrogen atom
- R 6 is selected from a CrC 3 -alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a Ci-C 3 -alkoxy group, a hydroxy group, a Ci-C 3 -haloalkyl group, and a C 3 -C 6 -cycloalkyl,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a Ci-C 3 -alkyl group, or a Ci-C 3 -haloalkyl group
- Y is CR 2 , where R 2 is a hydrogen atom, or a halogen atom;
- R 3 is selected from
- Ci-C 6 -alkyl group which is optionally substituted with a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a Ci-C 3 -alkyl group, a Ci-C 6 -alkoxy group which is optionally substituted with a group independently selected from
- Ci-C 3 -haloalkyl group
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded;
- a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more timew with a group independently selected from a halogen atom, and a CrC 3 -haloalkyl group,
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a Ci-C 3 -haloalkyl group, a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, and a cyano group,
- a group, a group, a group, a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a halogen atom, a Ci-C3-haloalkyl group,
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a Ci-C3-alkoxy group, a hydroxy group, a Ci-C3-haloalkyl group, and a C3-C6-cycloalkyl,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- both, R 1 and R 2 may not be a hydrogen atom at the same time;
- R 3 is selected from a -(CH2)-CH(CH3)2 group, a -(CH 2 ) 3 -0-CH 3 group, a -CH2-(morpholin- 4-yl) group, a -CH2-N(CH3)2 group,
- a cyclopent-1-en-1-yl group a -0-(CH 2 ) 2 -CH 3 group, a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -(CH 3 ) 2 group, a -0-(CH 2 ) 2 - C(CH 3 ) 3 group, a -0-CH 2 -CF 3 group, a -0-(CH 2 ) 2 -CF 3 group, a -0-(CH 2 )-CH(CH 3 )- OH group, a -0-(CH 2 )-C(CH 3 ) 2 -0H group, a -0-(CH 2 ) 2 -0-CH 3 group, a -0-CH 2 -cyclopropyl group, a -0-CH 2 -cyclobutyl group, a -0-( ethyl-oxetan-3-yl) group, a - 0-CH 2 -tetrahydofur
- a 4-chlorophenyl group a 4-fluoro-phenyl group, a 4-fluoro-2-methyl-phenyl group, a 3-fluoro-4-methyl-phenyl group, a 4-fluoro-2-trifluoromethyl-phenyl group, a piperidin1-yl group, a 3-hydroxy-piperidin-1-yl group, a 4,4-difluoro-piperidin-1-yl group, a 4-ethyl-4-hydroxy-piperidin-1-yl group, a 3,3-difluoroazetidin-1-yl group, 3- V ,. ⁇ *
- hydroxy-3-methylazetidin-1-yl a group, a group, a 3- hydroxy-3-methyl-pyrrolidin-1-yl group, a 4-cyano-piperidine group, a 4-methyl- piperazin-1-yl group, a 4-ethyl-4-hydroxy-piperazin-1-yl group, a 4,4- difluoropiperazinyl group, a piperazin-1-yl group, a morpholin-4-yl group, a 1 -methyl-1 , 2, 3, 6-tetrahydropyridin-4-yl group,
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-chloro-pyridin-6-yl group, a 3- fluoro-pyrazol-1-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1- difluoromethylpyrazol-4-yl group, a 4-trifluoro ethyl-1 ,2,3-triazol-2-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH(CH 3 )-
- cyclopropyl group a group, a -NH-cyclopentyl group, a -NH-(3-tetrahydrofuryl) group,
- a -NH-CH 2 -(pyrazol-3-yl) group a -NH-CH 2 -(pyrazol-5-yl) group, a -NH-CH 2 -pyrazin- 2-yl group, and a -NH-C(0)-CH 2 -CH 3 group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a CrC3-alkyl group, or a CrC3-haloalkyl group
- Y is CR 2 or N where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C2-C4-alkenyl group which is optionally substituted with a CrC3-alkoxy group, a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methyl group is excluded
