WO2020126968A2 - Dérivés d'urée - Google Patents

Dérivés d'urée Download PDF

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Publication number
WO2020126968A2
WO2020126968A2 PCT/EP2019/085239 EP2019085239W WO2020126968A2 WO 2020126968 A2 WO2020126968 A2 WO 2020126968A2 EP 2019085239 W EP2019085239 W EP 2019085239W WO 2020126968 A2 WO2020126968 A2 WO 2020126968A2
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Prior art keywords
chloropyridin
group
urea
salt
optionally substituted
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PCT/EP2019/085239
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WO2020126968A3 (fr
Inventor
Nico BRÄUER
Alexander Helmut Michael EHRMANN
Matyas GORJANACZ
Carlo STRESEMANN
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention covers urea compounds of general formula (I) as described and defined herein, methods of preparing said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer disorders, as a sole agent or in combination with other active ingredients.
  • the present invention covers urea compounds of general formula (I) which inhibit the function of SWI/SNF complex core component SMARCA2.
  • the multisubunit SWI/SNF complex is comprised of several chromatin binding subunits and of one of two mutually exclusive ATPase paralogues; SMARCA2 or SMARCA4. ATP hydrolysis by one of these two core enzymes provide the complex with the energy required for nucleosome sliding, eviction and replacement, thereby controlling gene expression and other key cellular processes.
  • SMARCA4 is one of the most frequently inactivated, or epigenetically silenced, subunits of the SWI/SNF complex across diverse cancer types including, but not limited to, lung cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, liver cancer, cervical cancer, breast cancer, ovarian cancer and other cancer types.
  • SMARCA2 is rarely mutated, and in certain conditions, due to functional redundancy, SMARCA2 can compensate for the loss of SMARCA4 and sustain the SWI/SNF complex functionality to support cell viability. Therefore the survival of SMARCA4-deficient cancer cells strongly depends on the function of SMARCA2.
  • the invention generally provides urea compounds of general formula (I) of the present invention as described and defined herein. As reported in detail below, it has now been found, and this partially constitutes the basis of the present invention, that the compounds of the present invention do have antiproliferative activity.
  • the present invention covers compounds of general formula (I):
  • A is a pyridinyl group which is optionally substituted by R 2 and/or R 3 ;
  • heterocycloalkyl group a -0-(Ci-C 3 -alkyl)-heterocycloalkyl
  • CrC3-haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“CrC3-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said CrC3-haloalkyl group is, for example, a fluoromethyl-, difluoromethyl-, trifluoromethyl-, 2-fluoroethyl-,
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C1-C4 means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3 or 4 carbon atoms.
  • 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.
  • 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, such as a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent such as a deuterium-containing reagent.
  • deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e.
  • WO2012/112363 are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). 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.
  • Rofecoxib F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295
  • Telaprevir F. Maltais et al., J. Med. Chem., 2009, 52, 7993.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.
  • 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 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 covers 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.
  • “pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the present invention covers compounds of general formula (I):
  • R 1 is a hydrogen atom or a methyl group
  • R 3 is a hydrogen atom, a halogen atom or a CrC3-alkyl group
  • B a phenyl group, which is optionally substituted with one or more substituents and each substituent is independently selected from
  • R 5 is a hydrogen atom, a CrC3-alkyl group, or a heteroaryl group; a pyridinyl group,
  • a C3-C6-cycloalkyl group a phenyl group, which is optionally substituted with a halogen atom, a Cr C 3 -alkyl group, Ci-C 3 -alkoxy group, a CN group, a NR 4 R 5 group; a heteroaryl group and
  • R 6 is a CrC 4 -alkyl group
  • a phenyl group which itself is optionally further substituted with a halogen atomor a Ci-C 3 -haloalkyl group, and
  • a pyrazolyl group which is optionally substituted one or more times with a C 1 -C 4 - alkyl group or a phenyl group which itself is optionally substituted with a halogen atom,
  • a thiadiazolyl group which is optionally substituted with a phenyl group which itself is optionally substituted with a Ci-C 3 -haloalkyl group, or a phenyl group which itself is optionally substituted with a halogen atom or a Ci-C 3 -haloalkyl group; a benzofuranyl group, which is optionally substituted with a C(0)NR 4 R 5 group, a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom;
