WO2023186881A1 - P38 map kinase inhibitors for use in the treatment of colorectal cancer - Google Patents

P38 map kinase inhibitors for use in the treatment of colorectal cancer Download PDF

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Publication number
WO2023186881A1
WO2023186881A1 PCT/EP2023/057981 EP2023057981W WO2023186881A1 WO 2023186881 A1 WO2023186881 A1 WO 2023186881A1 EP 2023057981 W EP2023057981 W EP 2023057981W WO 2023186881 A1 WO2023186881 A1 WO 2023186881A1
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Prior art keywords
compound
pharmaceutically acceptable
solvate
acceptable salt
optical isomer
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PCT/EP2023/057981
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French (fr)
Inventor
Stefan Laufer
Daniel Dauch
Michael Forster
Vanessa HALLER
Jule HARBIG
Mark KUDOLO
Philipp NAHIDINO
Tatu Pantsar
Lars Zender
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Baden-Württemberg Stiftung Ggmbh
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Publication of WO2023186881A1 publication Critical patent/WO2023186881A1/en

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    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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 with nitro or nitroso radicals directly attached to ring carbon atoms
    • C07D333/44—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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 with nitro or nitroso radicals directly attached to ring carbon atoms attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the invention relates to p38 MAP kinase inhibitors of formula (I) as shown below for use in the treatment of colorectal cancer.
  • MAP mitogene activated protein
  • TRT drug-target residence time
  • p38a MAP kinase inhibitors have resulted in a longer target residence time (TRT) by developing the novel type l 1 Z> binding mode, J. Med. Chem. 2017, 60, 19, 8027- 8054 and doctoral thesis Heike Wentsch, Eberhard Karls Universitat Tubingen 2017 as well as doctoral thesis Niklas Walter, Eberhard Karls Universitat Tubingen 2017. Inspite of all efforts, no p38a MAP kinase inhibitor has yet been launched into the market. Even drugs with a very high TRT failed, such as BIRB 796 (doramapimod).
  • Colorectal cancer is currently the 3rd most commonly diagnosed malignancy and the 2nd leading cause of cancer related death worldwide. In 2020, more than 1.8 million new cases and more than 900,000 deaths were reported. Surgical resection or endoscopic excision of localized tumors and polyps represents an efficient therapeutic option for patients. However, around one quarter of colorectal cancers are diagnosed at an advanced stage with a metastatic disease and ⁇ 20% of cases develop metachronous metastases upon surgical removal of the primary tumor, Lancet 2019;394(10207):1467-80 doi 10.1016/S0140- 6736(19)32319-0.
  • Stage IV colorectal cancer patients that were treated with a combination of Oxaliplatin- and Irinotecan based chemotherapies and monoclonal antibodies directed against VEGFR or EGFR only show a median survival between 2 and 2.5 years, Signal Transduct Target Ther 2020;5(1):22 doi 10.1038/s41392-020-0116-z.
  • Checkpoint blocking antibodies like anti-PD1 or anti-CTLA4 show only a limited activity against colorectal cancer.
  • the problem underlying the invention was therefore to provide compounds which are effective in the treatment of colorectal cancer.
  • R 1 is -CONR 6 R 7 ;
  • R 2 is alkyl or halogen
  • R 3 is H or halogen;
  • R 4 is -L 2 -R 5 ;
  • L 2 is i— NR 6 -CO- -NR 6 -CO-NR 6 -, or i-CH 2 CO-;
  • R 5 is selected from phenyl, optionally substituted with 1 or 2 substituents independently selected from halogen, alkoxy and haloalkyl, an aromatic 5- or 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from N, S and O, and cycloalkyl;
  • R 6 is H or alkyl
  • R 7 is selected from H, alkyl, alkyl which is substituted with a non-aromatic 5- or 6- membered heterocyclic group having 1 or 2 heteroatoms independently selected from N and O, alkyl substituted with 1 or 2 hydroxy groups and alkyl substituted with hydroxyalkyl-NR 6 -; wherein here and in any following occasion ⁇ in the meanings of L 2 indicates the attachment to ring C.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or optical isomer thereof for use in treating colorectal cancer, wherein the compound has a Target Residence Time (TRT) of at least 500 s, preferably at least 900 s, and in particular at least 1000 s, as determined by a fluorescence polarization assay by directly measuring the ADP formed by p38 MAPK kinase reaction.
  • TRT Target Residence Time
  • R 2 and R 3 are halogen or both of them are halogen.
  • R 2 is halogen and R 3 is H or halogen.
  • the halogen in these embodiments is preferably F or Cl, in particular F.
  • L 2 is ⁇ — NR 6 -CO- or -NR 6 -CO-NR 6 -, in particular ⁇ — NR 6 -CO-.
  • R 5 is an aromatic 5- or 6-membered heterocyclic group, it is preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, in particular thienyl or furyl, and more particularly thienyl.
  • R 5 is selected from phenyl, thienyl or cycloalkyl, in particular cycloalkyl. Cycloalkyl is preferably cyclopropyl.
  • L 2 is ⁇ — NR 6 -CO- or -NR 6 -CO-NR 6 - and R 5 is selected from thienyl or cycloalkyl, preferably cyclopropyl.
  • L 2 is ⁇ — CH2CO and R 5 is phenyl.
  • R 6 is H and R 7 is H.
  • R 6 is H and R 7 is alkyl, in particular Ci-Cs-alkyl or alkyl, preferably C2-C4 alkyl, substituted with a saturated non-aromatic 5- or 6-membered heterocyclic group having 2 heteroatoms independently selected from N and O.
  • the non-aromatic 5- or 6- membered heterocyclic group is preferably N-morpholinyl or N-piperazinyl, in particular morpholino-N-C2-C4 alkyl, such as morpholino-N-ethyl.
  • R 6 is H and R 7 is alkyl, in particular Ci-Cs-alkyl.
  • R 6 is H and R 7 is alkyl substituted with 1 or 2 hydroxy groups, such as 2-hydroxyethyl or 2,3-dihydroxypropyl.
  • R 6 is H and R 7 is C2-C4 alkyl which is substituted with with a hydroxy-C2-Cs alkylamino group.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use in treating colorectal cancer, wherein the compound is selected from the compounds of table 1 :
  • the invention relates to a compound of formula (la) having the formula or a pharmaceutically acceptable salt, solvate or optical isomer thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (la) or a pharmaceutically acceptable salt, solvate or optical isomer thereof, as well as to said compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use in treating cancer, in particular colorectal cancer.
  • the pharmaceutically acceptable salts of the compounds of the invention are especially acid or base addition salts with pharmaceutically acceptable acids or bases.
  • suitable pharmaceutically acceptable organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid, Ci-C4-alkylsulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid.
  • organic and inorganic bases are alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as calcium or magnesium hydroxide, ammonium hydroxide, organic nitrogen bases such as dimethylamine, trimethylamine, ethanolamine, diethanolamine, triethanolamine, choline, 2-amino-2-hydroxymethyl-propane- 1 ,3-diol, meglumine, procaine etc.
  • the invention also includes any tautomeric, crystal and polymorphic form of said compounds and salts and mixtures thereof.
  • the invention also includes solvates such as hydrates.
  • the compounds contemplated may contain one or more chiral centers, and exist in different optically active forms such enantiomers and diastereomers.
  • the invention also refers to the pro-drugs of the compounds of the invention.
  • prodrug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process.
  • An example, without limitation, of a pro-drug would be a compound of the present invention in the form of an ester.
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • pro-drugs include, but are not limited to, compounds with carboxylic acid substituents wherein the free hydrogen is replaced by (Ci-C4)alkyl, (Ci- Ci2)alkanoyloxy-methyl, (C4-Cg)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyl-oxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)- ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3- phthalidyl, 4-crotono-lactonyl, gamma
  • exemplary pro-drugs release an alcohol of Formula (I) wherein the free hydrogen of the hydroxyl substituent (e.g., R group contains hydroxyl) is replaced by (Ci-C6)alkanoyloxy-methyl, 1-((Ci-Ce)alkanoyloxy)- ethyl, 1-methyl-1-((Ci-C6)alkanoyloxy)ethyl, (Ci-Ci2)alkoxy-carbonyloxy-methyl, N-(Ci-Ce)- alkoxy-carbonylaminomethyl, succinoyl, (Ci-Ce)alkanoyl, a-amino(Ci-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(O)(OH)2, - P(
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine, and most preferably fluorine.
  • Alkyl is a straight-chain or branched alkyl group which is preferably a Ci-Ce-alkyl group, i.e. an alkyl group having from 1 to 6 carbon atoms, and more preferably a Ci-C4-alkyl group.
  • Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl.
  • alkyl is likewise applicable to any group which includes an alkyl group.
  • Cycloalkyl is a cycloaliphatic radical which is preferably Cs-Cs-cycloalkyl, i.e. a cycloalkyl group having from 3 to 8 carbon atoms and, in particular, 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • An aromatic heterocyclic group is a 5- or 6-membered monocyclic aromatic group having 1 or 2 heteroatoms independently selected from O, N and S.
  • the aromatic heterocyclic group may be bound to the neighboring group via a carbon atom (C-bound) or via a nitrogen heteroatom (N-bound). Examples are:
  • C-bound, 6-membered, heteroaromatic rings pyridin-2-yl, pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-5-yl;
  • N-bound, 5-membered, heteroaromatic rings pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl.
  • a non-aromatic 5- or 6-membered heterocyclic group is a saturated group and includes in general 1 or 2 heteroatoms selected from O, N and S.
  • the heterocyclic radicals may be bound via a carbon atom (C-bound) or a nitrogen atom (N-bound).
  • Preferred heterocyclic groups comprise 1 nitrogen atom as ring member atom and optionally 1 further heteroatom as ring members, which are selected, independently of each other from O, S and N. Examples are:
  • C-bound, 4-membered rings such as azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl
  • C-bound, 5-membered rings such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl;
  • C-bound, 6-membered rings such as tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan- 4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl;
  • N-bound, 4-membered rings such as azetidin-1-yl
  • N-bound, 5-membered rings such as tetrahydropyrrol- 1-yl (pyrrolidin-1 -yl), tetrahydropyrazol-1-yl;
  • N-bound, 6-membered rings such as morpholin-1-yl, piperazin-1 -yl, piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl (piperazin-1 -yl), hexahydro-pyridazin-1-yl;
  • Any group containing heteroatoms may contain 1 , 2 or 3 heteroatoms which may be the same or different.
  • compositions which comprise at least one compound of the invention, optionally together with an inert carrier (e.g. a pharmaceutically acceptable excipient) and, where appropriate, other drugs.
  • inert carrier e.g. a pharmaceutically acceptable excipient
  • other drugs e.g. a pharmaceutically acceptable excipient
  • compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intraperitoneally, intravenously, intramuscularly or intranasally.
  • suitable pharmaceutical compositions are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar- coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, or suppositories, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in- water emulsions, suspensions, for example lotions, injection preparations and infusion preparations.
  • liposomes or microspheres are examples of suitable pharmaceutical compositions.
  • the compounds of the invention are optionally mixed or diluted with one or more carriers (excipients).
  • Carriers can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound. Suitable carriers (excipients) are listed in the specialist medicinal monographs.