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a CrC3-haloalkyl group;
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C3-alkyl group and a CrC3-haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a CrC3-alkyl group, a halogen atom, and a CrC3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, and a CrC3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a CrC3-alkyl group, or a CrC3-haloalkyl group;
- Y is CR 2 or N where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a group independently selected from
- a C2-C4-alkenyl group which is optionally substituted with a CrC3-alkoxy group
- a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC3-haloalkyl group
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a CrC3-haloalkyl group;
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, and a cyano group;
- a partially unsaturated 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a Cr C3-alkyl group and a CrC3-haloalkyl group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a CrC3-alkyl group, a halogen atom, and a CrC3-haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, and a CrC3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
- Y is C-R 2 or N and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- R 3 is selected from
- a CrC4-alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded;
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, and a CrC3-haloalkyl group; a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, a CrC3-hydroxyalkyl group and a cyano group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a CrC3-alkyl group, and a C1-C3- haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC4-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, and a CrC3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
- Y is C-R 2 or N and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- R 3 is selected from
- a CrC4-alkoxy group which is optionally substituted with a group independently selected from
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, and a CrC3-haloalkyl group; a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC3-alkyl group, a CrC3-hydroxyalkyl group and a cyano group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a Ci-C3-alkyl group, and a C1-C3- haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC4-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, and a CrC3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- R 3 is selected from
- Ci-C4-alkyl group which is optionally substituted with a group independently selected from
- a CrC4-alkoxy group which is optionally substituted with a group independently selected from
- R 3 as an unsubstituted methoxy group is excluded and if Y is N, R 3 as an unsubstituted methyl group is excluded;
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, CrC3-alkyl group, and a CrC3-haloalkyl group; a 4- to 7-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a Ci-C3-alkyl group, a Ci-C3-hydroxyalkyl group and a cyano group;
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from a Ci-C3-alkyl group, and a C1-C3- haloalkyl group;
- R 5 is a hydrogen atom
- R 6 is selected from
- Ci-C4-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a Ci-C3-alkoxy group, a hydroxy group, and a Ci-C3-haloalkyl group,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -0-(CH 2 ) 2 -CH 3 group, a -O- (CH 2 ) 3 CH 3 group, a -0-CH 2 -(CH 3 ) 2 group, a -0-CH 2 -CF 3 group, a -0-(CH 2 ) 2 -CF 3 group, a -0-(CH 2 )-CH(CH 3 )-0H group, a -0-(CH 2 )-C(CH 3 ) 2 -0H group, a -0-(CH 2 ) 2 - 0-CH 3 group, a -0-CH 2 -cyclopropyl group, a -0-CH 2 -cyclobutyl group, a -O- (methyl-oxetan-3-yl) group, a -0-CH 2 -(methyl-azetidin-2-yl)- group, a -0-CH 2