  • an indazolyl group which is optionally substituted one or more substituents and each substituent independently selected from a halogen atom, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group,
  • the present invention covers compounds of general formula (I):
  • A is a pyridinyl group which is optionally substituted by R 2 and/or R 3 ;
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a halogen atom
  • R 3 is a hydrogen atom, a halogen atom or a CrC3-alkyl group
  • B a phenyl group, which is optionally substituted with one or more substituents and each substituent is independently selected from
  • R 4 is a hydrogen atom or a CrC 3 -alkyl group
  • R 5 is a hydrogen atom, a CrC 3 -alkyl group, or a heteroaryl group; a pyridinyl group,
  • a phenyl group which is optionally substituted with a halogen atom, a Cr C 3 -alkyl group, CrC 3 -alkoxy group, a CN group, a NR 4 R 5 group; a heteroaryl group and
  • R 6 is a CrC 4 -alkyl group
  • a pyrazolyl group which is optionally substituted one or more times with a C 1 -C 4 - alkyl group or a phenyl group which itself is optionally substituted with a halogen atom,
  • a thiadiazolyl group which is optionally substituted with a phenyl group which itself is optionally substituted with a CrC3-haloalkyl group, or a phenyl group which itself is optionally substituted with a halogen atom or a Ci-C3-haloalkyl group; a benzofuranyl group, which is optionally substituted with a C(0)NR 4 R 5 group, a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom;
  • an indazolyl group which is optionally substituted one or more substituents and each substituent independently selected from a halogen atom, a Ci-C3-alkyl group, a Ci-C3-haloalkyl group,
  • A is a group which is optionally substituted by R 2 and/or R 3 ;
  • R 1 is a hydrogen atom
  • R 2 is a halogen atom
  • R 3 is a hydrogen atom or a halogen atom
  • B is a phenyl group, which is optionally substituted with one or more substituents and each substituent is independently selected from
  • A is a group which is optionally substituted by R 2 and/or R 3 ;
  • a tautomer an N-oxide, a hydrate, a solvate, or a salt, a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide, a salt of a hydrate, a salt of a solvate, or a mixture of same.
  • R 3 is a hydrogen atom
  • B is a phenyl group, which is optionally substituted with one or more substituents and each substituent is independently selected from
  • the present invention covers compounds of general formula (I), supra which are selected from the group consisting of
  • the present invention covers compounds of general formula (I), supra which are selected from the group consisting of
  • the present invention covers compounds of general formula (I), supra which are selected from the group consisting of
  • the present invention covers compounds of general formula (I), supra which are selected from the group consisting of
  • the present invention covers compounds of general formula (I), supra which are selected from the group consisting of
  • the present invention covers compounds of general formula (I), supra which are selected from the group consisting of
  • the present invention covers compounds of general formula (I), supra, in which: group which is optionally substituted by R 2 and/or R 3 ;
  • R 1 is a hydrogen atom
  • R 2 is a chlorine atom
  • R 3 is a hydrogen atom
  • B a phenyl group, which is substituted with one or more substituents and each substituent is independently selected from
  • R 6 is a Ci-C4-alkyl group
  • R 1 is a hydrogen atom or a methyl group or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 1 is a hydrogen atom or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • A is a pyridinyl group, more particularly a 3- or 4-pyridinyl group, even more particularly a 4-pyridinyl group, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • A is a pyridinyl group which is substituted by a halogen atom, more particularly a 3- or 4- pyridinyl group which are substituted by a halogen atom, even more particularly a 4- pyridinyl group which is substituted by a halogen atom; or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • A is a pyridinyl group which is substituted by a fluorine atom or a chlorine atom, more particularly a 3- or 4-pyridinyl group which are substituted by a fluorine atom or a chlorine atom, even more particularly a 4-pyridinyl group which is substituted by a fluorine atom or a chlorine atom, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • A is a pyridinyl group which is substituted by a chlorine atom, more particularly a 3- or 4- pyridinyl group which are substituted by a chlorine atom, even more particularly a 4- pyridinyl group which is substituted by a chlorine atom, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 2 is a fluorine atom or a chlorine atom, particularly a chlorine atom, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 2 is a chlorine atom, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 2 is a fluorine atom, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • the present invention covers compounds of formula (I), supra, in which: R 3 is a hydrogen atom, a halogen atom or a CrC 3 -alkyl group or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 3 is a hydrogen atom or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 3 is a halogen atom or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 3 is a CrC 3 -alkyl group or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 3 is a hydrogen atom or a halogen atom or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 3 is a hydrogen atom, or a CrC 3 -alkyl group or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 3 is a halogen atom or a CrC 3 -alkyl group or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • the present invention covers compounds of formula (I), supra, in which:
  • R 2 is a fluorine atom or a chlorine atom, particularly a chlorine atom
  • R 3 is a hydrogen atom, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 4 is a hydrogen atom or a CrC3-alkyl group
  • R 5 is a hydrogen atom, a Ci-C3-alkyl group, or a heteroaryl group; a pyridinyl group,
  • a phenyl group which is optionally substituted with a halogen atom, a Cr C 3 -alkyl
  • R 6 is a Ci-C 4 -alkyl group
  • a pyrimidinyl group which is optionally substituted with a Ci-C 3 -alkyl group or a piperazinyl group which itself is optionally further substituted with a C 1 -C 3 - alkyl group;
  • thiazolyl group which is optionally substituted one or two times and each substituent is independently selected from
  • a phenyl group which itself is optionally further substituted with a halogen atom or a Ci-C 3 -haloalkyl group, and
  • a pyrazolyl group which is optionally substituted one or more times with a C 1 -C 4 - alkyl group or a phenyl group which itself is optionally substituted with a halogen atom;
  • a thiadiazolyl group which is optionally substituted with a phenyl group which itself is optionally substituted with a CrC 3 -haloalkyl group, or a phenyl group which itself is optionally substituted with a halogen atom or a Ci-C 3 -haloalkyl group; a benzofuran-3-yl group, which is optionally substituted with a C(0)NR 4 R 5 group; a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom;
  • an indazolyl group which is optionally substituted one or more substituents and each substituent independently selected from a halogen atom, a Ci-C 3 -alkyl group, a Ci-C 3 -haloalkyl group; an isoquinolinyl group which is optionally substituted with a halogen atom; and a dihydroindenyl group;
  • a phenyl group which is optionally substituted with one or more substituents and each substituent is independently selected from
  • R 4 is a hydrogen atom or a CrC3-alkyl group
  • R 5 is a hydrogen atom, a CrC3-alkyl group, a heteroaryl group a -(CrC 3 -alkyl)-0-heteroaryl group;
  • R 6 is a Ci-C4-alkyl group
  • a pyrimidinyl group which is optionally substituted with a CrC3-alkyl group, or a piperazinyl group which itself is optionally further substituted with a C1-C3- alkyl group;
  • thiazol-2-yl group which is optionally substituted one or two times and each substituent is independently selected from
  • a phenyl group which itself is optionally further substituted with a halogen atom or a Ci-C3-haloalkyl group, and
  • a pyrazol-5-yl group which is optionally substituted one or more times with a Cr C4-alkyl group or a phenyl group which itself is optionally substituted with a halogen atom;
  • a benzofuran-3-yl group which is optionally substituted with a C(0)NR 4 R 5 group
  • a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom
  • an indazol-7-yl group which is optionally substituted one or more substituents and each substituent independently selected from a halogen atom, a Ci-C3-alkyl group, a CrC3-haloalkyl group,
  • the present invention covers compounds of formula (I), supra, in which:
  • a phenyl group which is optionally substituted with one or more substituents and each substituent is independently selected from
  • R 6 is a CrC4-alkyl group
  • thiazol-2-yl group which is optionally substituted one or two times and each substituent is independently selected from
  • a phenyl group which itself is optionally further substituted with a halogen atom or a CrC3-haloalkyl group, and
  • a pyrazol-5-yl group which is optionally substituted one or more times with a Cr C4-alkyl group or a phenyl group which itself is optionally substituted with a halogen atom,
  • a benzofuran-3-yl group which is optionally substituted with a C(0)NR 4 R 5 group
  • a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom
  • an indazol-7-yl group which is optionally substituted one or more substituents and each substituent independently selected from a halogen atom, a Ci-C3-alkyl group, a Ci-C3-haloalkyl group;
  • a phenyl group which is optionally substituted with one or more substituents and each substituent is independently selected from
  • R 6 is a CrC4-alkyl group
  • a phenyl group which is optionally substituted with one or more substituents and each substituent is independently selected from
  • R 4 is a hydrogen atom or a CrC3-alkyl group
  • R 5 is a hydrogen atom, a CrC3-alkyl group, a heteroaryl group a -(Ci-C 3 -alkyl)-0-heteroaryl group;
  • each substituent is selected from a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifuloromethyl group, a cyano group, a hydroxy group, a nitro group, a pentafluorosulfanyl group, a sulfono-methyl group, a oxadiazolone group, a morpholino group, a -0-(CH 2 ) 2 -morpholino group, a -S(0) 2 -
  • a stereoisomer or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, a salt of a stereoisomer, a salt of a tautomer, a salt of a hydrate, a salt of a solvate, or a mixture of same.