  • the formulations can comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils.
  • auxiliary substances such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chel
  • a formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.
  • the compounds of the invention may also be suitable for combination with other therapeutic agents and therapeutic approaches.
  • the invention therefore further relates to a combination comprising a compound of the invention with one or more further therapeutic agents or therapeutic approaches.
  • Suitable agents and approaches for use in combination with the compounds of the invention include for example:
  • Antineoplastic agents and combinations thereof such as DNA alkylating agents (for example Cisplatin, Oxaliplatin, Carboplatin, Cyclophosphamide, nitrogen mustards like Ifosfamide, Bendamustine, Melphalan, Chlorambucil, Busulphan, Temozolamide and itrosoureas like Carmustine), antimetabolites (for example Gemcitabine and antifolates such as fluoropyrimidines like 5-Fluorouracil, Capecitabine and Tegafur, Raltitrexed, Methotrexate, Cytosine Arabinoside, and Hydroxyurea), anti-tumor antibiotics (for example anthracyclines like Bleomycin, Doxorubicin, Liposomal doxorubicin, Pirarubicin, Daunomycin, Valrubicin, Epirubicin, Idarubicin, Mitomycin-C, Dactinomycin, Amrubicin and Mithramycin), antimitotic agents (
  • Agents that inhibit protein-protein interactions for example Venetoclax, Navitoclax
  • proteasome for example Bortezomib, Carfilzomib, Ixazomib, Marizomib Delanzomib, Oprozomib
  • Agents that inhibit protein phosphorylation such as Abemaciclib, Acalabrutinib, Adavosertib, Afatinib, Aflibercept, Alectinib, Alisertib, Avapritinib, Axitinib, Berzosertib, Binimetinib, Bosutinib, Brigatinib, Cabozantinib, Capmatinib, Cetuximab, Ceritinib, Cobimetinib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Everolimus, Fedratinib, Fostamatinib, Gefitinib, Gilteritinib, Ibrutinib, Imatinib, Lapatinib, Larotrectinib, Lenvatinib, Lor
  • Agents that block angiogenesis such as compounds that inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody Bevacizumab and VEGF receptor tyrosine kinase inhibitors such as Vandetanib, Sorafenib, Regorafenib, Vatalanib, Sunitinib, Axitinib, Pazopanib and Cediranib, compounds such as those disclosed in W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds that work by other mechanisms (for example linomide, inhibitors of integrin czvB3 function and angiostatin), or inhibitors of angiopoietins and their receptors (Tie-I and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4).
  • vascular endothelial growth factor for example the anti-vascular
  • Immunotherapeutic approaches to increase the immunogenicity of patient tumor cells such as transfection with cytokines (for example interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor), approaches to decrease T-cell anergy or regulatory T-cell function, approaches that enhance T -cell responses to tumors, such as blocking antibodies to CTLA4 (for example ipilimumab and tremelimumab), B7HI, PD-I (for example BMS-936558 or AMP-514), PD-LI (for example MED14736) and agonist antibodies to CD137 and other immune checkpoint inhibitors, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, approaches using antibodies to tumor associated antigens, and antibodies that deplete target cell types (e.g.
  • cytokines for example interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin and anti-CD54 antibody Campath), approaches using anti-idiotypic antibodies, approaches that enhance Natural Killer cell function, and approaches that utilize antibodytoxin conjugates (e.g.
  • immunotoxins such as Moxetumumab Pasudotox, agonists of toll-like receptor 7 or toll-like receptor 9, cellular immunotherapies for example CAR-T cell therapy, NK cell therapy, CAR-NK cell therapy, tumor-infiltrating lymphocytes, recombinant T cells, vaccinations for example anti-tumor peptide vaccines, mRNA vaccines and dendritic cell vaccines.
  • the combination therapies of the invention may be administered adjunctively.
  • adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as addon therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of the invention and at least one further therapeutic agent are within the scope of the current invention.
  • a patient is typically stabilized on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component.
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
  • the invention also relates to the use of a compound of the invention for treating colorectal cancer. In another embodiment the invention also relates to the use of a compound of the invention for preparing apharmaceutical composition for treating colorectal cancer.
  • the invention also relates to a method of treating colorectal cancer which comprises administering an effective amount of a compound of the invention or a composition as defined above to a subject in need thereof.
  • the compounds of the invention are administered in a dosage of 5 to 50 mg/kg, in particular 10 to 30 mg/kg, for example 20 mg/kg, of the subject being treated.
  • the compounds can be administered once or several times a day.
  • the compounds are administered up to at least 10 weeks.
  • Preparative column chromatography was carried out with an Interchim Puri Flash 430 or Puri Flash XS420 automated flash chromatography system and were unless otherwise stated performed on normal phase silica gel (Grace Davison Davisil LC60A 20-45 micron or Merck Geduran Si60 63-200 micron).
  • MS Mass spectra were obtained using a Advion TLC-MS interface with electron spray ionization (ESI) in positive and/or negative mode. Instrument settings as follows: ESI voltage 3,50 kV, capillary voltage 187 V, source voltage 44 V, capillary temperature 250 °C, desolvation gas temperature 250 °C, gas flow 5 l/min nitrogen.
  • HPLC High Performance Liquid Chromatography: Purity of final compounds was determined using an Agilent 1100 Series LC with Phenomenex Luna C8 columns (150 x 4.6 mm, 5 pm) and detection was performed with a UV DAD at 254 nm and 230 nm wavelength. Elution was carried out with the following gradient: 0.01 M KH2PO4, pH 2.30 (solvent A), MeOH (solvent B), 40 % B to 85 % B in 8 min, 85 % B for 5 min, 85 % to 40 % B in 1 min, 40 % B for 2 min, stop time 16 min, flow 1 .5 ml/min. All final compounds showed a purity above 95% in the means of area percent at the two different wavelengths.
  • the compounds of the invention can be prepared by the synthetic procedures described in J Med Chem 2013, 56(1), 241-253, J. Med. Chem. 2017, 60, 19, 8027-8054, doctoral thesis Heike Wentsch, Eberhard Karls Universitat Tubingen 2017 and doctoral thesis Niklas Walter, Eberhard Karls Universitat Tubingen 2017 or analogous procedures.
  • As examplary procedures given in these publications the synthesis of compounds 1 and 4 (see table 1) is described in detail as follows:
  • Step 1 Dimethyl (E)-4-(3-chlorostyryl)isophthalate (S1).
  • Tetrabutylammoniumchloride (336 mg, 1.21 mmol, 0.1 eq) by heating under vacuum. Under argon atmosphere were added dimethyl 4- bromoisophthalate (3.31 g, 12.1 mmol, 1.0 eq), /V,/V-dicyclohexyl methylamine (3.54 g, 18.15 mmol, 1.5 eq), 3-chloro styrene (1.84 g, 13.31 mmol, 1.1 eq) and 20 mL dry dioxane.
  • Step 2 Dimethyl 4-(3-chlorophenethyl)isophthalate (S2).
  • the catalyst was removed by filtration over a bed of celite and was thoroughly washed with EtOAc. To remove the aliphatic inpurities of the previous step the filtrate was washed successively with 2 M KHSO4 (3x30 mL), water (30 mL), sat. NaHCOs (30 mL) and brine (30 ml). The organic phase was dried over Na2SO4, concentrated under reduced pressure and coevaporated several times with MeOH and DCM to remove traces of water. Yield: 3.07 g (87 %) as a clear viscous oil which crystallizes upon standing.
  • Step 3 Methyl 8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carboxylate (S3).
  • Step 4 8-Chloro-N-methyl-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide (S4).
  • Step 5.2 N-(5-Amino-2-fluorophenyl)cyclopropanecarboxamide (S5.2).
  • Step 6 8-((3-(Cyclopropanecarboxamido)-4-fluorophenyl)amino)-N-methyl-5-oxo-10,11- dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide (1)
  • Step 1.1 1-Cyclopropyl-3-(2-fluoro-5-nitrophenyl)urea (4.1).
  • Step 1.2 1-(5-Amino-2-fluorophenyl)-3-cyclopropylurea (4.2).
  • Step 3 8-((3-(3-Cyclopropylureido)-4-fluorophenyl)amino)-N-methyl-5-oxo-10,11-dihydro-5H- dibenzo[a,d][7]annulene-3-carboxamide 4.
  • Ketone derivatives were accessible via one of the above depicted synthetic routes starting from the 3-nitro phenylacetic acid derivatives or 3-nitro benzoic acid derivatives using either an activation to the acid chloride and a subsequent Friedel-Crafts acylation or the transformation to the corresponding Weinreb amide and subsequent reaction with organometallic reagents.
  • the aniline for Buchwald-Hartwig was then obtained by reduction of the nitro group using state of the art reductive methods like tin(ll)chloride in ethanol or elemental hydrogen in combination with palladium on charcoal.
  • Murine colon organoids were isolated from genetically modified mice as described before (Sato et al., Nature 459, 262-265, 2009). The tissue fragments were washed with ice-cold PBS (phosphate buffered saline), transferred to 2 mM EDTA chelating buffer and incubated for 30 mins at 4°C on an orbital shaker. Subsequently, the supernatant was removed and the tissue fragments were resuspended in medium containing 10% FCS (Fetal Calf Serum, table 3).
  • PBS phosphate buffered saline
  • FCS Fetal Calf Serum
  • the supernatant containing crypts were centrifuged at 150 g for 5 mins and colonic crypts were embedded in 50 pl domes of Growth Factor Reduced (GFR) MatrigelTM (Corning) in 24-well plates. Following polymerization for 10 mins at 37°C, MatrigelTM (Corning) domes were overlaid with murine colon medium (table 3), supplemented with 10.5 pM Y-27632 dihydrochloride (Invitrogen) for the three days.
  • GFR Growth Factor Reduced
  • ras G12D/+ x /Wyc OE x Trp53' 1 ' organoids were generated by a cre-mediated recombination of loxp sequences in Kras LSL x Trp53 m colonoids (Lipofectamine-mediated transfection of ere) and transposonbased integration of ectopically expressed, oncogenic Myc.
  • a constitutive active Braf mutation Ape 1 ' x Trp53' !
  • tumor digestion medium supplemented with 100 pg/ml DNasel and 10.5 pM Y-27632 dihydrochloride (Invitrogen). Tumor digestion was performed at 37°C on a shaker with 75 rpm rotation. The digestion was stopped by adding medium containing 10% FCS (table 3). The mixture was centrifuged for 5 mins at 300 g. Red blood cells were removed by incubating the pellet with ACK lysing buffer (Thermo Fisher) for 5 mins at RT.
  • ACK lysing buffer Thermo Fisher
  • the pellet was resuspended in medium and, after final centrifugation, the cells were adjusted to roughly 1000 cells in 50 pl Growth Factor Reduced (GFR) MatrigelTM (Corning) and plated in pre-warmed 24-well plates.
  • GFR Growth Factor Reduced
  • the ascites material was pelleted by centrifugation at 300 g and washed several times with ice-cold PBS before embedding the cells in domes of MatrigelTM (Corning).
  • the human CRC medium was supplemented with 10.5 pM Y- 27632 dihydrochloride (Invitrogen). The medium was refreshed every two to three days.
