WO2021064141A1 - Inhibiteurs de la kinase 1b régulée par phosphorylation de tyrosine à double spécificité - Google Patents

Inhibiteurs de la kinase 1b régulée par phosphorylation de tyrosine à double spécificité Download PDF

Info

Publication number
WO2021064141A1
WO2021064141A1 PCT/EP2020/077593 EP2020077593W WO2021064141A1 WO 2021064141 A1 WO2021064141 A1 WO 2021064141A1 EP 2020077593 W EP2020077593 W EP 2020077593W WO 2021064141 A1 WO2021064141 A1 WO 2021064141A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
heterocyclyl
alkylene
halogen
Prior art date
Application number
PCT/EP2020/077593
Other languages
English (en)
Inventor
Rutger Folmer
Koen F. W. HEKKING
Blaise CALPE
Gerhard Müller
Charles-Henry Fabritius
Original Assignee
Tolremo Therapeutics Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tolremo Therapeutics Ag filed Critical Tolremo Therapeutics Ag
Publication of WO2021064141A1 publication Critical patent/WO2021064141A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which act as inhibitors of dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) and are useful in the treatment of tumors.
  • the inventive compounds also inhibit dual specificity tyrosine- phosphorylation-regulated kinase 1A (DYRK1A).
  • BACKGROUND OF THE INVENTION Limited oxygen supply called hypoxia, plays a major role in the pathobiology of tumors. This widespread phenomenon is tightly associated with tumor progression, aggressiveness and therapy resistance. Intratumoral hypoxia leads to increased activity of the hypoxia- inducible factor (HIF) family of transcription factors.
  • HIF hypoxia- inducible factor
  • HIFs regulate the expression of genes whose products contribute to angiogenesis, metabolic reprogramming, metastasis, cancer stem cell maintenance, immune evasion, and therapy resistance.
  • Increased activity of HIFs highlights the central role of intratumoral hypoxia as a critical microenvironmental factor driving multiple key aspects of the cancer phenotype.
  • hypoxic responses and consequent metabolic changes play also an important role in tumor adaption to anti-angiogenic therapy leading to the development of resistance to anti-angiogenic drugs.
  • anti-angiogenic drugs approved by the FDA which are known to invariably induce a hypoxic response that, at least in certain cases, has been shown to contribute to drug resistance and tumor relapse.
  • hypoxic cancer cells target well oxygenated and proliferating cancer cells, while showing decreased efficacy against hypoxic cancer cells. Furthermore, there are no approved therapies that target hypoxic cancer cells, despite growing clinical and experimental evidence indicating that intratumoral hypoxia is a critical microenvironmental factor driving cancer progression, spread and therapy resistance. Moreover, hypoxic area and/or area characterized by nutrient and growth factors deprivation cause to a poorly mitogenic tumor microenvironment which harbors slow cycling or quiescent/dormant cancer cells. These dormant cells are resistant to therapy targeting rapidly proliferating cells and lead to tumor resistance and relapse.
  • DYRKs Dual specificity tyrosine- phosphorylation-regulated kinases
  • Mammalian DYRKs fall into two subgroups, class I (DYRK1A and DYRK1B) and class II (DYRK2, DYRK3 and DYRK4).
  • WO 2014/059149 discloses an inhibitor of DYRK1 activity for use in the treatment of a neoplasm in a patient.
  • WO 2012/098068 discloses pyrazolo[3,4-d]pyrimidines which act as inhibitors of DYRK1B and/or DYRK1A and are useful in the amelioration, treatment or control of cancer, especially solid tumors, or in the amelioration, treatment or control of Down syndrome or early onset of Alzheimer's disease. Further, Ashford et al, Biochem. J.
  • DYRK1B N-[2-methoxy-4-(4- methyl-1-piperazinyl) phenyl]-4-(1-methyl-1H-pyrrolo[2,3-c]pyridine-3-yl)-2-pyrimidinamine (known as AZ 191) as inhibitor of DYRK1B.
  • the problem of the present invention is to provide a compound for use as a therapeutically active substance and in particular in the treatment of tumors.
  • BRIEF SUMMARY OF THE INVENTION DYRK1B is essential for cancer cell survival in the context of a mitogen poor tumor microenvironment characterized by low abundance of nutrients and/or hypoxia.
  • DYRK1B maintains cells in a state of reversible quiescence by phosphorylating the cell cycle regulator p27 and cyclinD1.
  • DYRK1B drives cancer cells back into the cell cycle and produces synthetic lethality in hypoxic cancer cells in a tumor.
  • the compounds of the invention preferably also inhibit further members of the DYRK family, in particular DYRK1A including any of its isoforms.
  • alkyl refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond.
  • a "C 1-6 alkyl” denotes an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl).
  • alkyl preferably refers to C 1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
  • alkylene refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched.
  • C 1-6 alkylene denotes an alkylene group having 1 to 6 carbon atoms, and the term “C 0-3 alkylene” indicates that a covalent bond (corresponding to the option "C 0 alkylene”) or a C 1-3 alkylene is present.
  • Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH 3 )-), propylene (e.g., -CH 2 -CH 2 -CH 2 -, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(- CH 3 )-CH 2 -), or butylene (e.g., -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -).
  • alkylene preferably refers to C 1-4 alkylene (including, in particular, linear C 1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
  • carbocyclyl refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • carbocyclyl preferably refers to aryl, cycloalkyl or cycloalkenyl.
  • the number of carbon atoms in the carbocyclyl group is not particularly limited and is preferably 3 to 14, more preferably 3 to 7.
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, Si and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • heterocyclyl preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.
  • the number of carbon atoms in the carbocyclyl group is not particularly limited and is preferably 5 to 14, preferably 5 to 10.
  • aryl refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic).
  • Aryl may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), anthracenyl, or phenanthrenyl.
  • an "aryl” preferably has 5 to 14 ring atoms, more preferably 5 to 10 ring atoms, and most preferably refers to phenyl.
  • heteroaryl refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • aromatic ring group comprises one or more (such as, e.g., one, two,
  • Heteroaryl may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl (e.g., 3H-indolyl), indazoly
  • a “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized;
  • cycloalkyl refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings).
  • Cycloalkyl may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.
  • cycloalkyl preferably refers to a C 3-14 cycloalkyl, and more preferably refers to a C 3-7 cycloalkyl.
  • a particularly preferred "cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members.
  • heterocycloalkyl refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O
  • Heterocycloalkyl may, e.g., refer to oxetanyl, tetrahydrofuranyl, piperidinyl, piperazinyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl (e.g., morpholin-4-yl), pyrazolidinyl, tetrahydrothienyl, octahydroquinolinyl, octahydroisoquinolinyl, oxazolidinyl, isoxazolidinyl, azepanyl, diazepanyl, oxazepanyl, sulfolanyl, tetrahydro-2H-thiopyran 1,1-dioxide or 2-oxa-5-aza-bicyclo[2.2.1]hept- 5-yl.
  • heterocycloalkyl preferably refers to a 3 to 14 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring
  • cycloalkenyl refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond.
  • Cycloalkenyl may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, "cycloalkenyl” preferably refers to a C 3-14 cycloalkenyl, and more preferably refers to a C 3-7 cycloalkenyl.
  • a particularly preferred "cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.
  • heterocycloalkenyl refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms and carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring
  • Heterocycloalkenyl may, e.g., refer to 1,2,3,6-tetrahydropyridinyl. Unless defined otherwise, "heterocycloalkenyl” preferably refers to a 3 to 14 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, "heterocycloal
  • halogen refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I).
  • haloalkyl refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group.
  • Haloalkyl may, e.g., refer to -CF 3 , -CHF 2 , -CH 2 F, -CF 2 -CH 3 , -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 2 -CH 3 , -CH 2 -CF 2 -CF 3 , or -CH(CF 3 ) 2 .
  • alkoxy refers to a "substituted hydroxyl" of the formula (-OR'), wherein R' is an “alkyl”, as defined herein, and the oxygen moiety is directly attached to the parent molecule
  • C1-C6-alkoxy refers to straight chain or branched C1-C6-alkoxy which may be, for example, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neo-pentoxy, n-hexoxy.
  • Various groups are referred to as being “optionally substituted” in this specification.
  • these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety.
  • substituents such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety.
  • the "optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.
  • the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent.
  • the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent.
  • the expression “X is optionally substituted with Y" (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted.
  • a component of a composition is indicated to be “optional”
  • the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
  • a “solvate” refers to an association or complex of one or more solvent molecules and the compound of formula (I).
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, acetonitril, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water. It is to be understood that such solvates of compounds of the formula (I) also include solvates of pharmaceutically acceptable salts of the compounds of the formula (I).
  • a "cocrystal” refers to a crystalline structure that contains at least two different compounds that are solid in their pure form under ambient conditions.
  • Cocrystals are made from neutral molecular species, and all species remain neutral after crystallization; further, typically and preferably, they are crystalline homogeneous phase materials where two or more building compounds are present in a defined stoichiometric ratio. See hereto Wang Y and Chen A, 2013; and Springuel GR, et al., 2012; and US Patent 6,570,036.
  • substituent groups comprised in the compounds of formula (I) may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.
  • the term "about” preferably refers to ⁇ 10% of the indicated numerical value, more preferably to ⁇ 5% of the indicated numerical value, and in particular to the exact numerical value indicated.
  • compounds of formula (I) optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof are particularly useful as inhibitors of dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A):
  • R 1 is independently selected from halogen, –CH 3 , –CF 3 , –CHF 2 , CH 2 -OR*, CH 2 -NR*R*, –CN, –NO 2 , ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ OR*, ⁇ OC(O)R* and ⁇ OC(O)NR*R*; wherein each R* is independently selected from H, –CH 3 , –CF 3 , and – CHF 2 .
  • R 1 is independently selected from –CH 3 , –CF 3 , –F, –Cl, –Br, – NO 2 , –CN, –OCH 3 , NH 2 , NH-C(O)CH 3 and CH 2 NH 2 .
  • R 1 is independently selected from halogen, –CH 3 , –CF 3 , –CHF 2 , CH 2 -OR*, CH 2 -NR*R*, –CN, –NO 2 , ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ OR*, ⁇ OC(O)R* and ⁇ OC(O)NR*R*; wherein each R* is independently selected from H, –CH 3 , –CF 3 , and –CHF 2 .
  • R 1 is independently selected from –CH 3 , –CF 3 , –F, –Cl, –Br, –NO 2 , –CN, –OCH 3 , NH 2 , NH-C(O)CH 3 and CH 2 NH 2 .
  • Each R 2 is independently selected from hydrogen and R 1 .
  • each R 2 is independently selected from hydrogen, halogen, C 1 ⁇ 2 alkyl, C 1 ⁇ 2 haloalkyl, –CN, –NO 2 , ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ OR*, ⁇ OC(O)R* and ⁇ OC(O)NR*R*; wherein each R* is independently selected from H, C 1 ⁇ 2alkyl and C 1 ⁇ 2 haloalkyl.