  • a phenyl group which is optionally substituted with one or more substituents and each substituent is independently selected from
  • a stereoisomer or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, a salt of a stereoisomer, a salt of a tautomer, a salt of a hydrate, a salt of a solvate, or a mixture of same.
  • B is a phenyl group, which is optionally substituted with one or two substituents selected from the lists disclosed infra
  • R 6 is a Ci-C4-alkyl group
  • each substituent is independently selected from a fluorine atom, a chlorine atom, a cyano group, a , ethyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a cycloproyl group, a phenyl group, a 4-(2,2-dimethylpropanoyl)piperazin-1-yl group and a pyridinyl group
  • a pyrimidinyl group which is optionally substituted with a CrC3-alkyl group, or a piperazinyl group which itself is optionally further substituted with a C1-C3- alkyl group,
  • thiazol-2-yl group which is optionally substituted one or two times and each substituent is independently selected from
  • a phenyl group which itself is optionally further substituted with a halogen atom or a CrC3-haloalkyl group, more particularly which itself is optionally further substituted with a fluorine atom or a chlorine atom or a trifluoromethyl group, and
  • each substituent is independently selected from a methyl group a tert.-butyl group, a phenyl group which is itself substituted with a substituent selected from a fluorine atom, a bromine atom and a trifluoromethyl group, and a benzyl group which is optionally further substituted with a cyano group with the proviso that if R 2 is a chlorine atom and B is a thiazolyl group, it may not be mono-substituted with a methyl group;
  • a pyrazol-5-yl group which is optionally substituted one or more times with a Cr C4-alkyl group or a phenyl group which itself is optionally substituted with a halogen atom,
  • a thiadiazolyl group which is optionally substituted with a phenyl group which itself is optionally substituted with a CrC3-haloalkyl group, or a phenyl group which itself is optionally substituted with a halogen atom or a CrC3-haloalkyl group; more particularly which is optionally substituted with a phenyl group which itself is substituted with a trifluoromethyl group, or a phenyl group which is substituted with a further phenyl group which itself is substituted with a bromine atom and/or a trifluoromethyl group
  • a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom;
  • aprticularly which is optionally substituted with a fluorine at om or a chlorine atom
  • a pyrazolo[1 ,5-a]pyridinyl group which is optionally substituted with a halogen atom;
  • B is an indazol-7-yl group which is optionally substituted one or more substituents and each substituent independently selected from a halogen atom, a Ci-C3-alkyl group, a Ci-C3-haloalkyl group,
  • each substituent independently selected from a fluorine atom, a methyl group and a trifluoromethyl group
  • A is a pyridinyl group which is substituted with a chlorine atom and B is a phenyl group which is substituted according to any list disclosed infra or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • A is a pyridinyl group which is substituted with a chlorine atom and B is a pyridinyl group which is substituted according to any list disclosed infra or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 4 and R 5 are independently selected from the group consisting of a hydrogen atom, a CrC3-alkyl group, or a heteroaryl group with the proviso that R 4 and R 5 both can not be a heteroaryl group at the same time, or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 4 is a hydrogen atom or a Ci-C3-alkyl group
  • R 5 is a hydrogen atom, a Ci-C3-alkyl group or a heteroaryl group or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a salt of a stereoisomer, or a salt of a tautomer, or a salt of a hydrate, or a salt of a solvate, or a mixture of same.