  • Confluent organoids were split in splitting medium (Table 3) by mechanical dissociation into smaller cell clumps and replated in MatrigelTM (Corning) domes. Depending on the organoid culture the splitting ratio was 1 :2 to 1 :6 (once or twice per week).
  • Nicotinamide I M 10 mM Sigma Aldrich
  • Nicotinamide I M 10 mM Sigma Aldrich
  • Nicotinamide I M 10 mM Sigma Aldrich
  • organoids were mechanically dissociated and digested using TrypLE supplemented with 100 pg/ml DNasel and 10.5 pM Y-27632 dihydrochloride (Invitrogen) at 37°C. 1000 single cells per well were plated in all-white 96 well plates (Greiner) in culture medium (table 3) containing 10% Growth Factor Reduced (GFR) MatrigelTM (Corning). The treatment with different p38a inhibitors or corresponding amounts of DMSO was started after 24 hours. To analyze the treatment response, ATP level were measured 96 hours after treatment start using Cell-Titer Glo2.0 reagent (Promega) according to the manufacturers’ instructions. Results were normalized to vehicle (DMSO). Each assay was performed in three technical and biological replicates. The results are contained in the following table 4.
  • the flourescence polarization assay protocol for target residence time determination was recently also published by our group from Pantsar er al., Nature Communications 13, article number: 569 (2022); https://doi.org/10.1038/s41467-022-28164-4.
  • the assay adapted a commercially available fluorescence polarization assay kit (Transcreener ADP, BellBrook Labs).
  • the compounds were preincubated in 50 mM Tris [pH 7.5], 1 mM dithiothreitol, 10 mM MgCI2, 10 mM p-glycerophosphate, and 0.1 mM NasVC at a concentration of 20-fold IC50 with p38 MAPK (12.4 pg/mL) at room temperature for 1 h to enable the formation of an enzyme- inhibitor-complex. Then the formed complex was “jump diluted” 1 :100 (0.5 pL were diluted into 49.5 pL) in a 96 half area well plate with ATF2 (82 pM) as kinase substrate, ATP (40 pM) and ADP Kinase assay detection reagents.
  • the plate was immediately measured every 3 min for 4 h. Fluorescence polarization was detected using the plate reader VictorNivo by PerkinElmer. The assay was performed in triplicates. The obtained data were analyzed via integrated rate equation in Graphpad Prism version 7.0.0. for Windows (GraphPad Software, San Diego, CA, USA). The residence time in seconds was subsequently calculated by the reciprocal value of the rate constant of the dissociation of the drug-target-complex (k O ff). The results are provided in table 4.
  • mice In approved animal experiments tumor size during treatment was determined in a colon cancer model. Further, tumor development and survival of the mice was determined in a colon cancer - liver metastases model. All mice were housed and maintained under pathogen free conditions in accordance with the institutional guidelines of the University Hospital Tuebingen. Subcutaneous injection or splenic seeding of organoids was performed in 8 to 10 weeks old C57BL/6 mice. The corresponding organoids were dissociated into single cells, washed twice with PBS and filtered through a 100 pm mesh. 1x10 5 cells were injected into the left and right flanks or the spleen capsule of mice in a 1 :1 mixture of sterile PBS and growth factor reduced (GFR) MatrigelTM.
  • GFR growth factor reduced
  • mice were anaesthetized using ketamine (100 mg/kg i.p.) and xylazin (10 mg/kg i.p.) in NaCI and a small laparotomy below the thorax was performed.
  • ketamine 100 mg/kg i.p.
  • xylazin 10 mg/kg i.p.
  • the injection site was washed with pre-warmed H2O.
  • the mice were treated with the analgesics Carprofen und Metamizol.
  • In vivo treatment studies were performed in randomized groups with 20 mg/kg body weight of compound every day. The drugs were administered P.O.

Abstract

The invention relates to p38 MAP kinase inhibitors of formula (I) as shown in the description for use in the treatment of colorectal cancer. Further, the invention relates to p38 MAP kinase inhibitors specifically mentioned in the description, and a pharmaceutical composition comprising said inhibitors.

Description

p38 MAP Kinase Inhibitors for Use in the Treatment of Colorectal Cancer
The invention relates to p38 MAP kinase inhibitors of formula (I) as shown below for use in the treatment of colorectal cancer.
The role of p38a MAP kinase, which is part of the mitogene activated protein (MAP) kinase family, in the human body and its link to some severe diseases such as rheumatoid arthritis and psoriasis has already been investigated, Clin. Dev. Immunol. 2013, 569751 , J Med Chem 2013, 56(1), 241-253 and Ann. Rheum. Dis. 2008, 67, 909 - 916. Additional useful compounds are, for example, disclosed in WO 2006120010 and WO 2010040843. More recently, p38 MAP kinase was also associated with neurodegenerative diseases, such as Alzheimer, Parkinson, and atherosclerotic diseases. The optimization of the drug-target residence time (TRT) has been in the focus of drug development for quite some time. Optimization of p38a MAP kinase inhibitors has resulted in a longer target residence time (TRT) by developing the novel type l1Z> binding mode, J. Med. Chem. 2017, 60, 19, 8027- 8054 and doctoral thesis Heike Wentsch, Eberhard Karls Universitat Tubingen 2017 as well as doctoral thesis Niklas Walter, Eberhard Karls Universitat Tubingen 2017. Inspite of all efforts, no p38a MAP kinase inhibitor has yet been launched into the market. Even drugs with a very high TRT failed, such as BIRB 796 (doramapimod).
Colorectal cancer (CRC) is currently the 3rd most commonly diagnosed malignancy and the 2nd leading cause of cancer related death worldwide. In 2020, more than 1.8 million new cases and more than 900,000 deaths were reported. Surgical resection or endoscopic excision of localized tumors and polyps represents an efficient therapeutic option for patients. However, around one quarter of colorectal cancers are diagnosed at an advanced stage with a metastatic disease and ~ 20% of cases develop metachronous metastases upon surgical removal of the primary tumor, Lancet 2019;394(10207):1467-80 doi 10.1016/S0140- 6736(19)32319-0.
The therapeutic benefit for patients with advanced und metastatic tumors remains limited. Stage IV colorectal cancer patients that were treated with a combination of Oxaliplatin- and Irinotecan based chemotherapies and monoclonal antibodies directed against VEGFR or EGFR only show a median survival between 2 and 2.5 years, Signal Transduct Target Ther 2020;5(1):22 doi 10.1038/s41392-020-0116-z. Checkpoint blocking antibodies like anti-PD1 or anti-CTLA4 show only a limited activity against colorectal cancer. Only microsatellite instable tumors (which only account for ~ 3% of all colorectal tumors) eventually respond to checkpoint blocking antibodies, Therap Adv Gastroenterol 2020; 13: 1756284820917527 doi 10.1177/1756284820917527. Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer, Nature Cancer 2021 doi 10.1038/s43018-021 - 00247-z.
Overall, novel therapeutic options for patients suffering from advanced colorectal cancer are urgently needed. Due to its role in inflammation, autophagy, oncogenic signaling pathways and the tumor microenvironment, a potential role of p38a in colorectal cancer development was suggested, World J Gastroenterol 2014;20(29):9744-58 doi 10.3748/wjg.v20.i29.9744 and Cancer Letters 265 (2008), 16-26. However, treatment studies in colorectal cancer models with established p38a inhibitors did not lead to an efficient therapeutic strategy that exploit p38a targeting for the treatment of colorectal cancer patients. Although several clinical trials have been conducted to analyze the therapeutic potential of p38a inhibition in different tumor entities, p38a inhibitors have not yet been successful for cancer therapies.
The problem underlying the invention was therefore to provide compounds which are effective in the treatment of colorectal cancer.
Surprisingly, it has now been found that the compounds as defined below are effective in treating colorectal cancer (cancer of the colon and/or rectum). Thus, the problem underlying the invention was solved, according to one embodiment, by the provision of the compounds of formula (I)
Figure imgf000003_0001
or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use in treating colorectal cancer, wherein the variables in formula I have the following meanings:
R1 is -CONR6R7;
R2 is alkyl or halogen;
R3 is H or halogen; R4 is -L2-R5;
L2 is i— NR6-CO- -NR6-CO-NR6-, or i-CH2CO-;
R5 is selected from phenyl, optionally substituted with 1 or 2 substituents independently selected from halogen, alkoxy and haloalkyl, an aromatic 5- or 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from N, S and O, and cycloalkyl;
R6 is H or alkyl;
R7 is selected from H, alkyl, alkyl which is substituted with a non-aromatic 5- or 6- membered heterocyclic group having 1 or 2 heteroatoms independently selected from N and O, alkyl substituted with 1 or 2 hydroxy groups and alkyl substituted with hydroxyalkyl-NR6-; wherein here and in any following occasion ■ in the meanings of L2 indicates the attachment to ring C.
The following embodiments relate to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or optical isomer thereof for use in treating colorectal cancer:
In one embodiment, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or optical isomer thereof for use in treating colorectal cancer, wherein the compound has a Target Residence Time (TRT) of at least 500 s, preferably at least 900 s, and in particular at least 1000 s, as determined by a fluorescence polarization assay by directly measuring the ADP formed by p38 MAPK kinase reaction.
In another embodiment, at least one of R2 and R3 is halogen or both of them are halogen. In another embodiment, R2 is halogen and R3 is H or halogen. The halogen in these embodiments is preferably F or Cl, in particular F.
In another embodiment, L2 is ■— NR6-CO- or -NR6-CO-NR6-, in particular ■— NR6-CO-.
In another embodiment, if R5 is an aromatic 5- or 6-membered heterocyclic group, it is preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, in particular thienyl or furyl, and more particularly thienyl.
In another embodiment, R5 is selected from phenyl, thienyl or cycloalkyl, in particular cycloalkyl. Cycloalkyl is preferably cyclopropyl. In another embodiment, L2 is ■— NR6-CO- or -NR6-CO-NR6- and R5 is selected from thienyl or cycloalkyl, preferably cyclopropyl. In another embodiment, L2 is ■— CH2CO and R5 is phenyl.
In another embodiment, R6 is H and R7 is H.
In another embodiment, R6 is H and R7 is alkyl, in particular Ci-Cs-alkyl or alkyl, preferably C2-C4 alkyl, substituted with a saturated non-aromatic 5- or 6-membered heterocyclic group having 2 heteroatoms independently selected from N and O. The non-aromatic 5- or 6- membered heterocyclic group is preferably N-morpholinyl or N-piperazinyl, in particular morpholino-N-C2-C4 alkyl, such as morpholino-N-ethyl.
In another embodiment, R6 is H and R7 is alkyl, in particular Ci-Cs-alkyl.
In another embodiment, R6 is H and R7 is alkyl substituted with 1 or 2 hydroxy groups, such as 2-hydroxyethyl or 2,3-dihydroxypropyl.
In another embodiment, R6 is H and R7 is C2-C4 alkyl which is substituted with with a hydroxy-C2-Cs alkylamino group.
