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WO2024003259A1 - Inhibiteurs de tead - Google Patents

Inhibiteurs de tead Download PDF

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Publication number
WO2024003259A1
WO2024003259A1 PCT/EP2023/067846 EP2023067846W WO2024003259A1 WO 2024003259 A1 WO2024003259 A1 WO 2024003259A1 EP 2023067846 W EP2023067846 W EP 2023067846W WO 2024003259 A1 WO2024003259 A1 WO 2024003259A1
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Prior art keywords
carboxamide
trifluoromethyl
pyridine
phenoxy
methyl
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Inventor
Joseph BLUCK
Nico BRÄUER
Sylvia Grünewald
Martin Lange
Christian Lechner
Stefanie BUNSE
Naomi BARAK
Jörg WEISKE
Roman Hillig
Paul DIERKS
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention covers heterocyclic compounds of general formula (I) selected from the group consisting of pyridine-3-carboxamide compounds of general formula (1), pyridine-2-carboxamide compounds of general formula (2), pyrazine-carboxamide compounds of general formula (3), and pyrimidine-carboxamide compounds of general formula (4), as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer, as a sole agent or in combination with other active ingredients.
  • the present invention covers heterocyclic compounds of general formula (I) selected from the group consisting of pyridine-3-carboxamide compounds of general formula (1), pyridine-2-carboxamide compounds of general formula (2), pyrazine-carboxamide compounds of general formula (3), and pyrimidine-carboxamide compounds of general formula (4), which inhibit the activity of transcription enhancer associate domain (TEAD) (TEA/ATTS domain family) transcription factors, the downstream effectors of the Hippo pathway, leading to inhibition of YES-associated protein (YAP1) and /or its paralog transcriptional coactivator with PDZ-binding motif (TAZ) – TEAD mediated target gene transcription and blockade of cancer cell proliferation.
  • TEAD transcription enhancer associate domain
  • YAP1 YES-associated protein
  • TEAD paralog transcriptional coactivator with PDZ-binding motif
  • the Hippo pathway regulates cell proliferation and differentiation as well as organ size during embryonic development and has key roles in tissue regeneration, wound healing and immune modulation (Dey A. et al., Nat. Rev. Drug Disc.2020). It was first discovered in Drosophila, in which tumor-suppressive roles for the pathway were identified (Justice R. W., 1995; Tapon N. et al., Cell 2002; Jia J. et al., Genes Dev. 2003) and is well conserved in mammals where its dysregulation plays a role in various human cancers and other diseases.
  • the Hippo pathway integrates a network of signals that converge to a core kinase cascade to regulate the activity of the paralogous transcription regulators YAP1 and TAZ.
  • Upstream signals regulating the Hippo pathway include cell polarity and adhesion regulators through KIBRA/NF2, mechanical cues acting through Rho GTPase and actin dynamics, hormones and growth factors for GPCRs, and cellular stress signals (Ma et al., Annu. Rev. Biochem.2019).
  • MST1/2 sterile 20-like kinase 1/2
  • SAV1 adaptor protein Salvador homolog 1
  • LATS1/2 large tumor suppressor 1/2
  • LATS1/2 together with adaptor protein Mps one binder kinase activator 1A/B (MOB1A/B) phosphorylate YAP/TAZ which then associate with 14-3-3 proteins and are thus retained in the cytoplasm and directed to proteasomal degradation, preventing nuclear localisation and reducing target gene expression.
  • Deactivation of the Hippo pathway leads to hypo-phosphorylated YAP/TAZ being able to translocate into the nucleus and promoting transcription of downstream genes by forming complexes with various transcription factors, most notably TEAD family members.
  • TEADs can also bind to corepressors VGLL1-4 (Deng X.
  • TEADs are crucial in regulating the transcriptional output of the Hippo pathway and seem to be key mediators of the growth and tumorigenic potential of hyperactivated YAP/TAZ by inducing target genes such as canonical CTGF, Cyr61, ANKRD1, IGFBP3, FGF1 but also genes involved in DNA synthesis and repair or in mitosis.
  • target genes such as canonical CTGF, Cyr61, ANKRD1, IGFBP3, FGF1 but also genes involved in DNA synthesis and repair or in mitosis.
  • NF2-deficiency in papillary renal cell carcinoma cells causes YAP1 nuclear localisation and activation leading to expression of targets genes like BIRC5 (surviving), CTGF or CCDN1 driving cell growth (Sourbier et al. Oncotarget 2018). Furthermore, loss of SAV1 expression results in nuclear sequestration of YAP in patients with clear cell renal cell carcinoma (ccRCC) and YAP down-regulation impaired proliferation and migration of ccRCC cell lines as well as tumor growth in a ccRCC xenograft model (Scdazzling et al. Translational Oncology 2014).
  • TEAD function especially its ability to activate gene transcription through its interaction with YAP/TAZ may therefore be a promising approach for diseases, in particularly cancer, with deregulated Hippo pathway and hyperactivated YAP/TAZ.
  • TEAD proteins interact with co-transcription factors like YAP/TAZ and DNA through various interfaces that constitute potential target sites to interrupt their function (Pobbati A.V. & Rubin B.P. Molecules 2020; Holden J.K. & Cunningham C.N. Cancers 2018).
  • TEAD ⁇ s YAP/TAZ binding domain contains a hydrophobic central pocket with a conserved cysteine that is modified by post-translational palmitoylation.
  • This lipid modification has been shown to be required for TEAD stability and function and to be targetable by small-molecule inhibitors (Noland C.L. et al. Structure 2016; Pobbati A.V. et al. Structure 2015; Kaneda A. et al. Am J Cancer Res 2020; Karatas H. et al. J. Med. Chem.2020; Tang et al. Mol Cancer Ther 2021).
  • the state of the art does not describe the heterocyclic compounds of general formula (I) selected from the group consisting of pyridine-3-carboxamide compounds of general formula (1), pyridine-2-carboxamide compounds of general formula (2), pyrazine- carboxamide compounds of general formula (3), and pyrimidine-carboxamide compounds of general formula (4), of the present invention as described and defined herein. It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties. In particular, the compounds of the present invention have surprisingly been found to effectively inhibit YES-associated protein (YAP1) for which data are given in biological experimental section and may therefore be used for the treatment or prophylaxis of cancer.