  • each R 2 is independently selected from hydrogen, halogen, –CH 3 , –CF 3 , –CHF 2 , –CN, –NO 2 , ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ OR*, ⁇ OC(O)R* and ⁇ OC(O)NR*R*; wherein each R* is independently selected from H, –CH 3 , –CF 3 , and –CHF 2 .
  • each R 2 is independently selected from hydrogen and –CH 3 .
  • each R 2 is hydrogen.
  • Y 1 is selected from –S– and –O–.
  • Y 1 is –S–.
  • R 1 is selected from –(C 1 ⁇ 6 alkyl which is optionally substituted with one or more halogen), C 1 ⁇ 6 alkylene-OR*, C 1 ⁇ 6 alkylene-NR*R*, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*) ⁇ C(O)R*, ⁇ N(R*) ⁇ C(O) ⁇ OR*, ⁇ N(R*) ⁇ C(O) ⁇ NR*R*, ⁇ N(R*) ⁇ S(O) 2 R*, ⁇ OR*, ⁇ O ⁇ C(O)R*, ⁇ O ⁇ C(O) ⁇ NR*R*, ⁇ SR*, ⁇ S(O)R*, ⁇ S(O) 2 R*, and ⁇ S(O) 2 ⁇ NR*R*,
  • R 1 is selected from –(C 1 ⁇ 6 alkyl which is optionally substituted with one or more halogen), ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*) ⁇ C(O)R*, ⁇ N(R*) ⁇ C(O) ⁇ OR*, ⁇ N(R*) ⁇ C(O) ⁇ NR*R*, ⁇ N(R*) ⁇ S(O) 2 R*, ⁇ OR*, ⁇ O ⁇ C(O)R*, ⁇ O ⁇ C(O) ⁇ NR*R*, ⁇ SR*, ⁇ S(O)R*, ⁇ S(O) 2 R*, and ⁇ S(O) 2 ⁇ NR*R*, ⁇ N(R*) ⁇ S(O) 2 ⁇ NR*R; wherein each R* is independently selected from H and C 1 ⁇
  • R 1 is independently selected from halogen, C 1 ⁇ 2 alkyl, C 1 ⁇ 2 haloalkyl, C 1 ⁇ 2 alkylene- OR*, C 1 ⁇ 2 alkylene-NR*R*, –CN, –NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ OR*, ⁇ OC(O)R* and ⁇ OC(O)NR*R*; wherein each R* is independently selected from H, C 1 ⁇ 2 alkyl and C 1 ⁇ 2 haloalkyl.
  • R 1 is independently selected from halogen, –CH 3 , –CF 3 , –CHF 2 , CH 2 -OR*, CH 2 - NR*R*, –CN, –NO 2 , ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ OR*, ⁇ OC(O)R* and ⁇ OC(O)NR*R*, heterocyclyl which is optionally substituted with halogen or C 1-6 alkyl, carbocyclyl which is optionally substituted with halogen or C 1-6 alkyl; wherein each R* is independently selected from H, –CH 3 , –CF 3 , and –CHF 2 .
  • R 1 is independently selected from –CH 3 , –CF 3 , –F, –Cl, –Br, –NO 2 , –CN, –OCH 3 , NH 2 , NH-C(O)CH 3 and CH 2 NH 2 .
  • R 1 is selected from –F, –Cl, –CH3, –CN, –CF3 and –O–CH3.
  • A is a monocyclic, bicyclic or tricyclic group having at least a carbonyl group or nitrogen atom at the ortho position to the position at which A is connected to the remaining structure of the compound of formula (I).
  • A is selected from monocyclic, bicyclic and tricyclic heterocyclyl which is optionally substituted with one or more R 11 and furthermore optionally with one substituent selected from ⁇ (optionally substituted heterocyclyl), ⁇ (optionally substituted carbocyclyl), ⁇ (optionally substituted C 1 ⁇ 6 alkylene) ⁇ (optionally substituted heterocyclyl) and ⁇ (optionally substituted C 1 ⁇ 6 alkylene) ⁇ (optionally substituted carbocyclyl), wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C 1 ⁇ 6 alkylene is independently selected from R 11 , wherein R 11 is selected from –(C 1 ⁇ 6 alkyl which is optionally substituted with one or more halogen), C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R
  • A is selected from a monocyclic, bicyclic and tricyclic heterocyclyl, preferably from a monocyclic and bicyclic heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R 11 and furthermore optionally with one substituent selected from optionally substituted heterocyclyl, optionally substituted carbocyclyl, –C(O) ⁇ heterocyclyl wherein said heterocyclyl is optionally substituted, –C(O) ⁇ carbocyclyl wherein said carbocyclyl is optionally substituted, –C 1 ⁇ 6 alkylene ⁇ heterocyclyl wherein said –C 1 ⁇ 6 alkylene and said heterocyclyl of –C 1 ⁇ 6 alkylene ⁇ heterocyclyl are independently optionally substituted, and –C 1 ⁇ 6 alkylene ⁇ carbocyclyl wherein said –C 1 ⁇ 6 alkylene and said carbocyclyl of –C 1 ⁇ 6 alkylene ⁇ carbocyclyl wherein said –
  • said heterocyclyl has a carbonyl group or a heteroatom, preferably a nitrogen atom, at the ortho position to the position at which A is connected to the remaining structure of the compound of formula (I).
  • group A the monocyclic, bicyclic and tricyclic heterocyclyl is preferably a 5- or 6- membered (optionally aromatic) heterocyclic group.
  • the 5 or 6 membered heterocyclic group preferably has at least one of the substituents in the ortho position, with respect to the position at which it is bound to the ring containing Y 1 , Y 2 and Y 3 .
  • the 5 or 6 membered heterocyclic group is preferably selected from imidazole, triazole, pyridinone, pyridazinone. Furthermore, the 5 or 6 membered heterocyclic group is preferably a pyridinone which has at least one of the substituents in the meta position, with respect to the position at which it is bound to the ring containing Y 1 , Y 2 and Y 3 .
  • the position of the substituent selected from C 4-10 -alkyl, C 1-6 -alkylene-C 3-7 -cycloalkyl, C 1-6 - alkylene-heterocycloalkyl, C 1-6 -alkylene-aryl, C 1-6 -alkylene-heteroaryl, aryl and heteroaryl as defined above is preferably in meta' position (i.e. in case of a 6-membered ring para to the oxo substituent).
  • the position of the substituent selected from C 4-10 -alkyl, C 1-6 -alkylene-C 3-7 -cycloalkyl, C 1-6 -alkylene-heterocycloalkyl, C 1-6 -alkylene-aryl, C 1-6 -alkylene-heteroaryl, aryl and heteroaryl as defined above is preferably in meta position.
  • the heteroatom(s) in the 5- or 6-membered ring is/are preferably nitrogen.
  • the indication that the heterocycloalkyl can be bridged preferably indicates a saturated bridged heterocyclic ring having 5 to 8 ring carbon atoms and 0 to 2 heteroatoms (e.g., selected from N, O and S) in the ring, and 0 to 2 carbon atoms and 0 to 2 heteroatoms (e.g., selected from N, O and S) in the bridge, provided that there is at least one heteroatom in the saturated bridged heterocyclic ring, which may be either in the main ring or in the bridge.
  • the 5- or 6-membered ring is preferably selected from imidazole, triazole, pyridinone, and pyridazinone.
  • the 5- or 6-membered ring is preferably a 5-membered ring. It is to be understood in the above that the ortho, ortho', meta, meta', etc. referred to above are with respect to the position at which A is bound to the rest of the compound of formula (I), unless specifically indicated otherwise.
  • R 21 is hydrogen or methyl, preferably R 21 is hydrogen.
  • Y 1 is –S–.
  • A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein Z 1 is selected from –CH 2 –, –CH(R Z1 )–, –NH–, –N(R Z1 )– and –O–; Z 2 is selected from –CH–, –C(R Z2 )–, –N–; Z 3 is selected from –CH–, –C(R Z3 )–, –N–; wherein R Z1 and R Z2 are independently selected from –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R
  • R 3 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)S(O) 2 R*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)OR*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ N(R*)S(O) 2 R*, ⁇ OR*, ⁇ OC(O)R*, ⁇ OC(O)NR*R*, ⁇ SR*, ⁇ S(O
  • R 4 is selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 3 haloalkyl, –C 1 ⁇ 3 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ OR*, ⁇ OC(O)R*, ⁇ OC(O)NR*R*, ⁇ SR*, ⁇ S(O)R*, ⁇ S(O) 2 R*, wherein each R* is independently selected from H, C1 ⁇ 2alkyl, –C1 ⁇ 2haloalkyl, and wherein R 3 and R 4 can be optionally linked forming a C4- 7 cycloalkyl, wherein said formed C 4-7 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2
  • R 4 is selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 3 haloalkyl, –C 1 ⁇ 3 alkoxy, ⁇ halogen, and wherein R 3 and R 4 can be optionally linked forming a C 4-6 cycloalkyl, wherein said formed C 4-6 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ halogen.
  • R 4 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, ⁇ Cl, and wherein R 3 and R 4 can be optionally linked forming a C 4-6 cycloalkyl, wherein said formed C 4-6 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, ⁇ Cl.
  • R 4 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, and wherein R 3 and R 4 can be optionally linked forming a C 4-6 cycloalkyl, wherein said formed C 4-6 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl.
  • R 4 is selected from hydrogen, –C 1 ⁇ 2 alkyl, and wherein R 3 and R 4 can be optionally linked forming a C 5-6 cycloalkyl, wherein said formed C 5-6 cycloalkyl is optionally substituted by one or two –CH 3 .
  • R 4 is hydrogen.
  • A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein R Z11 and R Z12 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ N(R*)S(O) 2 R*, ⁇ OR*, ⁇ OC(O)R*, ⁇ OC(O)NR*R*, ⁇ SR*, ⁇ S(O)R*, ⁇ S(O) 2 R*, ⁇ S(O)
  • R Y15 is selected from hydrogen and –CH 3 and R Y16 is hydrogen.
  • R Y15 and R Y16 are hydrogen;
  • R 3 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)S(O) 2 R*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)OR*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ N(N(R*)
  • R 4 is selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 3 haloalkyl, –C 1 ⁇ 3 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ OR*, ⁇ OC(O)R*, ⁇ OC(O)NR*R*, ⁇ SR*, ⁇ S(O)R*, ⁇ S(O) 2 R*, wherein each R* is independently selected from H, C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, and wherein R 3 and R 4 can be optionally linked forming a C 4-7 cycloalkyl, wherein said formed C 4-7 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2
  • R 4 is selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 3 haloalkyl, –C 1 ⁇ 3 alkoxy, ⁇ halogen, and wherein R 3 and R 4 can be optionally linked forming a C 4-6 cycloalkyl, wherein said formed C 4-6 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ halogen.
  • R 4 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, ⁇ Cl, and wherein R 3 and R 4 can be optionally linked forming a C 4-6 cycloalkyl, wherein said formed C 4-6 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ F, ⁇ Cl.
  • R 4 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ F, and wherein R 3 and R 4 can be optionally linked forming a C 4-6 cycloalkyl, wherein said formed C 4-6 cycloalkyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl.
  • R 4 is selected from hydrogen, –C 1 ⁇ 2 alkyl, and wherein R 3 and R 4 can be optionally linked forming a C 5-6 cycloalkyl, wherein said formed C 5-6 cycloalkyl is optionally substituted by one or two –CH 3 .
  • R 4 is hydrogen.
  • R Z11 , R Z12 , R Z14 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted heterocyclyl, optionally substituted carbocyclyl, ⁇ C 1 ⁇ 6 alkylene ⁇ heterocyclyl wherein said ⁇ C 1 ⁇ 6 alkylene and said heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 6 alkylene ⁇ carbocyclyl wherein said ⁇ C 1 ⁇ 6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C 1 ⁇ 6 alkylene is independently selected from –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN,
  • RZ11 and R Z14 are independently selected from hydrogen, –C1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ⁇ C 1 ⁇ 3 alkylene ⁇ (mono or bicyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono or bicyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 3 alkylene ⁇ (mono- or bicyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 3 alkylene
  • R Z11 and R Z14 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ⁇ C 1 ⁇ 3 alkylene ⁇ (mono or bicyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono- or bicyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 3 alkylene ⁇ (mono- or bicyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 3 alkyl, –
  • R Z11 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ⁇ C 1 ⁇ 2 alkylene ⁇ (mono- or bicyclic heterocyclyl) wherein said ⁇ C1 ⁇ 2alkylene and said mono- or bicyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 2 alkylene ⁇ (mono- or bicyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2
  • R Z11 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy,
  • R Z14 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 2 alkylene is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy,
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, wherein the optional substituent of the optionally substituted monocyclic heterocyclyl and optionally substituted monocyclic carbocyclyl is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ halogen, and wherein R Z11 and R Z12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ halogen.
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-5 membered heterocyclyl, 3-5 membered monocyclic carbocyclyl, monocyclic 3-5 membered heterocyclyl optionally substituted with ⁇ CH 3 , ⁇ F and/or ⁇ Cl, 3-5 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 , ⁇ F and/or ⁇ Cl, and wherein R Z11 and R Z12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ halogen.