In another embodiment, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use in treating colorectal cancer, wherein the compound is selected from the compounds of table 1 :
Table 1
Figure imgf000005_0001
Figure imgf000006_0002
Compounds 1 and 4 are preferred. A part of the compounds of formula (I) including their preparation is described in J Med Chem 2013, 56(1), 241-253, J. Med. Chem. 2017, 60, 19, 8027-8054 and doctoral thesis Heike Wentsch, Eberhard Karls Universitat Tubingen 2017 and doctoral thesis Niklas Walter, Eberhard Karls Universitat Tubingen 2017. These publications are incorporated herein by reference in their entirety.
In another aspect, the invention relates to a compound of formula (la) having the formula
Figure imgf000006_0001
or a pharmaceutically acceptable salt, solvate or optical isomer thereof.
Further, the invention also relates to a pharmaceutical composition comprising the compound of formula (la) or a pharmaceutically acceptable salt, solvate or optical isomer thereof, as well as to said compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use in treating cancer, in particular colorectal cancer.
The term “compounds of the invention” as used herein includes the compounds of formula (I) and (la) as well as the pharmaceutically acceptable salts, solvates or optical isomers thereof.
The pharmaceutically acceptable salts of the compounds of the invention are especially acid or base addition salts with pharmaceutically acceptable acids or bases. Examples of suitable pharmaceutically acceptable organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid, Ci-C4-alkylsulfonic acids, such as methanesulfonic acid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid. Other utilizable acids are described, e.g., in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff. , Birkhauser Verlag, Basel and Stuttgart, 1966. Examples of suitable pharmaceutically acceptable organic and inorganic bases are alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as calcium or magnesium hydroxide, ammonium hydroxide, organic nitrogen bases such as dimethylamine, trimethylamine, ethanolamine, diethanolamine, triethanolamine, choline, 2-amino-2-hydroxymethyl-propane- 1 ,3-diol, meglumine, procaine etc. L-arginine, L-lysine, ethylenediamine, or hyd roxyethy I py rrol id i ne .
The invention also includes any tautomeric, crystal and polymorphic form of said compounds and salts and mixtures thereof.
The invention also includes solvates such as hydrates.
The compounds contemplated may contain one or more chiral centers, and exist in different optically active forms such enantiomers and diastereomers.
The invention also refers to the pro-drugs of the compounds of the invention. The term "prodrug" refers to an agent which is converted into the parent drug in vivo by some physiological chemical process. An example, without limitation, of a pro-drug would be a compound of the present invention in the form of an ester.
Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue. Exemplary pro-drugs include, but are not limited to, compounds with carboxylic acid substituents wherein the free hydrogen is replaced by (Ci-C4)alkyl, (Ci- Ci2)alkanoyloxy-methyl, (C4-Cg)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyl-oxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)- ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3- phthalidyl, 4-crotono-lactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl (such as p-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di(Ci-C2)-alkylcarbamoyl-(Ci- C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl. Other exemplary pro-drugs release an alcohol of Formula (I) wherein the free hydrogen of the hydroxyl substituent (e.g., R group contains hydroxyl) is replaced by (Ci-C6)alkanoyloxy-methyl, 1-((Ci-Ce)alkanoyloxy)- ethyl, 1-methyl-1-((Ci-C6)alkanoyloxy)ethyl, (Ci-Ci2)alkoxy-carbonyloxy-methyl, N-(Ci-Ce)- alkoxy-carbonylaminomethyl, succinoyl, (Ci-Ce)alkanoyl, a-amino(Ci-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(O)(OH)2, - P(O)(O(Ci-Ce)alkyl)2 or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate).
The organic moieties mentioned in the above definitions of the variables are collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group. As used herein the terms have the following meanings:
The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine or chlorine, and most preferably fluorine.
Alkyl is a straight-chain or branched alkyl group which is preferably a Ci-Ce-alkyl group, i.e. an alkyl group having from 1 to 6 carbon atoms, and more preferably a Ci-C4-alkyl group. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl.
The definition of alkyl is likewise applicable to any group which includes an alkyl group.
Cycloalkyl is a cycloaliphatic radical which is preferably Cs-Cs-cycloalkyl, i.e. a cycloalkyl group having from 3 to 8 carbon atoms and, in particular, 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
An aromatic heterocyclic group is a 5- or 6-membered monocyclic aromatic group having 1 or 2 heteroatoms independently selected from O, N and S. The aromatic heterocyclic group may be bound to the neighboring group via a carbon atom (C-bound) or via a nitrogen heteroatom (N-bound). Examples are:
C-bound, 5-membered, heterocyclic groups:
2-furyl, 3-furyl, 5-furyl, 2-thienyl, 3-thienyl, 5-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrrol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3- yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl;
C-bound, 6-membered, heteroaromatic rings: pyridin-2-yl, pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-5-yl;
N-bound, 5-membered, heteroaromatic rings: pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl.
A non-aromatic 5- or 6-membered heterocyclic group is a saturated group and includes in general 1 or 2 heteroatoms selected from O, N and S. The heterocyclic radicals may be bound via a carbon atom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclic groups comprise 1 nitrogen atom as ring member atom and optionally 1 further heteroatom as ring members, which are selected, independently of each other from O, S and N. Examples are:
C-bound, 4-membered rings, such as azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl; C-bound, 5-membered rings, such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl;
C-bound, 6-membered rings, such as tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan- 4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl;
N-bound, 4-membered rings, such as azetidin-1-yl;
N-bound, 5-membered rings, such as tetrahydropyrrol- 1-yl (pyrrolidin-1 -yl), tetrahydropyrazol-1-yl;
N-bound, 6-membered rings, such as morpholin-1-yl, piperazin-1 -yl, piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl (piperazin-1 -yl), hexahydro-pyridazin-1-yl;
Any group containing heteroatoms may contain 1 , 2 or 3 heteroatoms which may be the same or different.
The compounds of the invention are customarily administered in the form of pharmaceutical compositions which comprise at least one compound of the invention, optionally together with an inert carrier (e.g. a pharmaceutically acceptable excipient) and, where appropriate, other drugs. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intraperitoneally, intravenously, intramuscularly or intranasally.
Examples of suitable pharmaceutical compositions are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar- coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, or suppositories, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in- water emulsions, suspensions, for example lotions, injection preparations and infusion preparations. In addition, it is also possible to use liposomes or microspheres.
When producing the compositions, the compounds of the invention are optionally mixed or diluted with one or more carriers (excipients). Carriers (excipients) can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound. Suitable carriers (excipients) are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable auxiliary substances, such as wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.
The compounds of the invention may also be suitable for combination with other therapeutic agents and therapeutic approaches. The invention therefore further relates to a combination comprising a compound of the invention with one or more further therapeutic agents or therapeutic approaches. Suitable agents and approaches for use in combination with the compounds of the invention include for example:
Antineoplastic agents and combinations thereof, such as DNA alkylating agents (for example Cisplatin, Oxaliplatin, Carboplatin, Cyclophosphamide, nitrogen mustards like Ifosfamide, Bendamustine, Melphalan, Chlorambucil, Busulphan, Temozolamide and itrosoureas like Carmustine), antimetabolites (for example Gemcitabine and antifolates such as fluoropyrimidines like 5-Fluorouracil, Capecitabine and Tegafur, Raltitrexed, Methotrexate, Cytosine Arabinoside, and Hydroxyurea), anti-tumor antibiotics (for example anthracyclines like Bleomycin, Doxorubicin, Liposomal doxorubicin, Pirarubicin, Daunomycin, Valrubicin, Epirubicin, Idarubicin, Mitomycin-C, Dactinomycin, Amrubicin and Mithramycin), antimitotic agents (for example vinca alkaloids like Vincristine, Vinblastine, Vindesine and Vinorelbine and taxoids like Taxol and Taxotere and polokinase inhibitors) and topoisomerase inhibitors (for example epipodophyllotoxins like Etoposide and Teniposide, Amsacrine, Irinotecan, Topotecan and Camptothecin), inhibitors of DNA repair mechanisms such as CHK kinase inhibitors (for example Prexasertib), DNA-dependent protein kinase inhibitors (such as Omipalisib, AZD7648), inhibitors of poly (ADP-ribose) polymerase (PARP) (for example Olaparib), Hsp90 inhibitors (such as Tanespimycin and Retaspimycin), inhibitors of ATR kinase (such as AZD6738, Berzosertib, M1774), ATM kinase (such as AZD0156, AZD1390) and WEE1 kinase (such as Adavosertib, PD0166285).
Agents that inhibit protein-protein interactions (for example Venetoclax, Navitoclax) or the proteasome (for example Bortezomib, Carfilzomib, Ixazomib, Marizomib Delanzomib, Oprozomib)
Agents that inhibit protein phosphorylation (such as Abemaciclib, Acalabrutinib, Adavosertib, Afatinib, Aflibercept, Alectinib, Alisertib, Avapritinib, Axitinib, Berzosertib, Binimetinib, Bosutinib, Brigatinib, Cabozantinib, Capmatinib, Cetuximab, Ceritinib, Cobimetinib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Encorafenib, Entrectinib, Erdafitinib, Erlotinib, Everolimus, Fedratinib, Fostamatinib, Gefitinib, Gilteritinib, Ibrutinib, Imatinib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, LY3295668, Midostaurin, Neratinib, Nilotinib, Nintedanib, Osimertinib, Palbociclib, Panitumumab, Pazopanib, PD0166285, Pemigatinib, Pexidartinib, Ponatinib, Pralsetinib, Prexasertib, Regorafenib, Ribociclib, Ripretinib, Ruxolitinib, Selpercatinib, Selumetinib, Sirolimus, Sorafenib, Sunitinib, Temsirolimus, Trametinib, Tucatinib, Upadacitinib, Vandetanib, Vemurafenib, Zanubrutinib, Zunsemetinib),
Agents that block angiogenesis, such as compounds that inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody Bevacizumab and VEGF receptor tyrosine kinase inhibitors such as Vandetanib, Sorafenib, Regorafenib, Vatalanib, Sunitinib, Axitinib, Pazopanib and Cediranib, compounds such as those disclosed in W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds that work by other mechanisms (for example linomide, inhibitors of integrin czvB3 function and angiostatin), or inhibitors of angiopoietins and their receptors (Tie-I and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4).
Immunotherapeutic approaches to increase the immunogenicity of patient tumor cells (including ex-vivo and in-vivo approaches) such as transfection with cytokines (for example interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor), approaches to decrease T-cell anergy or regulatory T-cell function, approaches that enhance T -cell responses to tumors, such as blocking antibodies to CTLA4 (for example ipilimumab and tremelimumab), B7HI, PD-I (for example BMS-936558 or AMP-514), PD-LI (for example MED14736) and agonist antibodies to CD137 and other immune checkpoint inhibitors, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, approaches using antibodies to tumor associated antigens, and antibodies that deplete target cell types (e.g. unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin and anti-CD54 antibody Campath), approaches using anti-idiotypic antibodies, approaches that enhance Natural Killer cell function, and approaches that utilize antibodytoxin conjugates (e.g. antiCD33 antibody Mylotarg), immunotoxins such as Moxetumumab Pasudotox, agonists of toll-like receptor 7 or toll-like receptor 9, cellular immunotherapies for example CAR-T cell therapy, NK cell therapy, CAR-NK cell therapy, tumor-infiltrating lymphocytes, recombinant T cells, vaccinations for example anti-tumor peptide vaccines, mRNA vaccines and dendritic cell vaccines.
