WO2024079252A1 - Sos1 inhibitors - Google Patents

Sos1 inhibitors Download PDF

Info

Publication number
WO2024079252A1
WO2024079252A1 PCT/EP2023/078318 EP2023078318W WO2024079252A1 WO 2024079252 A1 WO2024079252 A1 WO 2024079252A1 EP 2023078318 W EP2023078318 W EP 2023078318W WO 2024079252 A1 WO2024079252 A1 WO 2024079252A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
mixture
cyclopropyl
general formula
acid
Prior art date
Application number
PCT/EP2023/078318
Other languages
French (fr)
Inventor
Felix PAPE
Timo Stellfeld
Steffen GRESSIES
Jeremie Xavier G. MORTIER
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2024079252A1 publication Critical patent/WO2024079252A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide

Definitions

  • the present invention covers phosphinoxide substituted pyrido[3,4-d]pyrimidine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.
  • BACKGROUND The present invention covers phosphinoxide substituted pyrido[3,4-d]pyrimidine compounds of general formula (I) which inhibit Ras-Sos1 interaction. Ras proteins play an important role in human cancer.
  • Ras proteins can be found in 20-30% of all human tumors and are recognized as tumorigenic drivers especially in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al. 2011 Nature Reviews Cancer).
  • Three human Ras genes are known that encode four different Ras proteins of 21 kDa size: H-Ras, N-Ras, and two splice variants of K-Ras, namely K-Ras 4A and K-Ras-4B. All Ras isoforms are highly conserved within the GTP-binding domain and differ mainly in the hypervariable C- terminal region.
  • Ras-isoforms are posttranslationally modified by lipidation (farnesylation, palmitoylation) to facilitate membrane anchorage.
  • the localization of Ras-proteins at the cytoplasmic membrane provides vicinity to transmembrane growth receptors and has been shown to be essential for transmitting growth signals from extracellular growth factor binding to intracellular downstream pathways.
  • upstream signals may activate Ras proteins depending on the cellular context, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), nerve growth factor receptor (NGFR) and others.
  • Activated Ras can signal through various downstream pathways, e.g. the Raf-MEK-ERK or the PI3K-PDK1-Akt pathways.
  • Ras proteins function as molecular switches. By binding GTP and GDP they exist in an active (GTP-bound) and inactive (GDP-bound) state in the cell. Active GTP-loaded Ras recruits other proteins by binding of their cognate Ras-binding domains (RBDs) resulting in activation of the effector BHC221035 EP protein followed by downstream signalling events of diverse functions, e.g. cytoskeletal rearrangements or transcriptional activation.
  • RGDs Ras-binding domains
  • the activity status of Ras is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs function as activators of Ras by promoting the nucleotide exchange from GDP to GTP.
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase activating proteins
  • GAPs deactivate Ras-GTP by catalyzing the hydrolysis of the bound GTP to GDP.
  • point mutations typically within the GTP-binding region at codon 12, eliminate the ability of RAS to efficiently hydrolyse bound GTP, even in the presence of a GAP. Therefore, cancer cells comprise increased levels of active mutated Ras-GTP, which is thought to be a key factor for driving cancer cell proliferation.
  • Three main families of RAS-specific GEFs have been identified so far (reviewed in Vigil 2010 Nature Reviews Cancer; Rojas et al 2011, Genes & Cancer 2(3) 298-305).
  • SOS1 and SOS2 Ras guanine nucleotide releasing proteins
  • Ras-GRP1-4 Ras guanine nucleotide releasing proteins
  • Ras-GRF1 and 2 Ras guanine nucleotide releasing factors
  • Ras protein itself has always been considered to be undruggable, i.e. the chance to identify small chemical molecules that would bind to and inhibit active Ras was rated extremely low.
  • Alternative approaches have been undertaken to reduce Ras signaling, e.g. by addressing more promising drug targets such as enzymes involved in the posttranslational modification of Ras proteins, especially farnesyltransferase and geranylgeranyltransferase (Berndt 2011 Nature Reviews Cancer).
  • Inhibitors of farnesyltransferase were identified and developed with promising antitumor effects in preclinical models. Unexpectedly, in clinical trials these inhibitors have been of limited efficacy. Targeting upstream and downstream kinases involved in Ras signaling pathways has been more successful.
  • Several drugs are and have been in clinical trials that inhibit different kinases, e.g. EGFR, Raf, MEK, Akt, PI3K (Takashima & Faller 2013 Expert Opin. Ther. Targets).
  • Marketed cancer drugs are available that inhibit Raf, EGFR or MEK. Nevertheless, there is still a large unmet need for the treatment of Ras-dependent tumors that are resistant against current therapies.
  • Ras small molecules have been reviewed in: Cox et al. 2014 Nature Reviews Drug Discovery, Spiegel et al.2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie, Marin- Ramos et al Seminars in Cancer Biology).
  • One group of inhibitors comprises small molecules that inhibit BHC221035 EP the interaction of Ras with its effectors Raf or PI3K.
  • Another group of compounds acts as covalent inhibitors of a specific cysteine mutant form of K-Ras (glycine to cysteine point mutation G12C). The specific targeting of the Ras-G12C mutant might have the benefit of reduced side effects, as the wildtype Ras proteins should not be affected.
  • the Epidermal Growth Factor Receptor is a tyrosine kinase (TK) receptor that is activated upon binding to the Epidermal Growth Factor and other growth factor ligands, triggering several downstream pathways, including RAS/MAPK, PI3K/Akt and STAT that regulate different cellular processes, including DNA synthesis and proliferation (Russo A, Oncotarget.4254, 2015).
  • the family of HER (ErbB) receptor tyrosine kinases consists of four members, ie, epidermal growth factor receptors [EGFR (HER1 or ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4)].
  • Erlotinib and Gefitinib are small molecule inhibitors of the EGFR/HER-1 (human epidermal growth factor receptor) tyrosine kinase.
  • Erlotinib and Gefitinib were developed as reversible and highly specific small- molecule tyrosine kinase inhibitors that competitively block the binding of adenosine triphosphate to its binding site in the tyrosine kinase domain of EGFR, thereby inhibiting autophosphorylation and blocking downstream signaling (Cataldo VD, N Engl J Med, 2011, 364, 947).
  • Second-generation inhibitors Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for the first-line treatment of patients with NSCLC whose tumors are driven by activating mutations of genes coding for epidermal growth factor receptor (EGFR).
  • TKI oral tyrosine kinase inhibitor
  • Afatinib is also an inhibitor of a specific EGFR mutation (T790M) that causes resistance to first-generation EGFR-targeted TKIs in about half of patients receiving those drugs.
  • T790M a specific EGFR mutation
  • Neratinib, a pan-HER inhibitor, irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways.
  • Neratinib has been shown to be BHC221035 EP effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clinical trials in breast cancers and other solid tumors, including those with HER2 mutation (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147). Dacomitinib is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell lines and xenograft studies, dacomitinib demonstrated activities against both activating EGFR mutations and EGFR T790M (Liao BC, Curr Opin Oncol.2015, 27(2), 94).
  • the third-generation EGFR-TKIs were designed to inhibit EGFR T790M while sparing wild-type EGFR.
  • AZD9291 AstraZeneca, Macclesfield, UK
  • a mono-anilino-pyrimidine compound is an irreversible mutant selective EGFR-TKI.
  • This drug is structurally different from the first and second-generation EGFR- TKIs. In preclinical studies, it potently inhibited phosphorylation of EGFR in cell lines with activating EGFR mutations (EGFR del19 and EGFR L858R) and EGFR T790M.
  • AZD9291 also caused profound and sustained tumor regression in tumor xenograft and transgenic mouse models harboring activating EGFR mutations and EGFR T790M.
  • AZD9291 was less potent in inhibiting phosphorylation of wild-type EGFR cell lines (Liao BC, Curr Opin Oncol.2015, 27(2), 94).
  • Rociletinib CO-1686 (Clovis Oncology, Boulder, Colo), a 2,4-disubstituted pyrimidine molecule, is an irreversible mutant selective EGFR-TKI.
  • HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea) is an orally administered, selective inhibitor for activating EGFR mutations and EGFR T790M. It has low activity against wild-type EGFR (Steuer CE, Cancer.2015, 121(8), E1). Hillig et al 2019 PNAS describe compounds like as a potent SOS1 inhibitor and as a tool compound for further investigation of RAS-SOS1 biology in vitro.
  • FR 3066761 (Universite d’Orleans et al) describes compounds like BHC221035 EP for the treatment of cancer.
  • WO 2018/134685 (Eisai Management Co. Ltd. et al) describes compounds like for the treatment and prevention of filarial worm infection.
  • WO 2018/172250 (Bayer Pharma AG) describes 2-methyl-quinazoline like as inhibiting Ras-Sos interaction.
  • WO 2018/115380 (Boehringer Ingelheim) describes benzylamino substituted quinazolines like as SOS1 inhibitors.
  • WO 2019/122129 (Boehringer Ingelheim) describes benzylaminosubstituted pyridopyrimidinones like BHC221035 EP as SOS1 inhibitors.
  • WO 2020/180768 and WO 2020/180770 describe compounds of the following formulas: as SOS1 inhibitors.
  • WO 2021/228028 Choa Tai TianQing Parmaceutical Group
  • SOS1-Inhibitors It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
  • the compounds of the present invention have surprisingly been found to effectively and selectively inhibit the Ras-Sos1 interaction and may therefore be used for the treatment or prophylaxis of hyper-proliferative disorders, in particular cancer.
  • Certain embodiments or compounds of the present invention display an IC 50 below 75 nM (determined in a Phophor ERK assay as described below).
  • Certain embodiments or compounds of the present invention dislplay an IC 50 below 10 nM (determined in a Ras-SOS1-interaction assay as described below). Certain embodiments or compounds of the present invention have an F max (as described below) of more than 60 % in rat hepatocytes. BHC221035 EP Certain embodiments or compounds of the present invention have an F max (as described below) of more than 60 % in human hepatocytes.
  • the present invention covers compounds of general formula (I): wherein R 1 and R 2 are independently selected from the group consisting of C 1-4 -alkyl; or R 1 and R 2 together with the phosphor atom they are attached to form a 4-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl or ; R 3 is selected from the group consisting of C 3-5 -cycloalkyl and 4 to 6 membered heterocycloalkyl, wherein said C 3-5 -cycloalkyl is optionally substituted with 1, 2, 3 or4 Fluor atoms, wherein said 5 membered heterocycloalkyl is optionally substituted with 1 or 2 Fluor atoms and wherein said 6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms; R 4 is selected from H, D, -CH 3 , or -CH 2 -CH 3 ; or R
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non- hydrogen substituent on any available carbon or nitrogen or ... atom.
  • the number of optional substituents when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”.
  • groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified.
  • the meanings of all groups which occur repeatedly are independent from one another.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
  • the C 1 -C 4 -alkoxy part can be attached to any carbon atom of the C 1 -C 4 -alkyl part of said (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • C 1 -C 6 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g.
  • said group has 1, 2, 3 or 4 carbon atoms (“C 1 -C 4 -alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 4 -alkyl e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 6 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g.
  • C 1 -C 6 -alkylsulfanyl means a linear or branched, saturated, monovalent group of formula (C 1 -C 6 -alkyl)-S-, in which the term “C 1 -C 6 -alkyl” is as defined supra, e.g.
  • C 1 -C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.
  • C 1 -C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 -C 6 -alkyl)-O-, in which the term “C 1 -C 6 -alkyl” is as defined supra, e.g.
  • C 1 -C 6 -haloalkoxy means a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • C 1 -C 6 -haloalkoxy group is, for BHC221035 EP example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C 2 -C 6 -alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C 2 -C 3 -alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then it is possible for said double bonds to be isolated from, or conjugated with, each other.
  • Said alkenyl group is, for example, an ethenyl (or “vinyl”), prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, 1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 2-methylbut-2-
  • C 2 -C 6 -alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C 2 -C 3 -alkynyl”).
  • Said C 2 -C 6 -alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-
  • said alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
  • C 3 -C 8 -cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms (“C 3 -C 8 -cycloalkyl”).
  • Said C 3 -C 8 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g.
  • C 4 -C 8 -cycloalkenyl means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms (“C 4 -C 6 -cycloalkenyl”).
  • Said C 4 -C 8 -cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.
  • C 3 -C 8 -cycloalkoxy means a saturated, monovalent, mono- or bicyclic group of formula (C 3 -C 8 -cycloalkyl)-O-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C 3 -C 8 -cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
  • spirocycloalkyl means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 11 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom.
  • Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-
  • “4- to 6-membered heterocycloalkyl” means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
  • heterocycloalkenyl means a monocyclic, unsaturated, non-aromatic heterocycle with 5, 6, 7 or 8 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkenyl group is, for example, 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.
  • heterospirocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-,
  • fused heterocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, which “fused heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said fused heterocycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl.
  • bridged heterocycloalkyl means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which “bridged BHC221035 EP heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C 1 -C 6 as used in the present text, e.g.
  • C 1 -C 6 -alkyl in the context of the definition of “C 1 -C 6 -alkyl”, “C 1 -C 6 -haloalkyl”, “C 1 -C 6 -hydroxyalkyl”, “C 1 -C 6 -alkoxy” or “C 1 -C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 8 as used in the present text, e.g.
  • C 3 -C 8 -cycloalkyl in the context of the definition of “C 3 -C 8 -cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e.3, 4, 5, 6, 7 or 8 carbon atoms.
  • BHC221035 EP When a range of values is given, said range encompasses each value and sub-range within said range.
  • C 1 -C 6 encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C 2 -C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C
  • the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphen
  • BHC221035 EP in the context of the invention means a straight-chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms, such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert- butyl, for example.
  • (C 1 -C 4 )-Alkoxy in the context of the invention means a straight-chain or branched alkoxy group having 1, 2, 3 or 4 carbon atoms, such as: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec- butoxy, and tert-butoxy, for example.
  • Mono-(C 1 -C 4 )-alkylamino in the context of the invention means an amino group with one straight-chain or branched alkyl substituent which contains 1, 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, for example.
  • Di-(C 1 -C 4 )-alkylamino in the context of the invention means an amino group with two identical or different straight-chain or branched alkyl substituents which each contain 1, 2, 3 or 4 carbon atoms, such as: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-methylamino, N-isopropyl-N-n-propylamino, N,N-diisopropylamino, N-n-butyl-N-methyl- amino, and N-tert-butyl-N-methylamino, for example.
  • BHC221035 EP (C 3 -C 6 )-Cycloalkyl in the context of the invention means a monocyclic, saturated carbocycle having 3, 4, 5 or 6 ring carbon atoms, such as: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, for example, particularly cyclopropyl and cyclobutyl, 4- to 7-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl in the context of the invention mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O, S, S(O) and S(O) 2 , and which can be bound via a ring carbon atom or via a ring nitrogen atom (if present), such as: azetidinyl, oxetanyl, thietanyl,
  • 5-membered aza-heteroaryl in the context of the invention means an aromatic heterocyclic group (heteroaromatic) having 5 ring atoms in total, which contains at least one ring nitrogen atom and optionally one or two further ring heteroatoms selected from N, O and S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency), in particular a 5-membered aza-heteroaryl containing one ring nitrogen atom and one or two further ring heteroatoms selected from N and O, such as: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, for example, particularly pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and oxa- diazolyl.
  • An oxo substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond. It is possible for the compounds of general formula (I) to exist as isotopic variants.
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • the term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • the expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, respectively.
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”).
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I).
  • These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general BHC221035 EP formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem.
  • deuterium-containing compound of general formula (I) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I).
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium- containing compounds of general formula (I) having a certain pattern of one or more deuterium- BHC221035 EP hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P 450 .
  • cytochrome P 450 sites of attack for metabolizing enzymes such as e.g. cytochrome P 450 .
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Preferred isomers are those which produce the more desirable biological activity.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or BHC221035 EP without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, it is possible for the compounds of the present invention to exist as tautomers.
  • any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 3H tautomer, or even a mixture in any amount of the two tautomers, namely : 1H tautomer 3H tautomer
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, BHC221035 EP in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g.
  • a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2- (4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2- naphthoic, nicotinic
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester means an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C 1 -C 6 alkoxymethyl esters, e.g. methoxymethyl, C 1 -C 6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxy-carbonyloxy-C 1 -C 6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl ; 1,3-dioxolen-2- onylmethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • Embodiment 1 A compound of general formula (I) wherein R 1 and R 2 are independently selected from the group consisting of C 1-4 -alkyl; or R 1 and R 2 together with the phosphor atom they are attached to form a 4-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl or ;
  • R 3 is selected from the group consisting of C 3-5 -cycloalkyl and 4 to 6 membered heterocycloalkyl, wherein said C 3-5 -cycloalkyl is optionally substituted with 1, 2, 3 or4 Fluor atoms, wherein said 5 membered heterocycloalkyl is optionally substituted with 1 BHC221035 EP or 2 Fluor atoms and wherein said 6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms;
  • R 4 is selected from H, D, -CH 3 , or -CH 2 -CH 3 ; or R
  • Embodiment 2 Compound according to embodiment 1 wherein R 1 and R 2 are both -CH 3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 3 Compound according to embodiment 1 wherein R 1 and R 2 together with the phosphor atom they are attached to form a 5 membered heterocycloalkyl or a 5 membered heterocycloalkenyl or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 4 Compound according to embodiment 1 wherein R 3 is selected from the group consisting of cyclopropyl, cyclobutyl or oxetan, wherein said cyclopropyl or cyclobutyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 5 Compound according to embodiment 1 wherein R 3 is selected from the group consisting of cyclopropyl or cyclobutyl and wherein said cyclopropyl or cyclobutyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 6 Compound according to embodiment wherein R 3 is selected from the group consisting of cyclopropyl or cyclobutyl or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • BHC221035 EP Embodiment 7: Compound according to embodiment 1 wherein R 4 is -CH 3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 8 Compound according to embodiment 1 wherein the combination of R 3 /R 4 are selected from the combinations of cyclopropyl/-CH 3 , cyclobutyl/-CH 3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 9 Compound according to embodiment 1 wherein R 4 is D (Deuterium) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 10 Compound according to embodiment 1 wherein R 3 and R 4 together with the carbon atom they are attached to form a cyclopropyl optionally substituted with one -CH 3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 11 Compound according to embodiment 1 wherein R 5 is F or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Embodiment 12 The compound according to embodiment 1, which is selected from the group consisting of: (2RS)-2-cyclopropyl-1- ⁇ 3-[(1R)-1- ⁇ [6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino ⁇ ethyl]-2-fluorophenyl ⁇ -1,1-difluoropropan-2-ol; (2R)-2-cyclopropyl-1- ⁇ 3-[(1R)-1- ⁇ [6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino ⁇ ethyl]-2-fluorophenyl ⁇ -1,1-difluoropropan-2-ol; (2S)-2-cyclopropyl-1- ⁇ 3-[(1R)-1- ⁇ [6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]
  • Embodiment 13 A compound of general formula (I) according to any one of embodiments 1 to 9 for use in the treatment or prophylaxis of a disease.
  • Embodiment 14 A pharmaceutical composition comprising a compound of general formula (I) according to any one of embodiments 1 to 9 and one or more pharmaceutically acceptable excipients.
  • Embodiment 15 A pharmaceutical combination comprising: • one or more first active ingredients, in particular compounds of general formula (I) according to any one of embodiments 1 to 9, and • one or more further active ingredients, in particular oncology agents like 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II,
  • Embodiment 16 Use of a compound of general formula (I) according to any one of embodiments 1 to 9 for the treatment or prophylaxis of a disease.
  • Embodiment 17 Use of a compound of general formula (I) according to any one of embodiments 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease.
  • the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula.
  • the present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
  • the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
  • the present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra. BHC221035 EP
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula, supra.
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to effectively inhibit Ras-Sos1 interaction and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative disorders in humans and animals.
  • Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder.
  • Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • BHC221035 EP Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the present invention also provides methods of treating angiogenic disorders including diseases associated with excessive and/or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J.
  • compounds of general formula (I) of the present invention can be utilized to treat and/or prevent any of the BHC221035 EP aforementioned angiogenesis disorders, for example by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation, or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
  • treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2.
  • the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
  • the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA BHC221035 EP damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention.
  • the cell is treated with at least one compound of general formula (I) of the present invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent, i.e.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell.
  • a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
  • the cell is in vitro.
  • the cell is in vivo.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a compound of general formula (I) as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at
  • the compounds according to the invention can have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • a suitable manner such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, BHC221035 EP ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual
  • compositions according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of a hyperproliferative disorder.
  • the present invention covers a pharmaceutical combination, which comprises: BHC221035 EP • one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and • one or more further active ingredients, in particular hyperproliferative disorder.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with known oncology agents.
  • oncology agents include: 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado- trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione,
  • the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than BHC221035 EP once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • EXPERIMENTAL SECTION NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the 1 H-NMR data of selected compounds are listed in the form of 1 H-NMR peaklists.
  • ⁇ 1 intensity 1
  • ⁇ 2 intensity 2
  • ⁇ i intensity i
  • ⁇ n intensity n
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation.
  • peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13 C satellite peaks, and/or spinning sidebands. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis BHC221035 EP of "by-product fingerprints".
  • An expert who calculates the peaks of the target compound by known methods can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H-NMR interpretation.
  • MestReC ACD simulation, or by use of empirically evaluated expectation values
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil ® or KP-NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
  • chromatography particularly flash column chromatography
  • prepacked silica gel cartridges e.g. Biotage SNAP cartidges KP-Sil ® or KP-NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
  • interconversion of any of the substituents can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled BHC221035 EP in the art (see for example P.G.M. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4'" edition, Wiley 2006). Specific examples are described in the subsequent paragraphs.
  • R b * could be for example (not-limiting), hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl.
  • R c * is either identical with R a * or identical with P(O)R 1 R 2 according to general BHC221035 EP formula (I).
  • LG represents a leaving group, such as, for example, halide, preferably chloro, alkylsulfonyl, alkylsulfonate, and, arylsulfonate, as depicted.
  • Step 1 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation:
  • halogen substituted benzoic acid derivative of general formula (II) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures.
  • derivative (II) is reacted with ammonia to form a derivative of general formula (III), preferably under elevated temperatures, optionally under high pressure, in water or an organic solvent or mixture thereof, such as for example, 1,2-dichloroethane, THF, methanol, ethanol.
  • WO2017069275 US20030199511 and US20030187026 and the references therein.
  • derivative (II) can be converted to the corresponding acid chloride, with for example thionyl chloride, oxalyl chloride, in an organic solvent, optionally with a drop of DMF, optionally at elevated temperature, in an organic solvent.
  • the corresponding acid chloride can be treated with an imidamide or a salt thereof, with an inorganic base such as for example, caesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as for example triethylamine, diisopropylethylamine or pyridine with or without DMAP, optionally using metal-catalyzed reactions, optionally in the presence of a ligand, in an organic solvent such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature.
  • an inorganic base such as for example, caesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as for example triethylamine, diisopropylethylamine or pyridine with or without DMAP
  • metal-catalyzed reactions optionally in the presence of a ligand, in an organic solvent such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature.
  • Step 2 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, amino substituted benzoic acid derivative of general formula (III) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (III) is reacted with acetamidine or an imidamide, optionally with a base such as for example potassium carbonate or sodium hydroxide or triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec- 7-ene or pyridine in an organic solvent such as for example DMF at elevated temperature.
  • a base such as for example potassium carbonate or sodium hydroxide or triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec- 7-ene or pyridine
  • organic solvent such as for example DMF at elevated temperature.
  • derivative (IV) could be reacted with an imidamide or a salt there of, an inorganic base such as for example, caesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or pyridine with or without DMAP, optionally BHC221035 EP using a metal-catalyzed reaction, optionally in the presence of a ligand, in an organic solvent such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature.
  • an inorganic base such as for example, caesium carbonate, sodium carbonate, potassium carbonate
  • organic base such as for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or pyridine with or without DMAP
  • derivative (V) could be reacted with a nitrile, carboxylic acid chloride, carboxylic acid anhydride, imidamide or a salt there of, in the presence of an acid or a base, in water or an organic solvent, or mixtures thereof, such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature.
  • a nitrile, carboxylic acid chloride, carboxylic acid anhydride, imidamide or a salt there of in the presence of an acid or a base, in water or an organic solvent, or mixtures thereof, such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature.
  • Step 7 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, amino benzoic acid amide derivative of general formula (VIII) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (VIII) could be reacted with an organic acid at elevated temperature, an organic acid amide or carboxylic acid BHC221035 EP anhydrides or using copper-catalyzed reactions, optionally with a base, water or an organic solvent or mixtures thereof, preferably at elevated temperatures. For example, see Eur. J. Org.
  • Step (IX) ⁇ (IX-A) (Scheme 1) Coupling of a phosphinoxide to an aryl halide
  • Compounds of general formula (IX-A) can be formed from compounds of general formula (IX), with compounds of general formula (XIII, scheme 2) using literature-known methods.
  • Compounds of general formula (XIII) are well-known in the public domain, commercially available or could be synthesized by known synthetic routes. For example (not-limiting), metal catalyzed reactions could be carried out.
  • Step (IX) ⁇ (X) (Scheme 1) Conversion of hydroxyl group into leaving group
  • compound (IX) can be converted to the corresponding derivative (X) bearing a leaving group (LG) in analogy to literature procedures.
  • LG chloro or bromo typically with phosphorus oxytrichloride or phosphorus oxytribromide, respectively, with or without N,N-dimethylaniline or N,N-diisopropylethylamine with or without an organic solvent such as for example toluene at elevated temperatures is used.
  • an organic solvent such as for example toluene at elevated temperatures.
  • LG 2,4,6-triisopropylbenzenesulfonate typically 2,4,6-triisopropylbenzenesulfonyl chloride, a base such as for example triethylamine and/or DMAP in an organic solvent such as for example dichloromethane is used.
  • LG tosylate typically 4-methylbenzene-1-sulfonyl chloride
  • a base such as for example triethylamine or potassium carbonate and/or DMAP in an organic solvent such as for example dichloromethane or acetonitrile is used.
  • organic solvent such as for example dichloromethane or acetonitrile
  • LG trifluoromethanesulfonate typically N,N-bis(trifluoromethylsulfonyl)aniline or trifluoromethanesulfonic anhydride
  • a base such as for example triethylamine or 1,8- diazabicyclo[5.4.0]undec-7-ene and/or DMAP in an organic solvent such as for example dichloromethane
  • an organic solvent such as for example dichloromethane
  • R 1 , R 2 , R 3 , R 4 , and R 5 are defined as in general formula (I) or (protected) derivatives thereof.
  • LG represents a leaving group, such as, for example, halide, preferably chloro, alkylsulfonyl, alkylsulfonate or arylsulfonate, as depicted in scheme 1.
  • PG is a standard hydroxy protective group, for example, but not limited to triethylsilyl, or H.
  • Compounds of general formula (XII) are well known in the public domain and can be formed from compounds of general formula (IX) with compounds of general formula (XI) using dehydrative conjugation methods.
  • a base such as for example triethylamine or potassium carbonate
  • DMAP organic solvent
  • organic solvent such as for example dichloromethane or acetonitrile.
  • R e is hydrogen or deuterium
  • the respective R d -M is a hydride source or reducing agent known to the person skilled in the art, such as, but not limited to, sodium borohydride, lithium aluminumhydride, diisobutylaluminum hydride, or derivatives or deuterated analogs thereof.
  • Step (XV) ⁇ (XIX) (Scheme 3) Compounds of formula (XIX) can be synthesized by a reaction of an ortho-metallated F-benzene- derivative, derived from (XV), e.g. by reaction with n-butyl lithium, with compound of formula (XVI).
  • Compounds of formula (XIX) can alternatively be synthesized by a reaction of azetophenone derivatives (XVII) with a compound of formula (XVIII) and subsequent reduction of the derived imine, for example, BHC221035 EP but not limited to, sodium borohydride. If the compound of formula (XVIII) is an enantiomerically pure compound, the formation of the compound of formula (XIX) can be achieved in a stereoselective manner.
  • Step (XIX) ⁇ (XX) (Scheme 3) The sulfinamide (XIX) can be converted to the corresponding amine (XX) in analogy to the numerous literature procedures.
  • the reaction can be performed using hydrogenchloride (HCl) in an aprotic organic solvent such as dioxane to give the corresponding HCl salt.
  • Basic aqueous work up gives the free NH 2 amine.
  • the free amine can be protected with a BOC protecting group.
  • This reaction is typically carried out with BOC-anhydride and aqueous sodium hydrogen carbonate in water/tetrahydrofuran.
  • Step (XX) ⁇ (XXII) (Scheme 3) Ullman coupling
  • the aryl iodide (XIX) can be transformed to the ester (XX) to form a new C-C bond trough literature procedure.
  • Such transformations are known to those skilled in the art as “Ullmann reaction”.
  • the aryl iodide and fluoroalkyl bromide are reacted in the presence of an excess of Cu(0) powder at elevated temperature.
  • Step (XXII) ⁇ (XXIII) (Scheme 3) Ester (XXII) can be directly transferred into amide (XXIII) by reacting it with N-methoxymethanamine hydrogen chloride.
  • the reaction is preferably performed in aprotic organic solvents like tetrahydrofurane at low temperature (e.g. -15 °C), in the presence of a base like diisorpropylethylamine, and 2- propylmagnesiumchloride (usually applied as 2 M solution in tetrahydrofuran.
  • (XXIII) can be obtained by a two-step process from (XIX) by saponification of the ester and sunsequent amide formation of the resulting carboxylic acid with N-methoxymethanamine hydrogen chloride.
  • Methods for amide formation are known to the person skilled in the art, typically using a base (for example, but not limited to, diisopropylethylamine, triethylamine) and a coupling reagent (HATU, DCC, EDCI*HCl, T3P, SOCl 2 , and/or oxalyl chloride) in organic solvent such as DMF.
  • a base for example, but not limited to, diisopropylethylamine, triethylamine
  • a coupling reagent HATU, DCC, EDCI*HCl, T3P, SOCl 2 , and/or oxalyl chloride
  • Step (XXIII) ⁇ (XI) (Scheme 3) Conversion of (XXIII) to compounds of formula (XI) comprises three steps: BHC221035 EP 1.) Formation of ketone (XXIV).
  • Such transformations are known to those skilled in the art known as “Grignard addition”. For example, such a transformation can be achieved by using a suitable alkyl magnesium chloride in THF. Aqueous workup delivers the ketone.
  • Analytical LC-MS Method 1 Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 ⁇ m, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
  • Method 2 Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 ⁇ m, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
  • Method 3 BHC221035 EP Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 ⁇ m, 50x2.1mm; eluent A: water + 0.2 vol-% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.7 min 1-45% B, 1.7-1.72 min 45-99% B, 1.72-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; ELSD.
  • Method 4 Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.750x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm
  • Method 5 Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C181.750x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6- 2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm
  • Instrument 6 Instrument: Waters Acquity UPLCMS
  • (2RS)-1- ⁇ 3-[(1R)-1-aminoethyl]-2-fluorophenyl ⁇ -2- cyclobutyl-1,1-difluoropropan-2-ol (intermediate 18, 1.00 g, 3.48 mmol) in DMF (5.0 ml) was added and the mixture was stirred overnight.
  • DMF 5.0 ml
  • ethyl acetate and water were separated and washed twice with water and with saturated aqueous sodium chloride solution. The organic phases were then dried over sodium sulfate and concentrated.
  • Trifluoroacetic acid (3.1 ml, 40 mmol) was added, and the mixture was stirred at RT for 2 h. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting oil (1.345 g, 89 % yield) was used without any further purification.
  • triethylsilyl trifluoromethanesulfonate (9.0 ml, 40 mmol) was added dropwise and the mixture was allowed to warm to RT and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added, and stirred for 10 min, before the phases were separated. The organic phases were dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane, ethanol), followed by a second purification (Biotage® Sfär Amino, ethyl acetate, hexane) to yield the title compound (2.53 g, 85 %).
  • triethylsilyl trifluoromethanesulfonate (7.5 ml, 33 mmol) was added dropwise and the mixture was allowed to warm to RT and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added, and stirred for 10 min, before the phases were separated. The organic phases were dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, BHC221035 EP dichloromethane, ethanol), followed by a second purification (Biotage® Sfär Amino, ethyl acetate, hexane) to yield the title compound (1.9 g, 78 %).
  • Example 1.2 (2R or S)-2-cyclopropyl-1- ⁇ 3-[(1R)-1- ⁇ [6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino ⁇ ethyl]-2-fluorophenyl ⁇ -1,1-difluoropropan-2-ol
  • Example 3 1-(4- ⁇ [(1R)-1- ⁇ 3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl ⁇ ethyl]amino ⁇ -2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one (2 Stereoisomers present) The title compound was synthesized as described for example 2, using (2RS)-1-(3- ⁇ (1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl ⁇ -2-fluorophenyl)-2-cyclopropyl-1,1-difluoropropan-2-ol (Intermediate 20, 125 mg, 252 ⁇ mol), 2,5-dihydro-1H-1lambda 5 -phosphol-1-one (25.8
  • Example 4 1-(4- ⁇ [(1R)-1- ⁇ 3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl ⁇ ethyl]amino ⁇ -2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one (2 Stereoisomers present)
  • the title compound was synthesized as described for example 2, using (2RS)-1-(3- ⁇ (1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl ⁇ -2-fluorophenyl)-2-cyclopropyl-1,1-difluoropropan-2-ol (Intermediate 20, 125 mg, 252 ⁇ mol), 1lambda 5 -phospholan-1-one (26.3 mg, 252 ⁇ mol), tetrakis(triphenyl
  • Example 5 1-(4- ⁇ [(1R)-1- ⁇ 3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl ⁇ ethyl]amino ⁇ -2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one (2 Stereoisomers present) The title compound was synthesized as described for example 2, using (2RS)-1-(3- ⁇ (1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl ⁇ -2-fluorophenyl)-2-cyclobutyl-1,1-difluoropropan-2-ol (Intermediate 19, 125 mg, 245 ⁇ mol), 2,5-dihydro-1H-1lambda 5 -phosphol-1-one (25.0 mg,
  • Example 7 BHC221035 EP (4-((R)-1-(3-((S or R)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide (diaste
  • Example 8 (4-(((R)-1-(3-((S or R)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide (diastereomer 2)
  • the reaction was performed das described for Intermediate 14 using (1R or S)-2-(3- ⁇ (1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl ⁇ -2-fluorophenyl)-1-cyclopropyl-2,2-difluoroethanol (diastereomer 2) (Intermediate 33, 70 mg, 145 ⁇ mol), dimethyl-lambda 5 -phosphanone (11 mg, 145 ⁇ mol), tetrakis(triphenylphosphin
  • EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. Examples were synthesized one or more times.
  • Biochemical assay hK-RasG12C interaction assay with hSOS1 BHC221035 EP This assay quantifies the equilibrium interaction of human SOS1 (SOS1) with human K-Ras G12C (K- RasG12C). Detection of the interaction is achieved by measuring homogenous time-resolved fluorescence resonance energy transfer (HTRF) from antiGST-Europium (FRET donor) bound to GST-K- RasG12C to anti-6His-XL665 bound to His-tagged hSOS1 (FRET-acceptor).
  • HTRF time-resolved fluorescence resonance energy transfer
  • the assay buffer containes 5 mM HEPES pH 7.4 (Applichem), 150 mM NaCl (Sigma), 10 mM EDTA (Promega), 1 mM DTT (Thermofisher), 0.05% BSA Fraction V, pH 7.0, (ICN Biomedicals), 0.0025% (v/v) Igepal (Sigma) and 100 mM KF (FLUKA).
  • the expression and purification of N-terminal GST-tagged K-RasG12C and N-terminal His-tagged SOS1 is described below. Concentrations of protein batches used are optimized to be within the linear range of the HTRF signal.
  • a Ras working solution is prepared in assay buffer containing typically 10 nM GST-hK- RasG12C and 2 nM antiGST-Eu(K) (Cisbio, France).
  • a SOS1 working solution is prepared in assay buffer containing typically 20nM His-hSOS1 and 10 nM anti-6His-XL665 (Cisbio, France).
  • An inhibitor control solution is prepared in assay buffer containing 10 nM anti-6His-XL665 without SOS1. Fifty nl of a 100-fold concentrated solution of the test compound in DMSO are transferred into a black microtiter test plate (384 or 1536, Greiner Bio-One, Germany).
  • a Hummingbird liquid handler Digilab, MA, USA
  • an Echo acoustic system (Labcyte, CA, USA) is used. All steps of the assay are performed at 20°C.
  • a volume of 2.5 ⁇ l of the Ras working solution is added to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After 2 min preincubation, 2.5 ⁇ l of the SOS1 working solution are added to all wells except for those wells at the side of the test plate that are subsequently filled with 2.5 ⁇ l of the inhibitor control solution.
  • IC50 values are calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland).
  • BHC221035 EP pERK HTRF in K-562 (ATCC CCL-243) 10000 K-562 cells are seeded in HTRF 384well low volume plate (Greiner bio-one #784075) in medium (RPMI 1640 + 10% FCS) and treated with varying concentrations of test compounds for 1h.
  • Next steps are performed to the supplier's manual Advanced phospho-ERK1/2 (#64AERPEH) Cisbio one-plate assay protocol.
  • the content of pERK is measured with PHERAstar HTRF protocol, calculated Ratio*1000.
  • the calculated ratio of DMSO-treated cells is set as 100% and the calculated ratio of negative control is set as 0% (maximum possible effect).
  • the IC50 values are determined by means of a 4 parameter fit.
  • In vitro metabolic stability in rat hepatocytes Hepatocytes from Han/Wistar rats were isolated via a 2-step perfusion method. After perfusion, the liver was carefully removed from the rat: the liver capsule was opened and the hepatocytes were gently shaken out into a Petri dish with ice-cold Williams’ medium E (WME).
  • the resulting cell suspension was filtered through sterile gaze in 50 ml falcon tubes and centrifuged at 50 ⁇ g for 3 min at room temperature.
  • the cell pellet was resuspended in 30 ml WME and centrifuged twice through a Percoll® gradient at 100 ⁇ g.
  • the hepatocytes were washed again with WME and resuspended in medium containing 5 % FCS. Cell viability was determined by trypan blue exclusion.
  • liver cells were distributed in WME containing 5 % FCS to glass vials at a density of 1.0 ⁇ 106 vital cells/ml. The test compound was added to a final concentration of 1 ⁇ M.
  • hepatocyte suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, BHC221035 EP 45 and 90 min, to which equal volumes of cold methanol were immediately added. Samples were frozen at -20 °C overnight, subsequently centrifuged for 15 minutes at 3000 rpm and the supernatant was analyzed with an Agilent 1200 HPLC-system with LC/MS-MS detection. The half-life of a test compound was determined from the concentration-time plot.
  • liver blood flow 4.2 L/h/kg, specific liver weight 32 g/kg, liver cells in vivo 1.1 x 108 cells/g liver, liver cells in vitro 1.0 x 106/ml.
  • the in vitro metabolic stability of test compounds was determined by incubation at 1 ⁇ M in a suspension of liver microsomes in 100 mM phosphate buffer pH 7.4 (NaH 2 PO 4 ⁇ H 2 O + Na 2 HPO 4 ⁇ 2H 2 O) and at a protein concentration of 0.5 mg/mL at 37 °C.
  • the microsomes were activated by adding a cofactor mix containing 8 mM glucose-6-phosphate, 4 mM MgCl 2 , 0.5 mM NADP, and 1 IU/mL glucose-6-phosphate dehydrogenase in phosphate buffer pH 7.4.
  • the metabolic assay was started shortly afterward by adding the test compound to the incubation at a final volume of 1 mL.
  • Organic solvent in the incubations was limited to ⁇ 0.01% DMSO and ⁇ 1% MeCN.
  • the microsomal suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, 45, and 60 min, to which an equal volume of cold MeOH was immediately added.
  • Samples were frozen at ⁇ 20 °C overnight and after thawing subsequently centrifuged for 15 min at 3000 rpm. The supernatant was analyzed with an Agilent 1200 HPLC system with LC-MS/MS detection. The half-life of a test compound was determined from the concentration–time plot.
  • the intrinsic clearances and the hepatic in vivo blood clearance (CL) and maximal oral bioavailability (F max ) were calculated using the “well-stirred” liver model (Pang, K. S.; Rowland, M. Hepatic clearance of drugs.
  • I Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance.
  • liver blood flow 5.4, 4.2, 2.1, and 1.32 L/h/kg for mouse, rat, dog, and human, respectively.
  • Specific liver weight 43, 32, 39, and 21 g/kg body weight for mouse, rat, dog, and human, respectively.
  • Microsomal protein content 40 mg/g for all species.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention covers phosphinoxide substituted pyrido[3,4-d]pyrimidine compounds of general formula (I) : in which R1, R2, R3 and R4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

