US20230167103A1 - Substituted aminothiazoles as dgkzeta inhibitors for immune activation - Google Patents

Substituted aminothiazoles as dgkzeta inhibitors for immune activation Download PDF

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US20230167103A1
US20230167103A1 US17/921,043 US202117921043A US2023167103A1 US 20230167103 A1 US20230167103 A1 US 20230167103A1 US 202117921043 A US202117921043 A US 202117921043A US 2023167103 A1 US2023167103 A1 US 2023167103A1
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group
alkyl
phenyl
cycloalkyl
amino
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Inventor
Norbert Schmees
Ulrike Roehn
Dennis KIRCHHOFF
Kirstin Petersen
Thi Thanh Uyen NGUYEN
Mareike Grees
Nicolas WERBECK
Ulf Boemer
Benjamin Bader
Detlef STOECKIGT
Rienk Offringa
Corinna LINK
Giambattista Testolin
Katrin Nowak-Reppel
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Nuvisan Icb GmbH
Deutsches Krebsforschungszentrum DKFZ
Bayer AG
Bayer Pharma AG
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Deutsches Krebsforschungszentrum DKFZ
Bayer AG
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Assigned to BAYER AKTIENGESELLSCHAFT reassignment BAYER AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STÖCKIGT, Detlef, Bömer, Ulf , GREES, Mareike, RÖHN, Ulrike
Assigned to BAYER AKTIENGESELLSCHAFT reassignment BAYER AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WERBECK, Nicolas, BADER, BENJAMIN, SCHMEES, NORBERT, KIRCHHOFF, Dennis, NGUYEN, Thi Thanh Uyen, PETERSEN, KIRSTIN
Assigned to NUVISAN ICB GMBH reassignment NUVISAN ICB GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STÖCKIGT, Detlef, Bömer, Ulf , RÖHN, Ulrike
Assigned to DEUTSCHES KREBSFORSCHUNGSZENTRUM reassignment DEUTSCHES KREBSFORSCHUNGSZENTRUM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GREES, Mareike
Assigned to NUVISAN ICB GMBH reassignment NUVISAN ICB GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOWAK-REPPEL, Katrin, TESTOLIN, Giambattista
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Assigned to BAYER AKTIENGESELLSCHAFT reassignment BAYER AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NUVISAN ICB GMBH
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Definitions

  • the present invention covers substituted aminothiazole 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 diacylglycerol kinase zeta (DGKzeta, DGK ⁇ ) regulated disorders, as a sole agent or in combination with other active ingredients.
  • DGKzeta, DGK ⁇ diacylglycerol kinase zeta
  • the compounds of general formula (I) inhibit DGK ⁇ and, by this, enhance T cell mediated immune response.
  • This is a new strategy to use the patient's own immune system to overcome immunoevasive strategies utilized by many neoplastic disorders, respectively cancer and by this enhancing anti-tumor immunity.
  • said compounds are used in particular to treat disorders such as viral infections or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling.
  • the present invention further relates to the use of the compounds of general formula (I) for manufacturing pharmaceutical compositions for enhancement of T cell mediated immune response.
  • the present invention further relates to the use of the compounds of general formula (I) for manufacturing pharmaceutical compositions for the treatment of cancer.
  • the present invention further relates to the use of the compounds of general formula (I) for manufacturing pharmaceutical compositions for the treatment or prophylaxis of virus infections, lymphoproliferative disorders, asthma, eye diseases, and type 2 diabetes insulin resistance.
  • DGKs Diacylglycerol kinases
  • DAG membrane lipid sn-1,2 diacylglycerol
  • PA phosphatidic acid
  • DAG is formed downstream of the T cell receptor (TCR) after activation of the gamma 1 isoform of phospholipase C (PLC ⁇ 1) and cleavage of phosphatidylinositol 4,5-biphosphate (PIP2) into DAG and an additional second messenger, inositol 1,4,5-triphosphate (IP3) (S. Krishna and X.-P. Zhong, Front. Immunol. 2013, 4, 178).