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ F, ⁇ Cl.
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ F, ⁇ Cl.
  • R Z12 is selected from hydrogen, –C1 ⁇ 2alkyl, – C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –CH 3 , –CHF 2 , –CF 3 , ⁇ F.
  • R Z12 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, cyclopropyl optionally substituted with ⁇ CH 3 and/or ⁇ F, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –CH 3 .
  • R Z15 is selected from hydrogen, –C 1 ⁇ 2 alkyl, – C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –CH 3 , –CHF 2 , –CF 3 , ⁇ F.
  • R Z15 is selected from hydrogen and –C 1 ⁇ 2 alkyl
  • A is of the formula , wherein R Z11 , R Z12 and R Z13 are as defined herein.
  • A is of the formula , wherein R Z14 , R Z15 and R Z16 are as defined herein.
  • A is of the formula wherei Y15 Y16 3 4 n R , R and R and R are as defined herein.
  • A is selected from a monocyclic or bicyclic heterocyclyl of any of the formula wherein R Z11 and R Z12 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ N(R*)S(O) 2 R*, ⁇ OR*, ⁇ OC(O)R*, ⁇ OC(O)NR*R*, ⁇ SR*, ⁇ S(O)R*, ⁇ S(O) 2 R*, ⁇ S(O) 2 NR*R*, ⁇ N
  • R Y15 is hydrogen;
  • R 3 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN, ⁇ NO 2 , oxo, ⁇ C(O)R*, ⁇ COOR*, ⁇ C(O)NR*R*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)S(O) 2 R*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)OR*, ⁇ C(O)NR*(C 1 ⁇ 4 alkylene)NR*R*, ⁇ NR*R*, ⁇ N(R*)C(O)R*, ⁇ N(R*)C(O)OR*, ⁇ N(R*)C(O)NR*R*, ⁇ N(R*)S(O) 2 R*, ⁇ OR*, ⁇ OC(O)R*, ⁇ OC(O)NR*, ⁇ OC
  • R Z11 , R Z12 , R Z14 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted heterocyclyl, optionally substituted carbocyclyl, ⁇ C 1 ⁇ 6 alkylene ⁇ heterocyclyl wherein said ⁇ C 1 ⁇ 6 alkylene and said heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 6 alkylene ⁇ carbocyclyl wherein said ⁇ C 1 ⁇ 6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C 1 ⁇ 6 alkylene is independently selected from –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, ⁇ CN,
  • R Z11 and R Z14 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ⁇ C 1 ⁇ 3 alkylene ⁇ (mono or bicyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono or bicyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 3 alkylene ⁇ (mono- or bicyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 3 alkyl, –C
  • R Z11 and R Z14 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ⁇ C 1 ⁇ 3 alkylene ⁇ (mono or bicyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono- or bicyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 3 alkylene ⁇ (mono- or bicyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 3 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 3 alkyl, –
  • R Z11 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted mono- or bicyclic heterocyclyl, optionally substituted mono- or bicyclic carbocyclyl, ⁇ C 1 ⁇ 2 alkylene ⁇ (mono- or bicyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said mono- or bicyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 2 alkylene ⁇ (mono- or bicyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said mono- or bicyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2
  • R Z11 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 3 alkylene is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy,
  • R Z14 is selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, – C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic heterocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 2 alkylene ⁇ (monocyclic carbocyclyl) wherein said ⁇ C 1 ⁇ 2 alkylene and said monocyclic carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyls, optionally substituted carbocyclyls, and optionally substituted C 1 ⁇ 2 alkylene is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy,
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, ⁇ halogen, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic carbocyclyl, wherein the optional substituent of the optionally substituted monocyclic heterocyclyl and optionally substituted monocyclic carbocyclyl is independently selected from –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ halogen, and wherein R Z11 and R Z12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ halogen.
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-5 membered heterocyclyl, 3-5 membered monocyclic carbocyclyl, monocyclic 3-5 membered heterocyclyl optionally substituted with ⁇ CH 3 , ⁇ F and/or ⁇ Cl, 3-5 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 , ⁇ F and/or ⁇ Cl, and wherein R Z11 and R Z12 can be optionally linked forming a 4-7 membered monocyclic heterocyclyl, wherein said formed 4-7 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ halogen.
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ F, ⁇ Cl.
  • R Z12 and R Z15 are independently selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, ⁇ F, ⁇ Cl.
  • R Z12 is selected from hydrogen, –C 1 ⁇ 2 alkyl, – C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –CH 3 , –CHF 2 , –CF 3 , ⁇ F.
  • R Z12 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, cyclopropyl optionally substituted with ⁇ CH3 and/or ⁇ F, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –CH 3 .
  • R Z15 is selected from hydrogen, –C 1 ⁇ 2 alkyl, – C 1 haloalkyl, –C 1 alkoxy, ⁇ F, ⁇ Cl, monocyclic 3-4 membered heterocyclyl, 3-4 membered monocyclic carbocyclyl, monocyclic 3-4 membered heterocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, 3-4 membered monocyclic carbocyclyl optionally substituted with ⁇ CH 3 and/or ⁇ F, and wherein R Z11 and R Z12 can be optionally linked forming a 4-6 membered monocyclic heterocyclyl, wherein said formed 4-6 membered monocyclic heterocyclyl is optionally substituted by one or two –CH 3 , –CHF 2 , –CF 3 , ⁇ F.
  • R Z15 is selected from hydrogen and –C 1 ⁇ 2 alkyl
  • A is of the formula , wherein R Z11 and R Z12 are as defined herein.
  • A is of the formula , wherein R Z14 and R Z15 are as defined herein.
  • A is of the formula wherein R Y15 and R 3 are as defined herein.
  • A is of the formula wherein R Y15 is selected from hydrogen, –C 1 ⁇ 3 alkyl, –C 1 ⁇ 3 haloalkyl, –C 1 ⁇ 3 alkoxy, ⁇ F, ⁇ Cl, ⁇ Br, ⁇ NO 2 , ⁇ NH 2 , ⁇ CN, phenyl and C 3 ⁇ 6 cycloalkyl, wherein preferably R Y15 is selected from hydrogen, –C 1 ⁇ 2 alkyl, –C 1 ⁇ 2 haloalkyl, –C 1 ⁇ 2 alkoxy, ⁇ F, ⁇ Cl and C 3 ⁇ 4 cycloalkyl, and wherein further preferably R Y15 is selected from hydrogen and –CH 3 .
  • R Y15 is hydrogen;
  • R 31 is selected from hydrogen, ⁇ OH, –C 1 ⁇ 6 alkyl, –C 1 ⁇ 6 haloalkyl, –C 1 ⁇ 6 alkoxy, NR*R*, OR*, C 1 ⁇ 4 alkylene)C(O)NR*R*, NR*(C 1 ⁇ 4 alkylene)S(O) 2 R*, NR*(C 1 ⁇ 4 alkylene)OR*, optionally substituted heterocyclyl, optionally substituted carbocyclyl, ⁇ C 1 ⁇ 6 alkylene ⁇ heterocyclyl wherein said ⁇ C 1 ⁇ 6 alkylene and said heterocyclyl are independently optionally substituted, and ⁇ C 1 ⁇ 6 alkylene ⁇ carbocyclyl wherein said ⁇ C 1 ⁇ 6 alkylene and said carbocyclyl are independently optionally substituted, wherein the optional substituent of the optionally substituted heterocyclyl, optionally substituted carbocyclyl, and optionally substituted C
  • said compound of formula (I) is a compound selected from any one of the compounds 00001 to 00284.
  • Pharmaceutically acceptable salts etc. The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation.
  • Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylam
  • Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nic
  • Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt.
  • a particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt.
  • the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.
  • the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form.
  • stereoisomers the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates).
  • racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization.
  • the present invention further encompasses any tautomers of the compounds provided herein.
  • the scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom.
  • the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D"). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium.
  • Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D).
  • the content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art.
  • a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D 2 O).
  • H/D exchange reaction e.g., heavy water (D 2 O).
  • deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014.
  • the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy.
  • the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I) is preferred.
  • the present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, 11 C, 13 N, 15 O, 76 Br, 77 Br, 120 I and/or 124 I.
  • Such compounds can be used as tracers or imaging probes in positron emission tomography (PET).
  • the invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11 C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all
  • the tumor to be treated can be a solid tumor or a non-solid tumor.
  • the expression “non-solid tumors” stands for tumors that affect hematopoietic structures including components of the immune system. Examples of non-solid tumors include leukemias, multiple myelomas and lymphomas. These tumor cells generally appear in the bone marrow and peripheral circulation.
  • the expression "solid tumors” stands for primary tumors and/or metastases (wherever located) other than tumors that affect hematopoietic structures, e.g.
  • brain and other central nervous system tumors e.g. tumors of the meninges, brain, spinal cord, cranial nerves and other parts of the central nervous system, e.g. glioblastomas or medulla blastomas); head and/or neck cancer; breast tumors; circulatory system tumors (e.g. heart, mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue); excretory system tumors (e.g. kidney, renal pelvis, ureter, bladder, other and unspecified urinary organs); gastrointestinal tract tumors (e.g.
  • oesophagus oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus and anal canal
  • vulva vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites associated with female genital organs, placenta, penis, prostate, testis, and other sites associated with male genital organs); respiratory tract tumors (e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer); skeletal system tumors (e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites); skin tumors (e.g.
  • malignant melanoma of the skin non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); and tumors involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites.
  • tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites
  • the cancer may be a B-cell proliferative cancer, leukemia, lymphoma, breast cancer or myeloma.
  • the tumor may be adrenocortical carcinoma, astrocytoma, basal cell carcinoma, carcinoid, cardiac, cholangiocarcinoma, chordoma, chronic myeloproliferative neoplasms, craniopharyngioma, ductal carcinoma in situ, ependymoma, intraocular melanoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, histiocytosis, leukemia ⁇ e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, myelogenous leukemia
  • ALL acute lympho
  • the tumor to be treated is treatment-resistant and preferably drug-resistant.
  • treatment-resistant tumor means the ability of tumor cells to survive and grow despite anti-cancer therapies and includes for example radiotherapy and medication intake.
  • drug-resistant tumor means that such an anti-cancer therapy is based on medication intake.
  • hypoxia is an environmental selection pressure that contributes to the development of therapy resistance.
  • the compounds according to the present invention allow overcoming therapy resistance since the remaining tumor comprises well-oxygenated and proliferating cancer cells which may be conventionally treated.
  • the tumor to be treated comprises hypoxic tumor cells and/or glycolytic cancer cells.
  • Most of the cancer cells feature increased glycolysis as a metabolic strategy.
  • the presence of oncogenes or loss of tumor suppressor genes lead to the activation of HIF and thereby to a glycolytic phenotype.
  • HIF can be activated through genetic and metabolic alterations in key metabolic genes.
  • the tumor comprises dormant, slow cycling or quiescent cancer cells. Dormant, slow cycling or quiescent cancer cells are known to reside in hypoxic area.