Description

BHC221035 EP SOS1 INHIBITORS The present invention covers phosphinoxide substituted pyrido[3,4-d]pyrimidine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients. BACKGROUND The present invention covers phosphinoxide substituted pyrido[3,4-d]pyrimidine compounds of general formula (I)
Figure imgf000002_0001
which inhibit Ras-Sos1 interaction. Ras proteins play an important role in human cancer. Mutations in Ras proteins can be found in 20-30% of all human tumors and are recognized as tumorigenic drivers especially in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al. 2011 Nature Reviews Cancer). Three human Ras genes are known that encode four different Ras proteins of 21 kDa size: H-Ras, N-Ras, and two splice variants of K-Ras, namely K-Ras 4A and K-Ras-4B. All Ras isoforms are highly conserved within the GTP-binding domain and differ mainly in the hypervariable C- terminal region. The C-termini of the different Ras-isoforms are posttranslationally modified by lipidation (farnesylation, palmitoylation) to facilitate membrane anchorage. The localization of Ras-proteins at the cytoplasmic membrane provides vicinity to transmembrane growth receptors and has been shown to be essential for transmitting growth signals from extracellular growth factor binding to intracellular downstream pathways. A variety of upstream signals may activate Ras proteins depending on the cellular context, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), nerve growth factor receptor (NGFR) and others. Activated Ras can signal through various downstream pathways, e.g. the Raf-MEK-ERK or the PI3K-PDK1-Akt pathways. On the molecular level, Ras proteins function as molecular switches. By binding GTP and GDP they exist in an active (GTP-bound) and inactive (GDP-bound) state in the cell. Active GTP-loaded Ras recruits other proteins by binding of their cognate Ras-binding domains (RBDs) resulting in activation of the effector BHC221035 EP protein followed by downstream signalling events of diverse functions, e.g. cytoskeletal rearrangements or transcriptional activation. The activity status of Ras is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs function as activators of Ras by promoting the nucleotide exchange from GDP to GTP. GAPs deactivate Ras-GTP by catalyzing the hydrolysis of the bound GTP to GDP. In a cancer cell, point mutations, typically within the GTP-binding region at codon 12, eliminate the ability of RAS to efficiently hydrolyse bound GTP, even in the presence of a GAP. Therefore, cancer cells comprise increased levels of active mutated Ras-GTP, which is thought to be a key factor for driving cancer cell proliferation. Three main families of RAS-specific GEFs have been identified so far (reviewed in Vigil 2010 Nature Reviews Cancer; Rojas et al 2011, Genes & Cancer 2(3) 298-305). There are two son of sevenless proteins (SOS1 and SOS2), 4 different isoforms of Ras guanine nucleotide releasing proteins (Ras-GRP1-4) and two Ras guanine nucleotide releasing factors (Ras-GRF1 and 2). The SOS proteins are ubiquitously expressed and are recruited to sites of activated growth factors. Ras-GRFs are expressed mainly in the nervous system, where they are involved in Calcium-dependent activation of Ras. In contrast, Ras GRP proteins are expressed in hematopoietic cells and act in concert with non-receptor tyrosine kinases. In the context of cancer, mainly SOS proteins have been found to be involved. Targeting Ras for cancer therapy has been a dream since the 1990s (Downward 2002 Nature Reviews Cancer, Krens et al.2010 Drug Discovery Today). Due to the compact nature, the high affinity towards GDP and GTP in combination with high intracellular GTP concentrations, the Ras protein itself has always been considered to be undruggable, i.e. the chance to identify small chemical molecules that would bind to and inhibit active Ras was rated extremely low. Alternative approaches have been undertaken to reduce Ras signaling, e.g. by addressing more promising drug targets such as enzymes involved in the posttranslational modification of Ras proteins, especially farnesyltransferase and geranylgeranyltransferase (Berndt 2011 Nature Reviews Cancer). Inhibitors of farnesyltransferase (FTIs) were identified and developed with promising antitumor effects in preclinical models. Unexpectedly, in clinical trials these inhibitors have been of limited efficacy. Targeting upstream and downstream kinases involved in Ras signaling pathways has been more successful. Several drugs are and have been in clinical trials that inhibit different kinases, e.g. EGFR, Raf, MEK, Akt, PI3K (Takashima & Faller 2013 Expert Opin. Ther. Targets). Marketed cancer drugs are available that inhibit Raf, EGFR or MEK. Nevertheless, there is still a large unmet need for the treatment of Ras-dependent tumors that are resistant against current therapies. Many research groups have been active to identify small molecules that target Ras directly (Ras small molecules have been reviewed in: Cox et al. 2014 Nature Reviews Drug Discovery, Spiegel et al.2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie, Marin- Ramos et al Seminars in Cancer Biology). One group of inhibitors comprises small molecules that inhibit BHC221035 EP the interaction of Ras with its effectors Raf or PI3K. Another group of compounds acts as covalent inhibitors of a specific cysteine mutant form of K-Ras (glycine to cysteine point mutation G12C). The specific targeting of the Ras-G12C mutant might have the benefit of reduced side effects, as the wildtype Ras proteins should not be affected. Furthermore, several reports show small molecules and peptides that interrupt the GEF assisted activation of Ras (Hillig et al 2019 PNAS; Gray et al 2019 Angewandte Chemie). There seem to be several different binding sites possible that result in this mode of action. Inhibitors may bind to Ras or to the GEF in an allosteric or orthosteric fashion. All these approaches of direct Ras-targeting are in preclinical research stage. Stabilized peptides have been shown to be active in the nanomolar range. (Leshchiner et al.2015 PNAS). Their usefulness as drugs in a clinical setting has to be awaited. The Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase (TK) receptor that is activated upon binding to the Epidermal Growth Factor and other growth factor ligands, triggering several downstream pathways, including RAS/MAPK, PI3K/Akt and STAT that regulate different cellular processes, including DNA synthesis and proliferation (Russo A, Oncotarget.4254, 2015). The family of HER (ErbB) receptor tyrosine kinases consists of four members, ie, epidermal growth factor receptors [EGFR (HER1 or ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4)]. Overexpression, mutation, or aberrant activity of these receptors has been implicated in various types of cancer (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147). First-generation inhibitors Erlotinib and Gefitinib are small molecule inhibitors of the EGFR/HER-1 (human epidermal growth factor receptor) tyrosine kinase. Erlotinib and Gefitinib were developed as reversible and highly specific small- molecule tyrosine kinase inhibitors that competitively block the binding of adenosine triphosphate to its binding site in the tyrosine kinase domain of EGFR, thereby inhibiting autophosphorylation and blocking downstream signaling (Cataldo VD, N Engl J Med, 2011, 364, 947). Second-generation inhibitors Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for the first-line treatment of patients with NSCLC whose tumors are driven by activating mutations of genes coding for epidermal growth factor receptor (EGFR). Afatinib is also an inhibitor of a specific EGFR mutation (T790M) that causes resistance to first-generation EGFR-targeted TKIs in about half of patients receiving those drugs. (Engle JA, Am J Health Syst Pharm 2014, 71 (22), 1933). Neratinib, a pan-HER inhibitor, irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be BHC221035 EP effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clinical trials in breast cancers and other solid tumors, including those with HER2 mutation (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147). Dacomitinib is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell lines and xenograft studies, dacomitinib demonstrated activities against both activating EGFR mutations and EGFR T790M (Liao BC, Curr Opin Oncol.2015, 27(2), 94). Third-generation inhibitors The third-generation EGFR-TKIs were designed to inhibit EGFR T790M while sparing wild-type EGFR. AZD9291 (AstraZeneca, Macclesfield, UK), a mono-anilino-pyrimidine compound, is an irreversible mutant selective EGFR-TKI. This drug is structurally different from the first and second-generation EGFR- TKIs. In preclinical studies, it potently inhibited phosphorylation of EGFR in cell lines with activating EGFR mutations (EGFR del19 and EGFR L858R) and EGFR T790M. AZD9291 also caused profound and sustained tumor regression in tumor xenograft and transgenic mouse models harboring activating EGFR mutations and EGFR T790M. AZD9291 was less potent in inhibiting phosphorylation of wild-type EGFR cell lines (Liao BC, Curr Opin Oncol.2015, 27(2), 94). Rociletinib (CO-1686) (Clovis Oncology, Boulder, Colo), a 2,4-disubstituted pyrimidine molecule, is an irreversible mutant selective EGFR-TKI. In preclinical studies, CO-1686 led to tumor regression in cell- lines, xenograft models, and transgenic mouse models harboring activating EGFR mutations and EGFR T790M (Walter AO, Cancer Discov, 2013, 3(12), 1404). HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea) is an orally administered, selective inhibitor for activating EGFR mutations and EGFR T790M. It has low activity against wild-type EGFR (Steuer CE, Cancer.2015, 121(8), E1). Hillig et al 2019 PNAS describe compounds like
Figure imgf000005_0001
as a potent SOS1 inhibitor and as a tool compound for further investigation of RAS-SOS1 biology in vitro. FR 3066761 (Universite d’Orleans et al) describes compounds like BHC221035 EP
Figure imgf000006_0001
for the treatment of cancer. WO 2018/134685 (Eisai Management Co. Ltd. et al) describes compounds like
Figure imgf000006_0002
for the treatment and prevention of filarial worm infection. WO 2018/172250 (Bayer Pharma AG) describes 2-methyl-quinazoline like
Figure imgf000006_0003
as inhibiting Ras-Sos interaction. WO 2018/115380 (Boehringer Ingelheim) describes benzylamino substituted quinazolines like
Figure imgf000006_0004
as SOS1 inhibitors. WO 2019/122129 (Boehringer Ingelheim) describes benzylaminosubstituted pyridopyrimidinones like BHC221035 EP
Figure imgf000007_0001
as SOS1 inhibitors. WO 2020/180768 and WO 2020/180770 (Revolution) describe compounds of the following formulas:
Figure imgf000007_0002
as SOS1 inhibitors. WO 2021/228028 (Chia Tai TianQing Parmaceutical Group) describes compounds of the following formula
Figure imgf000007_0003
as SOS1-Inhibitors. It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties. In particular, the compounds of the present invention have surprisingly been found to effectively and selectively inhibit the Ras-Sos1 interaction and may therefore be used for the treatment or prophylaxis of hyper-proliferative disorders, in particular cancer. Certain embodiments or compounds of the present invention display an IC50 below 75 nM (determined in a Phophor ERK assay as described below). Furthermore certain embodiments or compounds of the present invention dislplay an IC50 below 10 nM (determined in a Ras-SOS1-interaction assay as described below). Certain embodiments or compounds of the present invention have an Fmax (as described below) of more than 60 % in rat hepatocytes. BHC221035 EP Certain embodiments or compounds of the present invention have an Fmax (as described below) of more than 60 % in human hepatocytes. DESCRIPTION of the INVENTION In accordance with a first aspect, the present invention covers compounds of general formula (I):
Figure imgf000008_0001
wherein R1 and R2 are independently selected from the group consisting of C1-4-alkyl; or R1 and R2 together with the phosphor atom they are attached to form a 4-6 membered
Figure imgf000008_0002
heterocycloalkyl or a 5-6 membered heterocycloalkenyl or ; R3 is selected from the group consisting of C3-5-cycloalkyl and 4 to 6 membered heterocycloalkyl, wherein said C3-5-cycloalkyl is optionally substituted with 1, 2, 3 or4 Fluor atoms, wherein said 5 membered heterocycloalkyl is optionally substituted with 1 or 2 Fluor atoms and wherein said 6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms; R4 is selected from H, D, -CH3, or -CH2-CH3; or R3 and R4 together with the carbon atom they are attached to form a cyclopropyl, a cyclobutyl or a cyclopentyl, wherein said cyclopropyl, and cyclobutyl are optionally substituted with one or two -CH3; and R5 is selected from the group consisting of -H, -F and -CH3; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. DEFINITIONS The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible. BHC221035 EP The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non- hydrogen substituent on any available carbon or nitrogen or … atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3. As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”. When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent. As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond. The term “ring substituent” means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring. Should a composite substituent be composed of more than one parts, e.g. (C1-C4-alkoxy)-(C1-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the C1-C4-alkoxy part can be attached to any carbon atom of the C1-C4-alkyl part of said (C1-C4-alkoxy)-(C1-C4-alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom. The term “comprising” when used in the specification includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text. The terms as mentioned in the present text have the following meanings: The term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom. BHC221035 EP The term “C1-C6-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group. The term “C1-C6-hydroxyalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6-alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group. The term “C1-C6-alkylsulfanyl” means a linear or branched, saturated, monovalent group of formula (C1-C6-alkyl)-S-, in which the term “C1-C6-alkyl” is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl group. The term “C1-C6-haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl. The term “C1-C6-alkoxy” means a linear or branched, saturated, monovalent group of formula (C1-C6-alkyl)-O-, in which the term “C1-C6-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof. The term “C1-C6-haloalkoxy” means a linear or branched, saturated, monovalent C1-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C6-haloalkoxy group is, for BHC221035 EP example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy. The term “C2-C6-alkenyl” means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then it is possible for said double bonds to be isolated from, or conjugated with, each other. Said alkenyl group is, for example, an ethenyl (or “vinyl”), prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, 1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl, 3-methylbut-1-enyl, 2-methylbut-1-enyl, 1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, 3-methylpent-3-enyl, 2-methylpent-3-enyl, 1-methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1-methylpent-2-enyl, 4-methylpent-1-enyl, 3-methylpent-1-enyl, 2-methylpent-1-enyl, 1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1-ethylbut-2-enyl, 3-ethylbut-1-enyl, 2-ethylbut-1-enyl, 1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, 2-propylprop-1-enyl, 1-propylprop-1-enyl, 2-isopropylprop-1-enyl, 1-isopropylprop-1-enyl, 3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl or hexa-1,5-dienyl group. Particularly, said group is vinyl or allyl. The term “C2-C6-alkynyl” means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkynyl”). Said C2-C6-alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl. BHC221035 EP The term “C3-C8-cycloalkyl” means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms (“C3-C8-cycloalkyl”). Said C3-C8-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl. The term “C4-C8-cycloalkenyl” means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms (“C4-C6-cycloalkenyl”). Said C4-C8-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl. The term “C3-C8-cycloalkoxy” means a saturated, monovalent, mono- or bicyclic group of formula (C3-C8-cycloalkyl)-O-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C3-C8-cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group. The term "spirocycloalkyl" means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 11 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom. Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl. The terms “4- to 7-membered heterocycloalkyl” and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example. BHC221035 EP Particularly, “4- to 6-membered heterocycloalkyl” means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O. The term “5- to 8-membered heterocycloalkenyl” means a monocyclic, unsaturated, non-aromatic heterocycle with 5, 6, 7 or 8 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said heterocycloalkenyl group is, for example, 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl. The term “heterospirocycloalkyl” means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom. Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-. The term “fused heterocycloalkyl” means a bicyclic, saturated heterocycle with 6, 7, 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, which “fused heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said fused heterocycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl. The term “bridged heterocycloalkyl” means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which “bridged BHC221035 EP heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom. Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2.2]decyl. The term “heteroaryl” means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency). Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl. In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. The term “C1-C6”, as used in the present text, e.g. in the context of the definition of “C1-C6-alkyl”, “C1-C6-haloalkyl”, “C1-C6-hydroxyalkyl”, “C1-C6-alkoxy” or “C1-C6-haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5 or 6 carbon atoms. Further, as used herein, the term “C3-C8”, as used in the present text, e.g. in the context of the definition of “C3-C8-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e.3, 4, 5, 6, 7 or 8 carbon atoms. BHC221035 EP When a range of values is given, said range encompasses each value and sub-range within said range. For example: "C1-C6" encompasses C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C2-C6" encompasses C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C3-C10" encompasses C3, C4, C5, C6, C7, C8, C9, C10, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10; "C3-C8" encompasses C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C3-C6" encompasses C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C4-C8" encompasses C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C4-C7" encompasses C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6 and C6-C7; "C4-C6" encompasses C4, C5, C6, C4-C6, C4-C5 and C5-C6; "C5-C10" encompasses C5, C6, C7, C8, C9, C10, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7- C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10; "C6-C10" encompasses C6, C7, C8, C9, C10, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9- C10. As used herein, the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy. In the context of the present invention, the substituents and residues have the following meanings, unless specified otherwise: BHC221035 EP in the context of the invention means a straight-chain or branched alkyl group having 1, 2,
Figure imgf000016_0001
3 or 4 carbon atoms, such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert- butyl, for example. (C1-C4)-Alkoxy in the context of the invention means a straight-chain or branched alkoxy group having 1, 2, 3 or 4 carbon atoms, such as: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec- butoxy, and tert-butoxy, for example. Mono-(C1-C4)-alkylamino in the context of the invention means an amino group with one straight-chain or branched alkyl substituent which contains 1, 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, for example. Di-(C1-C4)-alkylamino in the context of the invention means an amino group with two identical or different straight-chain or branched alkyl substituents which each contain 1, 2, 3 or 4 carbon atoms, such as: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-methylamino, N-isopropyl-N-n-propylamino, N,N-diisopropylamino, N-n-butyl-N-methyl- amino, and N-tert-butyl-N-methylamino, for example. (C1-C4)-Alkylcarbonyl in the context of the invention means a straight-chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carbonyl group [-C(=O)- ], such as: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, and pivaloyl, for example. (C1-C4)-Alkoxycarbonyl in the context of the invention means a straight-chain or branched alkoxy group having 1, 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carbonyl group [-C(=O)- ], such as: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, and tert-butoxycarbonyl, for example. Mono-(C1-C4)-alkylaminocarbonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a carbonyl group [-C(=O)-] and which has one straight-chain or branched alkyl substituent having 1, 2, 3 or 4 carbon atoms, such as: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, and tert-butylaminocarbonyl, for example. Di-(C1-C4)-alkylaminocarbonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a carbonyl group [-C(=O)-] and which has two identical or different straight- chain or branched alkyl substituents having in each case 1, 2, 3 or 4 carbon atoms, such as: N,N- dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n- propylaminocarbonyl, N-isopropyl-N-methylaminocarbonyl, N,N-diisopropylaminocarbonyl, N-n-butyl- N-methylaminocarbonyl, and N-tert-butyl-N-methylaminocarbonyl, for example. BHC221035 EP (C3-C6)-Cycloalkyl in the context of the invention means a monocyclic, saturated carbocycle having 3, 4, 5 or 6 ring carbon atoms, such as: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, for example, particularly cyclopropyl and cyclobutyl, 4- to 7-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl in the context of the invention mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O, S, S(O) and S(O)2, and which can be bound via a ring carbon atom or via a ring nitrogen atom (if present), such as: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetra- hydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazinanyl, morpholinyl, thiomor- pholinyl, 1,1-dioxidothiomorpholinyl, azepanyl, 1,4-diazepanyl, and 1,4-oxazepanyl, for example, in particular a 4- to 6-membered heterocycloalkyl containing one ring nitrogen atom and optionally one further ring heteroatom from the series N, O or S(O)2 and a 5- or 6-membered heterocycloalkyl con- taining one ring nitrogen atom and optionally one further ring heteroatom from the series N or O: such as: azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, piperidinyl, piperazinyl, 1,2-oxazinanyl, morpholinyl, and thiomorpholinyl, particularly pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. 5-membered aza-heteroaryl in the context of the invention means an aromatic heterocyclic group (heteroaromatic) having 5 ring atoms in total, which contains at least one ring nitrogen atom and optionally one or two further ring heteroatoms selected from N, O and S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency), in particular a 5-membered aza-heteroaryl containing one ring nitrogen atom and one or two further ring heteroatoms selected from N and O, such as: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, for example, particularly pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and oxa- diazolyl. An oxo substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond. It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I). The term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. BHC221035 EP The term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. The expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998. Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 125I, 129I and 131I, respectively. With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3H or 14C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or 11C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies. Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. The term “deuterium-containing compound of general formula (I)” is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general BHC221035 EP formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s). The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound’s pharmacokinetic/ pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads. A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium- containing compounds of general formula (I) having a certain pattern of one or more deuterium- BHC221035 EP hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or BHC221035 EP without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976). The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, it is possible for the compounds of the present invention to exist as tautomers. For example, any compound of the present invention which contains an imidazopyridine moiety as a heteroaryl group for example can exist as a 1H tautomer, or a 3H tautomer, or even a mixture in any amount of the two tautomers, namely :