  • PLC ⁇ 1 gamma 1 isoform of phospholipase C
  • PIP2 phosphatidylinositol 4,5-biphosphate
  • IP3 inositol 1,4,5-triphosphate
  • DAG interacts with other proteins important in TCR signal transduction, such as Protein kinase C ⁇ (E. J. Quann et al., Nat. Immunol.
  • DGK ⁇ DGKalpha
  • DGK ⁇ DGKdelta
  • DGK ⁇ DGKzeta
  • only two, DGK ⁇ and DGK ⁇ are thought to play an important role in facilitating DAG metabolism downstream of the TCR (R. P. Joshi and G. A. Koretzky, Int. J. Mol. Sci. 2013, 14 (4), 6649-6673).
  • DGK ⁇ Deletion of DGK ⁇ in T cells leads to enhanced production of effector cytokines, such as 1L2, IFN ⁇ and enhanced proliferation (X.-P. Zhong et al., Nat. Immunol. 2003, 4, 882-890; B. A. Olenchock et al., Nat. Immunol. 2006, 7 (11), 1174-1181, E. M. Riese et al., J. Biol. Chem. 2011, 286, 5254-5264).
  • DGK ⁇ deficient T cell Adoptive transfer of DGK ⁇ deficient T cell reduced leukaemia burden after inoculation of C1498.SIY leukaemia cells compared to control. Also, DGK ⁇ deficient T cells are at least partially resistant to PD1 mediated inhibitory signals (W. Jing et al., Cancer Res. 2017, 77 (20), 5676-5686). In addition, DGK ⁇ deficient mice have reduced tumor sizes compared to control after orthotopic tumor injection of a pancreatic tumor model (E. M. Wesley et al., ImmunoHorizons, 2018, 2 (4), 107-118). Also, S. Wee et al.
  • DGK ⁇ mice suppressed growth of subcutaneously implanted tumor cells in the three model systems and the combination of DGK ⁇ -deficiency and anti-PD1 was additive in tumor control (S. Wee et al., Proceedings of the American Association for Cancer Research Annual Meeting 2019; Cancer Res. 2019, 79 (13 Suppl): Abstract nr 936).
  • CAR chimeric antigen receptor
  • DGK ⁇ -deficient mice mounted a more robust immune response to lymphocytic choriomeningitis virus infection than did wild-type mice (X.-P. Zhong et al., Nat. Immunol. 2003, 4, 882-890).
  • DGK ⁇ is also relevant in natural killer (NK) cells.
  • NK cells from mice lacking DGK ⁇ display increased cytokine production and degranulation in an ERK-dependent manner. Additionally, they have improved cytotoxic functions against tumor cell lines.
  • DGK ⁇ Apart from immune-cell regulation, DGK ⁇ also plays a role in cancer, mediating numerous aspects of cancer cell progression including proliferation, apoptosis, survival, invasion and tumorigenicity, e.g. in osteosarcoma, colon cancer, breast cancer, prostate cancer, glioma and leukemia models (W. Yu et al., Front. Oncol. 2019, 8:655; K. Cai et al., BMC Cancer 2014, 14:208; J. Diao et al., Mol. Neurobiol. 2016; 53, 5425-35; H. Li et al. Pharmazie 2019, 74(7): 418-422).
  • DGK ⁇ knock-out diminished both airway inflammation and airway hyperresponsiveness in mice and also reduced bronchoconstriction of human airway samples in vitro by blocking T helper 2 (TH2) differentiation (B. A. Singh et al., Sci. Signal. 2019, 12: eaax3332).
  • DGK ⁇ a has the potential to reverse the life-threatening Epstein-Barr virus (EBV) -associated immunopathology that occurs in X-linked lymphoproliferative disease (XLP-1) patients (E. Ruffo et al., Sci. Transl. Med. 2016, 8: (321):321ra7; S. Velnati et al., Eur. J. Med. Chem. 2019, 164, 378-390). Based on the underlying mode of action, it can be assumed that inhibition of DGK ⁇ would have a similar effect.