  • R 4 is a hydrogen atom or a CrC 3 -alkyl group
  • R 5 is a hydrogen atom, a CrC 3 -alkyl group, or a heteroaryl group and at least one of
  • R 4 and R 5 is a hydrogen atom
  • R 6 is a CrC 4 -alkyl group, ,
  • R 6 is a tert - butyl group or a pyridinyl group
  • the present invention covers combinations of two or more of the above mentioned embodiments under the heading“further embodiments of the first aspect of the present invention”.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula (I).
  • the present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
  • the compounds according to the invention of general formula (I) can be prepared according to the following schemes 1 , 2, 3, 4, and 5.
  • the schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in schemes 1 , 2, 3, 4, and 5 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, R 1 , R 2 , R 3 , R 4 , R 5 or R 6 can be achieved before and/or after the exemplified transformations.
  • Scheme 1 Route for the preparation of compounds of general formula (I) in which A and B are pyridine derivatives, but not necessarily identical, A is optionally substituted by R 2 and/or R 3 an whereby B is substituted as defined in any of the claims or aspects or any embodiment derived therefrom infra and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the meaning as given for general formula (I), supra.
  • the starting materials, the respective pyridine amines are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art.
  • a pyridine derivative A- NH2 or A-NR 1 is dissolved in a suitable solvent, such as e.g. THF, DMF, DMA, DMSO or NMP, in the presence of a base such as e.g. TEA, DIPEA and reacted with a pyridinylcarbamate which optionally substituted with R 2 and/or R 3 and which is dissolved in a polar aprotic solvent such as e.g. THF, DMF, DMA, DMSO or NMP at about 50 - 120°C for up to 2 days.
  • a suitable solvent such as e.g. THF, DMF, DMA, DMSO or NMP
  • Scheme 2 Route for the preparation of compounds of general formula (I) in which A is e.g. a 2-chloropyridine (as shown above) or a pyridine substituted with one or more substitutents and B is a pyridine but not necessarily identical with A, B is optionally substituted as defined in any of the claims or aspects or any embodiment derived therefrom and R 1 is a hydrogen atom or a CrC3-alkyl group such as a methyl group.
  • A is e.g. a 2-chloropyridine (as shown above) or a pyridine substituted with one or more substitutents
  • B is a pyridine but not necessarily identical with A
  • B is optionally substituted as defined in any of the claims or aspects or any embodiment derived therefrom
  • R 1 is a hydrogen atom or a CrC3-alkyl group such as a methyl group.
  • the starting materials, the respective pyridine amines, are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art.
  • a compound B-NH2 or B-NH R 1 which is optionally substituted as defined in any of claims 1 to 4 or aspects as defined in the description or any embodiment derived therefrom, is dissolved in a polar aprotic solvent such as e.g. DCM, DMF or NMP and reacted with 2- chloro-4-isocyanatopyridine and a base, such as e.g. an anorganic base, such as e.g. potassium carbonate, caesium carbonate or an organic base, such as e.g. TEA, DIPEA at room temperature up to 2 days.
  • a polar aprotic solvent such as e.g. DCM, DMF or NMP
  • 2- chloro-4-isocyanatopyridine and a base
  • a base such as e.g. an anorganic base, such as e.g. potassium carbonate, caesium carbonate or an organic base, such as e.g. TEA, DIPEA at room temperature up to 2 days
  • the starting materials, the respective pyridine amines, are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art.
  • the starting materials, the respective pyridine amines, are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art.
  • symmetrical urea derivatives of formula (I) it is possible to react A-NH2 with and B-NH 2 with di(1 H-imidazol-1-yl)methanone under addition of an organic base such as e.g. TEA or DIPEA in a suitable aprotic organic solvent such as e.g. THF, DMA or NMP at 50-120°C for about 2h.
  • an organic base such as e.g. TEA or DIPEA
  • a suitable aprotic organic solvent such as e.g. THF, DMA or NMP
  • the starting materials, the respective pyridine amines, are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art.
  • a solution of an amine A-NH 2 in a polar aprotic solvent such as e.g. dichloromethane (DCM), tetrahydrofurane (THF), dimethylformamide (DMF) is reacted with triphosgene under addition of a suitable organic base such as e.g. triethylamine (TEA) or diisopropylehtylamine (DIPEA) at 0°C.
  • a suitable organic base such as e.g. TEA or DIPEA at 0°C.
  • a suitable organic base such as e.g. TEA or DIPEA at 0°C.