Figure imgf000021_0001
1H tautomer 3H tautomer The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides. The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates. The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, BHC221035 EP in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates. Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention. The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19. A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2- (4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2- naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example. Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, BHC221035 EP N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2- amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N- trimethylammonium, choline or benzalkonium. Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods. The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition. As used herein, the term “in vivo hydrolysable ester” means an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-C1-C6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl ; 1,3-dioxolen-2- onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl ; and C1-C6-alkoxycarbonyloxyethyl esters, e.g.1-methoxycarbonyloxyethyl, it being possible for said esters to be formed at any carboxy group in the compounds of the present invention. BHC221035 EP An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio. Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body. The invention also covers the following embodimdents: Embodiment 1: A compound of general formula (I)
Figure imgf000024_0001
wherein R1 and R2 are independently selected from the group consisting of C1-4-alkyl; or R1 and R2 together with the phosphor atom they are attached to form a 4-6 membered
Figure imgf000024_0002
heterocycloalkyl or a 5-6 membered heterocycloalkenyl or ; R3 is selected from the group consisting of C3-5-cycloalkyl and 4 to 6 membered heterocycloalkyl, wherein said C3-5-cycloalkyl is optionally substituted with 1, 2, 3 or4 Fluor atoms, wherein said 5 membered heterocycloalkyl is optionally substituted with 1 BHC221035 EP or 2 Fluor atoms and wherein said 6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms; R4 is selected from H, D, -CH3, or -CH2-CH3; or R3 and R4 together with the carbon atom they are attached to form a cyclopropyl, a cyclobutyl or a cyclopentyl, wherein said cyclopropyl, and cyclobutyl are optionally substituted with one or two -CH3; and R5 is selected from the group consisting of -H, -F and -CH3; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 2: Compound according to embodiment 1 wherein R1 and R2 are both -CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 3: Compound according to embodiment 1 wherein R1 and R2 together with the phosphor atom they are attached to form a 5 membered heterocycloalkyl or a 5 membered heterocycloalkenyl or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 4: Compound according to embodiment 1 wherein R3 is selected from the group consisting of cyclopropyl, cyclobutyl or oxetan, wherein said cyclopropyl or cyclobutyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 5: Compound according to embodiment 1 wherein R3 is selected from the group consisting of cyclopropyl or cyclobutyl and wherein said cyclopropyl or cyclobutyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 6: Compound according to embodiment wherein R3 is selected from the group consisting of cyclopropyl or cyclobutyl or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. BHC221035 EP Embodiment 7: Compound according to embodiment 1 wherein R4 is -CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 8: Compound according to embodiment 1 wherein the combination of R3/R4 are selected from the combinations of cyclopropyl/-CH3, cyclobutyl/-CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 9: Compound according to embodiment 1 wherein R4 is D (Deuterium) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 10: Compound according to embodiment 1 wherein R3 and R4 together with the carbon atom they are attached to form a cyclopropyl optionally substituted with one -CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 11: Compound according to embodiment 1 wherein R5 is F or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 12: The compound according to embodiment 1, which is selected from the group consisting of: (2RS)-2-cyclopropyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol; (2R)-2-cyclopropyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol; (2S)-2-cyclopropyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol; (4-(((1R)-1-(3-((2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide; (4-(((1R)-1-(3-((2R)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide; BHC221035 EP (4-(((1R)-1-(3-((2S)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide; 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one; 1-(4-{[(1R)-1-{3-[(2R)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one; 1-(4-{[(1R)-1-{3-[(2S)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one; 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one; 1-(4-{[(1R)-1-{3-[(2R)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one; 1-(4-{[(1R)-1-{3-[(2S)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one; 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one; 1-(4-{[(1R)-1-{3-[(2R)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one; 1-(4-{[(1R)-1-{3-[(2S)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one; 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one; 1-(4-{[(1R)-1-{3-[(2R)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one; 1-(4-{[(1R)-1-{3-[(2S)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one; (2RS)-2-cyclobutyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol; (2R)-2-cyclobutyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol; BHC221035 EP (2S)-2-cyclobutyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. Embodiment 13: A compound of general formula (I) according to any one of embodiments 1 to 9 for use in the treatment or prophylaxis of a disease. Embodiment 14: A pharmaceutical composition comprising a compound of general formula (I) according to any one of embodiments 1 to 9 and one or more pharmaceutically acceptable excipients. Embodiment 15: A pharmaceutical combination comprising: • one or more first active ingredients, in particular compounds of general formula (I) according to any one of embodiments 1 to 9, and • one or more further active ingredients, in particular oncology agents like 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, BHC221035 EP enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, ribociclib, risedronic acid, rhenium- 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium BHC221035 EP (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]- octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. Embodiment 16: Use of a compound of general formula (I) according to any one of embodiments 1 to 9 for the treatment or prophylaxis of a disease. Embodiment 17: Use of a compound of general formula (I) according to any one of embodiments 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease. In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”. The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra. The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula. The present invention covers the compounds of general formula (I) which are disclosed in the Example Section of this text, infra. In accordance with a fifth aspect, the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra. The present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra. BHC221035 EP The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formula, supra. The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art. Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit Ras-Sos1 interaction and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative disorders in humans and animals. Compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder. Hyperproliferative disorders include, but are not limited to, for example : psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias. Examples of breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. BHC221035 EP Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. The present invention also provides methods of treating angiogenic disorders including diseases associated with excessive and/or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med., 1994, 331, 1480 ; Peer et al., Lab. Invest., 1995, 72, 638], age-related macular degeneration (AMD) [Lopez et al., Invest. Opththalmol. Vis. Sci., 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in- stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of general formula (I) of the present invention can be utilized to treat and/or prevent any of the BHC221035 EP aforementioned angiogenesis disorders, for example by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation, or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth. Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated patients, 6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments, 7. provide a longer time for tumour progression, and/or 8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects. In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention. In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize a cell to radiation, i.e. treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA BHC221035 EP damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with at least one compound of general formula (I) of the present invention. Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present invention in combination with conventional radiation therapy. The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell. In other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents. In other embodiments, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell. In one aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun. In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo. BHC221035 EP In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized. The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes. It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms. For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, BHC221035 EP ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • isotonicity agents (for example glucose, sodium chloride), • adsorbents (for example highly-disperse silicas), • viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine), • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose- sodium (such as, for example, AcDiSol®)), BHC221035 EP • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)), • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)), • capsule materials (for example gelatine, hydroxypropylmethylcellulose), • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), • penetration enhancers, • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), • flavourings, sweeteners, flavour- and/or odour-masking agents. The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention. In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of a hyperproliferative disorder. Particularly, the present invention covers a pharmaceutical combination, which comprises: BHC221035 EP • one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and • one or more further active ingredients, in particular hyperproliferative disorder. The term “combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts. A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture. A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known oncology agents. Examples of oncology agents include: 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado- trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, BHC221035 EP carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, BHC221035 EP Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]- octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than BHC221035 EP once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. EXPERIMENTAL SECTION NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The 1H-NMR data of selected compounds are listed in the form of 1H-NMR peaklists. Therein, for each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1 (intensity1), δ2 (intensity2), ... , δi (intensityi), ... , δn (intensityn). The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1H-NMR peaklist is similar to a classical 1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13C satellite peaks, and/or spinning sidebands. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis BHC221035 EP of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http://www.researchdisclosure.com/searching- disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. Chemical names were generated using ACD/Name software from ACD/Labs or ChemDraw Professional software from Perkin Elmer, respectively. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name or ChemDraw generated names. The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. Table 1: Abbreviations The following table lists the abbreviations used herein.
Figure imgf000042_0001
BHC221035 EP
Figure imgf000043_0001
Other abbreviations have their meanings customary per se to the skilled person. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. EXPERIMENTAL SECTION - GENERAL PART All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. BHC221035 EP The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. EXPERIMENTAL SECTION - GENERAL PROCEDURES The compounds of the present invention can be prepared as described in the following section. The schemes and the procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in the schemes can be modified in various ways. The order of transformations exemplified in the schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled BHC221035 EP in the art (see for example P.G.M. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4'" edition, Wiley 2006). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a "one-pot" reaction, as is well-known to the person skilled in the art. The syntheses of the compounds of the present invention are preferably carried out according to the general synthetic sequences, shown in schemes 1-3. Scheme 1
Figure imgf000045_0001
Scheme 1: Synthesis route for the preparation of compounds of general formula (IX) and (X), in which Ra* is a leaving group, for example (not limiting), halide, preferably bromo and Rb* represents a protecting group. Rb* could be for example (not-limiting), hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl. Rc* is either identical with Ra* or identical with P(O)R1R2 according to general BHC221035 EP formula (I). LG represents a leaving group, such as, for example, halide, preferably chloro, alkylsulfonyl, alkylsulfonate, and, arylsulfonate, as depicted. Step 1 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: In the first step halogen substituted benzoic acid derivative of general formula (II) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (II) is reacted with ammonia to form a derivative of general formula (III), preferably under elevated temperatures, optionally under high pressure, in water or an organic solvent or mixture thereof, such as for example, 1,2-dichloroethane, THF, methanol, ethanol. For example, see WO2017069275, US20030199511 and US20030187026 and the references therein. Alternatively, derivative (II) can be converted to the corresponding acid chloride, with for example thionyl chloride, oxalyl chloride, in an organic solvent, optionally with a drop of DMF, optionally at elevated temperature, in an organic solvent. The corresponding acid chloride can be treated with an imidamide or a salt thereof, with an inorganic base such as for example, caesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as for example triethylamine, diisopropylethylamine or pyridine with or without DMAP, optionally using metal-catalyzed reactions, optionally in the presence of a ligand, in an organic solvent such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature. For example, see WO2007134986, Bioorg. Med. Chem. Lett., 2015, 23, 3013 and the references therein. Step 2 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, amino substituted benzoic acid derivative of general formula (III) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (III) is reacted with acetamidine or an imidamide, optionally with a base such as for example potassium carbonate or sodium hydroxide or triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec- 7-ene or pyridine in an organic solvent such as for example DMF at elevated temperature. For example, see WO2004071460, WO2015155306 and Chem. Med. Chem., 2014, 9, 2516. Step 3 ^ General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, halogen substituted benzoic ester derivative of general formula (IV) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature. Typically, derivative (IV) could be reacted with an imidamide or a salt there of, an inorganic base such as for example, caesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or pyridine with or without DMAP, optionally BHC221035 EP using a metal-catalyzed reaction, optionally in the presence of a ligand, in an organic solvent such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature. For example, see Chem. Commun., 2008, 6333; Bioorg. Med. Chem. Lett., 2013, 23, 3325; WO2018118735, WO2007134986 and references therein. Step 4 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, amino substituted benzoic ester derivative of general formula (V) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (V) could be reacted with a nitrile, carboxylic acid chloride, carboxylic acid anhydride, imidamide or a salt there of, in the presence of an acid or a base, in water or an organic solvent, or mixtures thereof, such as for example DMF, toluene, 1,4-dioxane / water at elevated temperature. For example, see J. Med. Chem., 2018, 61, 3389; J. Med. Chem., 2019, 62, 9772; WO2004071460, WO2007134986 and references therein. Step 5 ^ General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, benzoxazinone derivative of general formula (VI) (which could be commercially available or could be prepared in analogy to literature procedures) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (VI) could be reacted with ammonium acetate in an organic solvent at elevated temperature. For example, see J. Med. Chem., 2019, 62, 9772; J. Med. Chem., 2011, 54, 6734; Bioorg. Med. Chem., 2014, 22, 5487 or WO2005105760 and references therein. Step 6 ^ General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, benzoic acid amide derivative of general formula (VII) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (VII) could be reacted with a base such as for example sodium hydroxide in a solvent such as for example water at elevated temperature. For example, see Monatshefte Für Chemie, 1987, 118, 399; WO2007134986, WO2013016999; WO2012028578 and references therein. Step 7 General Formula (IX) (Scheme 1) Bicyclic pyrimidine formation: Alternatively, amino benzoic acid amide derivative of general formula (VIII) (which could be commercially available or described in the literature) could be converted to the corresponding bicyclic pyrimidine (IX) in analogy to literature procedures. Typically, derivative (VIII) could be reacted with an organic acid at elevated temperature, an organic acid amide or carboxylic acid BHC221035 EP anhydrides or using copper-catalyzed reactions, optionally with a base, water or an organic solvent or mixtures thereof, preferably at elevated temperatures. For example, see Eur. J. Org. Chem., 2020, 2730; Polish Journal of Pharmacology and Pharmacy, 1985, 37, 541; Heterocycles, 2015, 90, 857; Yakugaku Zasshi, 1977, 97, 1022 and references therein. Step (IX) ^ (IX-A) (Scheme 1) Coupling of a phosphinoxide to an aryl halide Compounds of general formula (IX-A) can be formed from compounds of general formula (IX), with compounds of general formula (XIII, scheme 2) using literature-known methods. Compounds of general formula (XIII) are well-known in the public domain, commercially available or could be synthesized by known synthetic routes. For example (not-limiting), metal catalyzed reactions could be carried out. For examples, see the teachings of US2019/270704, 2019, A1; US2015/225436, 2015, A1 or J. Med. Chem. 2020, 63, 7081 and references therein. Step (IX) ^ (X) (Scheme 1) Conversion of hydroxyl group into leaving group In the next step (scheme 1) compound (IX) can be converted to the corresponding derivative (X) bearing a leaving group (LG) in analogy to literature procedures. For LG = chloro or bromo typically with phosphorus oxytrichloride or phosphorus oxytribromide, respectively, with or without N,N-dimethylaniline or N,N-diisopropylethylamine with or without an organic solvent such as for example toluene at elevated temperatures is used. For examples, see US2012/53174; WO2012/30912 or WO2012/66122 and references therein. For LG = 2,4,6-triisopropylbenzenesulfonate typically 2,4,6-triisopropylbenzenesulfonyl chloride, a base such as for example triethylamine and/or DMAP in an organic solvent such as for example dichloromethane is used. For example, see WO2010/99379, US2012/53176 and references therein. For LG = tosylate typically 4-methylbenzene-1-sulfonyl chloride, a base such as for example triethylamine or potassium carbonate and/or DMAP in an organic solvent such as for example dichloromethane or acetonitrile is used. For examples, see Org. Lett., 2011, 4374 or Bioorg. Med. Chem. Lett., 2013, 2663 and references therein. For LG = trifluoromethanesulfonate typically N,N-bis(trifluoromethylsulfonyl)aniline or trifluoromethanesulfonic anhydride, a base such as for example triethylamine or 1,8- diazabicyclo[5.4.0]undec-7-ene and/or DMAP in an organic solvent such as for example dichloromethane is used. For examples, see J. Am. Chem. Soc., 2015, 13433 or WO2014/100501 and references therein. BHC221035 EP Scheme 2
Figure imgf000049_0001
Scheme 2: Synthesis route for the preparation of compounds of general formula (I) in which Rc* is defined as described above (compare scheme 1). R1, R2, R3, R4, and R5 are defined as in general formula (I) or (protected) derivatives thereof. LG represents a leaving group, such as, for example, halide, preferably chloro, alkylsulfonyl, alkylsulfonate or arylsulfonate, as depicted in scheme 1. PG is a standard hydroxy protective group, for example, but not limited to triethylsilyl, or H. Compounds of general formula (XII) are well known in the public domain and can be formed from compounds of general formula (IX) with compounds of general formula (XI) using dehydrative conjugation methods. Such methods are known using coupling reagents like benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (pyBOP), see the teachings of J. Org. Chem., 2007, 72, 10194; Advanced Synthesis & Catalysis, 2018, 360, 4764; Bioorg. Med. Chem., 2019, 27, 931; WO 2011028741 A1; are in the public domain. Alternatively, compounds of general formula (XII) can be formed in a two-step process, whereby compounds of general formula (IX) are converted to compounds of general formula (X) using standard well-documented methods, such as, when LG = Cl using phosphorus oxytrichloride, or LG = Br using BHC221035 EP phosphorus oxytribromide, or LG = tosylate typically 4-methylbenzene-1-sulfonyl chloride, a base such as for example triethylamine or potassium carbonate and/or DMAP in an organic solvent such as for example dichloromethane or acetonitrile. For examples, see Org. Lett., 2011, 4374 or Bioorg. Med. Chem. Lett., 2013, 2663 and references therein. Subsequently the compounds of general formula (X) can be converted to compounds of general formula (XII), using a nucleophilic substitution reaction (SNAr) with compounds of general formula (XI) which are well-documented in the public domain and are known to those skilled in the art. Compounds of general formula (XIV) can be formed from compounds of general formula (XII), with compounds of general formula (XIII) using literature-known methods. Compounds of general formula (XIII) are well-known in the public domain, commercially available or could be synthesized by known synthetic routes. For example (not-limiting), metal catalyzed reactions could be carried out. For examples, see the teachings of US2019/270704, 2019, A1; US2015/225436, 2015, A1 or J. Med. Chem. 2020, 63, 7081 and references therein. Subsequently the compounds of general formula (XIV) can be converted to compounds of general formula (I) by using standard well-documented methods, such as (not-limiting) functional group manipulations. For example (not-limiting) when PG is not H, removal of protecting groups can be carried out. In the case, that Rc* represents P(O)R1R2, compounds of formula (XII) can directly be transferred to compounds of formula (I) by removal of the protecting group (PG). In the case, that Rc* represents P(O)R1R2, and PG is H, compounds of formula (XII) are identical with compounds of formula (I). Amine Syntheses