  • quiescence can also be induced by nutrient deprivation, ROS, drug treatment and other tumor microenvironmental effects.
  • DYRK1B is upregulated by these stresses and can cause cells to enter a state of reversible quiescence through phosphorylation of cyclin-dependent kinase inhibitor p27 on serine 10.
  • Quiescence promotes cells survival under unfavourable conditions and by inhibiting DYRK1B, the compounds of the present invention are therefore particularly useful to drive cells out of quiescence, which leads to cell death under harsh microenvironmental conditions and/or resensitize them to treatment targeting cycling cancer cells.
  • dormant cancer cells are known to be often the seed of metastasis.
  • the compounds of the present invention are particularly useful in the treatment of metastasis. It is believed that the compounds of the present invention are particularly useful in the treatment of quiescent cancer cells as a result of hypoxia.
  • the tumour may also be a tumour wherein AR is expressed, or in cancers in which there is activation of CBP and/or p300 function.
  • the cancers that can be treated include those which express AR or are otherwise associated with AR, those that harbour loss of function mutations in CBP or p300 and those which have activated CBP and/or p300. Cancers that may be treated include, but are not restricted to, prostate cancer, breast cancer, bladder cancer, lung cancer, lymphoma and leukaemia.
  • the prostate cancer may be, for instance, castration-resistant prostate cancer (CRPC).
  • the lung cancer may be, for instance, non-small cell lung cancer or small cell lung cancer.
  • “inhibiting” involves specific binding.
  • specific binding is meant a particular interaction between one binding partner and another binding partner, for example a compound of the present invention and a target such as DYRK1B and/or DYRK1A.
  • Interactions between one binding partner and another binding partner may be mediated by one or more, typically more than one, non-covalent bonds.
  • An exemplary way of characterising specific binding is by a specific binding curve. Such binding may be analysed using methods well known in the art, such as e.g. BIACORE.
  • the compounds of the present invention show inhibition of DYRK1B and/or DYRK1A to a higher extent than expected by the skilled person.
  • the inhibition may be expressed as IC 50 , i.e. the concentration necessary to inhibit activity to 50%.
  • the compounds have an IC 50 value of 12.500 nM or less, preferably 10.000 nM or less, more preferably 7.500 and even more preferably 5.000 nM or less.
  • the IC 50 value may be determined using methods such as those described in the examples. As such, a suitable method comprises the steps of incubating strep- DYRK1B (e.g. at 0.5nM) and DYRKtide (e.g.
  • the tumor comprises tumor stem cells.
  • a “tumor stem cell” means a cell which has self-replication capacity and cancer forming ability in combination and which is resistant to anti-cancer agents and/or radiation therapy and which is a causative cell of cancer recurrence.
  • Tumor stem cells often reside in a hypoxic niche.
  • DYRK1B By inhibiting DYRK1B by the compounds of the present invention, the number of tumor stem cells can be significantly reduced or even the birth of tumor stem cells can be avoided.
  • leukemic cancer stem cells are very hypoxic and can be effectively treated by the compounds of the present invention.
  • the growth of the tumor associated with the overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1B can be inhibited by the compound of the present invention.
  • Amplification of the DYRK1B occurs in many different cancers including pancreatic cancer, ovarian cancer and non-small cell lung cancer.
  • DYRK1B gene may act as a potential driver oncogene, that is, as a proto-oncogene having a genetic mutation that is considered to cause a mutation specific to cancer cells and to become a main cause of cancer development.
  • the patients can be stratified on the basis of having this amplification and then specifically be treated with the compounds of the present invention.
  • DYRK1B has, e.g., been found in Pancreatic cancer, Lung cancer, Ovarian cancer and Uterine cancer. Furthermore, cancers where DYRK1A/B is described as a target include sarcoma, leukemia, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer and glioblastoma. Other diseases
  • the present invention furthermore relates to the use of the compounds of formula I as a therapeutically active substance, and in particular for use in the treatment of disorders wherein hypoxic cells are involved. It has been surprisingly found by the present inventors that by inhibiting DYRK1A and/or DYRK1B, the compounds of the present invention are useful in the treatment of neurodegenerative diseases.
  • present invention furthermore relates to a method of treating, ameliorating or preventing cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s
  • the compounds provided herein may be administered as compounds per se or may be formulated as medicaments, e.g. as pharmaceutical composition or combination.
  • the medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers, or any combination thereof.
  • the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, di
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22 nd edition.
  • compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution.
  • Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • the compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled- release applications.
  • said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • Said compounds or pharmaceutical compositions may also be administered by sustained release systems.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include, e.g., polylactides (see, e.g., US 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U.
  • Sustained-release pharmaceutical compositions also include liposomally entrapped compounds.
  • Liposomes containing a compound of the present invention can be prepared by methods known in the art, such as, e.g., the methods described in any one of: DE3218121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP0052322; EP0036676; EP088046; EP0143949; EP0142641; JP 83-118008; US 4,485,045; US 4,544,545; and EP0102324.
  • Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route.
  • they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride.
  • a preservative such as a benzalkonium chloride.
  • they may be formulated in an ointment such as petrolatum. It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation.
  • dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to the emulsification/spray drying process disclosed in WO 99/16419 or WO 01/85136. Spray drying of solution formulations of the compounds of the present invention can be carried out, e.g., as described generally in the "Spray Drying Handbook", 5th ed., K. Masters, John Wiley & Sons, Inc., NY (1991), and in WO 97/41833 or WO 03/053411.
  • said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
  • the present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route.
  • parenteral route using injection techniques or infusion techniques, including by subcutaneous,
  • Particularly preferred routes of administration of the compounds or pharmaceutical compositions of the present invention are oral forms of administration.
  • a physician will determine the dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
  • a proposed, yet non-limiting dose of the compounds according to the invention for administration to a human may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose.
  • the unit dose may be administered, e.g., 1, 2, 3 or more times per day.
  • the unit dose may also be administered 1 to 7 times per week, e.g., with one, two or more administration(s) per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician.
  • the compounds of formula (I) can be used in combination with other therapeutic agents, including in particular other anticancer agents. When a compound of the invention is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone.
  • the combination of a compound of the present invention with a second therapeutic agent may comprise the administration of the second therapeutic agent simultaneously/concomitantly or sequentially/separately with the compound of the invention.
  • the present invention provides a pharmaceutical composition comprising a compound having the formula (I) as defined in any of claims 1 to 14, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).
  • the present invention further provides a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or the pharmaceutical composition as defined herein, wherein the compound or pharmaceutical composition is for use in the treatment, amelioration or prevention of cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis.
  • a method of treating, ameliorating or preventing cancer, Alzheimer, Parkinson, Down syndrome, Metabolic syndrome, Diabetes and/or osteoarthritis is also described herein.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition as described herein.
  • a method of treating, ameliorating or preventing cancer is also provided.
  • the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition as described herein, wherein the method further comprises administering to the patient in need thereof a second therapeutic agent.
  • Combination therapies The present invention furthermore relates to the use of a compound of formula (I) according to the present invention in combination with a second therapeutic agent. It has been found that DYRK1B is essential for cancer cell survival in the context of tumor hypoxia.
  • the second therapeutic agent is an anticancer drug.
  • the anticancer drug to be administered in combination with a compound of formula (I) according to the present invention is preferably selected from chemotherapeutics, anti-angiogenics, radiation, and targeted therapy such as by CDK4/6 inhibitors, mTOR inhibitors or EGFR inhibitors.
  • the present invention furthermore relates to a method of treating, ameliorating or preventing cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising a compound having the formula (I) as defined herein, optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s), wherein the method further comprises administering to the patient in need thereof a second therapeutic agent, wherein the second therapeutic agent is preferably selected from chemotherapeutics, anti-angiogenics, radiation, targeted therapy, CDK4/6 inhibitors, mTOR inhibitors and
  • Chemotherapeutics include a tumor angiogenesis inhibitor (for example, a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (for example, an antimetabolite, such as purine and pyrimidine analogue antimetabolites); and an antimitotic agent (for example, a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic.
  • a tumor angiogenesis inhibitor for example, a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor
  • a cytotoxic drug for example, an antimetabolite, such as purine and pyrimidine analogue antimetabolites
  • an antimitotic agent for example, a microtubule stabilizing drug or an antimitotic alkaloid
  • platinum coordination complex for example
  • a platinum coordination complex which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
  • a cytotoxic drug which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analogue antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analogue antimetabolites (such as cladribine, clofarabine, fludarabine, 6- mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analogue antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).
  • folic acid analogue antimetabolites such as aminopterin, methotrexate, pemetrexed, or raltitrexed
  • An antimitotic agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analogue (such as ixabepilone/azaepothilone B).
  • a taxane such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel
  • a Vinca alkaloid such as vinblastine
  • anti-angiogenic inhibitor stands for a substance that inhibits the growth of new blood vessels. It is known that the clinical resistance to anti-angiogenic inhibitors is quite likely due to tumor cells utilizing an alternative method for obtaining a vasculature. Further, anti-angiogenic therapy is known to induce hypoxia and thereby contribute to drug resistance. Interestingly, it could be shown that the inhibition of DYRK1B inhibits the resistance to anti- angiogenic therapy.