  • YAP1 YES-associated protein
  • the present invention covers compounds of general formula (1): wherein R 1 represents C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 5 , or R 8 R 9 N-; R 2 represents phenyl, or pyridyl, which is optionally substituted, one or more times, independently of each other, with R 6 ; R 3 represents hydrogen or C 1 -C 4 -alkyl; R 4 represents C 1 -C 6 -alkyl, C 2 -C 6 -hydroxyalkyl, C 1 -C 4 -haloalkyl, hydroxy-C 2 -C 6 - haloalkyl, R 8 R 9 N-(C 2 -C 4 -alkyl)-, (C 1 -C 1 -C
  • the present invention covers compounds of general formula (2): wherein R 1 represents C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 5 , or R 8 R 9 N-; R 2 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 6 ; R 3 represents hydrogen or C 1 -C 4 -alkyl; R 4 represents C 1 -C 6 -alkyl, C 2 -C 6 -hydroxyalkyl, C 1 -C 4 -haloalkyl, hydroxy-C 2 -C 6 - haloalkyl, R 8 R 9 N-(C 2 -C 4 -alkyl)-, (C 2 -C 4 -alkyl)-O-CO-NH-(C 2 -C 4 -alky
  • the present invention covers compounds of general formula (3): wherein R 1 represents C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 5 , or R 8 R 9 N-; R 2 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 6 ; R 3 represents hydrogen or C 1 -C 4 -alkyl; R 4 represents C 1 -C 6 -alkyl, C 2 -C 6 -hydroxyalkyl, C 1 -C 4 -haloalkyl, hydroxy-C 2 -C 6 - haloalkyl, R 8 R 9 N-(C 2 -C 4 -alkyl)-, (C 2 -C 4 -alkyl)-O-CO-NH-(C 2 -C 4 -alky
  • the present invention covers compounds of general formula (4): wherein R 1 represents C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 5 , or R 8 R 9 N-; R 2 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 6 ; R 3 represents hydrogen or C 1 -C 4 -alkyl; R 4 represents C 1 -C 6 -alkyl, C 2 -C 6 -hydroxyalkyl, C 1 -C 4 -haloalkyl, hydroxy-C 2 -C 6 - haloalkyl, R 8 R 9 N-(C 2 -C 4 -alkyl)-, (C 2 -C 4 -alkyl)-O-CO-NH-(C
  • the invention relates to compounds of formula (1) as described supra, wherein: R 1 represents cyclopropyl, 4- to 5-membered heterocycloalkyl, phenyl, or 5- or 6- membered heteroaryl, wherein said groups are optionally substituted, one or two times, with R 5 ; R 2 represents phenyl, or pyridyl, which is optionally substituted, one time with R 6 ; R 3 represents hydrogen or methyl; R 4 represents C 1 -C 3 -alkyl, C 2 -C 6 -hydroxyalkyl, hydroxy-C 2 -C 4 -haloalkyl, R 8 R 9 N-(C 2 - C 3 -alkyl)-, tert.-butyl-O-CO-NR 9 -(C 2 -C 4 -alkyl)-, R 8 R 9 N-CO-(C 1 -C 3 -alkyl)-, R 8 R 9 N-CO-(C 2 -C 3 -alkyl
  • the invention relates to compounds of formula (1) as described supra, wherein: R 1 represents cyclopropyl, azetidin-1-yl, pyrrolidin-1-yl, 1H-pyrazol-3-yl, phenyl, 3,3- dimethylazetidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl- 1H-pyrazol-3-yl, 1-methyl-1H-1,2,4-triazol-3-yl, 5-methyl-1,3-oxazol-2-yl, 3- fluoropyrrolidin-1-yl, 3,3-difluoroazetidin-1-yl, 5-methyl-1,3-thiazol-2-yl, 4-methyl- 1,3-thiazol-2-yl, 3-methylphenyl, 6-methylpyridin-2-yl, 4-methylpyridin-2-yl, 1,5- dimethyl-1H-pyrazol-3-yl
  • the invention in another embodiment, relates to compounds of formula (1) as described supra, wherein: R 1 represents 1-methyl-1H-pyrazol-3-yl; R 2 represents phenyl, which is substituted one time with R 6 ; R 3 represents hydrogen; R 4 represents ⁇ CHCH 3 CH 2 OH; R 6 represents trifluoromethyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded.
  • substituents and/or variables are permissible.
  • the term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • the term “comprising” when used in the specification includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.
  • the terms as mentioned in the present text have the following meanings:
  • the term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • C 1 -C 6 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or
  • said group has 1, 2, 3 or 4 carbon atoms (“C 1 -C 4 -alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 4 -alkyl e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 6 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g.
  • C 1 -C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.
  • hydroxy-C 1 -C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom and additionally one further hydrogen atom is replaced with a hydroxy group, e.g. a 1,1,1- trifluoro-3-hydroxypropan-2-yl, 3,3,3-trifluoro-2-hydroxypropyl, 4,4,4-trifluoro-3- hydroxybutan-2-yl group.
  • C 1 -C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 -C 6 -alkyl)-O-, in which the term “C 1 -C 6 -alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
  • C 1 -C 6 -haloalkoxy means a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C 3 -C 6 -cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms (“C 3 -C 6 -cycloalkyl”).
  • Said C 3 -C 6 -cycloalkyl group is for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.
  • spirocycloalkyl means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 11 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom.
  • Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
  • bridged heterocycloalkyl means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo-[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi-cyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-
  • “4- to 6-membered heterocycloalkyl” means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
  • heterospirocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-,
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9- membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • the heteroaryl groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the heteroaryl group is a pyrazolyl group.
  • C 1 -C 6 as used in the present text, e.g.
  • C 1 -C 6 -alkyl in the context of the definition of “C 1 -C 6 -alkyl”, “C 1 -C 6 -haloalkyl”, “C 1 -C 6 -hydroxyalkyl”, “C 1 -C 6 -alkoxy” or “C 1 -C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 8 as used in the present text, e.g.
  • C 3 -C 8 -cycloalkyl in the context of the definition of “C 3 -C 8 -cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e.3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range.
  • C 1 -C 6 encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 - C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C 2 -C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired.
  • one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, it is possible for the compounds of the present invention to exist as tautomers.
  • any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 3H tautomer, or even a mixture in any amount of the two tautomers, namely:
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g.