  • EBV Epstein-Barr virus
  • the DGK ⁇ -inhibitor II (R 59949 ) could suppress retinal neovascularization and protect retinal astrocytes in an Oxygen-Induced Retinopathy Model (L. Yang et al., J. Mol. Neurosci. 2015, 56, 78-88). Also, based on the underlying mode of action, it can be assumed that inhibition of DGK ⁇ would have a similar effect.
  • inhibiting DGK ⁇ activity has a therapeutic potential in targeting tumors directly as well as addressing virus infections, lymphoproliferative disorders, asthma, eye diseases, and type 2 diabetes insulin resistance.
  • WO2020006016 and WO2020006018 describe Naphthyridinone compounds as T cell activators, which inhibit the activity of DGK ⁇ and/or DGK ⁇ ; for treatment of viral infections and proliferative disorders, such as cancer.
  • WO2021041588 describes pyridopyrimidinonyl compounds as T cell activators, which inhibit the activity of DGK ⁇ and/or DGK ⁇ , for treatment of viral infections and proliferative disorders, such as cancer.
  • 2,4,5-trisubstituted triazole derivatives featuring a substituted amino group attached to C-2 of the thiazole core have been disclosed in published patent applications in various technical contexts but not in the context of DGK inhibition.
  • WO 2014181287 discloses heterocyclyl compounds as inhibitors of Interleukin 17 and Tumour Necrosis Factor alpha.
  • WO 2014173904 discloses compounds having antibacterial activity.
  • WO 2009149054 discloses small molecule inhibitors for the treatment or prevention of Dengue fever infection.
  • WO 2007130075 discloses aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors.
  • WO 2012064715 discloses compositions and methods relating to heat shock transcription factor activating compounds and targets thereof.
  • WO 2005103022 discloses substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators.
  • CN 106109467 discloses the medical application of aromatic compounds, including thiazoles, in treating pyrazinamide-resistant tuberculosis.
  • WO 2015199206 discloses compounds derived from a six-membered ring as TRPV4 inhibitors.
  • WO 2015046193 discloses aromatic heterocyclic amine derivatives as TRPV4 inhibitors.
  • CN 103159695 discloses thiazole compounds capable of restraining human immunodeficiency (HIV) virus replication and effective against drug-resistant HIV virus strains.
  • WO 2013056684 discloses thiazole derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors.
  • WO 2013033037 discloses compounds of various chemotypes, inter alia thiazole derivatives, as antiprion compounds.
  • WO 2012075393 discloses compounds of various chemotypes, inter alia thiazole derivatives, as activators of proteasomal degradation.
  • JP 2011032254 discloses compounds of various chemotypes, inter alia thiazole derivatives, as pest controlling agents.
  • WO 2009041790 discloses 2,4,5-trisubstituted thiazole derivatives as inhibitors of the sphingosylphosphorylcholine (SPC) receptor for treatment of inflammatory diseases.
  • WO 2008090382 discloses thiazole and oxazole derivatives for use in the treatment of prion diseases, cancer, and conditions of the central nervous system as well as in the regulation of stem cells.
  • WO 2007022415 discloses substituted 2-aminothiazoles for treating neurodegenerative diseases.
  • WO 2006122011 discloses thiazole compounds and methods of use in treating viral infections, particularly hepatitis C virus infections.
  • WO 2006078287 discloses derivatives of various 5-membered heteroarenes, inter alia thiazoles, as inhibitors of phosphodiesterase 4B.
  • WO 2005102318, WO 2005102325, WO 2005102326, WO 2005102346, WO 2005102455, WO 2005112920, WO 2005115304, WO 2005115385 all deal with c-Kit inhibitors of various chemotypes, including 2-aminothiazole derivatives, and various uses thereof.