BHC221035 EP
Figure imgf000051_0001
Scheme 3: Synthesis route for the preparation of compounds of general formula (XI), wherein R5 is defined as in general formula (I), and one of Rd and Re is identical with R3 in general formula (I), while the other is identical with R4 in general formula (I), reflecting the fact that the order in which R3 and R4 are introduced, could be either way for certain examples. Rc-M and Rd-M are organometal derivatives, as for example (not imiting) Grignard reagents or alkyl-Lithium reagents known to the person skilled in the art. In the case that Re is hydrogen or deuterium, the respective Rd-M is a hydride source or reducing agent known to the person skilled in the art, such as, but not limited to, sodium borohydride, lithium aluminumhydride, diisobutylaluminum hydride, or derivatives or deuterated analogs thereof. Step (XV) ^ (XIX) (Scheme 3) Compounds of formula (XIX) can be synthesized by a reaction of an ortho-metallated F-benzene- derivative, derived from (XV), e.g. by reaction with n-butyl lithium, with compound of formula (XVI). If the compound of formula (XVI) is an enantiomerically pure compound, the formation of the compound of formula (XIX) can be achieved in a stereoselective manner. Step (XVII) ^ (XIX) (Scheme 3) Compounds of formula (XIX) can alternatively be synthesized by a reaction of azetophenone derivatives (XVII) with a compound of formula (XVIII) and subsequent reduction of the derived imine, for example, BHC221035 EP but not limited to, sodium borohydride. If the compound of formula (XVIII) is an enantiomerically pure compound, the formation of the compound of formula (XIX) can be achieved in a stereoselective manner. Step (XIX) ^ (XX) (Scheme 3) The sulfinamide (XIX) can be converted to the corresponding amine (XX) in analogy to the numerous literature procedures. For example, the reaction can be performed using hydrogenchloride (HCl) in an aprotic organic solvent such as dioxane to give the corresponding HCl salt. Basic aqueous work up gives the free NH2 amine. For a review about sulfinimine and sulfonamide chemistry see for example Chem. Rev. 2010, 110, 3600–3740; Chem. Soc. Rev. 2009, 38, 1162–1186; Tetrahedron 2004, 60, 8003 or WO2013030138 and the references therein. The free amine can be protected with a BOC protecting group. This reaction is typically carried out with BOC-anhydride and aqueous sodium hydrogen carbonate in water/tetrahydrofuran. Step (XX) ^ (XXII) (Scheme 3) Ullman coupling The aryl iodide (XIX) can be transformed to the ester (XX) to form a new C-C bond trough literature procedure. Such transformations are known to those skilled in the art as “Ullmann reaction”. For example, The aryl iodide and fluoroalkyl bromide are reacted in the presence of an excess of Cu(0) powder at elevated temperature. For references for this chemistry and training and procedures, see Adv. Synth. Catal.2018, 360, 1605, Chem. Commun. 2012, 48, 7738 and/or E. J. Org. Chem.2016, 33, 5529 and the references therein. Step (XXII) ^ (XXIII) (Scheme 3) Ester (XXII) can be directly transferred into amide (XXIII) by reacting it with N-methoxymethanamine hydrogen chloride. The reaction is preferably performed in aprotic organic solvents like tetrahydrofurane at low temperature (e.g. -15 °C), in the presence of a base like diisorpropylethylamine, and 2- propylmagnesiumchloride (usually applied as 2 M solution in tetrahydrofuran. Alternatively, (XXIII) can be obtained by a two-step process from (XIX) by saponification of the ester and sunsequent amide formation of the resulting carboxylic acid with N-methoxymethanamine hydrogen chloride. Methods for amide formation are known to the person skilled in the art, typically using a base (for example, but not limited to, diisopropylethylamine, triethylamine) and a coupling reagent (HATU, DCC, EDCI*HCl, T3P, SOCl2, and/or oxalyl chloride) in organic solvent such as DMF. For references for this chemistry and training and procedures, see EP1007514, 2006, B1, E. J. Org. Chem.2017, 25, 3584, Org. Lett.2018, 20, 4691 and/or Adv. Synth. Catal.2020, 362, 1106 and the references therein. Step (XXIII) ^ (XI) (Scheme 3) Conversion of (XXIII) to compounds of formula (XI) comprises three steps: BHC221035 EP 1.) Formation of ketone (XXIV). Such transformations are known to those skilled in the art known as “Grignard addition”. For example, such a transformation can be achieved by using a suitable alkyl magnesium chloride in THF. Aqueous workup delivers the ketone. For references for this chemistry and training and procedures, see Bioorg. Med. Chem. 2016, 24, 2707, Adv. Synth. Catal. 2020, 362, 1106 and/or CN104803954, 2018, B (location in patent: 0045, 0047, 0054, 0061) and the references therein. 2.) Grigrand addition to ketone of formula (XXIV). Using the same conditions described for the synthesis of compounds of formula (XXIV), the addition of a further alkyl group to ketones (XXIV) give the corresponding tertiary alcohols. In certain cases, the alkyl groups introduced by that manner might have masked functional groups, which are compatible with the conditions of the Grignard reaction, and can be transferred to analogs according to compounds of formula (I) at a later stage. This includes for example, but not limited to, acetals or ketals, which can be transferred to aldehydes and ketones, which then can be transferred into alkyl fluorides. 3.) Removal of the BOC-protecting group, e.g. by treatment with trifluoroacetic acid in dichloromethane or hydrogen chloride in aprotic solvents like dioxan give the free amines of formula (XI). General Methods General Procedure 1: To a solution of the substrate (1 eq.), the corresponding phosphine oxide (1 eq.) and Et3N (3.5 eq.) in MeCN (0.2 M) under argon was added Pd(PPh3)4 (0.15 eq.) and the mixture was heated at 90 °C for the indicated time. The reaction mixture was filtered, concentrated under reduced pressure and purified by preperative HPLC (basic method). Analytical LC-MS Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 µm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. Method 2: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 µm, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. Method 3: BHC221035 EP Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 µm, 50x2.1mm; eluent A: water + 0.2 vol-% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.7 min 1-45% B, 1.7-1.72 min 45-99% B, 1.72-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; ELSD. Method 4: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.750x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm Method 5 : Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C181.750x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6- 2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm Method 6: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C181.7 µm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.7 min 1-45% B, 1.7- 1.72 min 45-99% B, 1.72-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. Preparative HPLC a) Autopurifier: acidic conditions System: Waters Autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C185.0 µm 100x30 mm Solvent: A = H2O + 0.1%vol. HCOOH (99%) B = acetonitrile Gradient: 0-0.5 min 5% B 25 ml/min, 0.51-5.5 min 10-100% B 70 ml/min, 5.51-6.5 min 100% B 70 ml/min Temperature: RT Solution: max.250 mg / max.2.5 ml DMSO or DMF Injection: 1 x 2.5 ml Detection: DAD scan range 210–400 nm, MS ESI+, ESI-, scan range 160-1000 m/z BHC221035 EP b) Autopurifier: basic conditions System: Waters Autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C185.0 µm 100x30 mm Solvent: A = H2O + 0.2%vol. NH3 (32%) B = acetonitrile Gradient: 0-0.5 min 5% B 25 ml/min, 0.51-5.5 min 10-100% B 70 ml/min, 5.51-6.5 min 100% B 70 ml/min Temperature: RT Solution: max.250 mg / max.2.5 ml DMSO or DMF Injection: 1 x 2.5 ml Detection: DAD scan range 210–400 nm, MS ESI+, ESI-, scan range 160-1000 m/z Intermediate 1 (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide
Figure imgf000055_0001
The reactions were performed as two batches in parallel: A mixture of (S)-2-methylpropane-2- sulfinamide (200 g, 1.65 mol), acetaldehyde (500 ml, 5 M in THF) and MgSO4 (750 g, 6.23 mol) in DCM (1.5 L) was stirred for 28 h at 20 °C. The two reaction mixture were combined and filtered. The filter cake was washed with DCM (1000 ml x 2). The combined filtrate was concentrated in vacuum. The residue was purified by chromatography on silica gel (3% EA in PE) to give (S,E)-N-ethylidene-2-methylpropane- 2-sulfinamide (410 g, 84.37% yield) as light yellow oil. 1H NMR (CDCl3400MHz) 8.07 (q, 1H), 2.23 (d, 2H), 1.16 (s, 9H) Intermediate 2 (S)-N-((R)-1-(2-fluoro-3-iodophenyl)ethyl)-2-methylpropane-2-sulfinamide BHC221035 EP
Figure imgf000056_0001
The reactions were performed as four batches in parallel: To a solution of n-BuLi (320 ml, 2.5 M in hexane) was added drop-wise DIPEA (120 ml, 849.10 mmol) in THF (300 ml) at -20 °C, then it was stirred for 1 h and cooled to -60 °C. A solution of 1-fluoro-2-iodo-benzene (180 g, 810.82 mmol) in THF (300 ml) was added drop-wise to the reaction. After stirred for 2 h, a solution of (S,E)-N-ethylidene-2- methylpropane-2-sulfinamide (100 g, 679.17 mmol) in THF (300 ml) was added drop-wise at -60 °C under N2. The mixture was warmed to 20 °C and stirred for 16 h. Each reaction solution was poured into sat. aq. Ammonium chloride (3 l) and extracted with MTBE (800 ml x 3). The combined organic solution was washed with brine (500 ml), dried over sodium sulfate, filtered and concentrated in vacuum. The four batches were combined and purified by chromatography on silica gel (PE: EA = 10:1 to 1:2) for three times to give the desired product (94 g, 254.58 mmol) as light brown oil (contained ~0.04 eq isomer). 1H NMR (CDCl3400MHz) 7.63-7.67 (m, 1H), 7.30-7.33 (m, 1H), 6.86-6.91 (m, 1H), 4.81-4.86 (m, 1H), 3.41 (d, 1H), 1.57 (d, 2H), 1.23 (s, 9H) Intermediate 3 (R)-1-(2-fluoro-3-iodophenyl)ethanamine hydrochloride
Figure imgf000056_0002
To a solution of (S)-N-[(1R)-1-(2-fluoro-3-iodo-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (94 g, 254.58 mmol) in dioxane (140 ml) was added HCl/dioxane (4 M, 140 ml) at 20 °C, then the reaction was stirred for 2 h. TLC (PE: EA = 1:1) showed the reaction completed. To the mixture was added MTBE (300 ml) and filtered. The filter cake was washed with MTBE (50 ml x 2) and dried in vacuum to give (R)-1-(2- fluoro-3-iodophenyl)ethanamine hydrochloride (67 g, 87.28% yield) as light yellow solid. 1H NMR (DMSO-d6400 MHz) 8.70 (s, 1H), 7.84-7.88 (m, 1H), 7.66-7.69 (m, 1H), 7.08-7.12 (m, 1H), 4.58- 4.61 (m, 1H), 1.52 (d, 3H) Intermediate 4 (R)-tert-butyl (1-(2-fluoro-3-iodophenyl)ethyl)carbamate BHC221035 EP Boc
Figure imgf000057_0001
To a solution of (R)-1-(2-fluoro-3-iodophenyl)ethanamine hydrochloride (67 g, 222.20 mmol) in water (300 ml) and THF (300 ml) was added NaHCO3 (70 g, 833.27 mmol), then Boc anhydride (52 g, 238.26 mmol) was added and the reaction was stirred at 25 °C for 1 h. TLC (DCM: MeOH = 10:1) showed the reaction completed. The mixture was extracted with MTBE (300 ml x 3). The combined organic solution was washed with brine (300 ml), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was triturated with PE (100 ml) and filtered. The filter cake was dried in vacuum to give (R)-tert- butyl (1-(2-fluoro-3-iodophenyl)ethyl)carbamate (75 g, 92.43% yield) as light yellow solid. 1H NMR (MeOD 400 MHz) 7.64-7.68 (m, 1H), 7.31-7.35 (m, 1H), 6.90-6.95 (m, 1H), 4.86-4.94 (m, 1H), 1.51 (d, 3H), 1.25 (s, 9H) Intermediate 5 (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate
Figure imgf000057_0002
A mixture of ethyl 2-bromo-2,2-difluoro-acetate (40 ml, 311.36 mmol) and Cu (40 g, 629.43 mmol) in DMSO (300 ml) was stirred at 20 °C for 1 h, then (R)-tert-butyl (1-(2-fluoro-3-iodophenyl)ethyl)carbamate (75 g, 205.38 mmol) was added and the reaction was heated and stirred at 80 °C for 5 h. TLC (PE: EA = 3:1) showed the reaction completed. The reaction was cooled and directly extracted with MTBE (500 ml x 4). The combined MTBE solution was washed with sat. NH4Cl (300 ml x 2), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by chromatography on silica gel (PE: EA = 20:1 ~ 5:1) to give (R)-ethyl 2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)-2,2- difluoroacetate (45 g, 60.64 % yield) as light yellow oil. 1H NMR (CDCl3400 MHz) 7.52-7.56 (m, 1H), 7.44-7.48 (m, 1H), 7.20-7.25 (m, 1H), 4.97 (br s, 3H), 4.33- 4.39 (m, 2H), 1.51 (d, 3H), 1.19-1.45 (m, 12H) Intermediate 6 BHC221035 EP tert-butyl (R)-(1-(3-(1,1-difluoro-2-(methoxy(methyl)amino)-2-oxoethyl)-2-fluorophenyl)- ethyl)carbamate
Figure imgf000058_0001
To a solution of ethyl (3-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-2-fluorophenyl)(difluoro)acetate (16.4 g, 45.4 mmol) and N-methoxymethanamine hydrogen chloride (1/1) (6.64 g, 68.1 mmol) in tetrahydrofurane (330 ml) under argon at -15 °C was added N,N-diisopropylethylamine (12 ml), and the solution was stirred for 5 min. Then, 2-propylmagnesiumchloride (2M in THF, 110 ml, 2.0 M, 230 mmol) was added dropwise and the resulting solution was stirred for 1h. at -15 °C to -10 °C. The reaction was quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phases were washed with sarurated aqueous sodium chloride solution, filter-dried and concentrated. The crude product was purified by flash column chromatography to give the title compound (13.8 g, 81 % yield). LC-MS (Method 2): Rt = 1.18 min; MS (ESIneg): m/z = 376 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.54), 1.172 (5.05), 1.190 (2.60), 1.274 (5.68), 1.291 (5.71), 1.342 (16.00), 1.987 (8.09), 2.327 (0.45), 2.518 (1.66), 2.523 (1.17), 2.669 (0.46), 3.198 (8.59), 3.223 (1.92), 3.999 (0.58), 4.017 (1.73), 4.035 (1.69), 4.053 (0.53), 4.843 (0.49), 4.862 (0.68), 4.880 (0.45), 7.333 (0.89), 7.353 (2.11), 7.372 (1.30), 7.483 (0.91), 7.500 (1.41), 7.516 (0.65), 7.545 (0.77), 7.562 (1.35), 7.584 (1.27), 7.605 (0.76). Intermediate 7 tert-butyl (R)-(1-(3-(2-cyclopropyl-1,1-difluoro-2-oxoethyl)-2-fluorophenyl)ethyl)-carbamate
Figure imgf000058_0002
To a solution of tert-butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2- fluorophenyl)ethyl]carbamate (Intermediate 6, 6.90 g, 18.3 mmol) in tetrahydrofuran (50 ml) at -10 °C was added dropwise bromido(cyclopropyl)magnesium (1 M in 2-methyltetrahydrofuran, 73 ml, 1.0 M, 73 mmol) and the mixture was stirred for 4 hours, during which the temperature went from -10 °C to +10 °C. To the mixture was then added saturated aqueous ammonium chloride solution. The resulting mixture was extracted twice with ethyl acetate. The organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. BHC221035 EP The crude product was purified by flash column chromatography to yield the title compound (5.30 g, 81 % yield). LC-MS (Method 2): Rt = 1.32 min; MS (ESIneg): m/z = 356 [M-H]- 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 1.02 - 1.22 (m, 5 H) 1.26 - 1.30 (m, 3 H) 1.36 (s, 9 H) 1.32 - 1.38 (m, 1 H) 4.81 - 4.95 (m, 1 H) 7.38 (s, 1 H) 7.51 - 7.67 (m, 3 H). Intermediate 8 tert-butyl ((1R)-1-(3-(2-cyclopropyl-1,1-difluoro-2-hydroxypropyl)-2-fluorophenyl)ethyl)-carbamate (mixture of diastereomers) H C CH 3 3 H3C O
Figure imgf000059_0001
To a solution of tert-butyl {(1R)-1-[3-(2-cyclopropyl-1,1-difluoro-2-oxoethyl)-2- fluorophenyl]ethyl}carbamate (Intermediate 7, 2.00 g, 5.60 mmol) in tetrahydrofuran (40 ml) at -10 °C was added dropwise bromido(methyl)magnesium (22 ml, 1.0 M, 22 mmol) and the mixture was stirred for 2.5 hours, whereas the mixture was allowed to slowly warm to room temperature. To the mixture was then added saturated aqueous ammonium chloride solution. The resulting mixture was extracted twice with ethyl acetate. The organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to yield the title compound 1.00 g (48 % yield). LC-MS (Method 2): Rt = 1.28 min; MS (ESIpos): m/z = 391 [M+NH3]+ 1H NMR (400 MHz, DMSO-d6) δ ppm -0.05 - 0.30 (m, 4 H) 0.92 - 1.03 (m, 1 H) 1.20 - 1.31 (m, 6 H) 1.35 (br d, J=1.77 Hz, 9 H) 4.80 - 4.96 (m, 1 H) 5.09 (d, J=10.39 Hz, 1 H) 7.13 - 7.24 (m, 1 H) 7.25 - 7.35 (m, 1 H) 7.39 - 7.61 (m, 2 H). Intermediate 9 1-(3-((R)-1-aminoethyl)-2-fluorophenyl)-2-cyclopropyl-1,1-difluoropropan-2-ol trifluoroacetic acid salt (mixture of diastereomers)
Figure imgf000059_0002
To a solution of a diastereomeric mixture of tert-butyl ((1R)-1-(3-(2-cyclopropyl-1,1-difluoro-2- hydroxypropyl)-2-fluorophenyl)ethyl)-carbamate (Intermediate 8, 1.00 g, 2.68 mmol) in BHC221035 EP dichloromethane (10 mlL) was added at 0 °C trifluoroacetic acid (3.1 ml, 40 mmol) and the mixture was stirred and allowed to warm to room temperature overnight. The mixture was concentrated to yield the title compound (731 mg) which was used for the following reaction without purification. LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 275 [M+H]+ Intermediate 10 (1R)-1-(3-(2-cyclopropyl-1,1-difluoro-2-((triethylsilyl)oxy)propyl)-2-fluorophenyl)ethan-1-amine (mixture of diastereomers)
Figure imgf000060_0001
To a solution of a diastereomeric mixture of 1-(3-((R)-1-aminoethyl)-2-fluorophenyl)-2-cyclopropyl-1,1- difluoropropan-2-ol trifluoroacetic acid salt (Intermediate 9, 5.36 g, 11.8 mmol) in dichloromethane (150 ml) was added at 0 °C 2,6-dimethylpyridine (9.6 ml, 82.4 mmol), followed after 5 minutes by triethylsilyl trifluoromethanesulfonate (10.7 ml, 47.1 mmol), and the mixture was stirred at room temperature overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic phases were dried with sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography to yield the title compound (2.77 g, 61 % yield). LC-MS (Method 2): Rt = 1.74 min; MS (ESIpos): m/z = 389 [M+H]+ Intermediate 11 6-bromo-N-((1R)-1-(3-(2-cyclopropyl-1,1-difluoro-2-((triethylsilyl)oxy)propyl)-2-fluorophenyl)ethyl)-2- methylpyrido[3,4-d]pyrimidin-4-amine (mixture of diastereomers)
Figure imgf000060_0002
To a solution of a diastereomeric mixture of (1R)-1-(3-(2-cyclopropyl-1,1-difluoro-2- ((triethylsilyl)oxy)propyl)-2-fluorophenyl)ethan-1-amine (Intermediate 10, 1.15 g, 2.97 mmol) in DMF (17 ml) were subsequently added 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (1.35 g, 4.46 mmol), 4-(dimethylamino)pyridine (363 mg, 2.97 mmol), and triethylamine (4.1 ml, 30 mmol). After the mixture BHC221035 EP was stirred at room temperature for 1 hour, 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (1.07 g, 4.46 mmol) in DMF (minimal amount to dissolve the reactant) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into water, and extracted with dichloromethane. The organic phases were dried with sodium sulfate and concentrated under reduces pressure. The residue was purified by flash column chromatography to yield the title compound 534 mg (29 % yield) as an orange oil. LC-MS (Method 2): Rt = 1.87 min; MS (ESIpos): m/z = 610 [M+H]+ Intermediate 12 (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-1-cyclopropyl-2,2-difluoroethan-1-one trifluoroacetic acid salt
Figure imgf000061_0001
To a solution of tert-butyl {(1R)-1-[3-(2-cyclopropyl-1,1-difluoro-2-oxoethyl)-2- fluorophenyl]ethyl}carbamate (Intermediate 7, 200 mg, 560 µmol) in dichloromethane (3.5 ml) was added trifluoroacetic acid (430 µl, 5.6 mmol), and the mixture was stirred at room temperature overnight. The mixture was then repeatedly diluted with toluene and concentrated (two times). The crude product (279 mg) was directly used in the following reaction. LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 258 [M+H]+ Intermediate 13 (R)-2-(3-(1-((6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino)ethyl)-2-fluorophenyl)-1-cyclopropyl- 2,2-difluoroethan-1-one
Figure imgf000061_0002
To a solution of 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 15, 148 mg, 616 µmol) and 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (204 mg, 672 µmol) in DMF (2 ml) was added triethylamine (230 µl, 1.7 mmol), and 4-(dimethylamino)pyridine (13.7 mg, 112 µmol), and the mixture was stirred at room temperature for 1 hour. Then, (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-1- cyclopropyl-2,2-difluoroethan-1-one trifluoroacetic acid salt (Intermediate 12, 208 mg, 560 µmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and dichloromethane. The organic layer was separated and washed twice with water BHC221035 EP and with saturated aqueous sodium chloride solution, dried with sodium sulfate, and concentrated. The residue was purified by flash chromatography to yield the title compound 210 mg (71 % yield). LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 479 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.055 (0.64), 1.060 (0.80), 1.065 (1.60), 1.074 (2.83), 1.080 (1.32), 1.085 (2.08), 1.091 (0.97), 1.154 (0.99), 1.159 (0.61), 1.168 (2.40), 1.172 (2.36), 1.178 (1.60), 1.189 (2.91), 1.196 (1.38), 1.574 (5.34), 1.591 (5.31), 1.987 (3.32), 2.364 (16.00), 2.397 (0.48), 2.406 (0.59), 2.417 (0.85), 2.428 (0.56), 2.437 (0.42), 2.518 (1.58), 2.523 (1.16), 4.017 (0.80), 4.034 (0.78), 5.652 (0.82), 5.670 (1.28), 5.687 (0.81), 7.326 (0.96), 7.345 (2.10), 7.365 (1.18), 7.577 (0.73), 7.594 (1.24), 7.611 (0.60), 7.705 (0.65), 7.723 (1.19), 7.740 (0.60), 8.659 (4.55), 8.807 (5.05), 8.895 (1.28), 8.912 (1.25). Intermediate 14 (R)-1-cyclopropyl-2-(3-(1-((6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino)ethyl)- 2-fluorophenyl)-2,2-difluoroethan-1-one
Figure imgf000062_0001
To a solution of (R)-2-(3-(1-((6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino)ethyl)-2- fluorophenyl)-1-cyclopropyl-2,2-difluoroethan-1-one (Intermediate 13, 100 mg, 209 µmol) and dimethyl-lambda5-phosphanone (16.3 mg, 209 µmol) in acetonitrile (2.3 ml) was added triethylamine (100 µl, 730 µmol) and tetrakis(triphenylphosphin)palladium(0) (48.2 mg, 41.7 µmol) and the mixture was stirred under an Argon atmosphere at 90 °C overnight. The mixture was cooled to room temperature, filtered and concentrated. The residue was submitted to preparative HPLC (acidic method) to yield the title compound (67 mg, 65 % yield). LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 477 [M+H]+ Intermediate 15 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol
Figure imgf000062_0002
To a solution of 5-amino-2-bromoisonicotinic acid (CAS 1242336-80-6, 50 g, 230 mmol) and ethanimidamide hydrochloride (1:1) (65 g, 691 mmol) in 2-methoxyethanol (300 ml) was added sodium BHC221035 EP acetate (57 g, 691 mmol) was stirred at 160 °C for 48 hours. The mixture was cooled to room temperature, diluted with water and stirred for 1 hour. The resulting precipitate was filtered off and dried in vacuum to yield the title compound (44 g, 76 % yield). LC-MS (Method 2): Rt = 0.48 min; MS (ESIpos): m/z = 240 [M+H]+ Intermediate 16 tert-butyl {(1R)-1-[3-(2-cyclobutyl-1,1-difluoro-2-oxoethyl)-2-fluorophenyl]ethyl}carbamate
Figure imgf000063_0001
To a solution of tert-butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}-2- fluorophenyl)ethyl]carbamate (Intermediate 6, 5.00 g, 13.3 mmol) in THF (80 ml) at 0 °C was slowly added bromide-(cyclobutyl)magnesium (6.35 g, 39.9 mmol). The reaction was allowed to warm to room temperature and stirred overnight. Then, the mixture was cooled to 0 °C and saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. Purification by column chromatography (silica, hexane, ethyl acetate) gave the title compound (4.04 g, 82 % yield). LC-MS (Method 2): Rt = 1.45 min; MS (ESIneg): m/z = 370 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.03), 1.166 (0.91), 1.171 (0.96), 1.189 (0.53), 1.211 (0.71), 1.263 (6.93), 1.280 (6.96), 1.345 (16.00), 1.750 (0.43), 1.753 (0.45), 1.760 (0.66), 1.763 (0.85), 1.770 (0.44), 1.773 (0.60), 1.777 (0.65), 1.780 (0.49), 1.784 (0.49), 1.787 (1.01), 1.789 (0.84), 1.796 (0.57), 1.798 (0.51), 1.810 (0.45), 1.957 (0.79), 1.979 (1.40), 1.985 (0.61), 1.986 (0.80), 2.000 (1.23), 2.005 (1.00), 2.023 (0.64), 2.026 (0.83), 2.061 (0.41), 2.071 (0.54), 2.083 (0.80), 2.093 (1.22), 2.102 (1.21), 2.111 (1.34), 2.121 (1.12), 2.132 (0.69), 2.142 (0.48), 2.166 (0.43), 2.186 (1.24), 2.200 (0.98), 2.208 (1.41), 2.223 (0.94), 2.230 (0.97), 2.236 (0.74), 2.250 (0.54), 2.518 (1.65), 2.523 (1.13), 3.323 (0.86), 3.354 (0.93), 3.565 (1.38), 3.767 (0.97), 3.788 (1.41), 3.810 (0.91), 4.832 (0.49), 4.850 (0.67), 4.867 (0.45), 7.351 (0.84), 7.371 (1.87), 7.390 (1.14), 7.518 (0.98), 7.535 (1.52), 7.551 (0.79), 7.555 (0.78), 7.577 (0.86), 7.591 (1.29), 7.606 (1.59), 7.625 (0.71). Intermediate 17 tert-butyl [(1R)-1-{3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]carbamate (2 Stereoisomers present) BHC221035 EP
Figure imgf000064_0001