  • a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the present invention covers compounds of general formula (1), supra, in which: R 1 represents C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 5 , or R 8 R 9 N-; R 2 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 6 ; R 3 represents hydrogen or C 1 -C 4 -alkyl; R 4 represents C 1 -C 6 -alkyl, C 2 -C 6 -hydroxyalkyl, C 1 -C 4 -haloalkyl, hydroxy-C 2 -C 6 - haloalkyl, R 8 R 9 N-(C 2 -C 4 -alkyl)-, (C 2 -C 4 -alkyl)-O-
  • the present invention covers compounds of general formula (1), supra, in which: R 1 represents cyclopropyl, 4- to 5-membered heterocycloalkyl, or 5-membered heteroaryl, wherein said groups are optionally substituted, one or two times, with R 5 ; R 2 represents phenyl, which is optionally substituted, one time with R 6 ; R 3 represents hydrogen or methyl; R 4 represents C 1 -C 3 -alkyl, C 2 -C 6 -hydroxyalkyl, hydroxy-C 2 -C 4 -haloalkyl, H 2 N-(C 2 -C 3 - alkyl)-, tert.-butyl-O-CO-NH-(C 2 -C 4 -alkyl)-, H 2 N-CO-(C 1 -C 3 -alkyl)-, H 2 N-CO-(C 2 - C 3 -hydroxyalkyl)-, (C 1 -C 3 ,
  • the present invention covers compounds of general formula (1), supra, in which: R 1 represents cyclopropyl, azetidin-1-yl, pyrrolidin-1-yl, 1H-pyrazol-3-yl, 3,3- dimethylazetidin-1-yl, 2-methylpyrrolidin-1-yl, 1-methyl-1H-pyrazol-4-yl, 1- methyl-1H-pyrazol-3-yl, 1-methyl-1H-1,2,4-triazol-3-yl, 5-methyl-1,3-oxazol-2-yl, 3-fluoropyrrolidin-1-yl, 3,3-difluoroazetidin-1-yl, 5-methyl-1,3-thiazol-2-yl, 4- methyl-1,3-thiazol-2-yl, 1,5-dimethyl-1H-pyrazol-3-yl, 2-methyltetrazol-5-yl, or 1-(difluoromethyl)pyrazol
  • the present invention covers compounds of general formula (2), supra, in which: R 1 represents 4- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl, wherein said groups are optionally substituted, one time, with R 5 , or R 8 R 9 N-; R 2 represents phenyl, which is optionally substituted, one time, with R 6 ; R 3 represents hydrogen; R 4 represents C 1 -C 2 -alkyl, C 3 -C 6 -hydroxyalkyl, H 2 N-CO-(C 3 -alkyl)-, methoxy-ethyl-, cyclopropyl, cyclopropyl-(C 1 -C 2 -alkyl)-, or 3,5-dimethyl-1H-pyrazol-4-yl; R 5 represents fluoro, methyl, or hydroxymethyl; R 6 represents trifluoromethyl; R 8 represents cyclopropyl; R 9 represents
  • the present invention covers compounds of general formula (3), supra, in which: R 1 represents phenyl or 1H-pyrazol-3-yl, wherein said groups are optionally substituted, one time, with R 5 ; R 2 represents phenyl, which is optionally substituted, one time, with R 6 ; R 3 represents hydrogen; R 4 represents C 2 -C 3 -hydroxyalkyl; R 5 represents fluoro or methyl; R 6 represents C 1 -haloalkyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which: R 1 represents 1-methyl-1H-pyrazol-3-yl or 3-fluorophenyl; R 2 represents 4-(trifluoromethyl)phenyl; R 3 represents hydrogen; R 4 represents ⁇ CHCH 3 CH 2 OH; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which: R 1 5-membered heteroaryl, which is optionally substituted, one time, with R 5 ; R 2 represents phenyl, which is optionally substituted, one time, with R 6 ; R 3 represents hydrogen; R 4 represents C 2 -C 4 -hydroxyalkyl, cyclopropyl-(C 2 -C 3 -hydroxyalkyl)-, or 5- membered heteroaryl, which is optionally substituted, one or two times, with R 7 ; R 5 represents methyl; R 6 represents trifluoromethyl; R 7 represents methyl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which: R 1 represents 1-methyl-1H-pyrazol-3-yl; R 2 represents 4-(trifluoromethyl)phenyl; R 3 represents hydrogen; R 4 represents ⁇ CHCH 3 CH 2 OH, 1-hydroxybutan-2-yl, 1-cyclopropyl-2-hydroxyethyl, or 3,5-dimethyl-1H-pyrazol-4-yl; and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder.
  • Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemo- therapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated patients, 6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments, 7.
  • the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
  • the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention.
  • the cell is treated with at least one compound of general formula (I) of the present invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
  • the cell is in vitro.
  • the cell is in vivo.
  • the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer.
  • the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer.
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • a compound of general formula (I) as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a compound of general formula (I) as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at
  • the compounds according to the invention can have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • a suitable manner such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention ⁇ apidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • compositions according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer.
  • the present invention covers a pharmaceutical combination, which comprises: • one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and • one or more further active ingredients, in particular “(chemotherapeutic) anti- cancer agents”.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • One example of a non- fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with known “(chemotherapeutic) anti-cancer agents”.
  • (chemotherapeutic) anti-cancer agents relates to any agent that reduces the survival or proliferation of a cancer cell, and includes but is not limited to 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepit
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13 C satellite peaks, and/or spinning sidebands.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compound by known methods can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H-NMR interpretation.
  • the compounds may be purified by crystallization.
  • impurities may be stirred out using a suitable solvent.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil ® or KP-NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
  • SP4 ® or Isolera Four ® Biotage autopurifier system
  • eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on- line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on- line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
  • Method 2 Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 ⁇ m, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
  • the reaction mixture was quenched with water and extracted with ethyl acetate.
  • the organic phase was separated and the aqueous extracted two more times with ethyl acetate.
  • the organic phases were then combined, dried over water-repellent filter, filtrated and the filtrate concentrated in vacuo.
  • the crude product was dissolved in DMSO and purified by preparative HPLC (method 2) to give 29.0 mg (32 % yield) of the target compound.
  • Step 2 5-(2-Methyl-2H-tetrazol-5-yl)-6-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxylic acid
  • Step 3 N-[(2R)-1-hydroxypropan-2-yl]-5-(2-methyl-2H-tetrazol-5-yl)-6-[4- (trifluoromethyl)phenoxy]pyridine-3-carboxamide
  • TEAD2 Purification, Crystallization and Crystal Structure Determination of TEAD2 in complex with Example 1.12
  • a construct of TEAD2 (UNIPROT accession code Q15562) comprising residues 217-447 with an additional N-terminal Met residue [all amino acid residue names in three-letter- code] and with a C-terminal hexa-His affinity tag for affinity purification (Leu-Glu-His-His- His-His-His-His) was expressed in E.coli, purified via Ni affinity chromatography and size exclusion chromatography, shock-frozen in liquid nitrogen and stored at -80°C.