  • a combination medicament comprising a compound of formula (I) and an anti-angiogenic inhibitor prevents or at least diminishes the danger of a medicament resistance and allows a long-term treatment against the tumor.
  • the anti-angiogenic inhibitor is selected from the group consisting of bevacizumab, erlotinib, lapatanib, sunitinib, pazopanib, imatinib, dasatanib, nilotinib, bortezomib, ibrutinib, semaxinib, vatalinib, sorafenib, leflunomide, canertinib, axitinib, nintedanib, regorafenib, pazobanib, cabozantinib, vandetanib, ziv-aflibercept, thalidomide, IMC-1C11, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide (AMG 706), 3-(4-bromo-2,6-d
  • the compounds of formula (I) can also be administered in combination with physical therapy, such as radiotherapy.
  • Radiotherapy may commence before, after, or simultaneously with administration of the compounds of the invention.
  • radiotherapy may commence 1-10 minutes, 1-10 hours or 24-72 hours after administration of the compounds.
  • these time frames are not to be construed as limiting.
  • the subject is exposed to radiation, preferably gamma radiation, whereby the radiation may be provided in a single dose or in multiple doses that are administered over several hours, days and/or weeks.
  • Gamma radiation may be delivered according to standard radiotherapeutic protocols using standard dosages and regimens.
  • a combination with radiation therapy may be particularly useful include lung cancer, colorectal cancer, ovarian cancer, uterine cancer, cervical cancer and other gynecological malignancies, head cancer, neck cancer and gastric cancer.
  • Many cancers are known to involve BRAF, MEK, ERK and/or EGFR expression.
  • the second therapeutic agent to be administered in combination with a compound of this invention may be an inhibitor of BRAF, MEK, ERK, EGFR, CDK4/6 and mTOR.
  • said BRAFi is vemurafenib, dabrafenib, encorafenib, LGX818, PLX4720, TAK- 632, MLN2480, SB590885, XL281, BMS-908662, PLX3603, RO5185426, GSK2118436 or RAF265,
  • said MEKi is AZD6244, trametinib, selumetinib, cobimetinib, binimetinib, MEK162, RO5126766, GDC-0623, PD 0325901, CI-1040, PD-035901, hypothemycin or TAK-733,
  • said ERKi is ulixertinib, corynoxeine, SCH772984, XMD8-92, FR 180204, GDC- 0994, ERK5-IN-1, DEL-22379, BIX 02189
  • EGFRi is cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, necitumumab, osimertinib, afatinib, AP26113, EGFR inhibitor (CAS No.
  • CDK4/6i is ribociclib, palbociclib or abemaciclib.
  • said mTORi is dactosilib, rapamycin, sirolimus, tmsirolimus, everolimus or ridaforolimus.
  • the second therapeutic agent administered in combination with a compound of the invention may be an immunotherapy agent, more particular immuno- oncology agent, such as, e.g. an agent targeting CD52, PD-L1, CTLA4, CD20, or PD-1.
  • Agents that may be used in combination with a compound of the present invention include, for example, alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, rituximab.
  • the second therapeutic agent may also be selected from: an alkylating agent (for example, a nitrogen mustard or a nitrosourea); an endocrine agent (for example, an adrenocorticosteroid, an androgen, an anti- androgen, an estrogen, an anti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analogue); or a compound that targets an enzyme or receptor that is overexpressed and/or otherwise involved in a specific metabolic pathway that is misregulated in the tumor cell (for example, ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors (for example, Abelson protein tyrosine kinase)) and the various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor (EGFR
  • An alkylating agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N,N'N'- triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine),
  • An anti-tumor antibiotic which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
  • an anthracycline such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin
  • a tyrosine kinase inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, afatinib, acalabrutinib, alectinib, apatinib, axitinib, bosutinib, cabozantinib, canertinib, crenolanib, cediranib, crizotinib, damnacanthal, dasatinib, entospletinib, entrectinib, erlotinib, foretinib, fostamatinib, gilteritinib, glesatinib, gefitinib, ibrutinib, icotinib, imatinib, linafanib, lapatinib, lestaurtinib, motesanib, mubritinib, nintedanib, nilotini
  • a topoisomerase-inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
  • a topoisomerase I inhibitor such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D
  • a topoisomerase II inhibitor such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin.
  • a PARP inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, BMN-673, olaparib, rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, or 3-aminobenzamide. Further anticancer drugs may also be used in combination with a compound of the present invention.
  • the anticancer drugs may comprise biological or chemical molecules, like TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitruc
  • biological drugs like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized” antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in proliferative diseases can be employed in co-therapy approaches with the compounds of the invention.
  • Antibodies may, for example, be immuno- oncology antibodies, such as ado-trastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, capromab, cetuximab, ipilimumab, necitumumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, trastuzumab, or rituximab.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation.
  • the individual components of such combinations may be administered either sequentially or simultaneously/concomitantly in separate or combined pharmaceutical formulations by any convenient route.
  • administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof) or the second therapeutic agent may be administered first.
  • administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions.
  • the two compounds When combined in the same formulation, it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation.
  • the present invention thus relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with an anticancer drug and/or in combination with radiotherapy.
  • the compounds of formula (I) can also be used in monotherapy, particularly in the monotherapeutic treatment or prevention of cancer (i.e., without administering any other anticancer agents until the treatment with the compound(s) of formula (I) is terminated).
  • the invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the monotherapeutic treatment or prevention of cancer.
  • the subject or patient may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • an animal e.g., a non-human animal
  • a vertebrate animal e.g.,
  • animals are to be treated which are economically, agronomically or scientifically important.
  • Scientifically important organisms include, but are not limited to, mice, rats, and rabbits.
  • Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches.
  • Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals.
  • the subject/patient is a mammal; more preferably, the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig); most preferably, the subject/patient is a human.
  • a non-human mammal such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang
  • treatment of a disorder or disease as used herein (e.g., “treatment” of cancer) is well known in the art.
  • Treatment of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject.
  • a patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).
  • the "treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only).
  • the "treatment" of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the "treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above).
  • the treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
  • the "amelioration" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease.
  • the term "prevention" of a disorder or disease as used herein is also well known in the art. For example, a patient/subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease.
  • the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
  • a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators.
  • a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms).
  • prevention comprises the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
  • PDA Photodiode Array
  • Method B Apparatus: Waters Prep 100 SFC UV/MS directed system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Diacel Chiralpak IC for SFC (250x20 mm, 5 ⁇ m); Column temp: 35°C; Flow: 70 ml/min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 50% B for 15 min; Detection: PDA (210-400 nm); Fraction collection: PDA TIC.
  • PDA Photodiode Array
  • Example 2 synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1,2,4-oxadiazole (017) A mixture of 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 74.1 mg, 0.31 mmol) and 1,2,4-oxadiazole-3-carbothioamide (40 mg, 0.31 mmol) in acetonitrile (3 mL) was heated in a sealed vial to 50 °C overnight.
  • Example 3 synthesis of 2-(1H-imidazol-4-yl)-5-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (038) To a solution of 7-azaindole (200 mg, 1.69 mmol) in dichloromethane (10 mL) under N 2 atmosphere was added aluminium trichloride (677 mg, 5.08 mmol). After heating for 3 min to 40 °C, a solution of 2-bromopropanoyl bromide (0.213 mL, 2.03 mmol) in dichloromethane (2 mL) was slowly added.
  • Example 4 synthesis of 5-chloro-2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (044) To a solution of 2-(1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (001, 26.8 mg, 0.10 mmol) in N,N-dimethylformamide (dry) (1.5 mL) was added N-chlorosuccinimide (15.5 mg, 0.12 mmol) and the reaction was stirred at room temperature for 4 d.
  • Example 5 synthesis of 5-(1H-imidazol-4-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,4- thiadiazole (045) To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (260 mg, 1.30 mmol) in N,N- dimethylformamide (3.5 mL), were added copper(I) iodide (24.8 mg, 0.13 mmol) and cesium fluoride (495 mg, 3.26 mmol).
  • reaction mixture was purged with Argon for 10 min, after which 1-(oxan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (399 mg, 1.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) were added and the reaction mixture was heated in a sealed vial to 90 °C for 16 h. Subsequently, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 5x with EtOAc. The combined organic layers were washed with brine and concentrated in vacuo.
  • Example 6 synthesis of 4-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- methyloxazole (046)
  • a solution of 5-methyl-1,3-oxazole-4-carbonitrile (126 mg, 1.17 mmol) in pyridine (4 mL) was purged with Argon 10 min, after which.
  • triethylamine (0.244 mL, 1.75 mmol) and ammonium sulfide (20% in water, 0.596 mL, 1.75 mmol) were added and the resulting solution was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and water.
  • Example 7 synthesis of 2-(5-methyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (058) O Br O N ) p N y H ri 2 d O in H e .
  • Example 8 synthesis of 2-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (064) This compound was prepared using procedures analogous to Example 7, but instead purified by preparative HPLC (method A), affording 2-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(1H- pyrrolo[2,3-b]pyridin-3-yl)thiazole (41 mg, 59%) as a white solid.
  • Example 9 synthesis of 2-(5-methyl-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (069)
  • a solution of 4-methylimidazole (1.0 g, 12.2 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.536 g, 13.4 mmol) in tetrahydrofuran (10 mL).
  • reaction mixture was partitioned between aq. sat. NH 4 Cl (30 mL) and diethyl ether (30 mL). The layers were separated and the aqueous layer was extracted with Et 2 O (30 mL). The combined organic layers were washed with aq. sat. NH 4 Cl (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Example 10 synthesis of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole (077)
  • N O N 1) p NH2OH.HCl, Ac2O S N nBuLi, yridine, 110 °C N DMF H N then HCl, MeOH H 2 N N N O THF N O N 2) p (N yr H id 4 i ) n 2 e S , , 5 E 0 t3 ° N C O O O O O O Br S N S N N N N N H N HCl/dioxane N N N N N N H O N NH MeCN, 50 °C O H 077 Preparation of tert-butyl 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl
  • Example 11 synthesis of 2-(1-methyl-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (078)
  • Example 12 synthesis of 2-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol- 2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (099) and 2-(5-methyl-1-((tetrahydro-2H- pyran-4-yl)methyl)-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (100)
  • the residue was purified by flash chromatography (silicagel, 5% to 100% EtOAc in heptane), yielding two regioisomers as separated product.
  • the first eluting isomer (23 mg, 0.048 mmol) was dissolved in in 1,4- dioxane (2 mL), hydrogen chloride (4N in dioxane, 0.4 mL, 1.6 mmol) was added and the reaction mixture was heated to 40 °C overnight.
  • the resulting mixture was concentrated, the resulting material purified by SCX-cartridge (eluted with 2.5N NH 3 /MeOH) and the resulting material was lyophilized from acetonitrile/water.
  • the second eluting isomer (13 mg, 0.027 mmol) was dissolved in in 1,4-dioxane (1.5 mL), hydrogen chloride (4N in dioxane, 0.2 mL, 0.8 mmol) was added and the reaction mixture was heated to 40 °C overnight. The resulting mixture was concentrated, the resulting material purified by SCX-cartridge (eluted with 2.5N NH 3 /MeOH) and the resulting material was lyophilized from acetonitrile/water.
  • Example 13 synthesis of 2-(5-phenyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (111) A solution of bromine (1.61 mL, 31.2 mmol) in acetic acid (40 mL) was added dropwise to a stirring solution of 1H-imidazole-4-carbaldehyde (2 g, 20.8 mmol) and sodium acetate (18.8 g, 229 mmol) in acetic acid (40 mL.
  • the aqueous phase was extracted 4x with EtOAc, the combined organic layers were washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated, and the resulting sticky solid was triturated overnight in diethyl ether.
  • the resulting material was dissolved in N,N-dimethylformamide (40 mL), cooled to 0 °C and sodium hydride (60% dispersion in mineral oil, 240 mg, 6.01 mmol) was added. After 20 min of stirring SEM-Cl (1.45 mL, 8.20 mmol) was and the resulting mixture was stirred at room temperature overnight for 20 h. The resulting mixture was diluted with water and extracted 3x with EtOAc.
  • Example 14 synthesis of 2-(5-isopropyl-1H-imidazol-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (113) To a stirring mixture of ethyl isocyanoacetate (1.94 mL, 17.7 mmol) in tetrahydrofuran (15 mL) were added isobutyric anhydride (3.23 mL, 19.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7- ene (2.91 mL, 19.5 mmol) and the reaction mixture was stirred at room temperature overnight.
  • Example 15 synthesis of 2-(5-isopropyl-1H-1,2,3-triazol-4-yl)-4-(1H-pyrrolo[2,3- b]pyridin-3-yl)thiazole (114)
  • Example 16 synthesis of 2-(4,5-dihydro-1H-imidazol-2-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3- yl)thiazole (115)
  • the reaction mixture was heated in a sealed vial to 150 °C for 16 h.
  • Example 17 synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-4-methyl-5- propylpyridin-2(1H)-one (117) and 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-4,5- diethylpyridin-2(1H)-one (118)
  • Example 19 synthesis of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid hydrochloride (121)
  • Example 20 synthesis of methyl 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo- 1,6-dihydropyridine-3-carboxylate hydrochloride (122)
  • a suspension of methyl 5-carbamothioyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6- dihydropyridine-3-carboxylate from Example 19; 84 mg, 0.25 mmol) in acetonitrile (1.5 mL) under Ar atmosphere were added 2-bromo-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (Intermediate 2, 59 mg, 0.25 mmol) and sodium hydrogen carbonate (31 mg, 0.37 mmol) and the reaction was heated to 50 °C overnight.
  • Example 21 synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5-(piperidine- 1-carbonyl)pyridin-2(1H)-one (123)
  • 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-6-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridine-3-carboxylic acid from Example 19; 50 mg, 0.11 mmol) and piperidine (0.021 mL, 0.213 mmol) in N,N-dimethylformamide (1.5 mL) were added diisopropylethylamine (0.056 mL, 0.320 mmol) and HATU (44.6 mg, 0.12 mmol) and the reaction mixture was stirred at room temperature overnight.
  • Example 23 synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- (morpholinomethyl)pyridin-2(1H)-one (205)
  • a suspension of O-benzylhydroxylamine hydrochloride (1.5 g, 9.40 mmol) in pyridine (5 mL) was stirred at room temperature for 2 h.
  • the mixture was cooled to 0 °C, ethyl chloroformate (0.90 mL, 9.40 mmol) was slowly added and the resulting mixture was stirred for 60 min at 0 °C and 2 d at room temperature.
  • Example 24 synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- (hydroxymethyl)pyridin-2(1H)-one (207) To a cooled (-5 °C) solution of 6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(4-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1,6-dihydropyridine-3- carboxylic acid (from Example 19, 0.100 g, 0.167 mmol) in tetrahydrofuran (1 mL) under Argon atmosphere were added triethylamine (0.028 ml, 0.200 mmol) and ethyl chloroformate (0.019 mL, 0.200 ).
  • the resulting material was suspended in tetrahydrofuran (1 mL) and water (0.25 mL) and 1M aq. NaOH (0.168 mL, 0.168 mmol) was added. Stirring was continued overnight at room temperature, after which additional tetrahydrofuran (1 mL), water (0.25 mL) and 1M aq. NaOH (0.336 mL, 0.336 mmol) were added. The mixture was heated to 35 °C for 5h, diluted with tetrahydrofuran and concentrated in vacuo.
  • Example 25 synthesis of 5-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-6- oxo-1,6-dihydropyridine-3-carboxylic acid (208) To a suspension of methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.5 g, 10.2 mmol) in N,N-dimethylformamide (40 ml) was added zinc cyanide (1.19 g, 10.2 mmol) and the mixture was degassed with Argon for 5 min.
  • tetrakis(triphenylphosphine)palladium(0) (1.17 g, 1.02 mmol) was added and the reaction mixture was heated to 100 °C overnight.
  • the reaction mixture was cooled to room temperature and the resulting solids were isolated by filtration, washed with 70 mL MeCN and dried under vacuum at 40 °C.
  • the mother liquor was diluted with 60 mL water, cooled in an ice bath for 1 h, and the resulting solids were isolated by filtration, washed with 30 mL water and dried under vacuum at 40 °C.
  • Example 26 synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1-methyl-5- (1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one (209)
  • To a solution of 1-methyl-6-oxo-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)thiazol-2-yl)-1,6-dihydropyridine-3-carboxylic acid from Example 25, 27 mg, 0.056 mmol) in N,N-dimethylformamide (1.5 mL) were added homomorpholine monochloride (15.9 mg, 0.12 mmol), N,N-diisopropylethylamine (0.04 mL, 0.23) and HATU (24.1 mg, 0.064 mmol) and the reaction mixture was stirred at room
  • Example 27 synthesis of 2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-4-(1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole (255) and 2-(1-ethyl-5-methyl-1H-imidazol-2-yl)-4-(1H- pyrazolo[3,4-b]pyridin-3-yl)thiazole (256)
  • a solution of di-tert-butyl dicarbonate (0.411 mL, 1.77 mmol) in tetrahydrofuran (40 mL) was added to 2-(4-methyl-1H-imidazol-2-yl)-4-(1H-pyrazolo[3,4-b]pyridin-3-yl)thiazole (072, 617 mg, 2.185 mmol).
  • Example 28 synthesis of 2-(5-methyl-1H-imidazol-2-yl)-4-(5-nitro-1H-pyrazolo[3,4- b]pyridin-3-yl)thiazole (265)
  • 2-bromo-1-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)ethan-1-one (Intermediate 18, 188 mg, 0.453 mmol) and 4-methyl-1H-imidazole- 2-carbothioamide (from Example 9, 70.3 mg, 0.50 mmol) in acetonitrile (4 mL) was added sodium hydrogen carbonate (36.1 mg, 0.43 mmol) and the reaction was heated to 50 °C overnight.
  • Example 29 synthesis of 4-((2-(4-(6-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-5- methyl-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (277) 2-(3-(2-(1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-5-methyl-1H-imidazol-2- yl)thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindoline-1,3-dione was prepared from 2-(3-(2- bromoacetyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindoline-1,3-dione (Intermediate 14) and 1-((1,1- dioxidotetrahydro-2H-
  • the first eluting isomer (59.7 mg, 0.11 mmol) was dissolved dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature overnight. After concentration in vacuo, the residue was redissolved in methanol (5 mL), ethylenediamine (0.074 mL, 1.10 mmol) was added and the mixture was heated to 40 °C for 2h.
  • the second eluting isomer (49.7 mg, 0.091 mmol) was dissolved dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature overnight. After concentration in vacuo, the residue was redissolved in methanol (5 mL), ethylenediamine (0.074 mL, 1.10 mmol) was added and the mixture was heated to 40 °C for 2h.
  • Example 31 synthesis of 3-(2-(5-methyl-1H-imidazol-2-yl)thiazol-4-yl)-1H-pyrazolo[3,4- b]pyridin-5-amine (280) Iron (15.3 mg, 0.27 mmol) and ammonium chloride (14.6 mg, 0.27 mmol) were taken up in water (2 mL) and a solution of 2-(5-methyl-1H-imidazol-2-yl)-4-(5-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)thiazole (from Example 28, 25 mg, 0.055 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL) was added.
  • Example 32 synthesis of 4-((2-(4-(5-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)thiazol-2-yl)- 5-methyl-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (281) 4-((5-Methyl-2-(4-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)thiazol-2-yl)-1H-imidazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide was prepared from the appropriate intermediates, following procedures described in Example 28.
  • Example 34 synthesis of 3-(4-(5-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)-1- methyl-5-(1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one (283)
  • 1-Methyl-3-(4-(5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol- 2-yl)-5-(1,4-oxazepane-4-carbonyl)pyridin-2(1H)-one was prepared following the procedures from Examples 25 and 26.
  • Example 35 synthesis of 3-(4-(5-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2- yl)-1-methyl-5-(morpholine-4-carbonyl)pyridin-2(1H)-one (284)
  • DYRK1B PROTEIN PRODUCTION Insect cells Sf9 (Merck-Millipore 71104-3) were grown in a flask under constant agitation at 28 °C in Sf-900 II SFM medium. For protein expression, 300 mL of Sf9 cells ( ⁇ 2*10 6 /mL) were transduced with 3 mL of N-strep-DYRK1B bacculovirus and grown for 3 days. Finally, cells were collected by centrifugation, washed with PBS and lysed in 40 mL NP buffer (50 mM NaH 2 PO 4 , 300 mM NaCl, pH8) supplemented with 1% Igepal CA-630.
  • NP buffer 50 mM NaH 2 PO 4 , 300 mM NaCl, pH8
  • the lysate was filtered through a 0.45 ⁇ m filter and loaded on a Strep-Tactin Superflow Plus Cartridge 5 mL column (Qiagen, Cat. No.30060) using a peristaltic pump (5mL/min). Purification steps were carried out according to manufacturer instructions (Strep-tag Protein Handbook). For buffer exchange and concentration, the eluate was loaded on an Amicon Ultra-1530kd filter (Merck-Milipore UFC903008) and centrifuged 15 min at 5000g.
  • kinase storage buffer 50mM Tris pH 7.5, 150mM NaCl, 0.5mM EDTA, 0.02% Triton-X, 2mM DTT
  • Concentrated DYRK1B solution was collected and mixed with 25% glycerol, aliquoted and stored at -80 °C.
  • IC 50 DETERMINATION OF DYRK1B INHIBITORS 11 concentrations (3 fold dilutions) of screening compounds in kinase reaction buffer (50mM HEPES pH 7.5, 20 mM MgCl 2 ,0.01% Triton X-100, were dispensed in white 384 well plates (3572, Corning, NY, USA) (2 ⁇ L/well). Next, 2 ⁇ L of ATP diluted in kinase reaction buffer (final concentration 100 ⁇ M) was added to the wells.
  • kinase reaction buffer 50mM HEPES pH 7.5, 20 mM MgCl 2 ,0.01% Triton X-100
  • the kinase reaction was started by adding 2 ⁇ L of a mix of N-strep-DYRK1B (0.5nM) and DYRKtide (50 ⁇ M) (Lucerna-Chem AG, D96-58) diluted in kinase reaction buffer supplemented with 0.1% DTT. The plate was briefly centrifuged after each steps and the kinase reaction was incubated for 30 min at room temperature. Next, 6 ⁇ L of ADP-GloTM reagent was dispensed and incubated for 40 min at room temperature.