To a solution of tert-butyl {(1R)-1-[3-(2-cyclobutyl-1,1-difluoro-2-oxoethyl)-2- fluorophenyl]ethyl}carbamate (Intermediate 16, 2.02 g, 5.44 mmol) in THF (50 ml) at 0 °C was slowly added bromido(methyl)magnesium (4.8 ml, 3.4 M, 16 mmol). The mixture was stirred for 30 min, and then allowed to warm to room temperature and stirred overnight. Then, the mixture was cooled to 0 °C and saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The product (2.12 g) was used for the following reaction without further purification. LC-MS (Method 2): Rt = 1.37 min; MS (ESIpos): m/z = 406 [M+H]+NH3 + ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.028 (4.83), 1.154 (0.90), 1.167 (0.61), 1.172 (1.92), 1.190 (1.57), 1.214 (0.95), 1.225 (0.58), 1.266 (3.34), 1.271 (3.48), 1.284 (3.43), 1.288 (3.32), 1.323 (0.72), 1.354 (16.00), 1.516 (0.91), 1.540 (1.22), 1.557 (0.79), 1.689 (0.59), 1.712 (0.85), 1.734 (0.97), 1.757 (0.74), 1.891 (0.56), 1.898 (0.57), 1.914 (0.79), 1.921 (0.80), 1.945 (0.73), 1.955 (0.63), 1.987 (2.77), 2.084 (1.18), 2.518 (1.73), 2.523 (1.22), 2.558 (0.62), 2.577 (0.41), 4.017 (0.52), 4.035 (0.52), 4.884 (0.49), 5.175 (2.05), 5.201 (3.39), 5.758 (2.27), 7.208 (0.58), 7.228 (1.52), 7.247 (1.20), 7.275 (0.89), 7.291 (1.17), 7.308 (0.50), 7.454 (0.68), 7.472 (1.14), 7.489 (0.62), 7.518 (0.48), 7.530 (0.60), 7.549 (0.49). Intermediate 18 (2RS)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2-cyclobutyl-1,1-difluoropropan-2-ol (2 Stereoisomers present)
Figure imgf000064_0002
To a solution of tert-butyl [(1R)-1-{3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2- fluorophenyl}ethyl]carbamate (Intermediate 17, 2.12 g, 5.47 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (4.2 ml, 55 mmol) and the mixture was stirred overnight at room temperature. To the mixture was then twice added toluene and the resulting mixture was concentrated under reduced pressure. The crude product was purified by chromatography (silica, ethanol, dichloromethane) to yield the title compound (1.56 g, 99 % yield). BHC221035 EP LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 288 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (13.21), 1.025 (14.50), 1.054 (0.52), 1.057 (0.89), 1.071 (0.70), 1.154 (3.61), 1.159 (0.67), 1.172 (6.79), 1.190 (3.25), 1.218 (15.74), 1.223 (15.77), 1.234 (16.00), 1.239 (15.30), 1.264 (0.92), 1.281 (0.81), 1.303 (0.48), 1.317 (0.51), 1.323 (0.50), 1.525 (2.53), 1.542 (3.44), 1.549 (3.14), 1.565 (2.53), 1.665 (0.86), 1.673 (0.91), 1.688 (1.60), 1.696 (1.80), 1.712 (2.91), 1.717 (2.87), 1.730 (4.13), 1.741 (2.87), 1.747 (2.41), 1.840 (0.96), 1.862 (0.78), 1.896 (3.85), 1.919 (7.68), 1.943 (4.40), 1.967 (2.62), 1.987 (12.45), 2.000 (1.76), 2.025 (1.10), 2.049 (0.41), 2.332 (1.27), 2.336 (0.57), 2.518 (7.95), 2.523 (6.06), 2.558 (1.81), 2.565 (1.60), 2.673 (1.31), 2.678 (0.56), 3.372 (0.55), 3.395 (0.53), 4.000 (0.87), 4.017 (2.64), 4.035 (2.63), 4.053 (0.84), 4.235 (1.25), 4.251 (3.69), 4.268 (3.65), 4.283 (1.16), 5.143 (11.55), 5.162 (11.45), 5.202 (0.67), 5.758 (13.08), 7.196 (2.11), 7.216 (6.05), 7.234 (5.52), 7.242 (3.85), 7.248 (4.46), 7.259 (3.88), 7.264 (4.20), 7.279 (2.02), 7.283 (1.72), 7.657 (2.05), 7.663 (2.27), 7.675 (3.95), 7.679 (3.84), 7.693 (2.14), 7.697 (1.97). Intermediate 19 (2RS)-1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2- cyclobutyl-1,1-difluoropropan-2-ol (2 Stereoisomers present)
Figure imgf000065_0001
To a solution of 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (intermediate 15, 919 mg, 3.83 mmol) and 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (1.26 g, 4.18 mmol) in DMF (13 ml) was added triethylamine (1.5 ml, 10 mmol) and 4-(dimethylamino)pyridine (85.0 mg, 696 µmol), and the mixture was stirred for 1 h at room temperature. Then, (2RS)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2- cyclobutyl-1,1-difluoropropan-2-ol (intermediate 18, 1.00 g, 3.48 mmol) in DMF (5.0 ml) was added and the mixture was stirred overnight. To the mixture was then added ethyl acetate and water, and the organic phases were separated and washed twice with water and with saturated aqueous sodium chloride solution. The organic phases were then dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica, ethyl acetate, hexane) to yield the title compound (1.38 g, 78 % yield). LC-MS (Method 2): Rt = 1.41 min; MS (ESIpos): m/z = 509 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (4.00), 1.070 (4.01), 1.154 (4.23), 1.172 (8.33), 1.189 (4.03), 1.489 (0.88), 1.510 (1.34), 1.565 (4.38), 1.568 (4.47), 1.583 (4.30), 1.586 (4.24), 1.620 (0.45), 1.643 (0.73), BHC221035 EP 1.665 (0.76), 1.689 (0.49), 1.739 (0.62), 1.837 (0.41), 1.862 (0.70), 1.886 (1.00), 1.909 (1.03), 1.935 (0.75), 1.964 (0.61), 1.987 (16.00), 2.327 (1.32), 2.331 (0.98), 2.336 (0.52), 2.361 (10.41), 2.375 (10.51), 2.518 (5.87), 2.523 (3.80), 2.565 (0.51), 2.591 (0.51), 2.669 (1.26), 2.673 (0.89), 2.737 (0.63), 3.999 (1.13), 4.016 (3.34), 4.035 (3.30), 4.053 (1.09), 5.182 (2.78), 5.223 (2.69), 5.687 (0.56), 5.705 (0.98), 5.726 (0.94), 5.744 (0.52), 7.179 (0.80), 7.198 (1.86), 7.217 (1.19), 7.287 (0.91), 7.305 (1.31), 7.324 (0.63), 7.544 (0.45), 7.559 (0.99), 7.575 (0.93), 8.679 (3.25), 8.681 (3.19), 8.803 (3.26), 8.807 (3.36), 8.855 (0.86), 8.878 (1.13), 8.897 (0.83). Intermediate 20 (2RS)-1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2- cyclopropyl-1,1-difluoropropan-2-ol (2 Stereoisomers present)
Figure imgf000066_0001
To a solution of 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (intermediate 15, 3.51 g, 14.6 mmol) and 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (4.84 g, 16.0 mmol) in DMF (20 ml) was added triethylamine (5.6 ml, 40 mmol) and 4-(dimethylamino)pyridine (325 mg, 2.66 mmol), and the mixture was stirred for 1 h at room temperature. Then, (2RS)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2- cyclopropyl-1,1-difluoropropan-2-ol trifluoroacetic acid salt (1:1) (Intermediate 9, 5.83 g, 88 % purity, 13.3 mmol) in DMF (20 ml) was added and the mixture was stirred overnight. To the mixture was then added ethyl acetate and water, and the organic phases were separated and washed twice with water and with saturated aqueous sodium chloride solution. The organic phases were then dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica, ethyl acetate, hexane) to yield the title compound (4.09 g, 62 % yield). LC-MS (Method 2): Rt = 1.28 min; MS (ESIpos): m/z = 495 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.014 (0.47), 0.029 (0.49), 0.036 (0.52), 0.041 (0.52), 0.051 (0.63), 0.063 (0.53), 0.072 (0.44), 0.129 (0.40), 0.141 (0.47), 0.149 (0.68), 0.154 (0.60), 0.162 (0.51), 0.169 (0.52), 0.177 (0.42), 0.229 (0.46), 0.236 (0.53), 0.241 (0.52), 0.252 (0.44), 0.976 (0.42), 0.998 (0.44), 1.154 (2.41), 1.171 (5.25), 1.189 (2.61), 1.242 (3.73), 1.253 (3.01), 1.568 (4.39), 1.586 (4.41), 1.986 (8.48), 2.366 (16.00), 2.518 (2.23), 2.523 (1.69), 3.356 (0.92), 3.998 (0.61), 4.016 (1.80), 4.034 (1.74), 4.052 (0.53), 5.102 (2.35), 5.108 (1.84), 5.696 (0.41), 5.714 (0.68), 5.731 (0.52), 5.744 (0.55), 5.757 (0.76), 7.162 (0.67), 7.182 (1.57), 7.201 (0.96), 7.288 (0.64), 7.305 (0.99), 7.324 (0.47), 7.549 (0.56), 7.565 (1.00), 7.582 (0.51), 8.685 (2.53), 8.687 (2.70), 8.689 (2.34), 8.805 (3.18), 8.808 (2.31), 8.848 (0.56), 8.865 (1.16), 8.882 (0.69). BHC221035 EP Intermediate 21 Tert-butyl {(1R)-1-[3-(1,1-difluoro-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate
Figure imgf000067_0001
Tert-butyl [(1R)-1-(3-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}phenyl)ethyl]carbamate (Intermediate 6, 3.6 g, 9.6 mmol) was dissolved in THF (135 mL) under nitrogen. Chloro(ethyl)magnesium (14.4 ml, 2.0 M in THF, 29 mmol) was added dropwise and the mixture was stirred at RT for 3 hours. Sat. aq. NH4Cl was added, and the aq. phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine and dried. The solvent was evaporated, and the residue was purified by flash column chromatography on silica gel to give the title compound (2.22 g, 67 %). LC-MS (Method 2): Rt = 1.34 min; MS (ESIpos): m/z = 363 [M+NH4]+ Intermediate 22 Tert-butyl [(1R)-1-{3-[(2RS)-1,1-difluoro-2-hydroxy-2-methylbutyl]-2-fluorophenyl}ethyl]carbamate (mixture of diastereomers)
Figure imgf000067_0002
Tert-butyl {(1R)-1-[3-(1,1-difluoro-2-oxobutyl)-2-fluorophenyl]ethyl}carbamate (Intermediate 21, 1.89 g, 4.9 mmol) was dissolved in THF (28 mL) under argon and cooled to -40 °C. Bromido(methyl)magnesium (13.1 ml, 1.5 M, 19.6 mmol) was added dropwise and the mixture was stirred at -20 °C for 60 minutes. Sat. aq. NH4Cl solution was added. The aq. phase was extracted with ethyl acetate twice. The combined organic phases were washed with brine and dried. The solvent was evaporated. The residue was purified by flash column chromatography on silica gel to give the title compound (756 mg, 42% yield, mixture of diastereomers). LC-MS (Method 2): Rt = 1.28 min; MS (ESIpos): m/z = 379 [M+NH4]+ The diastereomers were separated by preparative chiral SFC. Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5μ 250x30mm; eluent A: CO2; eluent B: methanol + 0.2 vol % aqueous ammonia (32 %); isocratic: 5 % B; gradient: no; flow: 100 ml/min; temperature: 40 °C; BPR: 150 bar; UV: 210 nm. Diastereomer 1 was collected at 5.0-7.0 min, diastereomer 2 was collected at 8.0-10.5 min. BHC221035 EP Intermediate 22.1 Tert-butyl [(1R)-1-{3-[(2R or S)-1,1-difluoro-2-hydroxy-2-methylbutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 1)
Figure imgf000068_0001
Analytical SFC: Rt = 1.67 min Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μ, 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32 %); eluent B: acetonitril; gradient: 0-1.6 min 1-99 % B, 1.6-2.0 min 99 % B; flow: 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 - 0.92 (m, 3 H) 1.12 (s, 3 H) 1.25 - 1.31 (m, 3 H) 1.36 (s, 9 H) 1.45 - 1.57 (m, 2 H) 4.83 - 4.97 (m, 1 H) 5.18 (s, 1 H) 7.21 - 7.27 (m, 1 H) 7.28 - 7.34 (m, 1 H) 7.44 - 7.51 (m, 1 H) 7.53 - 7.57 (m, 1 H) Intermediate 22.2 Tert-butyl [(1R)-1-{3-[(2R or S)-1,1-difluoro-2-hydroxy-2-methylbutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 2)
Figure imgf000068_0002
Analytical SFC: Rt = 2.48 min Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μ, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32 %); eluent B: acetonitril; gradient: 0-1.6 min 1-99 % B, 1.6-2.0 min 99 % B; flow: 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. Intermediate 23 (2R or S)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylbutan-2-ol trifluoroacetate (1:1) (diastereomer 1)
Figure imgf000068_0003
Tert-butyl [(1R)-1-{3-[(2R or S)-1,1-difluoro-2-hydroxy-2-methylbutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 1) (Intermediate 22.1, 1.582 g, 4.38 mmol) was dissolved in dichloromethane (30 mL). BHC221035 EP Trifluoroacetic acid (3.4 ml, 44 mmol) was added, and the mixture was stirred at RT for 2 h. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting oil (1.023 g, 62 % yield) was used without any further purification. LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos): m/z = 262 [M+H]+ Intermediate 24 (2R or S)-1-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylbutan-2-ol trifluoroacetate (1:1) (diastereomer 2)
Figure imgf000069_0001
Tert-butyl [(1R)-1-{3-[(2R or S)-1,1-difluoro-2-hydroxy-2-methylbutyl]-2-fluorophenyl}ethyl]carbamate (diastereomer 2) (Intermediate 22.2, 1.459 g, 4.04 mmol) was dissolved in dichloromethane (25 mL). Trifluoroacetic acid (3.1 ml, 40 mmol) was added, and the mixture was stirred at RT for 2 h. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting oil (1.345 g, 89 % yield) was used without any further purification. LC-MS (Method 2): Rt = 0.97 min; MS (ESIpos): m/z = 262 [M+H]+ Intermediate 25 6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-ol
Figure imgf000069_0002
The reaction was performed das described for Intermediate 14 using 6-bromo-2-methylpyrido[3,4- d]pyrimidin-4-ol (Intermediate 15, 5 g, 25.6 mmol), dimethyl-lambda5-phosphanone (2.1 g, 95 % purity, 25.6 mmol), tetrakis(triphenylphosphin)palladium(0) (4.68 g, 5.1 mmol), and triethylamine (12.5 ml, 89 mmol) in acetonitrile (130 ml). The product was obtained by filtration of the reaction mixture. The solids were washed with tert-butyl methyl ether to yield the title compound (6.91 g, 84 % purity, 96 % yield) as beige solid. LC-MS (Method 6): Rt = 0.49 min; MS (ESIpos): m/z = 238 [M+H]+ Intermediate 26 Tert-butyl [(1R)-1-{3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl]-2-fluorophenyl}ethyl]carbamate BHC221035 EP
Figure imgf000070_0001
Tert-butyl {(1R)-1-[3-(2-cyclopropyl-1,1-difluoro-2-oxoethyl)-2-fluorophenyl]ethyl}carbamate (Intermediate 7, 6.70 g, 18.7 mmol) was dissolved in ethanol (95 ml). The mixture was cooled to 0 °C, and sodium borohydride (851 mg, 22.5 mmol) was added in small portions. The mixture was allowed to warm to RT and stirred overnight. The mixture was then poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, the organic phases were washed with brine, dried over sodium sulphate, and concentrated. The residue was purified by flash chromatography (silica gel, hexane, ethyl acetate) to obtain the two separated diastereomers. Intermediate 26.1 Tert-butyl [(1R)-1-{3-[(2R or S)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl]-2-fluorophenyl}ethyl]- carbamate (diastereomer 1) Intermediate 26.1 was obtained as the first eluting fraction. LC-MS (Method 2): Rt = 1.19 min; MS (ESIpos): m/z = 377 [M+NH4]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.014 (0.40), 0.025 (0.57), 0.036 (0.58), 0.238 (0.53), 0.247 (0.73), 0.259 (0.68), 0.270 (0.54), 0.311 (0.48), 0.323 (0.51), 0.332 (0.54), 0.347 (0.57), 0.356 (0.56), 0.370 (0.68), 0.378 (0.57), 0.391 (0.49), 0.895 (0.51), 0.913 (0.46), 1.154 (0.51), 1.172 (1.24), 1.190 (0.97), 1.271 (6.22), 1.288 (6.24), 1.357 (16.00), 1.987 (1.45), 2.518 (1.40), 2.523 (1.04), 3.316 (0.53), 3.447 (0.46), 4.875 (0.45), 4.894 (0.63), 4.912 (0.41), 5.650 (1.08), 5.665 (0.93), 7.239 (0.82), 7.259 (1.89), 7.278 (1.20), 7.365 (0.79), 7.382 (1.15), 7.398 (0.56), 7.483 (0.69), 7.499 (1.16), 7.516 (0.60), 7.559 (0.77), 7.579 (0.73). Intermediate 26.2 Tert-butyl [(1R)-1-{3-[(2R or S)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl]-2-fluorophenyl}ethyl]- carbamate (diastereomer 2) Intermediate 26.2 was obtained as the second eluting fraction. LC-MS (Method 2): Rt = 1.19 min; MS (ESIpos): m/z = 377 [M+NH4]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.013 (0.43), 0.024 (0.59), 0.035 (0.59), 0.045 (0.45), 0.237 (0.55), 0.246 (0.75), 0.259 (0.70), 0.269 (0.55), 0.311 (0.50), 0.322 (0.53), 0.332 (0.56), 0.347 (0.58), 0.355 (0.59), 0.369 (0.68), 0.377 (0.58), 0.391 (0.49), 0.894 (0.53), 0.912 (0.47), 1.154 (1.11), 1.171 (2.49), 1.189 (1.58), 1.270 (6.23), 1.288 (6.20), 1.357 (16.00), 1.986 (3.33), 2.326 (0.52), 2.518 (1.83), 2.522 (1.26), 2.668 (0.52), 3.303 (0.58), 3.358 (0.76), 3.366 (0.40), 3.434 (0.42), 3.456 (0.40), 4.016 (0.65), 4.034 (0.64), 4.874 BHC221035 EP (0.46), 4.893 (0.64), 4.912 (0.41), 5.655 (0.92), 7.239 (0.81), 7.258 (1.89), 7.277 (1.20), 7.361 (0.71), 7.364 (0.80), 7.381 (1.16), 7.397 (0.55), 7.401 (0.50), 7.482 (0.70), 7.497 (1.17), 7.515 (0.60), 7.558 (0.78), 7.578 (0.72). Intermediate 27 (1R or S)-2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1-cyclopropyl-2,2-difluoroethan-1-ol trifluoroacetate (1/1) (diastereomer 1)
Figure imgf000071_0001
To a solution of tert-butyl [(1R)-1-{3-[(2R or S)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl]-2- fluorophenyl}ethyl]carbamate (diastereomer 1) (Intermediate 26.1, 2.87 g, 7.99 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (9.2 ml, 120 mmol), and the mixture was stirred at RT overnight. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting product (3.6 g) was used without any further purification. LC-MS (Method 2): Rt = 0.88 min; MS (ESIpos): m/z = 260 [M+H]+ Intermediate 28 (1R or S)-2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1-cyclopropyl-2,2-difluoroethan-1-ol trifluoroacetate (1/1) (diastereomer 2)
Figure imgf000071_0002
To a solution of tert-butyl [(1R)-1-{3-[(2R or S)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl]-2- fluorophenyl}ethyl]carbamate (diastereomer 2) (Intermediate 26.2, 2.39 g, 6.65 mmol) in dichloromethane (45 ml) was added trifluoroacetic acid (7.7 ml, 100 mmol), and the mixture was stirred at RT overnight. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting product (2.9 g) was used without any further purification. LC-MS (Method 2): Rt = 0.85 min; MS (ESIpos): m/z = 260 [M+H]+ Intermediate 29 (1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2-fluorophenyl)ethan-1-amine (diastereomer 1) BHC221035 EP
Figure imgf000072_0001
To a solution of trifluoroacetic acid (1R or S)-2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1-cyclopropyl-2,2- difluoroethan-1-ol (1/1) (diastereomer 1) (Intermediate 27, 3.60 g, 83 % purity, 7.96 mmol) in dichloromethane (50 ml) at 0 °C was added 2,6-lutidine (6.5 ml) and stirred for 5 min. After that, triethylsilyl trifluoromethanesulfonate (9.0 ml, 40 mmol) was added dropwise and the mixture was allowed to warm to RT and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added, and stirred for 10 min, before the phases were separated. The organic phases were dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane, ethanol), followed by a second purification (Biotage® Sfär Amino, ethyl acetate, hexane) to yield the title compound (2.53 g, 85 %). LC-MS (Method 2): Rt = 1.59 min; MS (ESIpos): m/z = 374 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.260 (0.45), 0.274 (0.42), 0.430 (0.46), 0.447 (1.12), 0.450 (0.76), 0.460 (1.30), 0.467 (2.88), 0.480 (2.98), 0.488 (2.97), 0.499 (2.89), 0.508 (1.27), 0.518 (1.41), 0.537 (0.43), 0.803 (0.78), 0.812 (0.46), 0.820 (7.25), 0.832 (0.88), 0.840 (16.00), 0.848 (0.73), 0.859 (5.32), 1.235 (3.49), 1.251 (3.36), 2.518 (0.99), 2.523 (0.68), 4.236 (0.63), 4.253 (0.62), 7.236 (0.41), 7.255 (1.00), 7.275 (0.63), 7.340 (0.41), 7.354 (0.54), 7.358 (0.56), 7.707 (0.53). Intermediate 29 (1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2-fluorophenyl)ethan-1-amine (diastereomer 2)
Figure imgf000072_0002
To a solution of trifluoroacetic acid (1R or S)-2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-1-cyclopropyl-2,2- difluoroethan-1-ol (1/1) (diastereomer 2) (Intermediate 28, 2.91 g, 85 % purity, 6.63 mmol) in dichloromethane (45 ml) at 0 °C was added 2,6-lutidine (5.4 ml) and stirred for 5 min. After that, triethylsilyl trifluoromethanesulfonate (7.5 ml, 33 mmol) was added dropwise and the mixture was allowed to warm to RT and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added, and stirred for 10 min, before the phases were separated. The organic phases were dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, BHC221035 EP dichloromethane, ethanol), followed by a second purification (Biotage® Sfär Amino, ethyl acetate, hexane) to yield the title compound (1.9 g, 78 %). LC-MS (Method 2): Rt = 1.59 min; MS (ESIpos): m/z = 374 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.364 (0.77), 0.381 (0.84), 0.384 (0.91), 0.402 (2.13), 0.421 (2.70), 0.441 (3.11), 0.451 (0.59), 0.460 (2.66), 0.479 (1.56), 0.488 (0.45), 0.497 (0.98), 0.517 (0.43), 0.783 (6.59), 0.792 (0.50), 0.795 (0.74), 0.804 (16.00), 0.812 (0.72), 0.823 (5.36), 0.840 (0.47), 1.216 (3.26), 1.232 (3.29), 2.518 (0.86), 2.523 (0.58), 4.265 (0.59), 4.281 (0.58), 7.258 (0.94), 7.277 (0.61), 7.350 (0.49), 7.353 (0.52), 7.733 (0.49). Intermediate 30 6-bromo-N-[(1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2- fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 1)
Figure imgf000073_0001
The reaction was performed as described for Intermediate 13 using 6-bromo-2-methylpyrido[3,4- d]pyrimidin-4-ol (Intermediate 15, 353 mg, 1.47 mmol), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (486 mg, 1.61 mmol), triethylamine (470 µl) DMAP (24.5 mg, 201 µmol), and (1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2-fluorophenyl)ethan-1-amine (diastereomer 1) (Intermediate 29, 500 mg, 1.34 mmol) in DMF (4.5 ml). The crude product was purified by flash chromatography (silica gel, ethyl acetate, hexane) to obtain the title compound (606 mg, 76 % yield). LC-MS (Method 2): Rt = 1.76 min; MS (ESIpos): m/z = 595 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.347 (0.61), 0.363 (0.81), 0.367 (0.78), 0.384 (2.34), 0.388 (1.09), 0.405 (2.78), 0.408 (2.63), 0.428 (2.79), 0.446 (1.61), 0.454 (0.56), 0.465 (0.98), 0.484 (0.40), 0.731 (6.82), 0.739 (0.49), 0.742 (0.71), 0.750 (16.00), 0.758 (0.68), 0.771 (4.97), 1.583 (2.34), 1.600 (2.33), 2.391 (8.76), 2.518 (1.50), 2.523 (1.12), 5.788 (0.54), 7.242 (0.44), 7.261 (0.93), 7.280 (0.54), 7.402 (0.51), 7.659 (0.48), 8.661 (2.04), 8.805 (2.33), 8.806 (2.40), 8.827 (0.61), 8.846 (0.58). Intermediate 31 6-bromo-N-[(1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2- fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 2) BHC221035 EP
Figure imgf000074_0001
The reaction was performed as described for Intermediate 13 using 6-bromo-2-methylpyrido[3,4- d]pyrimidin-4-ol (Intermediate 15, 1.17 g, 4.86 mmol), 2,4,6-tri(propan-2-yl)benzene-1-sulfonyl chloride (1.47 g, 4.86 mmol), triethylamine (1.4 ml, 9.7 mmol) DMAP (59.4 mg, 486 µmol), and (1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2-fluorophenyl)ethan-1-amine (diastereomer 2) (Intermediate 29, 500 mg, 1.34 mmol) in DMF (19 ml). The crude product was purified by flash chromatography (silica gel, ethyl acetate, hexane) to obtain the title compound (1.46 g, 90 % purity, 68 % yield). LC-MS (Method 2): Rt = 1.76 min; MS (ESIpos): m/z = 595 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.242 (0.43), 0.309 (0.81), 0.330 (1.03), 0.347 (2.24), 0.367 (2.67), 0.389 (2.50), 0.409 (2.41), 0.427 (1.45), 0.446 (1.03), 0.465 (0.69), 0.719 (7.05), 0.730 (0.83), 0.738 (16.00), 0.746 (0.90), 0.758 (5.48), 1.149 (0.61), 1.167 (1.26), 1.185 (0.67), 1.580 (2.66), 1.598 (2.66), 1.982 (2.15), 2.353 (8.64), 2.518 (0.84), 2.523 (0.56), 3.365 (0.49), 3.438 (0.75), 4.012 (0.48), 4.029 (0.46), 5.614 (0.41), 5.632 (0.64), 5.649 (0.40), 7.219 (0.48), 7.238 (1.08), 7.257 (0.66), 7.393 (0.61), 7.620 (0.58), 8.678 (2.25), 8.790 (2.70), 8.901 (0.70), 8.919 (0.66). Intermediate 32 (1R or S)-2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1- cyclopropyl-2,2-difluoroethanol (diastereomer 1)
Figure imgf000074_0002
To a solution of 6-bromo-N-[(1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2- fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 1) (Intermediate 30, 604 mg, 1.01 mmol) in dichloromethane (9 ml) was added trifluoroacetic acid (1.6 ml, 20 mmol), and the mixture was stirred at RT overnight. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting product was purified by flash chromatography (Biotage® Sfär Amino, ethyl acetate, hexane) to yield the title compound (489 mg, 100 %). BHC221035 EP LC-MS (Method 2): Rt = 1.19 min; MS (ESIpos): m/z = 481 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm -0.05 - 0.07 (m, 1 H) 0.18 - 0.44 (m, 3 H) 0.82 - 0.99 (m, 1 H) 1.58 (d, 3 H) 2.39 (s, 3 H) 3.37 - 3.54 (m, 1 H) 5.61 - 5.67 (m, 1 H) 5.69 - 5.79 (m, 1 H) 7.19 - 7.28 (m, 1 H) 7.35 - 7.45 (m, 1 H) 7.57 - 7.66 (m, 1 H) 8.68 (s, 1 H) 8.81 (s, 1 H) 8.83 - 8.90 (m, 1 H). Intermediate 33 (1R or S)-2-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1- cyclopropyl-2,2-difluoroethanol (diastereomer 2)
Figure imgf000075_0001
To a solution of 6-bromo-N-[(1R)-1-(3-{(2R or S)-2-cyclopropyl-1,1-difluoro-2-[(triethylsilyl)oxy]ethyl}-2- fluorophenyl)ethyl]-2-methylpyrido[3,4-d]pyrimidin-4-amine (diastereomer 2) (Intermediate 31, 611 mg, 1.0 mmol) in dichloromethane (9 ml) was added trifluoroacetic acid (1.6 ml, 21 mmol), and the mixture was stirred at RT overnight. All volatiles were removed, the residue was twice taken up in toluene and concentrated under reduced pressure, and the resulting product was purified by flash chromatography (Biotage® Sfär Amino, ethyl acetate, hexane) to yield the title compound (457 mg, 93 %). LC-MS (Method 2): Rt = 1.17 min; MS (ESIpos): m/z = 481 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm -0.13 - 0.08 (m, 1 H) 0.18 - 0.29 (m, 2 H) 0.32 - 0.48 (m, 1 H) 0.80 - 0.97 (m, 1 H) 1.48 - 1.63 (m, 3 H) 2.37 (s, 3 H) 3.37 - 3.54 (m, 1 H) 5.62 - 5.75 (m, 2 H) 7.18 - 7.27 (m, 1 H) 7.36 - 7.44 (m, 1 H) 7.55 - 7.64 (m, 1 H) 8.63 - 8.72 (m, 1 H) 8.81 (s, 1 H) 8.85 - 8.94 (m, 1 H). EXPERIMENTAL SECTION - EXAMPLES Example 1 (2RS)-2-cyclopropyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (mixture of diastereomers) BHC221035 EP
Figure imgf000076_0001