  • EP 1543824 and US 20050137239 disclose thiazole derivatives to counter glycation.
  • WO 2004014884 discloses thiazole derivatives as neuropeptide Y receptor ligands.
  • WO 2019133445 discloses aminothiazole derivatives as inhibitors of Vanin-1.
  • WO 2021043966 discloses substituted five-membered nitrogen containing heteroaryl compounds as inhibitors of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3).
  • DGK ⁇ regulated disorders comprise conditions with dysregulated immune responses, particularly in an immunologically supressed tumor microenvironment in cancer, autoimmune diseases, viral infections as well as other disorders associated with aberrant DGK ⁇ signalling.
  • Said compounds can be used as sole agent or in combination with other active ingredients.
  • the compounds of the present invention have surprisingly been found to effectively inhibit the DGK ⁇ protein and, by this, enhance T-cell mediated immunity. Accordingly, they provide novel structures for the treatment diseases of mammals, including humans, in particular of cancers, and may therefore be used for the treatment or prophylaxis of hyperproliferative disorders, such as cancer, for example.
  • the present invention covers compounds of general formula (I):
  • 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 atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3 or 4, in particular 1, 2 or 3.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • a composite substituent be composed of more than one part, e.g. (C 1 -C 2 -alkoxy)-(C 1 -C 6 -alkyl)-, it is possible for a given part to be attached at any suitable position of said composite substituent, e.g. it is possible for the C 1 -C 2 -alkoxy part to be attached to any suitable carbon atom of the C 1 -C 6 -alkyl part of said (C 1 -C 2 -alkoxy)-(C 1 -C 6 -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
  • 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, more particularly 1 or 2 carbon atoms (“C 1 -C 2 -alkyl”), e.g. a methyl or ethyl 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 -
  • C 1 -C 4 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 4 -alkyl” is defined supra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g.
  • C 1 -C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.
  • C 1 -C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 -C 6 -alkyl)-O—, in which the term “C 1 -C 6 -alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tent-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
  • C 1 -C 6 -haloalkoxy means a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C 3 -C 4 -alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 3 or 4 carbon atoms.
  • Said alkenyl group is, for example, a prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl, but-2-enyl or but-1-enyl group.
  • C 3 -C 4 -alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 3 or 4 carbon atoms.
  • Said C 3 -C 4 -alkynyl group is, for example, a prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl or but-3-ynyl group.
  • C 3 -C 7 -cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon ring atoms (“C 3 -C 7 -cycloalkyl”).
  • Said C 3 -C 7 -cycloalkyl group is for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
  • bicyclic C 6 -C 11 -cycloalkyl means a spirocycloalkyl, fused C 6 -C 10 -cycloalkyl or bridged C 7 -C 10 -cycloalkyl group as defined below:
  • fused C 6 -C 10 -cycloalkyl means a bicyclic, saturated, monovalent hydrocarbon group, in which the two rings share two adjacent ring atoms, such as bicyclo[4.2.0]octyl, octahydropentalenyl or decalinyl.
  • bridged C 7 -C 10 -cycloalkyl means a bicyclic, saturated, monovalent hydrocarbon group which the two rings share two common ring atoms which are not adjacent, e.g. bicyclo[2.2.1]heptyl (also known as norbornyl).
  • bicyclic C 5 -C 11 -cycloalkyl means a spirocycloalkyl, fused C 5 -C 10 -cycloalkyl or bridged C 5 -C 10 -cycloalkyl group as defined below:
  • monocyclic 4- to 7-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S.
  • Said monocyclic 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
  • monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one ring nitrogen atom and optionally one further ring heteroatom from the series N, O and S.
  • Said monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, for example; or a 5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or 1,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example.
  • a 4-membered ring such as azetidinyl, for example
  • a 5-membered ring such as pyrrolidiny
  • monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally benzocondensed means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one ring nitrogen atom and optionally one further ring heteroatom from the series N, O and S, in which two adjacent ring carbon atoms may be shared with a benzene ring optionally fused thereto, such group being one of the aforementioned monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl groups, such as pyrrolidinyl, piperidinyl, and the like, or benzocondensed groups e.g.