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1-difluoromethylpyrazol-4-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH-
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 or N and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- both, R 1 and R 2 may not be a hydrogen atom at the same time;
- a -0-CH 2 -CH 3 group a -0-(CH 2 ) 2 -CH 3 group, a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -CF 3 group, a -0-CH 2 -CHF 2 group, a -0-(CH 2 ) 2 -0H group, a -0-(CH 2 ) 2 -CF 3 group, a -O- (CH 2 ) 2 -0-CH 3 group, a -0-(CH 2 ) 2 -N(CH 3 ) 3 group, a -O-cyclopropyl group, a -O- cyclobutyl group, a -0-(oxetan-3-yl) group, a -0-CH 2 -tetrahydofuran-2-yl group, a 4-fluoro-phenyl group, a 2-fluoro-phenyl group, a 2-trifluoromethylphenyl group, a
- a piperidin1-yl group a 1-methyl-piperidin-4-yl group, a 3-hydroxy-pi peridin-1-yl group, a 4-cyano-piperidin-1-yl group, a 4,4-difluoro-piperidin-1-yl group, a 4-ethyl-4- hydroxy-piperidin-1-yl group, a 3-hydroxy-2-(propan-2-yl)azetidin-1-yl group, a 2- hydroxymethylazetidin-1-yl group, a 3,3-difluoroazetidin-1-yl group, 3-hydroxy-3-
- methylazetidin-1-yl a group, a group, a pyrrolidin-1-yl group, a 4-methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group,
- a pyridin-4-yl group a 6-methyl-pyridin-3-yl group, a 6-cyanopyridin-3-yl group, a piperazin-2-yl group, a pyrazol-4-yl group, a 1-methylpyrazol-4-yl group, a 1- ethylparazol-4-yl group, a 1-difluoromethylpyrazol-4-yl group, a 3-trifluoromethyl- pyrazol-1-yl group, a 4-trifluoromethyl-pyrazol-1-yl group, a 3,5-dimethyl-1 ,2- oxazol-4-yl group, a 4-trifluoromethyl-1 ,2,3-triazol-2-yl group, a 4-trifluoromethyl- 1 ,2,3-triazol-1-yl group, a 3-difluoromethyl-2H-1 ,2,4-triazol-1-yl group, a 3- difluoromethyl-1 H-1 ,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 or N and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- R 3 is selected from a -(CH 2 )-CH(CH3)2 group, a -(CH 2 ) 3 -0-CH 3 group, a -CH 2 -(morpholin- 4-yl) group, -CH 2 -piperidin-1-yl, a -CH 2 -N(CH3)2 group,
- a -0-CH 2 -CH 3 group a -0-(CH 2 ) 2 -CH 3 group, a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -CF 3 group, a -0-CH 2 -CHF 2 group, a -0-(CH 2 ) 2 -0H group, a -0-(CH 2 ) 2 -CF 3 group, a -O-
- 4-trifluoromethylphenyl group 4-methyl-3-trifluoromethylphenyl group, a 2,4- difluoro-phenyl group, a 4-fluoro-2-methyl-phenyl group, a 3-fluoro-4-methyl-phenyl group, a piperidin1-yl group, a 1-methyl-piperidin-4-yl group, a 3-hydroxy-pi peridin-1-yl group, a 4-cyano-piperidin-1-yl group, a 4,4-difluoro-piperidin-1-yl group, a 4-ethyl-4- hydroxy-piperidin-1-yl group, a 3-hydroxy-2-(propan-2-yl)azetidin-1-yl group, a 2- hydroxymethylazetidin-1-yl group, a 3,3-difluoroazetidin-1-yl group, 3-hydroxy-3-
- methylazetidin-1-yl a group, a group, a pyrrolidin-1-yl group, a 4-methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group,
- a pyridin-4-yl group a 6-methyl-pyridin-3-yl group, a 6-cyanopyridin-3-yl group, a piperazin-2-yl group, a pyrazol-4-yl group, a 1-methylpyrazol-4-yl group, a 1- ethylparazol-4-yl group, a 1-difluoromethylpyrazol-4-yl group, a 3-trifluoromethyl- pyrazol-1-yl group, a 4-trifluoromethyl-pyrazol-1-yl group, a 3,5-dimethyl-1 ,2- oxazol-4-yl group, a 4-trifluoromethyl-1 ,2,3-triazol-2-yl group, a 4-trifluoromethyl- 1 ,2,3-triazol-1-yl group, a 3-difluoromethyl-2H-1 ,2,4-triazol-1-yl group, a 3- difluoromethyl-1 H-1 ,