To a solution of 1-cyclopropyl-2-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-2,2-difluoroethan-1-one (Intermediate 14, 47.8 mg, 100 µmol) in tetrahydrofuran (1.2 ml) under an Argon atmosphere was added dropwise at -10 °C bromido(methyl)magnesium (220 µl, 1.0 M, 220 µmol), and the mixture was stirred for 30 min, whereas the solution was allowed to warm to 0 °C. The mixture was cooled again to -10 °C and further bromido(methyl)magnesium (220 µl, 1.0 M, 220 µmol) was added. The mixture was stirred for 30 min and warmed to 0 °C. Then, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography to yield the title compound 28.4 mg (95 % purity, 55 % yield). LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 493 [M+H]+ The two diastereomers were separated by preparative SFC chromatography. Preparative method: Instrument: Sepiatec Prep SFC100 Column: Chiral Art Amylose-SA 5μ 250x30mm Eluent A: CO2 Eluent B: 2-propanol + 0.4 vol % diethylamine Isocratic: 10 % B; gradient: no; flow: 100 ml/min Temperature: 40°C BPR: 150 bar Detection: UV (300 nm) Analytical method: Instrument: Waters Acquity UPC2 QDA Column: Chiral Art Amylose-SA 3μ 100x4.6mm Eluent A: CO2 BHC221035 EP Eluent B: 2-propanol + 0.4 vol % diethylamine Isocratic: 10 % B; gradient: no Flow: 4 ml/min Temperature: 37.5°C BPR: 1800 psi Detection: UV (280 nm) Example 1.1 (2R or S)-2-cyclopropyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol Isomer 1 of Example 1 Rt (analytical method): 3.37 min 1H NMR (400 MHz, DMSO-d6) δ ppm -0.04 - 0.11 (m, 2 H) 0.12 - 0.34 (m, 2 H) 0.91 - 1.06 (m, 1 H) 1.24 (s, 3 H) 1.55 - 1.62 (m, 3 H) 1.67 - 1.71 (m, 3 H) 1.72 - 1.74 (m, 3 H) 2.40 (s, 3 H) 5.10 (s, 1 H) 5.72 - 5.82 (m, 1 H) 7.18 (s, 1 H) 7.27 - 7.33 (m, 1 H) 7.53 - 7.65 (m, 1 H) 8.98 (d, J=6.08 Hz, 1 H) 9.09 (s, 1 H) 9.29 (d, J=7.35 Hz, 1 H). Example 1.2 (2R or S)-2-cyclopropyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol Isomer 2 of Example 1 Rt (analytical method): 4.84 min 1H NMR (400 MHz, DMSO-d6) δ ppm -0.05 - 0.05 (m, 1 H) 0.14 (br d, J=7.35 Hz, 2 H) 0.20 - 0.30 (m, 1 H) 0.98 (br s, 1 H) 1.25 (s, 3 H) 1.59 (d, J=7.10 Hz, 3 H) 1.69 (s, 3 H) 1.73 (s, 3 H) 2.40 (s, 3 H) 5.11 (s, 1 H) 5.77 - 5.86 (m, 1 H) 7.14 - 7.24 (m, 1 H) 7.27 - 7.35 (m, 1 H) 7.59 (s, 1 H) 8.95 - 9.02 (m, 1 H) 9.09 (s, 1 H) 9.21 - 9.32 (m, 1 H). Example 2 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one (2 Stereoisomers present) BHC221035 EP
Figure imgf000078_0001
To a solution of (2RS)-1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2- fluorophenyl)-2-cyclobutyl-1,1-difluoropropan-2-ol (Intermediate 19, 125 mg, 245 µmol), 1lambda5- phospholan-1-one (25.5 mg, 245 µmol), and triethylamine (120 µl, 860 µmol) in acetonitrile was added tetrakis(triphenylphosphin)palladium(0) (42.5 mg, 36.8 µmol) and the mixture was stirred at 90 °C overnight. The mixture was then cooled, concentrated and the residue was purified by preparative HPLC (basic conditions) to yield the title compound 93.0 mg (95 % purity, 68 % yield). LC-MS (Method 2): Rt = 1.23 min; MS (ESIneg): m/z = 531 [M-H]- NMR: ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.032 (5.33), 1.075 (4.87), 1.508 (1.42), 1.583 (5.77), 1.600 (5.61), 1.638 (0.70), 1.667 (0.69), 1.750 (0.79), 1.795 (0.86), 1.813 (1.23), 1.836 (1.64), 1.865 (1.61), 1.885 (1.56), 1.912 (1.20), 1.938 (1.04), 1.978 (1.69), 1.996 (2.21), 2.014 (2.01), 2.037 (1.67), 2.055 (1.47), 2.071 (1.12), 2.091 (1.69), 2.131 (1.18), 2.327 (4.00), 2.331 (2.81), 2.337 (1.23), 2.402 (12.64), 2.413 (14.08), 2.518 (16.00), 2.523 (11.16), 2.573 (0.61), 2.595 (0.64), 2.616 (0.41), 2.669 (4.01), 2.673 (2.76), 2.678 (1.23), 5.182 (5.08), 5.221 (4.37), 5.742 (0.70), 5.760 (1.15), 5.777 (0.89), 5.784 (1.04), 5.801 (0.61), 7.178 (1.16), 7.198 (2.71), 7.217 (1.75), 7.282 (1.20), 7.299 (1.70), 7.319 (0.82), 7.571 (0.54), 7.585 (1.26), 7.602 (1.27), 7.617 (0.53), 9.022 (2.87), 9.038 (2.83), 9.092 (4.07), 9.095 (3.87), 9.292 (1.05), 9.317 (1.40), 9.335 (1.12). Example 3 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one (2 Stereoisomers present)
Figure imgf000078_0002
The title compound was synthesized as described for example 2, using (2RS)-1-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2-cyclopropyl-1,1-difluoropropan-2-ol (Intermediate 20, 125 mg, 252 µmol), 2,5-dihydro-1H-1lambda5-phosphol-1-one (25.8 mg, 252 µmol), tetrakis(triphenylphosphin)palladium(0) (43.7 mg, 37.9 µmol), triethylamine (120 µl, 880 µmol), and BHC221035 EP acetonitrile (3.0 ml). Purification of the crude product by preparative HPLC (basic method) gave the title compound (60.0 mg, 95 % purity, 44 % yield). LC-MS (Method 2): Rt = 1.10 min; MS (ESIpos): m/z = 517 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.050 (0.61), 0.064 (0.70), 0.083 (0.56), 0.133 (0.50), 0.152 (0.75), 0.165 (0.59), 0.240 (0.56), 0.256 (0.56), 0.991 (0.49), 1.247 (4.18), 1.255 (3.50), 1.589 (4.45), 1.606 (4.48), 2.332 (2.02), 2.336 (0.90), 2.407 (15.03), 2.518 (16.00), 2.522 (10.17), 2.564 (1.07), 2.606 (1.25), 2.660 (1.07), 2.664 (2.13), 2.669 (2.89), 2.673 (2.14), 2.678 (0.95), 2.886 (1.15), 2.931 (0.86), 5.101 (2.86), 5.108 (2.33), 5.754 (0.43), 5.772 (0.75), 5.789 (0.74), 5.806 (0.61), 6.010 (2.52), 6.081 (2.55), 7.166 (0.62), 7.185 (1.46), 7.204 (0.92), 7.287 (0.70), 7.303 (1.05), 7.322 (0.54), 7.578 (0.60), 7.594 (1.11), 7.611 (0.60), 9.082 (4.53), 9.096 (1.59), 9.292 (0.60), 9.309 (1.31), 9.327 (0.76). Example 4 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclopropyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-1lambda5-phospholan-1-one (2 Stereoisomers present)
Figure imgf000079_0001
The title compound was synthesized as described for example 2, using (2RS)-1-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2-cyclopropyl-1,1-difluoropropan-2-ol (Intermediate 20, 125 mg, 252 µmol), 1lambda5-phospholan-1-one (26.3 mg, 252 µmol), tetrakis(triphenylphosphin)palladium(0) (43.7 mg, 37.9 µmol), triethylamine (120 µl, 880 µmol), and acetonitrile (3.0 ml). Purification of the crude product by preparative HPLC (basic method) gave the title compound (90.0 mg, 95 % purity, 65 % yield). LC-MS (§OA01b02): Rt = 1.12 min; MS (ESIpos): m/z = 519 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.039 (0.48), 0.045 (0.52), 0.050 (0.58), 0.060 (0.67), 0.071 (0.59), 0.082 (0.52), 0.132 (0.51), 0.143 (0.52), 0.150 (0.74), 0.155 (0.70), 0.164 (0.60), 0.232 (0.57), 0.240 (0.56), 0.254 (0.58), 0.989 (0.45), 1.004 (0.46), 1.245 (4.17), 1.254 (3.46), 1.582 (4.54), 1.600 (4.56), 1.796 (0.54), 1.813 (0.71), 1.832 (0.85), 1.849 (0.69), 1.867 (0.59), 1.961 (0.54), 1.979 (0.87), 1.997 (1.11), 2.015 (1.21), 2.037 (1.02), 2.055 (0.90), 2.071 (0.63), 2.093 (0.97), 2.106 (0.85), 2.123 (0.88), 2.141 (0.79), 2.159 (0.54), 2.332 (0.57), 2.403 (16.00), 2.518 (3.10), 2.523 (2.04), 2.673 (0.57), 5.099 (2.97), 5.106 (2.36), 5.752 (0.45), 5.770 (0.76), 5.787 (0.73), 5.803 (0.61), 7.161 (0.66), 7.181 (1.52), 7.200 (0.94), 7.282 (0.71), 7.300 BHC221035 EP (1.06), 7.319 (0.51), 7.575 (0.63), 7.592 (1.09), 7.608 (0.57), 9.030 (1.46), 9.046 (1.45), 9.094 (3.48), 9.289 (0.63), 9.306 (1.28), 9.324 (0.76). Example 5 1-(4-{[(1R)-1-{3-[(2RS)-2-cyclobutyl-1,1-difluoro-2-hydroxypropyl]-2-fluorophenyl}ethyl]amino}-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-1lambda5-phosphol-1-one (2 Stereoisomers present)
Figure imgf000080_0001
The title compound was synthesized as described for example 2, using (2RS)-1-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2-cyclobutyl-1,1-difluoropropan-2-ol (Intermediate 19, 125 mg, 245 µmol), 2,5-dihydro-1H-1lambda5-phosphol-1-one (25.0 mg, 245 µmol), tetrakis(triphenylphosphin)palladium(0) (42.5 mg, 36.8 µmol), triethylamine (120 µl, 880 µmol), and acetonitrile (3.0 ml). Purification of the crude product by preparative HPLC (basic method) gave the title compound (60.0 mg, 95 % purity, 44 % yield). LC-MS (§OA01b02): Rt = 1.20 min; MS (ESIneg): m/z = 529 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.033 (4.58), 1.076 (4.19), 1.514 (1.25), 1.589 (4.94), 1.607 (4.81), 1.643 (0.62), 1.664 (0.61), 1.751 (0.67), 1.840 (0.42), 1.864 (0.70), 1.887 (1.01), 1.913 (0.97), 1.939 (0.63), 1.971 (0.61), 2.331 (2.85), 2.336 (1.24), 2.404 (10.83), 2.416 (11.79), 2.518 (16.00), 2.523 (11.05), 2.562 (1.54), 2.604 (2.05), 2.647 (1.48), 2.673 (2.86), 2.678 (1.28), 2.869 (1.07), 2.882 (1.81), 2.927 (1.37), 2.941 (0.77), 5.184 (4.22), 5.223 (3.64), 5.744 (0.64), 5.762 (0.99), 5.786 (0.91), 5.804 (0.54), 6.009 (3.55), 6.081 (3.53), 7.183 (0.99), 7.202 (2.33), 7.221 (1.47), 7.286 (1.01), 7.303 (1.42), 7.322 (0.67), 7.574 (0.51), 7.587 (1.07), 7.603 (1.06), 7.618 (0.47), 9.071 (2.45), 9.080 (4.49), 9.085 (6.04), 9.296 (0.89), 9.319 (1.17), 9.338 (0.93). Example 6 (2RS)-2-cyclobutyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol (2 Stereoisomers present) BHC221035 EP
Figure imgf000081_0001
The title compound was synthesized as described for example 2, using (2RS)-1-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-2-cyclobutyl-1,1-difluoropropan-2-ol (200 mg, 393 µmol), dimethyl-lambda5-phosphanone (33.7 mg, 432 µmol), tetrakis(triphenylphosphin)palladium(0) (90.7 mg, 78.5 µmol), triethylamine (190 µl, 1.4 mmol), and acetonitrile (4.0 ml). Purification of the crude product by flash chromatography (silica, hexane, ethyl acetate) gave the title compound (150 mg, 90 % purity, 68 % yield). LC-MS (Method 2): Rt = 1.15 min; MS (ESIpos): m/z = 508 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.797 (0.65), 0.800 (0.60), 0.814 (0.68), 0.821 (0.74), 0.904 (0.75), 1.032 (4.08), 1.052 (1.65), 1.070 (3.53), 1.075 (4.03), 1.088 (0.77), 1.154 (1.26), 1.158 (0.93), 1.172 (2.45), 1.191 (1.23), 1.510 (1.17), 1.526 (1.05), 1.584 (4.59), 1.600 (4.56), 1.640 (0.66), 1.663 (0.73), 1.691 (12.42), 1.725 (12.55), 1.840 (0.43), 1.865 (0.69), 1.887 (0.95), 1.907 (1.87), 1.935 (0.57), 1.947 (0.46), 1.973 (0.54), 2.327 (1.02), 2.331 (0.74), 2.400 (9.14), 2.412 (9.55), 2.518 (5.00), 2.523 (3.37), 2.569 (0.52), 2.596 (0.50), 2.673 (0.74), 3.084 (0.53), 3.096 (0.55), 3.102 (0.54), 3.114 (0.49), 5.183 (3.43), 5.222 (3.28), 5.742 (0.57), 5.759 (16.00), 5.783 (0.85), 5.801 (0.50), 7.183 (0.84), 7.202 (2.00), 7.221 (1.29), 7.284 (0.89), 7.301 (1.32), 7.320 (0.64), 7.573 (0.43), 7.586 (1.00), 7.602 (0.98), 7.617 (0.41), 8.971 (2.22), 8.986 (2.23), 9.087 (3.08), 9.089 (3.12), 9.266 (0.80), 9.288 (1.16), 9.307 (0.80). The two diastereomers were separated by preparative SFC chromatography. Preparative method: Instrument: Sepiatec: Prep SFC100 Column: Chiral Art Amylose-SA 5μ 250x30mm Eluent A: CO2 Eluent B: 2-propanol + 0.4 vol % diethylamine Isocratic: 10 % B; gradient: no; flow: 100 ml/min Temperature: 40°C BPR: 150 bar Detection: UV (300 nm) BHC221035 EP Analytical method: Instrument: Waters Acquity UPC2 QDA Column: Chiral Art Amylose-SA 3μ 100x4.6mm Eluent A: CO2 Eluent B: 2-propanol + 0.4 vol % diethylamine Isocratic: 10 % B; gradient: no Flow: 4 ml/min Temperature: 40 °C BPR: 1800 psi Detection: UV (254 nm) Example 6.1 (2R or S)-2-cyclobutyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol Isomer 1 of Example 6 Rt (analytical method): 3.29 min LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 507 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.032 (3.79), 1.491 (0.44), 1.515 (0.70), 1.536 (0.46), 1.584 (2.95), 1.602 (2.96), 1.668 (0.44), 1.691 (6.11), 1.725 (6.07), 1.914 (0.53), 1.973 (0.48), 2.412 (9.94), 2.518 (1.99), 2.523 (1.40), 2.596 (0.43), 5.184 (2.45), 5.742 (0.51), 5.759 (16.00), 5.777 (0.48), 7.183 (0.47), 7.202 (1.09), 7.222 (0.70), 7.280 (0.41), 7.284 (0.48), 7.301 (0.67), 7.601 (0.66), 8.972 (1.14), 8.987 (1.14), 9.085 (2.74), 9.291 (0.83), 9.309 (0.78). Example 6.2 (2R or S)-2-cyclobutyl-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4- yl]amino}ethyl]-2-fluorophenyl}-1,1-difluoropropan-2-ol Isomer 2 of Example 6 Rt (analytical method): 4.71 min LC-MS (Method 2): Rt = 1.14 min; MS (ESIpos): m/z = 508 [M+H]+ Example 7 BHC221035 EP (4-(((R)-1-(3-((S or R)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide (diastereomer 1)
Figure imgf000083_0001
The reaction was performed das described for Intermediate 14 using (1R or S)-2-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1-cyclopropyl-2,2-difluoroethanol (diastereomer 1) (Intermediate 32, 76 mg, 153 µmol), dimethyl-lambda5-phosphanone (12 mg, 153 µmol), tetrakis(triphenylphosphin)palladium(0) (27 mg, 23 µmol), and triethylamine (75 µl, 536 µmol) in acetonitrile (1.7 ml). The product was purified by preparative TLC (silica gel, dichloromethane, ethanol) to yield the title compound (56 mg, 73 % yield). LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 479 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm -0.08 - 0.10 (m, 1 H) 0.17 - 0.43 (m, 3 H) 0.80 - 1.01 (m, 1 H) 1.60 (d, J=6.84 Hz, 3 H) 1.71 (dd, J=13.56, 1.14 Hz, 6 H) 2.42 (s, 3 H) 3.42 - 3.52 (m, 1 H) 5.52 - 5.71 (m, 1 H) 5.74 - 5.86 (m, 1 H) 7.19 - 7.28 (m, 1 H) 7.35 - 7.43 (m, 1 H) 7.60 - 7.67 (m, 1 H) 8.93 - 9.01 (m, 1 H) 9.07 - 9.12 (m, 1 H) 9.21 - 9.32 (m, 1 H). Example 8 (4-(((R)-1-(3-((S or R)-2-cyclopropyl-1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)dimethylphosphine oxide (diastereomer 2)
Figure imgf000083_0002
The reaction was performed das described for Intermediate 14 using (1R or S)-2-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1-cyclopropyl-2,2-difluoroethanol (diastereomer 2) (Intermediate 33, 70 mg, 145 µmol), dimethyl-lambda5-phosphanone (11 mg, 145 µmol), tetrakis(triphenylphosphin)palladium(0) (34 mg, 29 µmol), and triethylamine (71 µl, 509 µmol) in acetonitrile (1.6 ml). The product was purified by preparative TLC (silica gel, dichloromethane, ethanol) to yield the title compound (54 mg, 74 % yield). LC-MS (Method 2): Rt = 0.95 min; MS (ESIpos): m/z = 479 [M+H]+ BHC221035 EP 1H NMR (400 MHz, DMSO-d6) δ ppm -0.09 - 0.04 (m, 1 H) 0.17 - 0.30 (m, 2 H) 0.32 - 0.45 (m, 1 H) 0.81 - 0.95 (m, 1 H) 1.57 - 1.64 (m, 3 H) 1.67 - 1.74 (m, 6 H) 2.40 (s, 3 H) 3.39 - 3.55 (m, 1 H) 5.61 - 5.69 (m, 1 H) 5.71 - 5.82 (m, 1 H) 7.18 - 7.29 (m, 1 H) 7.34 - 7.44 (m, 1 H) 7.57 - 7.70 (m, 1 H) 8.93 - 9.01 (m, 1 H) 9.05 - 9.12 (m, 1 H) 9.27 - 9.35 (m, 1 H). Example 9 (1R or S)-1-cyclopropyl-2,2-difluoro-2-{2-fluoro-3-[(1R)-1-{[2-methyl-6-(1-oxidophospholan-1- yl)pyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]phenyl}ethanol (diastereomer 1)
Figure imgf000084_0001
The reaction was performed das described for Intermediate 14 using (1R or S)-2-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1-cyclopropyl-2,2-difluoroethanol (diastereomer 1) (Intermediate 32, 100 mg, 208 µmol), 1lambda-5-phospholan-1-one (22 mg, 208 µmol), tetrakis(triphenylphosphin)palladium(0) (48 mg, 42 µmol), and triethylamine (101 µl, 727 µmol) in acetonitrile (2.4 ml). The product was purified by preparative HPLC (acidic method) to yield the title compound (48 mg, 44 % yield). LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 505 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm -0.11 - 0.09 (m, 1 H) 0.18 - 0.43 (m, 3 H) 0.79 - 0.99 (m, 1 H) 1.53 - 1.65 (m, 3 H) 1.80 - 1.90 (m, 2 H) 1.92 - 2.20 (m, 6 H) 2.39 - 2.43 (m, 3 H) 3.44 - 3.51 (m, 1 H) 5.59 - 5.68 (m, 1 H) 5.76 - 5.86 (m, 1 H) 7.19 - 7.28 (m, 1 H) 7.34 - 7.46 (m, 1 H) 7.58 - 7.68 (m, 1 H) 8.99 - 9.05 (m, 1 H) 9.07 - 9.12 (m, 1 H) 9.26 - 9.35 (m, 1 H). Example 10 (1R or S)-1-cyclopropyl-2,2-difluoro-2-{2-fluoro-3-[(1R)-1-{[2-methyl-6-(1-oxidophospholan-1- yl)pyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]phenyl}ethanol (diastereomer 2)
Figure imgf000084_0002
The reaction was performed das described for Intermediate 14 using (1R or S)-2-(3-{(1R)-1-[(6-bromo-2- methylpyrido[3,4-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1-cyclopropyl-2,2-difluoroethanol BHC221035 EP (diastereomer 2) (Intermediate 33, 100 mg, 208 µmol), 1lambda-5-phospholan-1-one (22 mg, 208 µmol), tetrakis(triphenylphosphin)palladium(0) (48 mg, 42 µmol), and triethylamine (101 µl, 727 µmol) in acetonitrile (2.4 ml). The product was purified by preparative TLC (silica gel, dichloromethane, ethanol) to yield the title compound (54 mg, 74 % yield). LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 505 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm -0.10 - 0.09 (m, 1 H) 0.15 - 0.31 (m, 2 H) 0.34 - 0.44 (m, 1 H) 0.76 - 0.96 (m, 1 H) 1.60 (d, 3 H) 1.74 - 1.90 (m, 2 H) 1.93 - 2.23 (m, 6 H) 2.40 (s, 3 H) 3.39 - 3.58 (m, 1 H) 5.64 - 5.70 (m, 1 H) 5.71 - 5.81 (m, 1 H) 7.18 - 7.28 (m, 1 H) 7.34 - 7.44 (m, 1 H) 7.56 - 7.66 (m, 1 H) 8.98 - 9.05 (m, 1 H) 9.06 - 9.13 (m, 1 H) 9.23 - 9.37 (m, 1 H). Example 11 (2R or S)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylbutan-2-ol (diastereomer 1)
Figure imgf000085_0001
The reaction was performed as described for Intermediate 13 using 6-(dimethylphosphoryl)-2- methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 25, 69 mg, 0.291 mmol), (2R or S)-1-{3-[(1R)-1- aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylbutan-2-ol trifluoroacetate (1:1) (diastereomer 1) (Intermediate 23, 79 mg, 0.305 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (132 mg, 0.436 mmol), triethylamine (405 µl, 2.909 mmol), DMAP (36 mg, 0.295 mmol), and 3.5 ml DMF. The title compound was obtained after flash chromatography (silica gel, dichloromethane, methanol, 1:1) and subsequent preparative HPLC (basic method) as white solid (23 mg, 97 % purity, 16 % yield). LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 481 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 - 0.91 (m, 3 H) 1.11 - 1.13 (m, 3 H) 1.44 - 1.65 (m, 5 H) 1.66 - 1.77 (m, 6 H) 2.36 - 2.44 (m, 3 H) 5.17 (s, 1 H) 5.73 - 5.85 (m, 1 H) 7.17 - 7.26 (m, 1 H) 7.27 - 7.37 (m, 1 H) 7.51 - 7.69 (m, 1 H) 8.92 - 9.03 (m, 1 H) 9.09 (s, 1 H) 9.21 - 9.37 (m, 1 H). Example 12 (2R or S)-1-{3-[(1R)-1-{[6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-4-yl]amino}ethyl]-2- fluorophenyl}-1,1-difluoro-2-methylbutan-2-ol (diastereomer 2) BHC221035 EP
Figure imgf000086_0001
The reaction was performed as described for Intermediate 13 using 6-(dimethylphosphoryl)-2- methylpyrido[3,4-d]pyrimidin-4-ol (Intermediate 25, 70 mg, 0.295 mmol), (2R or S)-1-{3-[(1R)-1- aminoethyl]-2-fluorophenyl}-1,1-difluoro-2-methylbutan-2-ol trifluoroacetate (1:1) (diastereomer 2) (Intermediate 24, 81 mg, 0.31 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (134 mg, 0.443 mmol), triethylamine (411 µl, 2.951 mmol), DMAP (36 mg, 0.295 mmol), and 3.5 ml DMF. The title compound was obtained after flash chromatography (silica gel, dichloromethane, methanol, 1:1) and subsequent preparative HPLC (basic method) as white solid (23 mg, 96 % purity, 16 % yield). LC-MS (Method 2): Rt = 1.02 min; MS (ESIpos): m/z = 481 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 - 0.92 (m, 3 H) 1.13 - 1.18 (m, 3 H) 1.45 - 1.57 (m, 2 H) 1.57 - 1.61 (m, 3 H) 1.66 - 1.77 (m, 6 H) 2.38 - 2.44 (m, 3 H) 5.15 - 5.21 (m, 1 H) 5.73 - 5.84 (m, 1 H) 7.17 - 7.26 (m, 1 H) 7.27 - 7.35 (m, 1 H) 7.56 - 7.66 (m, 1 H) 8.94 - 9.00 (m, 1 H) 9.07 - 9.11 (m, 1 H) 9.23 - 9.33 (m, 1 H). EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch. Biochemical assay: hK-RasG12C interaction assay with hSOS1 BHC221035 EP This assay quantifies the equilibrium interaction of human SOS1 (SOS1) with human K-RasG12C (K- RasG12C). Detection of the interaction is achieved by measuring homogenous time-resolved fluorescence resonance energy transfer (HTRF) from antiGST-Europium (FRET donor) bound to GST-K- RasG12C to anti-6His-XL665 bound to His-tagged hSOS1 (FRET-acceptor). The assay buffer containes 5 mM HEPES pH 7.4 (Applichem), 150 mM NaCl (Sigma), 10 mM EDTA (Promega), 1 mM DTT (Thermofisher), 0.05% BSA Fraction V, pH 7.0, (ICN Biomedicals), 0.0025% (v/v) Igepal (Sigma) and 100 mM KF (FLUKA). The expression and purification of N-terminal GST-tagged K-RasG12C and N-terminal His-tagged SOS1 is described below. Concentrations of protein batches used are optimized to be within the linear range of the HTRF signal. A Ras working solution is prepared in assay buffer containing typically 10 nM GST-hK- RasG12C and 2 nM antiGST-Eu(K) (Cisbio, France). A SOS1 working solution is prepared in assay buffer containing typically 20nM His-hSOS1 and 10 nM anti-6His-XL665 (Cisbio, France). An inhibitor control solution is prepared in assay buffer containing 10 nM anti-6His-XL665 without SOS1. Fifty nl of a 100-fold concentrated solution of the test compound in DMSO are transferred into a black microtiter test plate (384 or 1536, Greiner Bio-One, Germany). For this, either a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA) is used. All steps of the assay are performed at 20°C. A volume of 2.5 µl of the Ras working solution is added to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After 2 min preincubation, 2.5 µl of the SOS1 working solution are added to all wells except for those wells at the side of the test plate that are subsequently filled with 2.5 µl of the inhibitor control solution. After 60 min incubation the fluorescence is measured with a Pherastar (BMG, Germany) using the HTRF module (excitation 337nm, emission 1: 620nm, emission 2: 665nm). The ratiometric data (emission 2 divided by emission 1) are normalized using the controls (DMSO = 0% inhibition, inhibition control wells with inhibitor control solution = 100% inhibition). Compounds are tested in duplicates at up to 11 concentrations (for 20 µM, 5,7 µM, 1,6 µM, 0,47 µM, 0,13 µM, 38 nM, 11 nM, 3,1 nM, 0,89 nM, 0,25 nM and 0,073 nM). IC50 values are calculated by 4-Parameter fitting using a commercial software package (Genedata Screener, Switzerland). BHC221035 EP
Figure imgf000088_0001
pERK HTRF in K-562 (ATCC CCL-243) 10000 K-562 cells are seeded in HTRF 384well low volume plate (Greiner bio-one #784075) in medium (RPMI 1640 + 10% FCS) and treated with varying concentrations of test compounds for 1h. Next steps are performed to the supplier's manual Advanced phospho-ERK1/2 (#64AERPEH) Cisbio one-plate assay protocol. The content of pERK is measured with PHERAstar HTRF protocol, calculated Ratio*1000. The calculated ratio of DMSO-treated cells is set as 100% and the calculated ratio of negative control is set as 0% (maximum possible effect). The results given as IC50 reflecting the inhibition of formation of pERK compared to DMSO control and negative control and normalized according to cell number. The IC50 values are determined by means of a 4 parameter fit. In vitro metabolic stability in rat hepatocytes. Hepatocytes from Han/Wistar rats were isolated via a 2-step perfusion method. After perfusion, the liver was carefully removed from the rat: the liver capsule was opened and the hepatocytes were gently shaken out into a Petri dish with ice-cold Williams’ medium E (WME). The resulting cell suspension was filtered through sterile gaze in 50 ml falcon tubes and centrifuged at 50 × g for 3 min at room temperature. The cell pellet was resuspended in 30 ml WME and centrifuged twice through a Percoll® gradient at 100 × g. The hepatocytes were washed again with WME and resuspended in medium containing 5 % FCS. Cell viability was determined by trypan blue exclusion. For the metabolic stability assay liver cells were distributed in WME containing 5 % FCS to glass vials at a density of 1.0 × 106 vital cells/ml. The test compound was added to a final concentration of 1 µM. During incubation, the hepatocyte suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, BHC221035 EP 45 and 90 min, to which equal volumes of cold methanol were immediately added. Samples were frozen at -20 °C overnight, subsequently centrifuged for 15 minutes at 3000 rpm and the supernatant was analyzed with an Agilent 1200 HPLC-system with LC/MS-MS detection. The half-life of a test compound was determined from the concentration-time plot. From the half-life the intrinsic clearances and the hepatic in vivo blood clearance (CL) and maximal oral bioavailability (Fmax) were calculated using the ‘well stirred’ liver model together with the additional parameters liver blood flow, specific liver weight and amount of liver cells in vivo and in vitro. The following parameter values were used: Liver blood flow 4.2 L/h/kg, specific liver weight 32 g/kg, liver cells in vivo 1.1 x 108 cells/g liver, liver cells in vitro 1.0 x 106/ml. In Vitro Metabolic Stability in Liver Microsomes The in vitro metabolic stability of test compounds was determined by incubation at 1 μM in a suspension of liver microsomes in 100 mM phosphate buffer pH 7.4 (NaH2PO4·H2O + Na2HPO4·2H2O) and at a protein concentration of 0.5 mg/mL at 37 °C. The microsomes were activated by adding a cofactor mix containing 8 mM glucose-6-phosphate, 4 mM MgCl2, 0.5 mM NADP, and 1 IU/mL glucose-6-phosphate dehydrogenase in phosphate buffer pH 7.4. The metabolic assay was started shortly afterward by adding the test compound to the incubation at a final volume of 1 mL. Organic solvent in the incubations was limited to ≤0.01% DMSO and ≤1% MeCN. During incubation, the microsomal suspensions were continuously shaken at 580 rpm and aliquots were taken at 2, 8, 16, 30, 45, and 60 min, to which an equal volume of cold MeOH was immediately added. Samples were frozen at −20 °C overnight and after thawing subsequently centrifuged for 15 min at 3000 rpm. The supernatant was analyzed with an Agilent 1200 HPLC system with LC-MS/MS detection. The half-life of a test compound was determined from the concentration–time plot. From the half-life, the intrinsic clearances and the hepatic in vivo blood clearance (CL) and maximal oral bioavailability (Fmax) were calculated using the “well-stirred” liver model (Pang, K. S.; Rowland, M. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J. Pharmacokinet. Biopharm.1977, 5, 625– 653, DOI: 10.1007/BF01059688) together with the additional parameters liver blood flow, specific liver weight, and microsomal protein content. The following parameter values were used: liver blood flow: 5.4, 4.2, 2.1, and 1.32 L/h/kg for mouse, rat, dog, and human, respectively. Specific liver weight: 43, 32, 39, and 21 g/kg body weight for mouse, rat, dog, and human, respectively. Microsomal protein content: 40 mg/g for all species. BHC221035 EP
Figure imgf000090_0001