  • TEAD2 Frozen aliquots of TEAD2 (concentrated to 5.5 mg/mL) were thawed and crystallized using the hanging drop method. Drops made from 1 ⁇ L of protein solution were mixed with 1 ⁇ L of reservoir buffer (100 mM HEPES pH 7.2, 1.86-2.00 M sodium formate) and stored at 20 °C. Plate-shaped and rod-shaped crystals grew within 2 to 13 days. Crystals were soaked for 3 days with 3 mM Example 12 (from a 100 mM Stock solution in DMSO), briefly immersed in reservoir buffer supplemented with 25% glycerol and 5 mM inhibitor, and cryo-cooled in liquid nitrogen.
  • reservoir buffer 100 mM HEPES pH 7.2, 1.86-2.00 M sodium formate
  • Example 1.12 shows the stereochemistry at carbon atom C10: see FIGURE 1/1.
  • the following examples were prepared in analogy to example 1.12.
  • Example 1.18 N-[3-Hydroxy-2-methylpropyl]-5-(1-methyl-1H-pyrazol-3-yl)-6-[4- (trifluoromethyl)phenoxy]pyridine-3-carboxamide, racemate
  • Step 2 N-(2-Aminoethyl)-5-(1-methyl-1H-pyrazol-3-yl)-6-[4-(trifluoromethyl) phenoxy]pyridine-3-carboxamide A solution of 73 mg (144 ⁇ mol) tert-butyl [2-( ⁇ 5-(1-methyl-1H-pyrazol-3-yl)-6-[4- (trifluoromethyl)phenoxy] pyridine-3-carbonyl ⁇ amino)ethyl]carbamate, 5 eq.
  • the reaction mixture was treated with water and extracted with ethyl acetate.
  • the organic phase was isolated and the aqueous extracted two more times with ethyl acetate.
  • the organic phases were combined, dried over water-repellent filter and the filtrate concentrated in vacuo.
  • the crude material was purified by preparative HPLC (method 3, basic gradient A) to give 52.0 mg (35% yield) of the title compound.
  • Step 2 N-(3-Aminopropyl)-5-(1-methyl-1H-pyrazol-3-yl)-6-[4-(trifluoromethyl) phenoxy]pyridine-3-carboxamide
  • tert-butyl [3-( ⁇ 5-(1-methyl-1H-pyrazol-3-yl)-6-[4- (trifluoromethyl)phenoxy]pyridine-3-carbonyl ⁇ amino)propyl]carbamate in 0.5 ml dioxane was added 0.084 ml 4M HCl solution in dioxane (337 ⁇ mol) and the mixture stirred at room temperature until complete conversion.
  • Step 2 tert-Butyl [(2R) or (2S)-2-( ⁇ 5-(1-methyl-1H-pyrazol-3-yl)-6-[4-(trifluoromethyl) phenoxy]pyridine-3-carbonyl ⁇ amino)propyl]carbamate, isomer A Separation of enantiomers via preparative chiral HPLC (instrument: PrepCon Labomatic HPLC-3; column: YMC Amylose SA 5 ⁇ , 250x30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: methanol; gradient: 0-15 min 0-5% B; flow: 50 ml/min; temperature: 25°C; UV: 280 nm) yields 52 mg of the title compound (isomer A, retention time: 4.5-6.3 min) alongside 62 mg of the isomer B (retention time: 6.6-9.1 min).
  • Analytical chiral HPLC (instrument: Thermo Fisher UltiMate 3000; column: YMC Amylose SA 3 ⁇ , 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: methanol; isocratic: 95%A+5%B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm): retention time 2.10 min (ee: 100%).
  • Step 3 N-[(2R) or (2S)-1-Aminopropan-2-yl]-5-(1-methyl-1H-pyrazol-3-yl)-6-[4- (trifluoromethyl)phenoxy]pyridine-3-carboxamide, isomer A
  • Analytical chiral HPLC (instrument: Thermo Fisher UltiMate 3000; column: YMC Amylose SA 3 ⁇ , 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethyl amine; eluent B: methanol; isocratic: 95%A+5%B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm): retention time 3.27 min (ee: 94.7%).
  • Step 2 N-[(2R) or (2S)-1-Aminopropan-2-yl]-5-(1-methyl-1H-pyrazol-3-yl)-6-[4- (trifluoromethyl)phenoxy]pyridine-3-carboxamide, isomer B
  • reaction mixture was evaporated to dryness in vacuo.5ml of saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were evaporated dryness and the obtained material purified by preparative HPLC (method 1) to give 22 mg of the title compound.
  • Analytical chiral HPLC instrument: Waters Alliance 2695; Column: Chiralpak IF 3 ⁇ , 100x4.6; eluent A: water + 0.1 vol % formic acid; eluent B: acetonitrile; isocratic: 55%A+45%B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm): retention time 3.42 min (ee: 100%).
  • Analytical chiral HPLC instrument: Waters Alliance 2695; Column: Chiralpak IF 3 ⁇ , 100x4.6; eluent A: water + 0.1 vol % formic acid; eluent B: acetonitrile; isocratic: 55%A+45%B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm): retention time 4.26 min (ee: 95.6%).
  • Analytical chiral HPLC (instrument: Thermo Fisher UltiMate 3000; column: YMC Amylose SA 3 ⁇ , 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95%A+5%B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm): retention time 3.07 min (ee: 100%).
  • Analytical chiral HPLC (instrument: Thermo Fisher UltiMate 3000; column: YMC Amylose SA 3 ⁇ , 100x4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95%A+5%B; flow: 1.4 ml/min; temperature: 25°C; UV: 280 nm): retention time 4.59 min (ee: 100%).
  • Example 1.91 5-(3-Fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-[4-(trifluoromethyl) phenoxy] pyridine-3-carboxamide
  • a mixture of Intermediate 1.15a (100 mg, 265 ⁇ mol), (2R)-2-aminopropan-1-ol (41 ⁇ l, 530 ⁇ mol; CAS-RN:[35320-23-1]), DIPEA (180 ⁇ l, 1.1 mmol; CAS-RN:[7087-68-5]), HATU (302 mg, 795 ⁇ mol; CAS-RN:[148893-10-1]) in 2.7 ml DMF was stirred at r.t. until complete conversion.