  • bicyclic 6-11 membered heterocycloalkyl means a 6- to 11-membered heterospirocycloalkyl, a 6- to 10-membered fused heterocycloalkyl or a 7- to 10-membered bridged heterocycloalkyl group as defined below:
  • bicyclic nitrogen containing 6-11 membered heterocycloalkyl means a heterospirocycloalkyl, fused heterocycloalkyl or bridged heterocycloalkyl group as defined supra, however containing one ring nitrogen atom and optionally one or two further ring heteroatoms from the series N, O and S; it being possible for said bicyclic nitrogen containing 6-11 membered heterocycloalkyl group to be attached to the rest of the molecule via a nitrogen atom or any one of the carbon atoms, except a spiro carbon atom.
  • bicyclic 5-11 membered heterocycloalkyl means a 5-11 membered heterospirocycloalkyl, a 5-11 membered fused heterocycloalkyl or a 5-11 membered bridged heterocycloalkyl group as defined below:
  • bicyclic nitrogen containing 5-11 membered heterocycloalkyl means a 5-11 membered heterospirocycloalkyl, 5-11 membered fused heterocycloalkyl or 5-11 membered bridged heterocycloalkyl group as defined supra, however containing one ring nitrogen atom and optionally one or two further ring heteroatoms from the series N, O and S; it being possible for said bicyclic nitrogen containing 5-11 membered heterocycloalkyl group to be attached to the rest of the molecule via a nitrogen atom or any one of the carbon atoms, except a spiro carbon atom.
  • heteroaryl means a monovalent, monocyclic or bicyclic aromatic ring having 5, 6, 8, 9 or 10 ring atoms (a “5- to 10-membered heteroaryl” group), 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, if valency allows as e.g. in pyrrol-1-yl, a nitrogen atom.
  • 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 (herein also referred to as pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, thiazolopyridiny
  • 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. 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 7 as used in the present text, e.g. in the context of the definition of “C 3 -C 7 -cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms.
  • 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 5 , and C 5 -C 6 ;
  • C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , 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 .
  • 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: a halogen atom, in particular a fluorine atom, a chlorine atom, a bromine atom or an iodide atom, being displaced as 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)
  • dipolar aprotic solvent means a solvent selected from acetone, acetonitrile, priopionitrile, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide, 1-methyl-2-pyrrolidinone, 1-ethyl-2-pyrrolidinone, 1-methyl-2-piperidinone and 1-ethyl-2-piperidinone, or mixtures thereof.
  • said dipolar aprotic solvent is acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or 1-methyl-2-pyrrolidinone.
  • room temperature means a temperature in the range from 15° C. to 25° C.
  • 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).
  • 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.
  • 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 examples 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 p, 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.
  • 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 p, 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
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”).
  • 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 CDN Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, Mass., USA; and CombiPhos Catalysts, Inc., Princeton, N.J., 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 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. 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.
  • 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
  • Kassahun et al., WO2012112363 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.
  • deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) isare attached to a carbon atom and/or isare 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 .
  • the present invention concerns a deuterium-containing compound of general formula (I) having 1, 2, 3 or 4 deuterium atoms, particularly with 1, 2 or 3 deuterium atoms.
  • 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 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 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.
  • the compounds of the present invention may contain a pyridone moiety and can exist as a pyridone, or as an hydroxypyridine, or even a mixture in any amount of the two tautomers, namely:
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio.
  • polar solvents in particular water
  • 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 may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • suffixes to chemical names or structural formulae relating to salts such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or “x HCl”, “x CF 3 COOH”, “x Na + ”, for example, mean a salt form, the stoichiometry of which salt form not being specified.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the invention further includes all possible cyclodextrin clathrates, i.e. alpha-, beta-, or gamma-cyclodextrins, hydroxypropyl-beta-cyclodextrins, methylbetacyclodextrins.