Agents that enhance the efficacy of drugs, such as leucovorin.
The combination therapies of the invention may be administered adjunctively. By adjunctive administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as addon therapeutic administration. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of the invention and at least one further therapeutic agent are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilized on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component. The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.
In an embodiment the invention also relates to the use of a compound of the invention for treating colorectal cancer. In another embodiment the invention also relates to the use of a compound of the invention for preparing apharmaceutical composition for treating colorectal cancer.
In an embodiment the invention also relates to a method of treating colorectal cancer which comprises administering an effective amount of a compound of the invention or a composition as defined above to a subject in need thereof. In an embodiment, the compounds of the invention are administered in a dosage of 5 to 50 mg/kg, in particular 10 to 30 mg/kg, for example 20 mg/kg, of the subject being treated. The compounds can be administered once or several times a day. The compounds are administered up to at least 10 weeks.
SYNTHETIC METHODS
GENERAL:
Chemical synthesis of the compounds of the invention was carried out using commonly applied techniques and general procedures. All starting materials and reagents were of commercial quality and were used without further purification unless otherwise stated. Microwave-assisted reactions were performed in a CEM Discover 908005 System in pressure-sealed glass tubes. Thin layer chromatography (TLC) was carried out on Merck 60 F254 and Macherey Nagel ALUGRAM® Xtra SIL G/UV254 silica plates and were visualized under UV light (254 nm and 366 nm) or developed with an appropriate staining reagent. Preparative column chromatography was carried out with an Interchim Puri Flash 430 or Puri Flash XS420 automated flash chromatography system and were unless otherwise stated performed on normal phase silica gel (Grace Davison Davisil LC60A 20-45 micron or Merck Geduran Si60 63-200 micron).
Analytical Methods and Instrumentation:
NMR: 1H and 13C spectra were recorded on Bruker Avance 200, Bruker Avance 400, Bruker A vance III HD 400 or Bruker Avance III HDX 600 instruments. The samples were dissolved in deuterated solvents and chemical shifts are given in relation to tetramethylsilane (TMS). Spectra were calibrated using the residual peaks of the used solvent.
MS: Mass spectra were obtained using a Advion TLC-MS interface with electron spray ionization (ESI) in positive and/or negative mode. Instrument settings as follows: ESI voltage 3,50 kV, capillary voltage 187 V, source voltage 44 V, capillary temperature 250 °C, desolvation gas temperature 250 °C, gas flow 5 l/min nitrogen.
HRMS: High resolution mass spectra were measured by the mass spectrometry department, Institute of Organic Chemistry, Eberhard Karls University Tuebingen on a Bruker maXis 4G ESI-TOF from Daltonik/Bremen. The instrument was run in ESI+ Mode, settings were as follows: nebulizer gas 1.2 bar, gas flow, 6.0 l/min, source temperature 200 °C, capillary voltage +4500 V, end plate offset -500 V. m/z range from 80 to 1000 m/z.
HPLC (High Performance Liquid Chromatography): Purity of final compounds was determined using an Agilent 1100 Series LC with Phenomenex Luna C8 columns (150 x 4.6 mm, 5 pm) and detection was performed with a UV DAD at 254 nm and 230 nm wavelength. Elution was carried out with the following gradient: 0.01 M KH2PO4, pH 2.30 (solvent A), MeOH (solvent B), 40 % B to 85 % B in 8 min, 85 % B for 5 min, 85 % to 40 % B in 1 min, 40 % B for 2 min, stop time 16 min, flow 1 .5 ml/min. All final compounds showed a purity above 95% in the means of area percent at the two different wavelengths.
Abbreviations:
BrettPhosPdG3 [(2-di-Cyclohexylphosphino-3,6-dimethoxy-2',4',6'- tri isopropyl- 1 , 1 biphenyl)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll)-methanesulfonate
DCM dichloromethane
DIPEA diisopropylethylamine DMAP dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide
EA, EtOAc ethylacetate iPrOH isopropanol mCPBA m-chloroperoxybenzoic acid MeCN acetonitrile
MeOH methanol
Pd(dppf)Ch (1 ,1 '-Bis(diphenylphosphino)ferrocene)palladium(l I) dichloride
TBAF tetrabutylammonium fluoride
TBTLI 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate
THF tetrahydrofurane
TLC thin layer chromatography
TsCI tosylchloride tBuOH tert-butanol
Experimental Procedures:
The compounds of the invention can be prepared by the synthetic procedures described in J Med Chem 2013, 56(1), 241-253, J. Med. Chem. 2017, 60, 19, 8027-8054, doctoral thesis Heike Wentsch, Eberhard Karls Universitat Tubingen 2017 and doctoral thesis Niklas Walter, Eberhard Karls Universitat Tubingen 2017 or analogous procedures. As examplary procedures given in these publications the synthesis of compounds 1 and 4 (see table 1) is described in detail as follows:
Compound No. 1 :
8-((3-(Cyclopropanecarboxamido)-4-fluorophenyl)amino)-N-methyl-5-oxo-10,11- dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide
Figure imgf000016_0001
Step 1 : Dimethyl (E)-4-(3-chlorostyryl)isophthalate (S1).
Figure imgf000016_0002
In an oven dried schlenk tube was dried Tetrabutylammoniumchloride (336 mg, 1.21 mmol, 0.1 eq) by heating under vacuum. Under argon atmosphere were added dimethyl 4- bromoisophthalate (3.31 g, 12.1 mmol, 1.0 eq), /V,/V-dicyclohexyl methylamine (3.54 g, 18.15 mmol, 1.5 eq), 3-chloro styrene (1.84 g, 13.31 mmol, 1.1 eq) and 20 mL dry dioxane. The mixture was degassed carefully with three vacuum/argon cycles before tri-tert- butylphosphonium tetrafluoroborate (140 mg, 484 pmol, 0.04 eq) and tris(dibenzylideneacetone)dipalladium(0) (111 mg, 121 pmol, 0.01 eq) were transferred with additional 5 mL of dry dioxane to the reaction vessel. The mixture was degassed again and was then heated up to 70 °C oil bath temperature. Reaction control via HPLC indicated complete conversion after six hours of stirring. The resultant green suspension was poured on 1M aqueous KHSO4 solution followed by extraction with ethyl acetate (2 x 50 mL). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to almost dryness under reduced pressure. At the onset of crystallization, evaporation was stopped and the resultant slurry was triturated with cyclohexane. The solids were isolated by vacuum filtration washed with additional cyclohexane and dried in vacuo. Yield: 3.78 g (95%) as white amorphous solid. 1H NMR (400 MHz, DMSO) 5 8.37 (d, J = 1.7 Hz, 1 H), 8.11 (dd, J = 8.3, 1.7 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 7.91 (d, J = 16.4 Hz, 1 H), 7.65 - 7.60 (m, 1 H), 7.59 - 7.53 (m, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.40 - 7.35 (m, 1 H), 7.32 (d, J = 16.4 Hz, 1 H), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, DMSO) 5 166.2, 165.1 , 141.9, 138.8, 133.6, 132.2, 131.7, 131.0, 130.5, 128.7, 128.4, 128.0, 127.3, 127.2, 126.4, 125.3, 52.4, 52.2; HPLC tret = 9.92 min.
Step 2: Dimethyl 4-(3-chlorophenethyl)isophthalate (S2).
Figure imgf000017_0001
S2
In an oven dried schlenk flask were suspended S1 (3.49 g, 10.55 mmol, 1.0 eq) and 175 mg palladium on activated carbon (10% Pd on C) in 105 ml EtOAc (30 mL/g). The stirred mixture was cooled with an ice bath and the catalyst was saturated with hydrogen by bubbling through the suspension for 5 min. The flask was sealed and a hydrogen balloon was attached at the schlenk port to ensure a slightly positive pressure of hydrogen during the reaction. The ice bath was allowed to melt and the internal temperature should be maintained just below 20 °C to avoid hydrodehalogenation. The conversion was monitored via TLC (hexane/THF 4:1) until complete consumption of starting material (overnight stirring necessary at this scale). The catalyst was removed by filtration over a bed of celite and was thoroughly washed with EtOAc. To remove the aliphatic inpurities of the previous step the filtrate was washed successively with 2 M KHSO4 (3x30 mL), water (30 mL), sat. NaHCOs (30 mL) and brine (30 ml). The organic phase was dried over Na2SO4, concentrated under reduced pressure and coevaporated several times with MeOH and DCM to remove traces of water. Yield: 3.07 g (87 %) as a clear viscous oil which crystallizes upon standing. 1H NMR (400 MHz, DMSO) 5 8.36 (d, J = 1.8 Hz, 1 H), 8.04 (dd, J = 8.0, 1.8 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.33 - 7.27 (m, 2H), 7.26 - 7.22 (m, 1 H), 7.17 - 7.13 (m, 1 H), 3.86 (s, 6H), 3.27 - 3.19 (m, 2H), 2.87 - 2.79 (m, 2H); 13C NMR (100 MHz, DMSO) 5 166.3, 165.3, 147.8, 143.6, 132.8, 132.2, 131.7, 130.9, 130.0, 129.6, 128.1 , 127.7, 127.0, 125.9, 52.2, 52.2, 36.3, 35.3; HPLC tret = 10.03 min.
Step 3: Methyl 8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carboxylate (S3).
Figure imgf000017_0002
Under argon atmosphere was added S2 (3.04 g, 9.13 mmol) to 15 ml Eaton’s reagent (5 mL/g) at ambient temperature. The flask was evacuated and backfilled with argon three times while stirring before the mixture was heated up to 80 °C oil bath temperature. After stirring overnight, reaction control indicated complete conversion. The reaction mixture was added dropwise to 150 ml water, which resulted in agglomeration of a brown sticky mass at the stirring bar. The supernatant was decanted off and the residue was triturated with MeOH I water (1 :1) to produce a crystalline solid. The crude product was filtered off, dried in vacuo and recrystallized from MeOH to yield 2.11 g (77 %) of the title compound as beige crystalline solid. 1H NMR (400 MHz, DMSO) 68.43 (s, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.89 (d, J = 8.3 Hz, 1 H), 7.56 - 7.31 (m, 3H), 3.87 (s, 3H), 3.26 - 3.05 (m, 4H); 13C NMR (100 MHz, DMSO) 5 192.2, 165.4, 147.2, 144.2, 137.6, 137.4, 136.1 , 132.6, 132.3, 131.1 , 130.4, 129.1 , 128.1 , 126.7, 52.2, 33.8, 33.3; HPLC t = 7.96 min.
Step 4: 8-Chloro-N-methyl-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide (S4).