Abstract

La présente invention concerne des composés de formule (I), éventuellement sous la forme d'un sel pharmaceutiquement acceptable, d'un solvate, d'un co-cristal, d'un tautomère, d'un racémate, d'un énantiomère ou d'un diastéréomère ou d'un mélange de ceux-ci (I), en particulier pour une utilisation dans le traitement, le soulagement ou la prévention du cancer, de la maladie d'Alzheimer, de la maladie de Parkinson, du syndrome de Down, du syndrome métabolique, du diabète et/ou de l'arthrose.
PCT/EP2020/077593 2019-10-02 2020-10-01 Inhibiteurs de la kinase 1b régulée par phosphorylation de tyrosine à double spécificité WO2021064141A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19201007 2019-10-02
EP19201007.2 2019-10-02

Publications (1)

Publication Number Publication Date
WO2021064141A1 true WO2021064141A1 (fr) 2021-04-08

Family

ID=68136208

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/077593 WO2021064141A1 (fr) 2019-10-02 2020-10-01 Inhibiteurs de la kinase 1b régulée par phosphorylation de tyrosine à double spécificité

Country Status (1)

Country Link
WO (1) WO2021064141A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022251565A1 (fr) * 2021-05-27 2022-12-01 Brown University Traitement d'une maladie neurodégénérative à l'aide de composés de type csa et indy

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
EP0036676A1 (fr) 1978-03-24 1981-09-30 The Regents Of The University Of California Procédé de préparation de liposomes de taille identique et les liposomes ainsi obtenus
EP0052322A2 (fr) 1980-11-10 1982-05-26 Gersonde, Klaus, Prof. Dr. Méthode de préparation de vésicules lipidiques par traitement aux ultra-sons, utilisation de ce procédé et l'appareillage ainsi utilisé
EP0088046A2 (fr) 1982-02-17 1983-09-07 Ciba-Geigy Ag Lipides en phase aqueuse
DE3218121A1 (de) 1982-05-14 1983-11-17 Leskovar, Peter, Dr.-Ing., 8000 München Arzneimittel zur tumorbehandlung
EP0102324A2 (fr) 1982-07-29 1984-03-07 Ciba-Geigy Ag Lipides et composés tensio-actifs en phase aqueuse
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
EP0133988A2 (fr) 1983-08-02 1985-03-13 Hoechst Aktiengesellschaft Préparations pharmaceutiques contenant des peptides régulateurs à libération retardée et procédé pour leur préparation
EP0142641A2 (fr) 1983-09-26 1985-05-29 Udo Dr. Ehrenfeld Moyen et produit pour le diagnostic et la thérapie de tumeurs ainsi que pour le traitement de déficiences du système immunitaire cellulaire et humoral
EP0143949A1 (fr) 1983-11-01 1985-06-12 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Composition pharmaceutique contenant de l'urokinase
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
WO1997041833A1 (fr) 1996-05-08 1997-11-13 Inhale Therapeutic Systems Compositions dispersibles a base de macromolecules, procedes de preparation et techniques d'utilisation
WO1999016419A1 (fr) 1997-09-29 1999-04-08 Inhale Therapeutic Systems, Inc. Microparticules perforees et procedes d'utilisation
WO2001085136A2 (fr) 2000-05-10 2001-11-15 Alliance Pharmaceutical Corporation Poudres a base de phospholipides permettant de distribuer un medicament
US6570036B1 (en) 1999-03-05 2003-05-27 Reuter Chemische Apparatebau Kg [De/De] Co-crystallization process
WO2003053411A1 (fr) 2001-12-19 2003-07-03 Nektar Therapeutics Administration pulmonaire d'aminoglycosides
WO2005103050A2 (fr) * 2004-04-02 2005-11-03 Vertex Pharmaceuticals Incorporated Azaindoles utiles en tant qu'inhibiteurs de la proteine serine/threonine kinase superhelice de la famille rho (rock) et d'autres proteines kinases
WO2008005457A2 (fr) * 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Inhibiteurs de pyridinonyle pdk1
JP2008118008A (ja) 2006-11-07 2008-05-22 Nippon Telegr & Teleph Corp <Ntt> シリコン化合物薄膜の形成方法
WO2008095943A1 (fr) * 2007-02-06 2008-08-14 Eisai R&D Management Co. Ltd. Utilisation de 7-azaindoles dans l'inhibition de c-jun n-terminal kinase
WO2011044157A1 (fr) * 2009-10-06 2011-04-14 Biogen Idec Ma Inc. Composes heterocycliques utilises comme inhibiteurs de pdk1
US20120184508A1 (en) * 2011-01-19 2012-07-19 Wenjian Liu Pyrazolo pyrimidines
WO2014059149A1 (fr) 2012-10-10 2014-04-17 Felicitex Therapeutics, Inc. Traitement du cancer par le ciblage de cellules cancéreuses quiescentes
US20140271823A1 (en) 2013-03-14 2014-09-18 Universiti Putra Malaysia Inhibition of hypoxia-inducible factor activity with carica papaya extracts