  • cyclodextrin clathrates i.e. alpha-, beta-, or gamma-cyclodextrins, hydroxypropyl-beta-cyclodextrins, methylbetacyclodextrins.
  • the present invention covers compounds of general formula (I), supra, in which:
  • the present invention covers compounds of general formula (I), supra, in which:
  • C 3 -C 7 -cycloalkyl, and the C 3 -C 5 -cycloalkyl within said (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)- group are optionally substituted one or two times, each substituent independently selected from a fluorine atom or a group selected from cyano, methyl and C 1 -fluoroalkyl,
  • the present invention covers compounds of general formula (I), supra, in which:
  • the present invention covers compounds of general formula (I), supra, in which:
  • the present invention covers compounds of general formula (I), supra, in which:
  • the present invention covers compounds of general formula (I), supra, in which:
  • the present invention covers compounds of general formula (I), supra, in which:
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 4a represents a group selected from)—N(R 10 )(R 11 ), —C( ⁇ O)—N(R 15 )(R 16 ), —C( ⁇ O)—OR 17 , phenyl and a 5- or 6-membered heteroaryl group selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl,
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers isomeric mixtures of compounds of formula (I), supra, in which:
  • the present invention covers compounds of formula (I), supra, in which: R 10 and R 11 , together with the nitrogen atom to which they are attached, represent a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, each substituent independently selected from a fluorine atom or a group selected from cyano, oxo, C 1 -C 2 -alkyl, C 1 -C 2 -fluoroalkyl and (C 1 -C 2 -alkyl)-C( ⁇ O)—,
  • 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 the compounds of general formula (I) which are disclosed in the Example Section of this text, infra.
  • 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 DGK ⁇ and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably conditions with dysregulated immune responses, particularly cancer or other disorders associated with aberrant DGK ⁇ signaling, in mammals, including humans.
  • Disorders and conditions particularly suitable for treatment with an DGK ⁇ inhibitor of the present invention are liquid and 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, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, 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.
  • ovarian cancer examples include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
  • cervical cancer examples include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • esophageal cancer examples include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.
  • gastric cancer examples include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
  • pancreatic cancer examples include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • kidney cancer examples include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
  • bladder cancer examples include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
  • 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, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:
  • 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 are used in combination with radiation: i.e. radiation treatment sensitizes cancers to anti-tumor immune responses by induction of tumor cell death and subsequent presentation of tumor neoantigens to tumor-reactive Tcells.
  • radiation treatment sensitizes cancers to anti-tumor immune responses by induction of tumor cell death and subsequent presentation of tumor neoantigens to tumor-reactive Tcells.
  • DGK ⁇ is enhancing the antigen specific activation of T cells, the overall effect results in a much stronger cancer cell attack as compared to irradiation treatment alone.
  • the present invention also provides a method of killing a tumor, wherein conventional radiation therapy is employed previous to administering one or more of the compounds of the present invention.
  • 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:
  • 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, ave
  • the compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-1-L1 axis antagonists.
  • immune checkpoint inhibitors e.g. aPD-1-L1 axis antagonists.
  • PD-1 along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation.
  • PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells. This results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses.
  • M. E. Keir et al. Annu. Rev. Immunol. 2008, 26, 677-704.
  • the present invention covers combinations comprising one or more of the compounds of general formula (I), as described herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, and one or more immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is a aPD-1-L1 axis antagonist.
  • the compounds of the invention can further be combined with inhibitors of DGK ⁇ , such as those inhibitors of DGK ⁇ disclosed in WO2020006016, WO2020006018 and WO 2021041588.
  • inhibitors of DGK ⁇ such as those inhibitors of DGK ⁇ disclosed in WO2020006016, WO2020006018 and WO 2021041588.