Figure imgf000018_0001
S4
A screw-top reaction vial was charged with S3 (0.8 g, 2.65 mmol), MeOH (4 mL) and aqueous MeNH2 solution (40%wt, 8 mL at ambient temperature. The mixture was stirred at 50°C oilbath temperature until TLC indicated complete conversion. The reaction was diluted with water and cooled in an ice bath. The resulting precipitate was collected by filtration and washed with water. The filtercake was dried in a convection oven at 60°C to yield the crude title compound as off-white solid. The material was stirred in MeCN at 60°C oil-bath temperature for about two hours and was then filltered and dried to obtain the pure product as white solid. Yield: 0.46 g (58%). 1H NMR (400 MHz, DMSO) 5 8.64 - 8.51 (m, 1 H), 8.36 (d, J = 1.9 Hz, 1 H), 7.96 (dd, J = 7.9, 1.9 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 1.9 Hz, 1 H), 7.48 - 7.35 (m, 2H), 3.27 - 3.13 (m, 4H), 2.79 (d, J = 4.5 Hz, 3H). 13C NMR (101 MHz, DMSO) 5 192.9, 165.6, 144.8, 144.3, 137.4, 137.3, 136.4, 132.9, 132.2, 131.0, 129.9, 129.3, 129.0, 126.8, 33.6, 33.5, 26.3. TLC-MS (ESI) m/z = 354.6 [M+Na+MeOH]+ HPLC tret = 9.19 min.
Step 5.1 : N-(2-Fluoro-5-nitrophenyl)cyclopropanecarboxamide (S5.1)
Figure imgf000018_0002
S5.1
2-Fluoro-5-nitroaniline (1.26 g, 8.07 mmol) was dissolved in DCM (40 mL) and pyridine (0.85 mL) was added to the stirred solution. Then cyclopropane carbonylchloride (0.88 mL) was added in one portion and stirring was continued until TLC indicated complete conversion (about 90 min). The reaction was diluted with DCM and washed with 2N HCI and sat. NaHCOs. The organic phase was dried, evaporated and the crude product was triturated with pentane and a small amount of DCM. After aging in the freezer, the precipitate was isolated by filtration and washed with cold pentane. After drying in vacuo, the title compound was yielded as off- white crystalline solid. Yield: 1.73 g (96%). 1H NMR (400 MHz, DMSO) 5 10.41 (s, 1 H), 9.01 (dd, J = 6.8, 3.0 Hz, 1 H), 7.99 (ddd, J = 9.1 , 4.1 , 3.0 Hz, 1 H), 7.55 (dd, J = 10.3, 9.1 Hz, 1 H), 2.19 - 2.00 (m, 1 H), 0.96 - 0.78 (m, 4H). 13C NMR (101 MHz, DMSO) 5 173.0, 155.9 (d, J = 255.5 Hz), 143.7 (d, J = 2.6 Hz), 127.5 (d, J = 13.2 Hz), 119.8 (d, J = 9.5 Hz), 117.8 (d, J = 4.2 Hz), 116.5 (d, J = 22.5 Hz), 14.1 , 8.0. TLC-MS (ESI) m/z = 222.9 [M-H]’ HPLC tret = 5.77 min.
Step 5.2: N-(5-Amino-2-fluorophenyl)cyclopropanecarboxamide (S5.2).
Figure imgf000019_0001
To a stirred solution of S5.1 (1.7 g, 7.58 mmol) in THF/EtOAc/MeOH (1 :1 :1 , 50 mL) was added Pd/C (100 mg) and hydrogen was bubbled through the solution for about fifteen minutes. Then the flask was sealed and a hydrogen balloon was attached to the reaction vessel. Stirring was continued overnight at ambient temperature. TLC indicated complete conversion at this point and the catalyst was filtered off and washed with EtOAc and MeOH. The filtrate was concentrated to a yellowish oil, which was layered with hexane and agitated under ice-cooling until precipitation of a white solid occured. The precipitate was triturated with hexane and a small amount of DCM and aged in the freezer for about one hour. The product was isolated by filtration, washed with cold hexane and dried in vacuo. HPLC indicated contamination with a not further characterized side product and therefore the crude product was purified via flash chromatography (DCM I MeOH 1-5%). The pure title compound was obtained as white solid. Yield: 1.24 g (84%). 1H NMR (400 MHz, DMSO) 5 9.65 (s, 1 H), 7.13 (d, J = 4.5 Hz, 1 H), 6.85 (dd, J = 10.8, 8.8 Hz, 1 H), 6.33 - 6.16 (m, 1 H), 4.91 (br s, 2H), 2.04 - 1.87 (m, 1 H), 0.85 - 0.65 (m, 4H). 13C NMR (101 MHz, DMSO) 5 171.8, 145.7 (d, J = 232.5 Hz), 144.9 (d, J = 1.4 Hz), 126.1 (d, J = 12.5 Hz), 115.0 (d, J = 20.2 Hz), 109.4 (d, J = 6.2 Hz), 109.3 - 109.1 (m), 14.0, 7.2. TLC-MS (ESI) m/z = 249.4 [M+Na+MeOH]+ HPLC tret = 1 .47 min.
Step 6: 8-((3-(Cyclopropanecarboxamido)-4-fluorophenyl)amino)-N-methyl-5-oxo-10,11- dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide (1)
Figure imgf000019_0002
In a 50 mL schlenk-flask were combined S4 (0.5 g, 1.67 mmol), S5.2 (0.32 g 1 .67 mmol) and CS2CO3 (1.09 g. 3.35 mmol) and degassed dioxane/tBuOH (4:1 , 20 mL) was added subsequently. The suspension was further degassed with five vacuum/argon cycles, then BrettPhos Pd G3 (8 mg, 9 pmol) was added and the degassing procedure was repeated again. The flask was sealed and heated to 90°C oil-bath temperature. TLC indicated complete conversion after two hours and therefore the reaction was cooled to ambient temperature, diluted with EtOAc and transferred to a separatory funnel with half-sat. NaCI. After shaking and separating, the aqueous phase was extracted once more with EtOAc (40ml) and the combined extracts were washed with brine prior to drying over Na2SO4 and evaporation. The crude product was taken up in 7.5 ml MeOH, resulting in the precipitation of a yellow solid. The suspension was heated to 60°C oil-bath temperature under stirring for one hour. The suspension was cooled first to ambient temperature then for 30 min in an ice-bath. The solids were collected by filtration, washed with chilled MeOH and dried in a vacuum oven at 60°C to yield the title substance as bright yellow solid. Yield: 0.70 g (92%). 1H NMR (400 MHz, DMSO) 5 10.02 (s, 1 H), 8.84 (s, 1 H), 8.55 (q, J = 4.2 Hz, 1 H), 8.33 (d, J = 1.9 Hz, 1 H), 8.01 (d, J = 8.9 Hz, 1 H), 7.90 (dd, J = 7.9, 1.9 Hz, 1 H), 7.89 - 7.83 (m, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.21 (dd, J = 10.7, 8.9 Hz, 1 H), 6.97 - 6.90 (m, 2H), 6.82 (d, J = 2.1 Hz, 1 H), 3.15 - 3.02 (m, 4H), 2.78 (d, J = 4.5 Hz, 3H), 2.08 - 1.98 (m, 1 H), 0.85 - 0.76 (m, 4H). 13C NMR (101 MHz, DMSO) 5 190.2, 172.2, 165.9, 148.7, 148.6 (d, J = 240.1 Hz), 145.3, 144.4, 138.9, 133.4, 130.2, 129.0, 128.9, 127.1 (d, J = 1.8 Hz), 126.8 (d, J = 12.6 Hz), 116.0 (d, J = 7.0 Hz), 115.7 (d, J = 20.7 Hz), 115.5 (d, J = 1.7 Hz), 113.9, 112.5, 35.4, 33.7, 26.2, 14.0, 7.4. TLC-MS (ESI) m/z = 480.2 [M+Na]+. HRMS (ESI) [M+Na]+ calcd for C27H24FN3NaO3+, 480.16939; found 480.16984. HPLC tret = 7.11 min.
Compound no. 4 8-((3-(3-Cyclopropylureido)-4-fluorophenyl)amino)-N-methyl-5-oxo-10,11-dihydro-5H- dibenzo[a,d][7]annulene-3-carboxamide (4).
Figure imgf000020_0001
Step 1.1 : 1-Cyclopropyl-3-(2-fluoro-5-nitrophenyl)urea (4.1).
Figure imgf000020_0002
4.1
2-Fluor-5-nitroaniline (0.78 g, 5.0 mmol) was dissolved in dioxane (20 mL) at ambient temperature and pyridine (0.40 mL) was added subsequently. Phenylchloroformate (0.63 mL) was added dropwise as solution in dioxane under vigorous stirring, resulting in formation of a precipitate. After about 15 min, TLC indicated complete conversion to the carbamate intermediate and cyclopropylamine (1.04 mL) was added slowly. The flask was placed in an oil-bath at 80°C and stirring was continued until TLC indicated complete consumption of the phenyl carbamate (about 2 hours). After cooling to ambient temperature, the mixture was diluted with EA and the organic phase was successively washed with water, 1 M NaOH (2x), 2N HCI and brine. The organic phase was dried over Na2SO4 and evaporated. The yellow residue was recrystallized from MeOH to obtain the pure title compound as pale yellowish solid. Yield: 0.76 g (64%). 1H NMR (200 MHz, DMSO) 5 9.10 (dd, J = 7.0, 2.8 Hz, 1 H), 8.59 (d, J = 1.8 Hz, 1 H), 7.88 - 7.73 (m, 1 H), 7.53 - 7.34 (m, 1 H), 6.93 (d, J = 1.9 Hz, 1 H), 2.63 - 2.51 (m, 1 H), 0.72 - 0.58 (m, 2H), 0.48 - 0.30 (m, 2H). 13C NMR (50 MHz, DMSO) 5 155.3,
154.7 (d, J = 251.8 Hz), 144.0 (d, J = 2.4 Hz), 129.4 (d, J = 12.2 Hz), 117.0 (d, J = 9.3 Hz),
115.8 (d, J = 22.2 Hz), 114.4 (d, J = 4.3 Hz), 22.3, 6.3. TLC-MS (ESI) m/z = 262.2 [M+Na]+ HPLC t = 5.56 min.
Step 1.2: 1-(5-Amino-2-fluorophenyl)-3-cyclopropylurea (4.2).
Figure imgf000021_0001
To a solution of 4.1 (1.27 g, 5.31 mmol) in EtOAc (15 mL) and THF (15 mL) was added Pd/C (120 mg) and the mixture was purged with hydrogen for several minutes. The flask was sealed and the reaction was stirred under hydrogen overnight at ambient temperature. HPLC indicated complete conversion after about 24 hours. The catalyst was filtered off, washed with EA and the filtrate was evaporated under reduced pressure. The title compound was obtained as off-white solid. Yield: 1.08 g (97%). 1H NMR (200 MHz, DMSO) 5 7.79 (d, J = 1.8 Hz, 1 H), 7.35 (dd, J = 7.2, 2.6 Hz, 1 H), 6.84 - 6.67 (m, 2H), 6.13 - 5.98 (m, 1 H), 4.82 (br s, 2H), 2.57 - 2.47 (m, 1 H), 0.68 - 0.54 (m, 2H), 0.42 - 0.28 (m, 2H). 13C NMR (50 MHz, DMSO) 5 155.9, 145.4 (d, J = 1.7 Hz), 144.6 (d, J = 227.9 Hz), 128.3 (d, J = 11.3 Hz), 114.7 (d, J = 19.7 Hz), 106.7 (d, J = 6.8 Hz), 106.1 (d, J = 1.1 Hz), 22.6, 6.6. TLC-MS (ESI) m/z = 232.2 [M+Na]+ HPLC t = 1.42 min.