- a -NH-(CH 2 ) 2 -0-CH 3 group a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CF 3 group, a -NH-CH(CH 2 CH 3 )-CH 2 -OH group, a
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 or N and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- R 3 is selected from a a -(CH 2 ) 3 -0-CH 3 group, a -CH 2 -(morpholin-4-yl) group, -CH 2 - piperidin-1-yl, a -CH2-N(CH3)2 group,
- a -O-CH2-CH3 group a -0-(CH 2 )2-CH 3 group, a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -CF 3 group, a -0-CH 2 -CHF 2 group, a -0-(CH 2 ) 2 -OH group, a -0-(CH 2 ) 2 -CF 3 group, a -O- (CH 2 ) 2 -0-CH 3 group, a -0-(CH 2 ) 2 -N(CH 3 ) 3 group, a -O-cyclopropyl group, a -O- cyclobutyl group, a -0-(oxetan-3-yl) group, a -0-CH 2 -tetrahydofuran-2-yl group, a 4-fluoro-phenyl group, a 2-fluoro-phenyl group, a 2-trifluoromethylphenyl group, a 2- trifluo
- a piperidin1-yl group a 1-methyl-piperidin-4-yl group, a 3-hydroxy-pi peridin-1-yl group, a 4-cyano-piperidin-1-yl group, a 4,4-difluoro-piperidin-1-yl group, a 4-ethyl-4- hydroxy-piperidin-1-yl group, a 3-hydroxy-2-(propan-2-yl)azetidin-1-yl group, a 2- hydroxymethylazetidin-1-yl group, a 3,3-difluoroazetidin-1-yl group, 3-hydroxy-3-
- methylazetidin-1-yl a group, a group, a pyrrolidin-1-yl group, a 4-methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group,
- a pyridin-4-yl group a 6-methyl-pyridin-3-yl group, a 6-cyanopyridin-3-yl group, a piperazin-2-yl group, a pyrazol-4-yl group, a 1-methylpyrazol-4-yl group, a 1- ethylparazol-4-yl group, a 1-difluoromethylpyrazol-4-yl group, a 3-trifluoromethyl- pyrazol-1-yl group, a 4-trifluoromethyl-pyrazol-1-yl group, a 3,5-dimethyl-1 ,2- oxazol-4-yl group, a 4-trifluoromethyl-1 ,2,3-triazol-2-yl group, a 4-trifluoromethyl- 1 ,2,3-triazol-1-yl group, a 3-difluoromethyl-2H-1 ,2,4-triazol-1-yl group, a 3- difluoromethyl-1 H-1 ,
- a -NH-(CH 2 )2-0-CH 3 group a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CF 3 group, a -NH-CH(CH 2 CH 3 )-CH 2 -OH group, a
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- both, R 1 and R 2 may not be a hydrogen atom at the same time;
- R 3 is selected from a -(CH2)-CH(CH3)2 group, a -(CH 2 ) 3 -0-CH 3 group, a -CH 2 -(morpholin- 4-yl) group, -CH 2 -piperidin-1-yl, a -CH2-N(CH3)2 group,
- a -O-CH2-CH3 group a -0-(CH 2 ) 2 -CH 3 group, a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -CF 3 group, a -0-CH 2 -CHF 2 group, a -0-(CH 2 ) 2 -OH group, a -0-(CH 2 ) 2 -CF 3 group, a -O- (CH 2 )2-0-CH 3 group, a -0-(CH 2 )2-N(CH 3 )3 group, a -O-cyclopropyl group, a -O- cyclobutyl group, a -0-CH 2 -(oxolan-2-yl) group, a -0-(oxetan-3-yl) group, a -O- CH 2 -tetrahydofuran-2-yl group,
- a 4-fluoro-phenyl group a 2-fluoro-phenyl group, a 2-difluoromethylphenyl group, a 2- trifluoromethylphenyl group, a 2-trifluoromethoxyphenyl group, a 4-fluoro-2- methoxyphenyl group, a 4-fluoro-2-trifluoromethylphenyl group, a 4-chloro-2- trifluoromethylphenyl group, a 3-methyl-4-trifluoromethylphenyl group, a 4-methyl- 3-trifluoromethylphenyl group, a 2,4-difluoro-phenyl group, a 4-fluoro-2-methyl- phenyl group, a 3-fluoro-4-methyl-phenyl group,
- methylazetidin-1-yl a group, a group, a pyrrolidin-1-yl group, a 3-hydroxy-3-methyl-pyrrolidin group, a 4-methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group,