  • Example 1.102 5-(3-Fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-[3- (trifluoromethyl)phenoxy]pyridine-3-carboxamide
  • a mixture of Intermediate 1.15b (92.0 mg, 244 ⁇ mol), (2R)-2-aminopropan-1-ol (27.5 mg, 366 ⁇ mol; CAS-RN:[35320-23-1]), DIPEA (85 ⁇ l, 0.488 mmol; CAS-RN:[7087-68-5]), HATU (139 mg, 366 ⁇ mol; CAS-RN:[148893-10-1]) in 2.6 ml DMSO was stirred at r.t. until complete conversion.
  • Example 1.139 2-( ⁇ 5-(3-Fluorophenyl)-6-[4-(trifluoromethyl)phenoxy]pyridine-3- carbonyl ⁇ amino) -N-methylethan-1-aminium trifluoroacetate
  • TFA 46 ⁇ l, 600 ⁇ mol
  • CAS-RN [76-05-1]
  • Example 1.133 tert-Butyl N- ⁇ 5-(3-fluorophenyl)-6-[4-(trifluoromethyl)phenoxy]pyridine-3- carbonyl ⁇ -D-alaninate
  • a mixture of Intermediate 1.15a (90.6 mg, 240 ⁇ mol), 1.1 eq. tert-butyl D-alaninate hydrochloride (1:1) (48.0 mg, 264 ⁇ mol), 1.1 eq. HATU (100 mg, 264 ⁇ mol; CAS-RN: [148893-10-1]), 4.0 eq. DIPEA (170 ⁇ l, 960 ⁇ mol; CAS-RN: [7087-68-5]) in 2.0 ml DMSO was stirred at r.t. overnight.
  • Example 1.134 N- ⁇ 5-(3-Fluorophenyl)-6-[4-(trifluoromethyl)phenoxy]pyridine-3- carbonyl ⁇ glycine
  • Step 1 Methyl N- ⁇ 5-(3-fluorophenyl)-6-[4-(trifluoromethyl)phenoxy]pyridine-3- carbonyl ⁇ glycinate
  • 41.0 mg (25 % yield) of the title compound were obtained from 140 mg Intermediate 15a (371 ⁇ mol) and 1.1 eq. methyl glycinate hydrochloride (1:1) (51.2 mg, 408 ⁇ mol).
  • Example 1.138 5-(2-Fluorophenyl)-N-[(2R)-1-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenoxy] pyridine-3-carboxamide
  • a mixture of Intermediate 1.16 (77.5 mg, 185 ⁇ mol), 1.5 eq. (2-fluorophenyl)boronic acid (38.8 mg, 277 ⁇ mol; CAS-RN:[1993-03-9]), 0.05 eq. [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (6.76 mg, 9.24 ⁇ mol; CAS- RN:[72287-26-4]), 2.0 eq. aq.
  • Example 1.147 6-(4-Chlorophenoxy)-5-(3-fluorophenyl)-N-[(2R)-1-hydroxypropan-2- yl]pyridine-3-carboxamide
  • Example 1.153 N-[(2R)-1-Hydroxypropan-2-yl]-4-methyl-2'-[4- (trifluoromethyl)phenoxy][2,3'-bipyridine]-5'-carboxamide
  • Example 1.154 was prepared from Intermediate 1.22b in analogy to the procedure described for example 1.153.
  • Example 2.7 N-[(2R)-1-hydroxypropan-2-yl]-6-(1-methyl-1H-pyrazol-3-yl)-5-[4- (trifluoromethyl)phenoxy]pyridine-2-carboxamide
  • the reaction mixture was treated with water and extracted with ethyl acetate three times.
  • the combined organic phases were concentrated in vacuo and the remaining material purified by preparative HPLC (method 2) to give 57 mg of the title compound.
  • Example 2.21 6-(Azetidin-1-yl)-N-[(2R)-1-hydroxypropan-2-yl]-5-[4- (trifluoromethyl) phenoxy]pyridine-2-carboxamide
  • a mixture of 98 mg intermediate 2.7 (234 ⁇ mol), 63 ⁇ l azetidine (940 ⁇ mol), 152 mg caesium carbonate (468 ⁇ mol) and 2 ml NMP was stirred for 3 hours at 70°C. Water and ethyl acetate were added and the aqueous layer extracted with ethyl acetate (3-times). The combined organic phases were evaporated to dryness under vacuo and the remaining material purified by preparative HPLC (method 2) to give 31 mg of the title compound.
  • Examples 2.33-2.37 were heated at 90°C for 12 hours.
  • Examples 2.38-2.39 were heated at 90°C for 3 hours.
  • EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. Examples were synthesized one or more times.
  • In vitro assay 1 Assay for the detection of YAP1/TAZ activity in MDA-MB-231-TEAD-Luc reporter cells
  • the YAP/TAZ Dual Reporter Assay quantifies the activity of endogenous YAP1 and/or TAZ in MDA-MB-231 cells.
  • the cells contain a stable Firefly luciferase reporter under control of a TEAD-promoter (base pairs 27-304), as described under SEQ ID No.
  • the cells were kept in routine culture in DMEM low glucose, 10% fetal bovine serum (FBS), 1% Glutamax, 250 ⁇ g/ml Hygromycin, 0,5 ⁇ g/ml Puromycin, harvested, cryopreserved in 90% culture medium + 10% dimethylsulphoxide (DMSO) and stored as frozen aliquots of typically 10-50 million cells/vial at -150°C or below until further use.
  • FBS fetal bovine serum
  • DMSO dimethylsulphoxide
  • the cells were centrifuged for 5 min at 44 ⁇ g (gravitational force). The supernatant was removed and the cell pellet was resuspended in fresh medium to give a suspension of 2.0E+05 cells/ml.
  • the cell concentration may vary depending on the cryopreserved cell batch used.
  • the inhibitor control solution contained assay medium without cells. The assay was performed in white 384-well or 1536-well microplates (Greiner Bio-One, Frickenhausen, Germany) with a total volume of five microliter ( ⁇ l) or four ⁇ l, respectively. Fifty nl (40 nl in 1536-well microplates) of a 100-fold concentrated solution of the test compound in DMSO were transferred into a 384-well microtiter test plate.
  • a Hummingbird liquid handler Digilab, MA, USA
  • an Echo acoustic system (Labcyte, CA, USA) was used.
  • Five ⁇ l of a freshly prepared cell suspension were added to the wells of a test plate.