Step 3: 8-((3-(3-Cyclopropylureido)-4-fluorophenyl)amino)-N-methyl-5-oxo-10,11-dihydro-5H- dibenzo[a,d][7]annulene-3-carboxamide 4.
Figure imgf000021_0002
A suspension of S4 (0.6 g, 2.0 mmol) and 92.2 (0.42 g, 2.0 mmol) in dioxane I tBuOH (4:1 , 20 mL) was degassed via several vacuum/argon cycles. Then BrettPhos Pd G3 (9 mg) was added as suspension in dioxane I tBuOH followed by addition of NaOtBu as solution in THF (2M, 3.5 mL). The degassing procedure was repeated, the flask was sealed and placed in an oil-bath at 80°C. TLC indicated complete conversion after 90 min and the reaction was quenched by dilution with EtOAc I dioxane (40 ml each) and addition of water. The organic phase was sequentially washed with half-sat. NaCI and sat. NaCI, dried over Na2SO4 and evaporated under reduced pressure.
The solid residue was taken up in 12 ml aqueous MeCN (90% v/v) and stirred at 60°C for one hour. Then the suspension was slowly cooled to ambient temperature and finally cooled in an ice-bath for 30 min. The solids were isolated by filtration and the filtercake was washed with additional aqueous MeCN. The product was dried in a vacuum oven at 60°C for 48 hours. Yield: 0.82 g (87%). 1H NMR (400 MHz, DMSO) 5 8.79 (s, 1H), 8.54 (q, J = 4.2 Hz, 1 H), 8.33 (d, J= 1.8 Hz, 1H), 8.19 - 8.12 (m, 1H), 8.08 (dd, J= 7.3, 2.6 Hz, 1H), 8.01 (d, J= 8.8 Hz, 1 H), 7.90 (dd, J = 7.9, 1.9 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1 H), 7.14 (dd, J = 11.1 , 8.8 Hz, 1 H), 6.95 (dd, J = 8.8, 2.2 Hz, 1 H), 6.86 - 6.79 (m, 2H), 6.78 - 6.70 (m, 1 H), 3.20 - 2.98 (m, 4H), 2.79 (d, J = 4.5 Hz, 3H), 2.59 - 2.52 (m, 1H), 0.69 - 0.58 (m, 2H), 0.44 - 0.33 (m, 2H). 13C NMR (101 MHz, DMSO) 5 190.2, 166.0, 155.5, 149.0, 147.3 (d, J = 236.5 Hz), 145.4, 144.5, 139.0, 137.1 (d, J = 2.1 Hz), 133.5, 132.8, 130.2, 129.1 , 128.9, 128.7 (d, J = 11.4 Hz), 126.8, 115.2 (d, J = 20.2 Hz), 113.9, 113.1 (d, J = 7.1 Hz), 112.5, 112.3 - 112.0 (m), 35.5, 33.8, 26.3, 22.3, 6.3. TLC-MS (ESI) m/z = 495.3 [M+Na]+. HRMS (ESI) [M+Na]+ calcd for C27H25FN4NaO3+, 495.18029; found 495.18060. HPLC tret = 7.16 min.
Compounds of formula (I), wherein L2 is ■— CH2CO-, can be prepared as exemplified in the following reaction scheme 4 according to conventional procedures. Conversion to the final products can be carried out according to the procedures given in J. Med. Chem. 2013, 56(1), 241-253, J. Med. Chem. 2017, 60, 19, 8027-8054, doctoral thesis Heike Wentsch, Eberhard Karls Universitat Tubingen 2017 and doctoral thesis Niklas Walter, Eberhard Karls Universitat Tubingen 2017 or analogous procedures. The reaction scheme is illustrated below for two reaction sequences leading to intermediates for preparing compounds of formula (I), wherein L2 is ■— CH2CO- and R5 is phenyl or thienyl. Reaction scheme 1
Figure imgf000023_0001
Ketone derivatives were accessible via one of the above depicted synthetic routes starting from the 3-nitro phenylacetic acid derivatives or 3-nitro benzoic acid derivatives using either an activation to the acid chloride and a subsequent Friedel-Crafts acylation or the transformation to the corresponding Weinreb amide and subsequent reaction with organometallic reagents. The aniline for Buchwald-Hartwig was then obtained by reduction of the nitro group using state of the art reductive methods like tin(ll)chloride in ethanol or elemental hydrogen in combination with palladium on charcoal.
The exemplary preparation of two derivatives of this class of residues is described in detail below:
2-(2,4-Difluoro-5-nitrophenyl)acetyl chloride (A.1).
Figure imgf000023_0002
A solution of 2,4-difluoro-5-nitrophenylacetic acid (4.71 g, 20 mmol) in thionyl chloride (40 mL) and a catalytic amount of DMF was refluxed for 2 hours. The volatiles were removed under reduced pressure and the residue was co-evaporated twice with dry toluene. The crude acid chloride as obtained in quantitative yield and was used directly in the next step without further purification.
2-(2,4-Difluoro-5-nitrophenyl)-1-phenylethan-1-one (A.2).
Figure imgf000023_0003
To a solution of AlC (1.27 g, 9.5 mmol) in benzene (50 mL) was added dropwise A.1 (1.50 g, 6.4 mmol) under cooling conditions. After TLC indicated complete conversion, the reaction was poured on ice and 6M HCL was added. The aqueous phase was extracted with DCM (3 x 30 mL), the combined extracts were washed with water dried over Na2SO4 and evaporated to dryness to obtain the title substance as yellow crystalline solid. Yield: 1.06 g (83%). 1H-NMR (200 MHz, CDCh) 5 8.12 - 8.04 (m, 2H), 7.75 - 7.44 (m, 3H), 7.11 (dd, J = 10.3, 9.0 Hz, 2H), 4.43 (s, 2H).
2-(5-Amino-2,4-difluorophenyl)-1-phenylethan-1-one (A.3).
Figure imgf000024_0001
To a solution of A.2 (1.0 g 3.6 mmol) in 30 mL EtOH was added SnCh dihydrate (4.06 g, 18 mmol) and the reaction was heated to reflux until TLC indicated complete conversion. Solid NaHCCh (6 g) was added to the stirred solution and subsequently the majority of EtOH was removed under reduced pressure. The residue was triturated with EtOAc and filtered over celite. The filtrate was evaporated to obtain the title substance as brownish solid. Yield: 0.86 g (96%). 1H-NMR (200 MHz, CDCh) 6 8.05 - 7.97 (m, 2H), 7.63 - 7.42 (m, 3H), 6.79 (dd, J = 10.6, 9.4 Hz, 1 H), 6.64 (dd, J = 9.6, 7.4 Hz, 1 H), 4.19 (s, 2H), 3.38 (s, 2H).
2-(2,4-Difluoro-5-nitrophenyl)-N-methoxy-N-methylacetamide (B.1).
Figure imgf000024_0002
To a solution of /\/,O-dimethylhydroxylamine hydrochloride (91 mg, 0.94 mmol) and Et3N (172 mg, 1 ,70 mmol) in DCM (5 mL) was added A.1 (200 mg, 0.85 mmol) dropwise under ice cooling. After TLC indicated complete conversion, water was added and the aqueous phase was extracted with DCM (3 x 15 mL). The combined extracts were washed with brine and evaporated to dryness to obtain the title substance as yellow solid. Yield: 200 mg (90%). 1H- NMR (400 MHz, CDCh) 6 8.10 (t, J = 7.8 Hz, 1 H), 7.03 (dd, J = 10.4, 9.0 Hz, 1 H), 3.84 (s, 2H), 3.77 (s, 3H), 3.23 (s, 3H).
2-(2,4-Difluoro-5-nitrophenyl)-1-(thiophen-2-yl)ethan-1-one (B.2).
Figure imgf000024_0003
A three necked flask was charged with magnesium turnings (129 mg, 5.38 mmol) and THF (8 mL) under argon atmosphere. To this was added a small portion of a solution of 2- bromothiophene (877 mg, 5.38 mmol) in THF (3 mL). Upon onset of the reaction indicated by formation of turbidity, the residual amount of the solution was added slowly in a rate that kept the exothermic reaction under control. Stirring was continued for one hour at ambient temperature, before it was cooled in an ice bath and a solution of B.1 (700 mg, 2.69 mmol) in THF (8 mL) was added slowly. After stirring overnight at ambient temperature, aqueous NH4CI was added and the mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography to obtain the title compound as yellow solid. Yield: 67 mg (9%). 1H-NMR (400 MHz, CDCh) 6 8.12 (t, J = 7.8 Hz, 1 H), 7.85 (dd, J = 3.8, 1.1 Hz, 1 H), 7.73 (dd, J = 5.0, 1.1 Hz, 1 H), 7.20 (dd, J = 4.9, 3.9 Hz, 1 H), 7.07 (dd, J = 10.3, 9.0 Hz, 1 H), 4.30 (s, 2H).
2-(5-Amino-2,4-difluorophenyl)-1-(thiophen-2-yl)ethan-1-one (B.3).
Figure imgf000025_0001
The preparation of this compound was performed like described above for compound A.3 starting from 83 mg B.2 and yielding 59 mg (81 %) of the desired product B.3 as yellowish oil. 1H-NMR (200 MHz, CDCh) 6 7.79 (d, J = 3.3 Hz, 1 H), 7.65 (d, J = 4.8 Hz, 1 H), 7.13 (t, 1 H), 6.85 - 6.62 (m, 2H), 4.11 (s, 2H), 3.58 (bs, 2H).
Compounds of the invention obtained according to the above-mentioned procedures are given in the following table 2.
Table 2:
Figure imgf000025_0002
Figure imgf000026_0001
Biological results
Generation of murine and human organoid cultures
Murine colon organoids were isolated from genetically modified mice as described before (Sato et al., Nature 459, 262-265, 2009). The tissue fragments were washed with ice-cold PBS (phosphate buffered saline), transferred to 2 mM EDTA chelating buffer and incubated for 30 mins at 4°C on an orbital shaker. Subsequently, the supernatant was removed and the tissue fragments were resuspended in medium containing 10% FCS (Fetal Calf Serum, table 3). The supernatant containing crypts were centrifuged at 150 g for 5 mins and colonic crypts were embedded in 50 pl domes of Growth Factor Reduced (GFR) MatrigelTM (Corning) in 24-well plates. Following polymerization for 10 mins at 37°C, MatrigelTM (Corning) domes were overlaid with murine colon medium (table 3), supplemented with 10.5 pM Y-27632 dihydrochloride (Invitrogen) for the three days.
To generate a rasG12D;Apc+A; Trp53'A (KAP) CRC organoid culture which was predominantly used to test different p38a inhibitors (Table 4), untransformed colonoids were transformed into a CRC culture in vitro by CRISPR/Cas9-mediated gene editing of Ape and cre-mediated recombination of the floxed rasG12D and Trp53 alleles.