- a pyridin-4-yl group a 6-methyl-pyridin-3-yl group, a 6-cyanopyridin-3-yl group, a piperazin-2-yl group, a pyrazol-4-yl group, a 1-methylpyrazol-4-yl group, a 1- ethylpyrazol-4-yl group, a 1-difluoromethylpyrazol-4-yl group, a 3-trifluoromethyl- pyrazol-1-yl group, a 4-trifluoromethyl-pyrazol-1-yl group, a 3,5-dimethyl-1 ,2- oxazol-4-yl group, a 4-trifluoromethyl-1 H-1 ,2,3-triazol-2-yl group, a 4- trifluoromethyl-2H-1 ,2,3-triazol-1-yl group, a 3-difluoromethyl-2H-1 ,2,4-triazol-1-yl group, a 3-difluoromethyl
- a -NH-(CH 2 ) 2 -0-CH 3 group a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CF 3 group, a -NH-CH(CH 2 CH 3 )-CH 2 -OH group, a
- a cyano group or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- R 3 is selected from a -(CH 2 ) 3 -0-CH 3 group, a -CH 2 -(morpholin-4-yl) group, -CH 2 - piperidin-1-yl, a -CH 2 -N(CH 3 )2 group,
- a -0-CH 2 -CH 3 group a -0-(CH 2 ) 2 -CH 3 group, a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -CF 3 group, a -0-CH 2 -CHF 2 group, a -0-(CH 2 ) 2 -0H group, a -0-(CH 2 ) 2 -CF 3 group, a -O- (CH 2 ) 2 -0-CH 3 group, a -0-(CH 2 ) 2 -N(CH 3 ) 3 group, a -O-cyclopropyl group, a -O- cyclobutyl group, a -0-CH 2 -(oxolan-2-yl) group, a -0-(oxetan-3-yl) group, a -O- CH 2 -tetrahydofuran-2-yl group,
- a 4-fluoro-phenyl group a 2-fluoro-phenyl group, a 2-difluoromethylphenyl group, a 2- trifluoromethylphenyl group, a 2-trifluoromethoxyphenyl group, a 4-fluoro-2- methoxyphenyl group, a 4-fluoro-2-trifluoromethylphenyl group, a 4-chloro-2- trifluoromethylphenyl group, a 3-methyl-4-trifluoromethylphenyl group, a 4-methyl- 3-trifluoromethylphenyl group, a 2,4-difluoro-phenyl group, a 4-fluoro-2-methyl- phenyl group, a 3-fluoro-4-methyl-phenyl group,
- methylazetidin-1-yl a group, a group, a pyrrolidin-1-yl group, a 3-hydroxy-3-methyl-pyrrolidin group, a 4-methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group, a 1-methyl-1 ,2,3,6-tetrahydropyridin-4-yl group, a 2,5-dihydro-1 H-pyrrol-3-yl group, a 1 -methyl-2, 5-dihydro-1 H-pyrrol-3-yl group;
- a pyridin-4-yl group a 6-methyl-pyridin-3-yl group, a 6-cyanopyridin-3-yl group, a piperazin-2-yl group, a pyrazol-4-yl group, a 1-methylpyrazol-4-yl group, a 1- ethylpyrazol-4-yl group, a 1-difluoromethylpyrazol-4-yl group, a 3-trifluoromethyl- pyrazol-1-yl group, a 4-trifluoromethyl-pyrazol-1-yl group, a 3,5-dimethyl-1 ,2- oxazol-4-yl group, a 4-trifluoromethyl-1 H-1 ,2,3-triazol-2-yl group, a 4- trifluoromethyl-2H-1 ,2,3-triazol-1-yl group, a 3-difluoromethyl-2H-1 ,2,4-triazol-1-yl group, a 3-difluoromethyl
- a -NH-(CH 2 )2-0-CH 3 group a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CF 3 group, a -NH-CH(CH 2 CH 3 )-CH 2 -OH group, a
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, or a fluorine atom
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a CH2-N(CH3)2 group, a -(CH 2 ) 3 -0- CH 3 group,
- a -0-(CH 2 ) 2 -CH 3 group a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -CH 3 group, a -0-CH 2 -CHF 2 group, a -0-(CH 2 ) 2 -CF 3 group, a -0-(CH 2 ) 2 -0-CH 3 group, a -0-CH 2 - tetrahydropyran-2-yl group, a -O-cyclopropyl group, a -O-cyclobutyl group, a -O- (oxetan-3-yl) group,
- a 2-fluoro-phenyl group a 2-trifluoromethylphenyl group, a 2-difluoromethylphenyl group, a 4-fluoro-2-trifluoromethyl-phenyl group, a 2,4-difluorophenyl group, a 4- chloro-2-trifluoromethylphenyl group,