Claims

BHC221035 EP CLAIMS 1) A compound of general formula (I)
Figure imgf000091_0001
wherein R1 and R2 are independently selected from the group consisting of C1-4-alkyl; or R1 and R2 together with the phosphor atom they are attached to form a 4-6 membered
Figure imgf000091_0002
heterocycloalkyl or a 5-6 membered heterocycloalkenyl or ; R3 is selected from the group consisting of C3-5-cycloalkyl and 4 to 6 membered heterocycloalkyl, wherein said C3-5-cycloalkyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms, wherein said 5 membered heterocycloalkyl is optionally substituted with 1 or 2 Fluor atoms and wherein said 6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms; R4 is selected from H, D, -CH3, or -CH2-CH3; or R3 and R4 together with the carbon atom they are attached to form a cyclopropyl, a cyclobutyl or a cyclopentyl, wherein said cyclopropyl, and cyclobutyl are optionally substituted with one or two -CH3; and R5 is selected from the group consisting of -H, -F and -CH3; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2) Compound according to claim 1 wherein R1 and R2 are both -CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 3) Compound according to claim 1 wherein R1 and R2 together with the phosphor atom they are attached to form a 5 membered heterocycloalkyl or a 5 membered heterocycloalkenyl or or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. BHC221035 EP 4) Compound according to claim 1 wherein R3 is selected from the group consisting of cyclopropyl, cyclobutyl or oxetan, wherein said cyclopropyl or cyclobutyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 5) Compound according to claim 1 wherein R3 is selected from the group consisting of cyclopropyl or cyclobutyl and wherein said cyclopropyl or cyclobutyl is optionally substituted with 1, 2, 3 or 4 Fluor atoms or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 6) Compound according to claim 1 wherein R3 is selected from the group consisting of cyclopropyl or cyclobutyl or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 7) Compound according to claim 1 wherein R4 is -CH3 or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 8) Compound according to claim 1 wherein the combination of R3/R4 are selected from the combinations of cyclopropyl/-CH3, cyclobutyl/-CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 9) Compound according to claim 1 wherein R4 is D (Deuterium) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 10) Compound according to claim 1 wherein R3 and R4 together with the carbon atom they are attached to form a cyclopropyl optionally substituted with one -CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 11) Compound according to claim 1 wherein R5 is F or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 12) A compound of general formula (I) according to any one of claims 1 to 9 for use in the treatment or prophylaxis of a disease. 13) A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients. 14) A pharmaceutical combination comprising: • one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 9, and BHC221035 EP • one or more further active ingredients, in particular oncology agents like 131I- chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon BHC221035 EP gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, BHC221035 EP tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. 15) Use of a compound of general formula (I) according to any one of claims 1 to 9 for the treatment or prophylaxis of a disease. 16) Use of a compound of general formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease.
PCT/EP2023/078318 2022-10-13 2023-10-12 Sos1 inhibitors WO2024079252A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22201408.6 2022-10-13
EP22201408 2022-10-13

Publications (1)

Publication Number Publication Date
WO2024079252A1 true WO2024079252A1 (en) 2024-04-18

Family

ID=83693134

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/078318 WO2024079252A1 (en) 2022-10-13 2023-10-12 Sos1 inhibitors

Country Status (1)

Country Link
WO (1) WO2024079252A1 (en)

Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030187026A1 (en) 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
WO2004071460A2 (en) 2003-02-12 2004-08-26 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
WO2005105760A1 (en) 2004-04-30 2005-11-10 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof as an mmp-13 inhibitor
EP1007514B1 (en) 1997-08-25 2006-11-15 Bayer Corporation Heterocyclic ketones as npy y5 antagonists
WO2007134986A1 (en) 2006-05-23 2007-11-29 F. Hoffmann-La Roche Ag Pyridopyrimidinone derivatives
WO2010099379A1 (en) 2009-02-27 2010-09-02 Ambit Biosciences Corporation Jak kinase modulating quinazoline derivatives and methods of use thereof
WO2011028741A1 (en) 2009-09-03 2011-03-10 Bristol-Myers Squibb Company Quinazolines as potassium ion channel inhibitors
US20120053174A1 (en) 2010-09-01 2012-03-01 Hadd Michael J Quinazoline compounds and methods of use thereof
US20120053176A1 (en) 2010-09-01 2012-03-01 Ambit Biosciences Corp. Adenosine a3 receptor modulating compounds and methods of use thereof
WO2012028578A1 (en) 2010-09-03 2012-03-08 Bayer Cropscience Ag Substituted fused pyrimidinones and dihydropyrimidinones
WO2012030912A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation 7-cyclylquinazoline derivatives and methods of use thereof
WO2012066122A1 (en) 2010-11-18 2012-05-24 Syngenta Participations Ag 2 - (pyridin- 2 -yl) -quinazoline derivatives and their use as microbicides
WO2012112363A1 (en) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
WO2013016999A1 (en) 2011-08-04 2013-02-07 江苏豪森药业股份有限公司 Heteroaryl-pyrimidine derivatives, and preparation method therefor and use thereof
WO2013030138A1 (en) 2011-09-01 2013-03-07 F. Hoffmann-La Roche Ag Pyrrolopyrazine kinase inhibitors
WO2014100501A1 (en) 2012-12-20 2014-06-26 Sanford-Burnham Medical Research Institute Small molecule agonists of neurotensin receptor 1
US20150225436A1 (en) 2008-05-21 2015-08-13 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
WO2015155306A1 (en) 2014-04-11 2015-10-15 Almirall, S.A. New trpa1 antagonists
WO2017069275A1 (en) 2015-10-22 2017-04-27 田辺三菱製薬株式会社 Novel bicyclic heterocyclic compound
CN104803954B (en) 2015-04-30 2018-01-26 上海应用技术学院 A kind of preparation method of fosamprenavir intermediate
WO2018115380A1 (en) 2016-12-22 2018-06-28 Boehringer Ingelheim International Gmbh Novel benzylamino substituted quinazolines and derivatives as sos1 inhibitors
WO2018118735A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. 6,6-fused heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
WO2018134685A2 (en) 2017-01-17 2018-07-26 Liverpool School Of Tropical Medicine Compounds
WO2018172250A1 (en) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-methyl-quinazolines
FR3066761A1 (en) 2017-05-23 2018-11-30 Centre National De La Recherche Scientifique NOVEL IONIC CHANNEL INHIBITOR COMPOUNDS
WO2019122129A1 (en) 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Novel benzylamino substituted pyridopyrimidinones and derivatives as sos1 inhibitors
US20190270704A1 (en) 2018-03-05 2019-09-05 Bristol-Myers Squibb Company Phenylpyrrolidinone formyl peptide 2 receptor agonists
WO2020180768A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2020180770A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
WO2021228028A1 (en) 2020-05-09 2021-11-18 正大天晴药业集团股份有限公司 Sos1 inhibitor containing phosphorus
CA3195519A1 (en) * 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines as sos1 inhibitors

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1007514B1 (en) 1997-08-25 2006-11-15 Bayer Corporation Heterocyclic ketones as npy y5 antagonists
US20030187026A1 (en) 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
US20030199511A1 (en) 2001-12-13 2003-10-23 Qun Li Kinase inhibitors
WO2004071460A2 (en) 2003-02-12 2004-08-26 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
WO2005105760A1 (en) 2004-04-30 2005-11-10 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof as an mmp-13 inhibitor
WO2007134986A1 (en) 2006-05-23 2007-11-29 F. Hoffmann-La Roche Ag Pyridopyrimidinone derivatives
US20150225436A1 (en) 2008-05-21 2015-08-13 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
WO2010099379A1 (en) 2009-02-27 2010-09-02 Ambit Biosciences Corporation Jak kinase modulating quinazoline derivatives and methods of use thereof
WO2011028741A1 (en) 2009-09-03 2011-03-10 Bristol-Myers Squibb Company Quinazolines as potassium ion channel inhibitors
US20120053174A1 (en) 2010-09-01 2012-03-01 Hadd Michael J Quinazoline compounds and methods of use thereof
WO2012030912A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation 7-cyclylquinazoline derivatives and methods of use thereof
US20120053176A1 (en) 2010-09-01 2012-03-01 Ambit Biosciences Corp. Adenosine a3 receptor modulating compounds and methods of use thereof
WO2012028578A1 (en) 2010-09-03 2012-03-08 Bayer Cropscience Ag Substituted fused pyrimidinones and dihydropyrimidinones
WO2012066122A1 (en) 2010-11-18 2012-05-24 Syngenta Participations Ag 2 - (pyridin- 2 -yl) -quinazoline derivatives and their use as microbicides
WO2012112363A1 (en) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
WO2013016999A1 (en) 2011-08-04 2013-02-07 江苏豪森药业股份有限公司 Heteroaryl-pyrimidine derivatives, and preparation method therefor and use thereof
WO2013030138A1 (en) 2011-09-01 2013-03-07 F. Hoffmann-La Roche Ag Pyrrolopyrazine kinase inhibitors
WO2014100501A1 (en) 2012-12-20 2014-06-26 Sanford-Burnham Medical Research Institute Small molecule agonists of neurotensin receptor 1
WO2015155306A1 (en) 2014-04-11 2015-10-15 Almirall, S.A. New trpa1 antagonists
CN104803954B (en) 2015-04-30 2018-01-26 上海应用技术学院 A kind of preparation method of fosamprenavir intermediate
WO2017069275A1 (en) 2015-10-22 2017-04-27 田辺三菱製薬株式会社 Novel bicyclic heterocyclic compound
WO2018115380A1 (en) 2016-12-22 2018-06-28 Boehringer Ingelheim International Gmbh Novel benzylamino substituted quinazolines and derivatives as sos1 inhibitors
WO2018118735A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. 6,6-fused heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
WO2018134685A2 (en) 2017-01-17 2018-07-26 Liverpool School Of Tropical Medicine Compounds
WO2018172250A1 (en) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-methyl-quinazolines
FR3066761A1 (en) 2017-05-23 2018-11-30 Centre National De La Recherche Scientifique NOVEL IONIC CHANNEL INHIBITOR COMPOUNDS
WO2019122129A1 (en) 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Novel benzylamino substituted pyridopyrimidinones and derivatives as sos1 inhibitors
US20190270704A1 (en) 2018-03-05 2019-09-05 Bristol-Myers Squibb Company Phenylpyrrolidinone formyl peptide 2 receptor agonists
WO2020180768A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2020180770A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
WO2021228028A1 (en) 2020-05-09 2021-11-18 正大天晴药业集团股份有限公司 Sos1 inhibitor containing phosphorus
CA3195519A1 (en) * 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines as sos1 inhibitors

Non-Patent Citations (65)

* Cited by examiner, † Cited by third party
Title
"Isotopic Compositions of the Elements 1997", PURE APPL. CHEM., vol. 70, no. 1, 1998, pages 217 - 235
A. E. MUTLIB ET AL.: "Efavirenz", TOXICOL. APPL. PHARMACOL., vol. 169, 2000, pages 102, XP001083816, DOI: 10.1006/taap.2000.9055
A. M. SHARMA ET AL.: "Nevirapine", CHEM. RES. TOXICOL., vol. 26, 2013, pages 410, XP055708688, DOI: 10.1021/tx3004938
ADV. SYNTH. CATAL., vol. 360, 2018, pages 1605
ADV. SYNTH. CATAL., vol. 362, 2020, pages 1106
ADVANCED SYNTHESIS & CATALYSIS, vol. 360, 2018, pages 4764
AIELLO ET AL., NEW ENGL. J. MED., vol. 331, 1994, pages 1480
B. TESTA ET AL., INT. J. PHARM., vol. 19, no. 3, 1984, pages 271
BIOORG. MED. CHEM. LETT., vol. 23, 2013, pages 2663
BIOORG. MED. CHEM. LETT., vol. 23, 2015, pages 3013
BIOORG. MED. CHEM., vol. 22, 2014, pages 5487
BIOORG. MED. CHEM., vol. 24, 2016, pages 2707
BIOORG. MED. CHEM., vol. 27, 2019, pages 931
C. J. WENTHUR ET AL., J. MED. CHEM., vol. 56, 2013, pages 5208
C. L. PERRIN ET AL., J. AM. CHEM. SOC., vol. 127, 2005, pages 9641
C. L. PERRIN ET AL., J. AM. CHEM. SOC., vol. 129, 2007, pages 4490
CATALDO VD, N ENGL J MED, vol. 364, 2011, pages 947
CHEM. COMMUN., 2008, pages 6333
CHEM. COMMUN., vol. 48, 2012, pages 7738
CHEM. MED. CHEM., vol. 9, 2014, pages 2516
CHEM. REV., vol. 110, 2010, pages 3600 - 3740
CHEM. SOC. REV., vol. 38, 2009, pages 1162 - 1186
COX ET AL., NATURE REVIEWS DRUG DISCOVERY, 2014
CROMM, ANGEWANDTE CHEMIE, 2015
E. J. ORG. CHEM., vol. 25, 2017, pages 3584
E. J. ORG. CHEM., vol. 33, 2016, pages 5529
ENGLE JA, AM J HEALTH SYST PHARM, vol. 71, no. 22, 2014, pages 1933
EUR. J. ORG. CHEM., 2020, pages 2730
F. MALTAIS ET AL.: "Telaprevir", J. MED. CHEM., vol. 52, 2009, pages 7993, XP055054210, DOI: 10.1021/jm901023f
F. SCHNEIDER ET AL.: "Rofecoxib", ARZNEIM. FORSCH. / DRUG. RES., vol. 56, 2006, pages 295, XP001206685
GRAY ET AL., ANGEWANDTE CHEMIE, 2019
HETEROCYCLES, vol. 90, 2015, pages 857
HILLIG ET AL., PNAS, 2019
J. AM. CHEM. SOC., 2015, pages 13433
J. MED. CHEM., vol. 54, 2011, pages 6734
J. MED. CHEM., vol. 61, 2018, pages 3389
J. MED. CHEM., vol. 62, 2019, pages 9772
J. MED. CHEM., vol. 63, 2020, pages 7081
J. ORG. CHEM., vol. 72, 2007, pages 10194
J. PHARMACOKINET. BIOPHARM., vol. 5, 1977, pages 625 - 653
KRENS ET AL., DRUG DISCOVERY TODAY, 2010
LESHCHINER ET AL., PNAS, 2015
LIAO BC, CURR OPIN ONCOL, vol. 27, no. 2, 2015, pages 147
LOPEZ ET AL., INVEST. OPTHTHALMOL. VIS. SCI., vol. 37, 1996, pages 855
MALUMBRESBARBACID, NATURE REVIEWS CANCER, 2002
MARIN-RAMOS ET AL., SEMINARS IN CANCER BIOLOGY
MONATSHEFTE FUR CHEMIE, vol. 118, 1987, pages 399
ORG. LETT., 2011, pages 4374
ORG. LETT., vol. 20, 2018, pages 4691
P.G.M. WUTST.W. GREENE: "Protective Groups in Organic Synthesis", 2006, WILEY
PEER ET AL., LAB. INVEST., vol. 72, 1995, pages 638
POLISH JOURNAL OF PHARMACOLOGY AND PHARMACY, vol. 37, 1985, pages 541
PURE APPL CHEM, vol. 45, 1976, pages 11 - 30
PYLAYEVA-GUPTA ET AL., NATURE REVIEWS CANCER, 2011
ROJAS ET AL., GENES & CANCER, vol. 2, no. 3, 2011, pages 298 - 305
RUSSO A, ONCOTARGET, 2015, pages 4254
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
SPIEGEL ET AL., NATURE CHEMICAL BIOLOGY, 2014
STEUER CE, CANCER, vol. 121, no. 8, 2015, pages E1
SYNTH. CATAL., vol. 362, 2020, pages 1106
TAKASHIMAFALLER, EXPERT OPIN. THER. TARGETS, 2013
TETRAHEDRON, vol. 60, 2004, pages 8003
VIGIL, NATURE REVIEWS CANCER
WALTER AO, CANCER DISCOV, vol. 3, no. 12, 2013, pages 1404
YAKUGAKU ZASSHI, vol. 97, 1977, pages 1022

Similar Documents

Publication Publication Date Title
US11787797B2 (en) 4,5-annulated 1,2,4-triazolones
US20240083857A1 (en) 2-Methyl-Quinazolines
EP3319945B1 (en) 2-aryl- and 2-arylalkyl-benzimidazoles as midh1 inhibitors
EP3325451B1 (en) Fused imidazoles as midh1 inhibitors
EP3781565A1 (en) 2-methyl-aza-quinazolines
WO2021074227A1 (en) 2-methyl-aza-quinazolines
EP4214204A1 (en) Pyrido[2,3-d]pyrimidin-4-amines as sos1 inhibitors
CA2992364A1 (en) 5-hydroxyalkylbenzimidazoles as midh1 inhibitors
WO2022219035A1 (en) Phosphorus derivatives as novel sos1 inhibitors
WO2022081842A1 (en) Substituted acyl sulfonamides for treating cancer
EP3383865B1 (en) Furane derivatives as inhibitors of atad2
WO2024079252A1 (en) Sos1 inhibitors
WO2020048826A1 (en) 5-substituted 1-oxa-3,9-diazaspiro[5.5]undecan-2-one compounds
WO2024056782A1 (en) Sulfone-substituted pyrido[3,4-d]pyrimidine derivatives for the treatment of cancer
WO2020048831A1 (en) 5-aryl-3,9-diazaspiro[5.5]undecan-2-one compounds
WO2020048827A1 (en) 1, 3, 9-triazaspiro[5.5] undecan-2-one compounds
WO2018078009A1 (en) Amido-substituted cyclohexane derivatives