  • the inhibitor control cell suspension was added to empty wells at the side of the test plate, followed by incubation at 37°C in a 5% carbon dioxide atmosphere for 20-24 hours.
  • luminescence detection one ⁇ l of the Dual-Glo-Luciferase detection solution, prepared as recommended by the supplier, were added to all wells.
  • test plate was centrifuged for two minutes at 1200 rpm in a microplate centrifuge (Eppendorf model 5810), incubated at 20°C for 10 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Then, one ⁇ l of the Dual-Glo-Stop&Glo Luciferase detection solution, prepared as recommended by the supplier, were added to all wells. The test plate was centrifuged for two minutes at 1200 rpm, incubated at 20°C for 10 min before measurement of the renilla luminescence in a microplate reader.
  • Table 2 YAP1/TAZ activity: IC 50 values of examples in in vitro assay 1
  • Cancer cell proliferation assays quantifies the effect of test compound addition on viability and proliferation of cancer cells. Cancer cells were seeded at appropriate cell numbers in 30 ⁇ l of their appropriate growth medium (1000 cells/well for cell lines NCI- H226, NCI-H2052, NCI-H2452 and NCI-H28 in RPMI 1640 medium (Biochrom FG 1215) with 10% FCS (Sigma F2442)) in 384-well plates and incubated in a humidified 37°C incubator for 24 h.
  • growth medium 1000 cells/well for cell lines NCI- H226, NCI-H2052, NCI-H2452 and NCI-H28 in RPMI 1640 medium (Biochrom FG 1215) with 10% FCS (Sigma F2442)
  • test compounds were added to cells by means of a HP D300 digital dispenser in a 20-step dilution series (e.g.10 ⁇ M, 6.2 ⁇ M, 3.8 ⁇ M, 2.3 ⁇ M, 1.4 ⁇ M, 0.89 ⁇ M, 0.55 ⁇ M, 0.34 ⁇ M, 0.21 ⁇ M, 0.13 ⁇ M, 79 nM, 49 nM, 30 nM, 18 nM, 12 nM, 6.9 nM, 3.9 nM, 2.6 nM, 1.3 nM, 0.86 nM).
  • a 20-step dilution series e.g.10 ⁇ M, 6.2 ⁇ M, 3.8 ⁇ M, 2.3 ⁇ M, 1.4 ⁇ M, 0.89 ⁇ M, 0.55 ⁇ M, 0.34 ⁇ M, 0.21 ⁇ M, 0.13 ⁇ M, 79 nM, 49 nM, 30 nM, 18 nM, 12 nM, 6.9 nM
  • Luminescence which corresponds to viable cell number, was determined on an Infinite M1000 Tecan plate reader.
  • Target gene expression assays explore the effect of TEAD inhibitors on expression levels of genes that are dependent on TEAD function for transcription. Cancer cells covering various indications (mesothelioma, lung cancer (SCLC, NSCLC), soft tissue sarcoma, urinary tract, kidney, liver, gastric, breast and pharyngeal cancer) were seeded into 6- well plates at appropriate cell numbers in 2 ml of their respective medium and incubated in a humidified 37°C incubator for 24 h. Then, cells were treated with test compounds at a concentration of 1 ⁇ M or 10 ⁇ M or with 0.1% DMSO as control or were left untreated.
  • RNA samples (0.5-1 ⁇ g) were reverse- transcribed to complementary DNA (cDNA) using SuperScriptTM III First-Strand Synthesis SuperMix (Invitrogen).
  • cDNA levels of respective genes were quantified by real-time PCR using TaqMan Gene Expression Assays (Applied Biosystems) on a 7500 Fast Real-Time or a ViiA 7 Real-Time PCR System (Applied Biosystems). The evaluated genes and TaqMan Gene Expression Assays are listed in Table 3 below.
  • Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as a housekeeping gene. Relative mRNA expression was calculated using the ⁇ Ct method and endogenous GAPDH mRNA expression as reference.
  • Caco-2 Permeability Assay 4 Caco-2 Permeability Assay Caco-2 cells [purchased from the German Collection of Microorganisms and Cell Cultures (DSMZ), Braunschweig, Germany] were seeded at a density of 4.5 ⁇ 10 4 cells/well on 24- well insert plates, 0.4 ⁇ m pore size (Costar) and grown for 13-15 days in DMEM supplemented with 10% FCS, 1% GlutaMAX (100 ⁇ , Gibco), 100 U/mL penicillin, 100 ⁇ g/mL streptomycin (Gibco), and 1% nonessential amino acids (100 ⁇ , Thermo Fischer Scientific). Cells were maintained at 37 °C in a humidified 5% CO2 atmosphere. Medium was changed every 2 ⁇ 3 days.
  • test compounds were pre-dissolved in DMSO and added either to the apical or basolateral compartment at a final concentration of 2 ⁇ M.
  • the organic solvent in the incubations was limited to ⁇ 1% dimethylsulfoxide (DMSO).
  • samples were taken from both compartments and analyzed by LC ⁇ MS/MS after precipitation with MeOH.
  • the efflux ratio (ER) basolateral (B) to apical (A) was calculated by dividing Papp B ⁇ A by Papp A ⁇ B. In addition, the compound recovery was calculated.
  • As assay control reference compounds were analyzed in parallel.
  • In vitro assay 5 Metabolic Stability in Liver Microsomes The in vitro metabolic stability of test compounds was determined by incubating them at 1 ⁇ M in a suspension of liver microsomes in 100 mM phosphate buffer, pH 7.4 (NaH 2 PO 4 ⁇ H 2 O + Na 2 HPO 4 ⁇ 2H 2 O) and at a protein concentration of 1 mg/mL at 37 °C.
  • the microsomes were activated by adding a cofactor mix containing 8 mM glucose-6- phosphate (G-6-P), 0.5 mM NADP, and 1 IU/mL G-6-P dehydrogenase in phosphate buffer, pH 7.4.
  • the metabolic assay was started shortly afterwards by adding the test compound to the incubation at a final volume of 0.55 mL (or 1.21 mL).
  • the organic solvent in the incubations was limited to ⁇ 1% dimethylsulfoxide (DMSO) and acetonitrile.
  • DMSO dimethylsulfoxide
  • the microsomal suspensions were continuously shaken at 550 rpm (or 375 rpm) and aliquots were taken at 2, 8, 16, 30, 45, and 60 min, to which double volumes of cold acetonitrile were immediately added.
  • the samples were frozen at ⁇ 20 °C overnight, subsequently centrifuged for 15 min at 3700 rpm, and the supernatant was analyzed by LC-MS/MS.