  • a warming up to room temperature was allowed and the mixture stirred overnight, concentrated and purified by column chromatography.
  • a compound of formula (I) wherein A and B are pyridine rings is obtained.
  • the starting materials, the respective pyridine amines, are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art.
  • a pyridineamine is reacted with 2,2,2-trichloroethyl carbonochloridate in a polar aprotic solvent such as e.g. dichloromethane (DCM), tetrahydrofurane (THF), dimethylformamide (DMF) is in the presence of an amine such as e.g. trimethylamine at 0°C and the mixture stirred for 1 hour at 0°C and addtional 3 hours at room temperature. The mixture is filtered and purified by column chromatography.
  • a polar aprotic solvent such as e.g. dichloromethane (DCM), tetrahydrofurane (THF), dimethylformamide (DMF)
  • DCM dichloromethane
  • THF tetrahydrofurane
  • DMF dimethylformamide
  • R 1 may be hydrogen
  • the present invention covers methods of preparing compounds of general formula (I) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (II) :
  • R 1 , A and B are as defined supra.
  • the present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder.
  • Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • BPH benign prostate hyperplasia
  • solid tumours such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

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Abstract

La présente invention concerne des composés d'urée de formule générale (I) dans laquelle R1, A et B 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 la fabrication de compositions pharmaceutiques pour le traitement ou la prophylaxie de maladies, en particulier de troubles hyperprolifératifs, en tant qu'agent unique ou en combinaison avec d'autres principes actifs.
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CN112279834A (zh) * 2020-12-29 2021-01-29 北京鑫开元医药科技有限公司 一种fgfr4抑制剂、制备方法、药物组合物及其应用
WO2021042022A1 (fr) * 2019-08-30 2021-03-04 University Of Rochester Inhibiteurs de la septine destinés au traitement de cancers
CN112641782A (zh) * 2020-12-29 2021-04-13 北京鑫开元医药科技有限公司 一种fgfr4抑制剂的制剂组合物、制备方法及其用途
WO2021207343A1 (fr) * 2020-04-08 2021-10-14 Rheos Medicines, Inc. Inhibiteurs de malt1 et leurs utilisations
WO2022078533A1 (fr) * 2020-10-13 2022-04-21 Ustav Experimentalni Botaniky Av Cr, V.V.I. Dérivés 1,3-diphénylurée substitués et dérivés 1-phényl-3-pyridylurée pour la biotechnologie végétale, préparations contenant ces composés et leur utilisation
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US11958846B2 (en) 2018-08-17 2024-04-16 Novartis Ag Urea compounds and compositions as SMARCA2/BRM ATPase inhibitors
US12358906B2 (en) 2018-08-17 2025-07-15 Novartis Ag Urea compounds and compositions as SMARCA2/BRM ATPase inhibitors
WO2021042022A1 (fr) * 2019-08-30 2021-03-04 University Of Rochester Inhibiteurs de la septine destinés au traitement de cancers
US12433876B2 (en) 2019-08-30 2025-10-07 University Of Rochester Septin inhibitors for treatment of cancers
WO2021207343A1 (fr) * 2020-04-08 2021-10-14 Rheos Medicines, Inc. Inhibiteurs de malt1 et leurs utilisations
WO2022078533A1 (fr) * 2020-10-13 2022-04-21 Ustav Experimentalni Botaniky Av Cr, V.V.I. Dérivés 1,3-diphénylurée substitués et dérivés 1-phényl-3-pyridylurée pour la biotechnologie végétale, préparations contenant ces composés et leur utilisation
CN112279834A (zh) * 2020-12-29 2021-01-29 北京鑫开元医药科技有限公司 一种fgfr4抑制剂、制备方法、药物组合物及其应用
CN112641782A (zh) * 2020-12-29 2021-04-13 北京鑫开元医药科技有限公司 一种fgfr4抑制剂的制剂组合物、制备方法及其用途
CN112641782B (zh) * 2020-12-29 2022-02-11 北京鑫开元医药科技有限公司 一种fgfr4抑制剂的制剂组合物、制备方法及其用途
WO2023283921A1 (fr) * 2021-07-16 2023-01-19 北京深蓝泰医药科技有限公司 Inhibiteur de dpd, composition pharmaceutique et utilisation

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