- a -NH-(CH 2 ) 2 -0-CH 3 group a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CH 3 group, a -NH-CH(CH 2 OH)CH 2 -CH 3 group, a -NH- cyclopentyl group, a -NH-CH 2 -C(-CH 2 -CH 2 -CH 2 -)-CH 2 -OH group, a -NH-CH 2 -(3- pyrazolyl) group and a -NH-CH 2 -pyrazin-2-yl group,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 or N and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- both, R 1 and R 2 may not be a hydrogen atom at the same time;
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -CH 2 -N(CH 3 ) 2 group,
- a 1-methyl-2,5-didehydro-1 H-pyrrol-3-yl group a -0-CH 2 -CH 3 group, a -0-CH 2 -CHF 2 group, a -O-cyclopropyl group, a -O-cyclobutyl group, a -0-(oxetan-3-yl) group, a -0-CH 2 -tetrahydofuran-2-yl group,
- N hydroxymethylazetidin-1-yl group a group, a 3-hydroxy-3-myethyl- pyrrolidin-1-yl group, a 4-methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group, an azepan-1-yl group,
- a 6-methyl-pyridin-3-yl group a 1-difluoromethylpyrazol-4-yl group, a 3- trifluoromethyl-pyrazol-1-yl group, a 3-trifluoromethyl-1 ,2,5-triazol-2-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CH 3
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- a -0-(CH 2 ) 2 -CH 3 group a -0-(CH 2 ) 3 CH 3 group, a -0-(CH 2 ) 2 -CF 3 group, a -0-(CH 2 ) 2 -0- CH 3 group, a -0-CH 2 -tetrahydropyran-2-yl group,
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a fluorine atom, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- both, R 1 and R 2 may not be a hydrogen atom at the same time;
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -CH 2 -N(CH 3 ) 2 group,
- a -0-CH 2 -CH 3 group a -0-CH 2 -CHF 2 group, a -O-cyclopropyl group, a -O-cyclobutyl group, a -0-(oxetan-3-yl) group, a -0-CH 2 -tetrahydofuran-2-yl group,
- a 3-hydroxy-piperidin-1-yl group a 4-cyano-piperidin-1-yl group, a 4,4-difluoro- piperidin-1-yl group, a 4-ethyl-4-hydroxy-piperidin-1-yl group, a 2- hydroxymethylazetidin-1-yl group, a 3-hydroxy-3-myethyl-pyrrolidin-1-yl group, a 4- methyl-piperazin-1-yl group, a piperazin-1-yl group, a morpholin-4-yl group, an azepan-1-yl group,
- a 6-methyl-pyridin-3-yl group a 1-difluoromethylpyrazol-4-yl group, a 3- trifluoromethyl-pyrazol-1-yl group, a 3-trifluoromethyl-1 ,2,5-triazol-2-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH-CH 2 -CH(OH)CH 3 group, a -NH-CH 2 -CH(OCH 3 )CH 3
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a fluorine atom or a trifluoromethyl group
- Y is N
- R 3 is selected from a NH-(CH 2 ) 2 -0-CH 3 group, a group, a
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom, a trifluoromethyl group
- Y is N
- R 3 is selected from a NH-(CH 2 ) 2 -0-CH 3 group, a
- a -NH-cyclopentyl group a -NH-CH 2 -(pyrazol-3-yl) group, a pyrazol-1-yl group, a 3-trifluoromethyl-1-H-pyrazol group, a 4-cyano-piperidin-1-yl group, a 4,4-difluoro- piperidin-1-yl group, a 3,3-difluoroazetidin-1-yl group, a 3-hydroxy-3-methylazetidin-1-yl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom or a trifluoromethyl group
- Y is N or C-R 2 and R 2 is a hydrogen atom
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- the present invention includes compounds of general formula (I), supra, in which
- R 1 is a hydrogen atom or a trifluoromethyl group
- Y is N
- R 3 is a group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a halogen atom, a CrC 3 -alkyl group, or a CrC 3 -haloalkyl group;
- Y is CR 2 , where R 2 is a hydrogen atom, or a halogen atom
- R 3 is selected from
- a CrC 6 -alkyl group which is optionally substituted with a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a CrC 3 -alkyl group