  • the half-life of a test compound was determined from the concentration ⁇ time plot. From the half-life, the intrinsic clearances were calculated.
  • liver blood flow 1.32 L/(h ⁇ kg) (human), 4.2 L/(h kg) (rat); specific liver weight 21 g/kg (human), 32 g/kg (rat), and microsomal protein content 40 mg/g.
  • the cell pellet was resuspended in WME (30 mL) and centrifuged twice through a Percoll gradient at 100 g. The hepatocytes were washed again with WME and resuspended in a medium containing 5 % FCS. Cell viability was determined by trypan blue exclusion. For the metabolic stability assay, liver cells were distributed in WME containing 5 % FCS into glass vials at a density of 1.0 ⁇ 10 6 vital cells/mL. The test compound was added to a final concentration of 1 ⁇ M.
  • the hepatocyte suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, 45, and 90 min, to which an equal volume of cold MeOH was immediately added.
  • the samples were frozen at ⁇ 20°C overnight, subsequently centrifuged for 15 min at 3000 rpm, and the supernatant was analyzed by LC-MS/MS. The half-life of a test compound was determined from the concentration ⁇ time plot.
  • liver blood flow 4.2 L/(h kg); specific liver weight 32 g/kg body weight; liver cells in vivo 1.1 ⁇ 10 8 cells/g liver; and liver cells in vitro 1.0 ⁇ 10 6 /mL.
  • the cells contain a stable Firefly luciferase reporter under control of a TEAD-promoter (base pairs 27-304), as described under SEQ ID No.1 ( Figure 2). Signals are detected by measuring firefly luminescence using the OneGlo-luciferase assay system detection kit (Promega, part # E605A, E606A). The cells were kept in culture in DMEM/Ham ⁇ s F12, 10% fetal bovine serum (FBS), 1% Glutamax, 250 ⁇ g/ml Hygromycin.
  • FBS fetal bovine serum
  • the assay was performed in white 384-well microplates (Greiner Bio-One, Frickenhausen, Germany) with a total volume of 20 microliter ( ⁇ l).2000 cells were seeded per well and incubated overnight at 37°C 5% CO2 in a humidified atmosphere. After 16h, test compounds dissolved in DMSO were added in triplicates at up to 11 concentrations (for example 20 ⁇ M, 5.7 ⁇ M, 1.6 ⁇ M, 0.47 ⁇ M, 0.13 ⁇ M, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM) by Hp Dispenser. The cells were incubated for 24h at 37°C 5% CO2 in a humidified atmosphere.
  • In vitro assay 8 PXR Nuclear Receptor Activation A HepG2 cell line stably-cotransfected with a vector for human PXR and a Luciferase reporter gene under the control of a human CYP3A4 promotor or commercially available DPX2 cells (hepatoma cell line stably-cotransfected with a vector for human PXR and a Luciferase reporter gene under the control of two human CYP3A4 promotors; Puracyp, Carlsbad, CA) were applied.
  • hERG cells were transferred to the cell reservoir of a 384 channel automated patch clamp device and stored there at 20°C until usage.
  • hERG cells were transferred to a 384 well patch clamp chip (pipette resistance of ⁇ 2-3 M ⁇ ) prefilled with external solution (containing in mM: 143 NaCl, 4 KCl, 2 CaCl 2 , 1 MgCl 2 , 5 glucose, 10 HEPES; pH 7.4 (NaOH)). Underpressure was applied underneath the glass bottom of the patch clamp chip to position the hERG cells on the recording sites in the glass bottom of the chip.
  • a seal enhancing solution (containing in mM: 78 NaCl, 60 NMDG, 4 KCl, 10 CaCl 2 , 1 MgCl 2 , 5 glucose, 10 HEPES; pH 7.4 (HCl)) was added to the hERG cells to facilitate the formation of stable seals between the membranes of the hERG cells and the glass next to the recording sites. Then, hERG cells were washed several times with wash solution (containing in mM: 87 NaCl, 60 NMDG, 4 KCl, 2 CaCl 2 , 1 MgCl 2 , 5 glucose, 10 HEPES; pH 7.4 (HCl)) to remove excess seal enhancing solution.
  • wash solution containing in mM: 87 NaCl, 60 NMDG, 4 KCl, 2 CaCl 2 , 1 MgCl 2 , 5 glucose, 10 HEPES; pH 7.4 (HCl)
  • the membrane parts of the hERG cells covering the recording sites were exposed to internal solution (containing in mM: 10 NaCl, 123 KF, 10 EGTA, 10 HEPES; pH 7.2 (KOH)) supplemented with 5-20 ⁇ M Escin, and the perforated patch configuration was established.
  • the holding potential was stepwise adjusted to -80 mV, capacitance was compensated, and a series of defined voltage commands was initiated to trigger the hERG current response from the hERG cells (-80 mV for 200 ms, +20 mV for 1000 ms, -40 mV for 500 ms; repeated at a frequency of 0.1 Hz).
  • a negative control i.e. wash solution supplemented with 0.3% DMSO and 0.01% HSA
  • a solution containing the test item at a final concentration of (0.1, 1, or 10) ⁇ M was applied for 10 min to measure eventual inhibitory effects of the test item on the hERG current (- the test item solution was produced from a 10 mM DMSO stock by using an automated pipetting device and sequential dilution).
  • a positive control i.e.
  • hERG tail current amplitudes were averaged from three consecutive current responses at the end of the negative control phase, test item phase, and positive control phase, respectively.
  • hERG tail current amplitudes were normalized to the mean hERG tail current amplitude at the end of the negative control phase with nominal 0% inhibition as well as the hERG tail current amplitude at the end of the positive control phase with nominal 100% inhibition. Then, the effect of the test item was calculated as a percentage inhibition value at the test item concentration applied. Finally, percentage inhibition values from all successful recordings at a particular test item concentration were averaged and combined to construct a standard sigmoidal dose response curve, determine the half maximal inhibitory concentration (IC 50 ) of the test item as well as extrapolate its IC 20 .
  • IC 50 half maximal inhibitory concentration
  • In vivo assay 1 In vivo pharmacodynamic and efficacy studies All mouse experiments were approved by the relevant regulatory agency (federal state of Berlin, Austinamt für Pass und touches Berlin) and were conducted in compliance with the German Animal Welfare Act. Animals were kept in a 12-hour light / dark cycle and maintained under standard conditions at a housing temperature of 23°C. Food and water was available ad libitum. The in vivo efficacy of TEAD inhibitory compound was evaluated at maximal tolerated dose (MTD) or sub-MTD dose in a NCI-H226 mesothelioma tumor xenograft model in NMRI nude mice.