To test the most efficient p38a compounds in CRC organoid cultures with different genetic backgrounds, additional murine CRC organoid cultures were generated. rasG12D/+ x /WycOE x Trp53'1' organoids were generated by a cre-mediated recombination of loxp sequences in KrasLSL x Trp53m colonoids (Lipofectamine-mediated transfection of ere) and transposonbased integration of ectopically expressed, oncogenic Myc. To generate CRC organoids, with a constitutive active Braf mutation (Ape1' x Trp53'!'x Braf*600^, a full loss of Ape and Trp53 was induced through cre-mediated recombination (Ape) or CRISPR/Cas9-mediated (Trp53) gene knockout followed by a retroviral delivery of ectopically expressed Bra^6005. The genetic manipulation of cultures was confirmed by PCR or western blot analyses.
Human CRC organoids were isolated from primary colorectal tumors or ascites material of patients. All patients gave their consent.
Primary tumor material was washed in ice-cold splitting medium and cut into small pieces. The tissue was transferred into tumor digestion medium supplemented with 100 pg/ml DNasel and 10.5 pM Y-27632 dihydrochloride (Invitrogen). Tumor digestion was performed at 37°C on a shaker with 75 rpm rotation. The digestion was stopped by adding medium containing 10% FCS (table 3). The mixture was centrifuged for 5 mins at 300 g. Red blood cells were removed by incubating the pellet with ACK lysing buffer (Thermo Fisher) for 5 mins at RT. Afterwards the pellet was resuspended in medium and, after final centrifugation, the cells were adjusted to roughly 1000 cells in 50 pl Growth Factor Reduced (GFR) MatrigelTM (Corning) and plated in pre-warmed 24-well plates.
The ascites material was pelleted by centrifugation at 300 g and washed several times with ice-cold PBS before embedding the cells in domes of MatrigelTM (Corning).
Within the first week of culture the human CRC medium was supplemented with 10.5 pM Y- 27632 dihydrochloride (Invitrogen). The medium was refreshed every two to three days.
Confluent organoids were split in splitting medium (Table 3) by mechanical dissociation into smaller cell clumps and replated in MatrigelTM (Corning) domes. Depending on the organoid culture the splitting ratio was 1 :2 to 1 :6 (once or twice per week).
All organoid cultures were characterized histologically (staining for the CRC markers Cytokeratin 20 and Cdx2). The genetic background of human CRC cultures was determined by panel sequencing (CeGAT GmbH). Table 3: media used for organoid culture
Splitting medium
Substance Stock concentration Final concentration Company
Gibco™ Advanced DMEM/F- lx lx Thermo Fisher
12
GlutaMAX lOOx lx Thermo Fisher
HEPES I M 10 mM Thermo Fisher
Primocin™ 50 mg/ml 125 pg/ml Invivogen
Murine colon medium
Substance Stock concentration Final concentration Company
Splitting medium lx lx
B-27® Supplement 50x lx Thermo Fisher
N-2 Supplement lOOx lx Thermo Fisher
Nicotinamide I M 10 mM Sigma Aldrich
N-Acetyl-L-cysteine 500 mM 1.25 mM Sigma Aldrich
Recombinant Murine Noggin 100 pg/ml 100 ng/ml Peprotech
Recombinant Human R- 500 pg/ml 500 ng/ml Peprotech
Spondin-1
EGF Recombinant Mouse 500 pg/ml 50 ng/ml Thermo Fisher
Protein
Recombinant Human Wnt-3a 100 pg/ml 100 ng/ml R&D Systems
Protein Murine CRC medium
Substance Stock concentration Final concentration Company
Splitting medium lx lx
B-27® Supplement 50x lx Thermo Fisher
N-2 Supplement lOOx lx Thermo Fisher
Nicotinamide I M 10 mM Sigma Aldrich
N-Acetyl-L-cysteine 500 mM 1.25 mM Sigma Aldrich
Recombinant Murine Noggin 100 pg/ml 100 ng/ml Peprotech
Human CRC medium
Substance Stock concentration Final concentration Company
Splitting medium lx lx
B-27® Supplement 50x lx Thermo Fisher
N-2 Supplement lOOx lx Thermo Fisher
Nicotinamide I M 10 mM Sigma Aldrich
N-Acetyl-L-cysteine 500 mM 1.25 mM Sigma Aldrich
Recombinant Murine Noggin 100 pg/ml 100 ng/ml Peprotech
Recombinant Human R- 500 pg/ml 500 ng/ml Peprotech
Spondin-1
Animal-Free Recombinant 50 pg/ml 50 ng/ml Peprotech
Human EGF
Recombinant Human Wnt-3a 100 pg/ml 100 ng/ml R&D Systems
Protein
A83-01 0,5 mM 0,5 pM TOCRIS
Gastrinl 10 pM 10 nM TOCRIS
PGE2 I mM 1 pM R&D Systems
Tumor digestion medium
Splitting medium lx lx
Collagenase II 2,5 mg/ml Thermo Fisher
Collagenase IX 2,5 mg/ml Sigma Aldrich
Dispase ll lmg/ml Sigma Aldrich
Treatment studies in organoid cultures
For the treatment studies, organoids were mechanically dissociated and digested using TrypLE supplemented with 100 pg/ml DNasel and 10.5 pM Y-27632 dihydrochloride (Invitrogen) at 37°C. 1000 single cells per well were plated in all-white 96 well plates (Greiner) in culture medium (table 3) containing 10% Growth Factor Reduced (GFR) Matrigel™ (Corning). The treatment with different p38a inhibitors or corresponding amounts of DMSO was started after 24 hours. To analyze the treatment response, ATP level were measured 96 hours after treatment start using Cell-Titer Glo2.0 reagent (Promega) according to the manufacturers’ instructions. Results were normalized to vehicle (DMSO). Each assay was performed in three technical and biological replicates. The results are contained in the following table 4.
Determination of Target Residence Time
The flourescence polarization assay protocol for target residence time determination was recently also published by our group from Pantsar er al., Nature Communications 13, article number: 569 (2022); https://doi.org/10.1038/s41467-022-28164-4. The assay adapted a commercially available fluorescence polarization assay kit (Transcreener ADP, BellBrook Labs). The compounds were preincubated in 50 mM Tris [pH 7.5], 1 mM dithiothreitol, 10 mM MgCI2, 10 mM p-glycerophosphate, and 0.1 mM NasVC at a concentration of 20-fold IC50 with p38 MAPK (12.4 pg/mL) at room temperature for 1 h to enable the formation of an enzyme- inhibitor-complex. Then the formed complex was “jump diluted” 1 :100 (0.5 pL were diluted into 49.5 pL) in a 96 half area well plate with ATF2 (82 pM) as kinase substrate, ATP (40 pM) and ADP Kinase assay detection reagents. The plate was immediately measured every 3 min for 4 h. Fluorescence polarization was detected using the plate reader VictorNivo by PerkinElmer. The assay was performed in triplicates. The obtained data were analyzed via integrated rate equation in Graphpad Prism version 7.0.0. for Windows (GraphPad Software, San Diego, CA, USA). The residence time in seconds was subsequently calculated by the reciprocal value of the rate constant of the dissociation of the drug-target-complex (kOff). The results are provided in table 4.
Table 4
Figure imgf000030_0001
Figure imgf000031_0001
Animal studies
In approved animal experiments tumor size during treatment was determined in a colon cancer model. Further, tumor development and survival of the mice was determined in a colon cancer - liver metastases model. All mice were housed and maintained under pathogen free conditions in accordance with the institutional guidelines of the University Hospital Tuebingen. Subcutaneous injection or splenic seeding of organoids was performed in 8 to 10 weeks old C57BL/6 mice. The corresponding organoids were dissociated into single cells, washed twice with PBS and filtered through a 100 pm mesh. 1x105 cells were injected into the left and right flanks or the spleen capsule of mice in a 1 :1 mixture of sterile PBS and growth factor reduced (GFR) Matrigel™. For splenic seeding, mice were anaesthetized using ketamine (100 mg/kg i.p.) and xylazin (10 mg/kg i.p.) in NaCI and a small laparotomy below the thorax was performed. Upon injection into the capsule of the spleen, the injection site was washed with pre-warmed H2O. Within the first week after operation, the mice were treated with the analgesics Carprofen und Metamizol. In vivo treatment studies were performed in randomized groups with 20 mg/kg body weight of compound every day. The drugs were administered P.O. via oral gavage dissolved in Phosal50PG/Ethanol/PEG400 (60%/10%/30%) or Cremophor/Ethanol/H2O (12.5%/12.5%75%). For cancer treatment studies, the therapies were started after 1 week (subcutaneous KAP tumors and KMP metastases) or 5 weeks (KAP metastases) after tumor initiation. The results are shown in figures 1 and 2 for compound no. 1. Upon treatment with compound no.1 tumor volume remains essentially constant after 12 days of treatment (fig. 1) and survival time of the mice increased significantly (fig. 2).

Claims

Claims
1 . A compound of formula I
Figure imgf000033_0001
or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use in treating colorectal cancer, wherein the variables in formula I have the following meanings:
R1 is -CONR6R7;
R2 is alkyl or halogen;
R3 is H or halogen;
R4 is -L2-R5;
L2 is i— NR6-CO-, i-NR6-CO-NR6-, or i-CH2CO-;
R5 is selected from phenyl, optionally substituted with 1 or 2 substituents independently selected from halogen, alkoxy and haloalkyl, an aromatic 5- or 6-membered heterocyclic group having 1 or 2 heteroatoms independently selected from N, S and O, and cycloalkyl;
R6 is H or alkyl; R7 is selected from
H, alkyl, alkyl which is substituted with 1 or 2 hydroxy groups or with a non-aromatic 5- or 6- membered heterocyclic group having 1 or 2 heteroatoms independently selected from N and O, and alkyl substituted with hydroxyalkyl-NR6-; wherein ■ in the meanings of L2 indicates the attachment to ring C.
2. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to claim 1 , wherein R2 is halogen and R3 is H or halogen.
3. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to claim 1 or 2, wherein R2 is F and R3 is H or F.
4. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein L2 is ■— NR6-CO- or -NR6-CO-
NR6-, in particular ■— NR6-CO-.
5.. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of claims 1 to 3, wherein L2 is ■— CH2CO.
6. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein R5 is selected from phenyl, thienyl or cycloalkyl, in particular cyclopropyl.
7. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of claims 1 to 4, wherein L2 is ■— NR6-CO- or -NR6-CO-NR6- and R5 is selected from thienyl or cycloalkyl.
8. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to claim 5, wherein L2 is ■— CH2CO and R5 is selected from phenyl.
9. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein R7 is alkyl, in particular methyl or ethyl.
10. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of claims 1 to 8, wherein R7 is C2-C4 alkyl which is substituted with a morpholino group or C2-C4 alkyl which is substituted with a hydroxy-C2-Cs alkylamino group.
11. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein the compound is selected from the compounds of the formulae
Figure imgf000035_0001
12. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein the compound has a Target Residence Time (TRT) of at least 500 s, preferably at least 900 s, and in particular at least 1000 s, as determined by a fluorescence polarization assay by directly measuring the ADP formed by p38 MAPK kinase reaction.
13. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein the compound is used as a monotherapy.
14. A compound or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for use according to any one of the preceding claims, wherein the compound is used in a dosage of of 5 to 50 mg/kg, in particular 10 to 30 mg/kg.
15. A method for treating colorectal cancer which comprises administering a compound of formula I as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt, solvate or optical isomer thereof to a subject in need thereof.
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