- a CrC 6 -alkoxy group which is optionally substituted with a group independently selected from CrC 3 -haloalkyl group, a hydroxy group, a CrC 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group which itself can be substituted with a CrC 3 -alkyl group, a 4- to 6-membered heterocycloalkyl group which itself can be substituted with a CrC 3 -alkyl group, and a 5- to 6-membered heteroaryl group,
- a 4- to 6-membered cycloalkoxy group which is optionally substituted one or more timew with a group independently selected from a halogen atom, and a C 1 -C 3 - haloalkyl group,
- a phenyl group which is substituted one or more times with a group independently selected from halogen atom, and a CrC 3 -haloalkyl group,
- a 4- to 6-membered heterocycloalkyl group which is optionally substituted one or more times with a group independently selected from a halogen atom, a hydroxy group, a CrC 3 -alkyl group, and a cyano group,
- a 5- to10-membered heteroaryl group which is optionally substituted one or more times with a group independently selected from an amino group, a halogen atom, a CrC 3 -haloalkyl group,
- R 5 is a hydrogen atom
- R 6 is selected from
- a CrC3-alkyl group which is substituted one or more times with a group independently selected from a 5- to 6-membered heteroaryl group, a CrC3-alkoxy group, a hydroxy group, a CrC3-haloalkyl group, and a C3-C6-cycloalkyl,
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- both, R 1 and R 2 may not be a hydrogen atom at the same time;
- R 3 is selected from a -(CH2)-CH(CH3)2 group, a -(CH 2 ) 3 -0-CH 3 group, a -CH2-(morpholin- 4-yl) group, a -CH2-N(CH3)2 group,
- hydroxy-3-methylazetidin-1-yl a group, a group, a 3- hydroxy-3-methyl-pyrrolidin-1-yl group, a 4-cyano-piperidine group, a 4-methyl- piperazin-1-yl group, a 4-ethyl-4-hydroxy-piperazin-1-yl group, a 4,4- difluoropiperazinyl group, a piperazin-1-yl group, a morpholin-4-yl group, a 1 -methyl-1 , 2, 3, 6-tetrahydropyridin-4-yl group,
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-chloro-pyridin-6-yl group, a 3-fluoro-pyrazol-1-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1- difluoromethylpyrazol-4-yl group, a 4-trifluoromethyl-1 ,2,3-triazol-2-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH(CH 3 )-
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
- a -0-(CH 2 ) 2 -CH 3 group a -0-(CH 2 ) 3 CH 3 group, a -0-CH 2 -(CH 3 ) 2 group, a -0-(CH 2 ) 2 - C(CH 3 ) 3 group, a -0-CH 2 -CF 3 group, a -0-(CH 2 ) 2 -CF 3 group, a -0-(CH 2 )-CH(CH 3 )-
- a 4-chlorophenyl group a 4-fluoro-phenyl group, a 4-fluoro-2-methyl-phenyl group, a 3-fluoro-4-methyl-phenyl group, a 4-fluoro-2-trifluoromethyl-phenyl group, a piperidin1-yl group, a 3-hydroxy-piperidin-1-yl group, a 4,4-difluoro-piperidin-1-yl group, a 4-ethyl-4-hydroxy-piperidin-1-yl group, a 3,3-difluoroazetidin-1-yl group, 3-
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-chloro-pyridin-6-yl group, a 3-fluoro-pyrazol-1-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1- difluoromethylpyrazol-4-yl group, a 4-trifluoromethyl-1 ,2,3-triazol-2-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH-CH 2 -CH(OH)CF 3 group, a -NH-CH(CH 3 )-
- cyclopropyl group a group, a -NH-cyclopentyl group, a -NH- (3-tetrahydrofuryl) group, -NH-CH 2 -(pyrazol-3-yl) group, a -NH-CH 2 -(pyrazol-5-yl) group, a -NH-CH 2 -pyrazin-2-yl group, and