  • MTD maximal tolerated dose
  • sub-MTD dose sub-MTD dose
  • NCI-H226 tumor cells were cultivated in RPMI 1640 with GlutaMax (Gibco, Invitrogen GmbH) containing 10% fetal bovine serum (FBS; Sigma) at 37 °C and 5% CO 2 .5x10 6 tumor cells in 100 ⁇ l 100% Matrigel were subcutaneously injected into the right flank of female NMRI nude mice.
  • GlutaMax Gibco, Invitrogen GmbH
  • FBS fetal bovine serum
  • the animals were randomized to treatment and control groups with 12 animals each, and treatment was started the following day. Treatment of each animal was based on individual body weight.
  • Formulation of test compound was in Solutol/Ethanol/water (40/10/50) and applied orally via gavage at different doses and schedules. All application volumes were 10 ml/kg.
  • Tumor diameters were measured using a caliper at least twice a week.
  • Tumor volume (mm 3 ) was calculated using the formula 0.5 a ⁇ b 2 , where a and b are the long and short diameters of the tumor, respectively.
  • the animal body weight was monitored at least twice a week as a measure for treatment-related toxicity.
  • Control groups were stopped according to animal welfare criteria by decapitation of animals under isofluran anesthesia and tumors, blood and organs (e.g. lung, kidney, liver, spleen, colon, stomach, heart, pancreas, brain) collected for further analysis (necropsy I). Treatment was continued in responding groups until tumor regression flattened out and 3-4 animals per group were subjected to necropsy II.
  • PK analysis blood samples were collected after decapitation in tubes containing EDTA (Sarstedt) 1, 3, 7 and 24h after the last dose, centrifuged for 5 min at 10000 x g and the plasma supernatant was snap frozen and stored at -20°C. Tumors and selected organs were removed, their weights determined and subsequently divided into two pieces, one of which was snap-frozen and stored at -80°C and one formalin-fixed and paraffin-embedded.
  • RNA samples 0.5-1 ⁇ g were reverse-transcribed to complementary DNA (cDNA) using SuperScriptTM III First-Strand Synthesis SuperMix (Invitrogen). After dilution, cDNA levels of respective genes were quantified by real-time PCR using TaqMan Gene Expression Assays (Applied Biosystems) on a 7500 Fast Real-Time or a ViiA 7 Real-Time PCR System (Applied Biosystems. The evaluated genes and TaqMan Gene Expression Assays are listed in Table 4 below. Relative mRNA expression was calculated using the ⁇ Ct method and endogenous GAPDH mRNA expression as reference.
  • In vivo assay 2 Pharmacokinetics in Rats All animal studies were conducted in accordance with the German Animal Welfare Act and the ethical guidelines of Bayer AG and were approved by the local ethics committee. Female and male Wistar rats were obtained from Charles River (Germany) and had access to food and water ad libitum. All animals were housed according to institutional guidelines under a 12 h/12 h light/dark cycle and maintained under standard conditions (20 ⁇ 22 °C, 50 ⁇ 70% humidity). Rats were housed in Makrolon cages type IV, five animals per cage, fed a pelleted diet (Ssniff, Germany), and used for in vivo studies with a weight of 200 ⁇ 300 g.
  • test compounds were administered to female or male Wistar rats intravenously at a dose of 0.3 mg/kg and po at a dose of 0.6 mg/kg formulated as solutions using solubilizers such as PEG400 and EtOH in well-tolerated amounts.
  • Blood samples were collected, for example, at 2 (iv only), 8, 15, 30, and 45 min and 1, 2, 4, 7, and 24 after dosing from the vena jugularis into lithium heparin tubes (Monovette, Sarstedt) and centrifuged for 15 min at 3000 rpm. An aliquot of 100 ⁇ L from the supernatant (plasma) was taken and precipitated by the addition of cold acetonitrile (400 ⁇ L).
  • TEAD2 (Acc. No Q15562; aa 217-447), TEAD3 (Acc. No Q99594; aa 219-435) and TEAD4 (Acc. No Q15561; aa 217-434) were cloned into N-terminal His - tag vector using Gateway technologies.
  • the vector was transfected into E. coli BL21(DE3) using LB 184 medium in the presence of 200 ⁇ g/mL Ampicillin.
  • the cells were grown at 37°C until the OD550 reached 1, at which point 0.3 mM IPTG was add and the temperature was lowered to 17°C.
  • the cells were harvested after 24 hours.E.
  • coli cell pellet from 10-liter fermenter was resuspended in 800 mL lysis buffer (25 mM Hepes pH 7.5, 300 mM NaCl, 20 mM Imidazole, 5% Glycerol, Complete-EDTAfree protease inhibitor, 1 mM DTT, 2 ⁇ g Benzonase) and lysed by Microfluidics.
  • the soluble protein was separated by centrifugation at 27500 xg for an hour at 4°C.
  • the protein was purified via HisTrap HP affinity chromatography using buffer (25 mM Hepes pH 7.5, 300 mM NaCl, 5% Glycerol, 1 mM DTT) with 40 mM Imidazole for washing and 500 mM Imidazole for elution.
  • the eluted protein was then concentrated and further purified by size exclusion chromatography (Superdex 75 26/60) in 25 mM Hepes pH 7.5, 300 mM NaCl, 5% Glycerol, 1 mM DTT. Pools of Eluate were frozen in nitric oxygen.

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Abstract

La présente invention concerne des composés hétérocycliques de formule générale (I) : Formule (I), dans laquelle (I'), formule (I') représente un cycle hétérocyclique, ledit composé de formule générale (I) étant choisi dans le groupe constitué par : Formule (1), formule (2), formule (3) et formule (4), dans lesquelles R1, R2, R3 et R4 sont tels que définis dans la description. L'invention concerne également des procédés de préparation desdits composés, des composés intermédiaires utiles pour préparer lesdits composés, des compositions et combinaisons pharmaceutiques comprenant lesdits composés et l'utilisation desdits composés pour produire des compositions pharmaceutiques destinées au traitement ou à la prophylaxie de maladies, en particulier le cancer, en monothérapie ou en combinaison avec d'autres principes actifs.
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WO2025190406A1 (fr) * 2024-03-15 2025-09-18 Insilico Medicine Ip Limited Combinaisons d'inhibiteurs de tead et leurs utilisations

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