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
EP0036676A1 (fr) 1978-03-24 1981-09-30 The Regents Of The University Of California Procédé de préparation de liposomes de taille identique et les liposomes ainsi obtenus
EP0052322A2 (fr) 1980-11-10 1982-05-26 Gersonde, Klaus, Prof. Dr. Méthode de préparation de vésicules lipidiques par traitement aux ultra-sons, utilisation de ce procédé et l'appareillage ainsi utilisé
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
EP0088046A2 (fr) 1982-02-17 1983-09-07 Ciba-Geigy Ag Lipides en phase aqueuse
DE3218121A1 (de) 1982-05-14 1983-11-17 Leskovar, Peter, Dr.-Ing., 8000 München Arzneimittel zur tumorbehandlung
EP0102324A2 (fr) 1982-07-29 1984-03-07 Ciba-Geigy Ag Lipides et composés tensio-actifs en phase aqueuse
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
EP0133988A2 (fr) 1983-08-02 1985-03-13 Hoechst Aktiengesellschaft Préparations pharmaceutiques contenant des peptides régulateurs à libération retardée et procédé pour leur préparation
EP0142641A2 (fr) 1983-09-26 1985-05-29 Udo Dr. Ehrenfeld Moyen et produit pour le diagnostic et la thérapie de tumeurs ainsi que pour le traitement de déficiences du système immunitaire cellulaire et humoral
EP0143949A1 (fr) 1983-11-01 1985-06-12 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Composition pharmaceutique contenant de l'urokinase
WO1997041833A1 (fr) 1996-05-08 1997-11-13 Inhale Therapeutic Systems Compositions dispersibles a base de macromolecules, procedes de preparation et techniques d'utilisation
WO1999016419A1 (fr) 1997-09-29 1999-04-08 Inhale Therapeutic Systems, Inc. Microparticules perforees et procedes d'utilisation
US6570036B1 (en) 1999-03-05 2003-05-27 Reuter Chemische Apparatebau Kg [De/De] Co-crystallization process
WO2001085136A2 (fr) 2000-05-10 2001-11-15 Alliance Pharmaceutical Corporation Poudres a base de phospholipides permettant de distribuer un medicament
WO2003053411A1 (fr) 2001-12-19 2003-07-03 Nektar Therapeutics Administration pulmonaire d'aminoglycosides
WO2005103050A2 (fr) * 2004-04-02 2005-11-03 Vertex Pharmaceuticals Incorporated Azaindoles utiles en tant qu'inhibiteurs de la proteine serine/threonine kinase superhelice de la famille rho (rock) et d'autres proteines kinases
WO2008005457A2 (fr) * 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Inhibiteurs de pyridinonyle pdk1
JP2008118008A (ja) 2006-11-07 2008-05-22 Nippon Telegr & Teleph Corp <Ntt> シリコン化合物薄膜の形成方法
WO2008095943A1 (fr) * 2007-02-06 2008-08-14 Eisai R&D Management Co. Ltd. Utilisation de 7-azaindoles dans l'inhibition de c-jun n-terminal kinase
WO2011044157A1 (fr) * 2009-10-06 2011-04-14 Biogen Idec Ma Inc. Composes heterocycliques utilises comme inhibiteurs de pdk1
US20120184508A1 (en) * 2011-01-19 2012-07-19 Wenjian Liu Pyrazolo pyrimidines
WO2012098068A1 (fr) 2011-01-19 2012-07-26 F. Hoffmann-La Roche Ag Pyrazolopyrimidines en tant qu'inhibiteurs de dyrk1a et dyrk1b
WO2014059149A1 (fr) 2012-10-10 2014-04-17 Felicitex Therapeutics, Inc. Traitement du cancer par le ciblage de cellules cancéreuses quiescentes
US20140271823A1 (en) 2013-03-14 2014-09-18 Universiti Putra Malaysia Inhibition of hypoxia-inducible factor activity with carica papaya extracts

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
ANNA CARBONE ET AL: "Novel 1 H -Pyrrolo[2,3- b ]pyridine Derivative Nortopsentin Analogues: Synthesis and Antitumor Activity in Peritoneal Mesothelioma Experimental Models", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 17, 23 August 2013 (2013-08-23), US, pages 7060 - 7072, XP055661760, ISSN: 0022-2623, DOI: 10.1021/jm400842x *
ASHFORD ET AL., BIOCHEM. J., vol. 457, 2014, pages 43 - 56
ATZRODT J ET AL., BIOORG MED CHEM, vol. 20, no. 18, 2012, pages 5658 - 5667
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1049738-54-6
EPSTEIN ET AL., PROC. NATL. ACAD. SCI. (USA, vol. 82, 1985, pages 3688 - 3692
HWANG ET AL., PROC. NATL. ACAD. SCI. (USA, vol. 77, 1980, pages 4030 - 4034
K. MASTERS: "Spray Drying Handbook", 1991, JOHN WILEY & SONS, INC.
MODVIG A ET AL., J ORG CHEM, vol. 79, 2014, pages 5861 - 5868
PARRINO BARBARA ET AL: "Synthesis, antitumor activity and CDK1 inhibiton of new thiazole nortopsentin analogues", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 138, 27 June 2017 (2017-06-27), pages 371 - 383, XP085163760, ISSN: 0223-5234, DOI: 10.1016/J.EJMECH.2017.06.052 *
PATRIZIA DIANA ET AL: "Synthesis and Antitumor Activity of 3-(2-Phenyl-1,3-thiazol-4-yl)-1H-indoles and 3-(2-Phenyl-1,3-thiazol-4-yl)-1H-7-azaindoles", CHEMMEDCHEM, vol. 6, no. 7, 4 July 2011 (2011-07-04), pages 1300 - 1309, XP055069743, ISSN: 1860-7179, DOI: 10.1002/cmdc.201100078 *
R. LANGER ET AL., J. BIOMED. MATER. RES., vol. 15, 1981, pages 167 - 277
R. LANGER, CHEM. TECH., vol. 12, 1982, pages 98 - 105
SIDMAN, U. ET AL., BIOPOLYMERS, vol. 22, 1983, pages 547 - 556
WILLIAM JS ET AL., JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 53, no. 11-12, 2010, pages 635 - 644

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022251565A1 (fr) * 2021-05-27 2022-12-01 Brown University Traitement d'une maladie neurodégénérative à l'aide de composés de type csa et indy

Similar Documents

Publication Publication Date Title
JP7086251B2 (ja) ヘテロ環式化合物およびそれらの使用
ES2466565T3 (es) Inhibidores dihidropiridoftalazinona de poli(ADP-ribosa)polimerasa (PARP)
TW202124383A (zh) 醫藥化合物
WO2018024602A1 (fr) 2,7-diazaspiro [4,4] nonanes
EA032416B1 (ru) Соединения триазолопиримидина и их применения
EP3562809B1 (fr) Composés pyrazolopyrimidine et leurs procédés d&#39;utilisation
KR20210097124A (ko) 화합물, 약제 조성물, 및 화합물 제조 방법 및 atr 키나제 억제제로서의 이것들의 사용 방법
JP2015534993A (ja) 自閉症性障害の処置のためのｍＧｌｕ２／３アンタゴニスト
EA028035B1 (ru) Производные пиразолопирролидин-4-она и их применение при лечении заболевания
CN114174292A (zh) 作为atr激酶抑制剂的取代的2-吗啉代吡啶衍生物
CN114302878A (zh) 酪氨酸激酶非受体1(tnk1)抑制剂及其用途
JP2023522250A (ja) 免疫活性化のためのｄｇｋｚｅｔａ阻害剤としての置換アミノチアゾール類
US20230106032A1 (en) Imidazotriazines acting on cancer via inhibition of cdk12
US20230067929A1 (en) Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment, amelioration or prevention of cancer
AU2020360709B2 (en) Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment or amelioration of cancer
WO2021064141A1 (fr) Inhibiteurs de la kinase 1b régulée par phosphorylation de tyrosine à double spécificité
WO2018210729A1 (fr) Dérivés de sulfonamide aromatiques utilisés en tant qu&#39;antagonistes ou modulateurs allostériques négatifs du récepteur p2x4
CA3213359A1 (fr) Inhibiteurs d&#39;alk-5 et leurs utilisations
WO2016135138A1 (fr) Dérivés d&#39;oxoquinoléine en tant qu&#39;inhibiteurs de mth1 pour la thérapie du cancer
WO2020048826A1 (fr) Composés de la 1-oxa-3,9-diazaspiro[5.5]undécan-2-one substituée en position 5
WO2016135140A1 (fr) Dérivés de 4-aminoquinazoline en tant qu&#39;inhibiteurs de mth1 pour la thérapie du cancer
CA3212085A1 (fr) Derives heterocycliques, compositions pharmaceutiques et leur utilisation dans le traitement ou le soulagement du cancer
CN116829143A (zh) 非受体型酪氨酸激酶1（tnk1）抑制剂的形式和制剂
CN117500803A (zh) 用于治疗具egfr突变的癌症的氨基取代杂环

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20789022

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20789022

Country of ref document: EP

Kind code of ref document: A1