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -0-(CH 2 ) 2 -CH 3 group, a -O- (CH 2 )3CH 3 group, a -0-CH 2 -(CH 3 )2 group, a -O-CH2-CF3 group, a -0-(CH 2 )2-CF 3 group, a -0-(CH 2 )-CH(CH 3 )-0H group, a -0-(CH 2 )-C(CH 3 ) 2 -0H group, a -0-(CH 2 ) 2 - O-CH3 group, a -O-CFh-cyclopropyl group, a -0-CH 2 -cyclobutyl group, a -O- (methyl-oxetan-3-yl) group, a -0-CH 2 -(methyl-azetidin-2-yl)- group, a -0-CH 2 -(4
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1-difluoromethylpyrazol-4-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH- CH2-CH(OH)CF3 group, a -NH-CH(CH3)-cyclopropyl group, a -NH-cyclopentyl group, a -NH-(3-tetrahydrofuryl) group, and; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -0-(CH 2 ) 2 -CH 3 group, a -O- (CH 2 ) 3 CH 3 group, a -0-CH 2 -(CH 3 ) 2 group, a -0-CH 2 -CF 3 group, a -0-(CH 2 ) 2 -CF 3 group, a -0-(CH 2 )-CH(CH 3 )-0H group, a -0-(CH 2 )-C(CH 3 ) 2 -0H group, a -0-(CH 2 ) 2 - 0-CH 3 group, a -0-CH 2 -cyclopropyi group, a -0-CH 2 -cyclobutyi group, a -O-
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1-difluoromethylpyrazol-4-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH- CH 2 -CH(OH)CF 3 group, a -NH-CH(CH 3 )-cyclopropyl group, a -NH-cyclopentyl group, a -NH-(3-tetrahydrofuryl) group, and
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -0-(CH 2 ) 2 -CH 3 group, a -O-
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1-difluoromethylpyrazol-4-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH- CH 2 -CH(OH)CF 3 group, a -NH-CH(CH 3 )-cyclopropyl group, a -NH-cyclopentyl group, a -NH-(3-tetrahydrofuryl) group, and
- the present invention includes compounds of general formula (I), supra, in which: R 1 is a trifluoromethyl group,
- Y is C-R 2 and R 2 is a hydrogen atom
- R 3 is selected from a -CH 2 -(morpholin-4-yl) group, a -0-(CH 2 ) 2 -CH 3 group, a -O- (CH 2 )3CH 3 group, a -0-CH2-(CH 3 )2 group, a -O-CH2-CF3 group, a -0-(CH 2 )2-CF 3 group, a -0-(CH 2 )-CH(CH 3 )-0H group, a -0-(CH 2 )-C(CH 3 ) 2 -0H group, a -0-(CH 2 ) 2 -
- O-CH3 group a -0-CH 2 -cyclopropyi group, a -0-CH 2 -cyclobutyi group, a -O- (methyl-oxetan-3-yl) group, a -0-CH 2 -(methyl-azetidin-2-yl)- group, a -0-CH 2 -(4H)- pyrazol-3-yl, a -0-CH 2 -pyrazin-2-yl, a -0-(3-methylcyclobutyl) group, a -O- (cyclopentyl) group, V oH
- a pyridin-4-yl group a 2-amino-pyridin-4-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1-difluoromethylpyrazol-4-yl group, a -NH-(CH 2 ) 2 -0-CH 3 group, a -NH- CH2-CH(OH)CF3 group, a -NH-CH(CH3)-cyclopropyl group, a -NH-cyclopentyl group, and a -NH-(3-tetrahydrofuryl) group;
- the present invention includes compounds of general formula (I), supra, in which:
- R 1 is a trifluoromethyl group
- Y is C-R 2 and R 2 is a hydrogen atom
- R 3 is a -NH-C(0)-CH 2 -CH 3 group
- the present invention includes compounds of general formula (I), supra, selected from
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Abstract
La présente invention concerne des composés de formule générale (I) dans laquelle R1, Y et R3 sont tels que définis dans la description, des procédés de préparation desdits composés, des composés intermédiaires utiles pour préparer lesdits composés, des compositions pharmaceutiques et des combinaisons comprenant lesdits composés et l'utilisation desdits composés pour fabriquer des compositions pharmaceutiques destinées au traitement ou à la prophylaxie de maladies hyperprolifératives, en particulier des maladies de nom générique, en monothérapie ou en association avec d'autres principes actifs.
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