  • DGK ⁇ in T cells operates in a similar fashion as DGK ⁇ , a dual inhibition profoundly enhances T cell effector functions compared with cells with deletion of either DGK isoform alone or wild-type cells.
  • CAR-T cells chimeric antigen receptor T cells
  • Axicabtagen-Ciloleucel or Tisagenlecleucel The activity of CAR-T cells can be suppressed by the tumor micro environment (TME). Knock out of DGKs by techniques such as Crispr had been shown to enhance CAR-T cell activity in a suppressive TME (I. Y. Jung et al., Mol. Cells 2018, 41 (8), 717-723).
  • the present invention covers combinations comprising one or more compounds of general formula (I), as described herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, with chimeric antigen receptor T cells, (CAR-T cells), CAR-NKT cells or CAR-NK cells.
  • CAR-T cells chimeric antigen receptor T cells
  • CAR-NKT cells CAR-NKT cells
  • CAR-NK cells CAR-NK cells
  • the chimeric antigen receptor T cells are Axicabtagen-Ciloleucel or Tisagenlecleucel.
  • the present invention further provides the use of the compounds according to the invention for expansion of T cells including CAR-T and tumor infiltrated lymphocytes ex-vivo.
  • the present invention covers compounds of general formula (I), as described herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the expansion of T cells including CAR-T cells, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes ex-vivo.
  • the present invention also relates to the use of the compounds according to the invention for the expansion of T cells, including CAR-T cell, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes, ex-vivo.
  • the present invention also comprises an ex-vivo method for the expansion of T cells, including CAR-T cells, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes, contacting said T cells with compounds according to the invention.
  • Compounds of the present invention can be utilized to inhibit, block, reduce or decrease DGK ⁇ activity resulting in the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy that will eventually lead to reduction of tumour growth.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
  • the present invention also provides methods of treating a variety of other disorders wherein DGK ⁇ is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, virus infections, lymphoproliferative disorders, asthma, eye diseases, and type 2 diabetes insulin resistance.
  • the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their activity as DGK ⁇ inhibitors.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours.
  • the present invention covers the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours.
  • the present invention covers the use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours.
  • the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours.
  • a pharmaceutical composition preferably a medicament
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • a compound of general formula (I) as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a 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).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • 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.
  • the compounds according to the invention 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.
  • 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, filmswafers, filmslyophylisates, 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; tabletsfilmswaferscapsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tabletsfilmswaferscapsules for lingual, sublingual or buccal administration
  • 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,
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK ⁇ signaling, particularly liquid and solid tumours.
  • the present invention covers a pharmaceutical combination, which comprises:
  • 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.
  • 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.
  • 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 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 mgkg to about 200 mgkg body weight per day, and preferably from about 0.01 mgkg to about 20 mgkg 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. 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 once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mgkg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mgkg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mgkg 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 mgkg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mgkg 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.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution, or coupling reactions such as amide couplings (couplings of carboxylic acids with amines) or transition metal catalysed coupling reactions (such as the well-known Suzuki coupling) known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further modification of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3 1d edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • Said intermediate compounds of formula (V-a) can subsequently be reacted with compounds of formula (VI), in which R 2 has the meaning as given for general formula (I), and in which LG 2 represents a leaving group as defined herein, preferably a chlorine, bromine, or iodine atom, or a (methylsulfonyl)oxy or [(4-methylphenyl)sulfonyl]oxy group, more preferably a bromine atom, in a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide, at a temperature in the range from 60° C. to 120° C., preferably 80° C.
  • Said conversion of intermediate compounds of formula (V-a) into compounds of the present invention of formula (I-a) by reacting with compounds of formula (VI) can also be accomplished advantageously in a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide, at a temperature in the range from 0° C. to 60° C., preferably 10° C. to 40° C., more preferably at room temperature as defined herein, for a time in the range from 6 hours to 48 hours, preferably from 12 hour to 24 hours.
  • a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide
  • Said intermediate compounds of formula (V-b) can subsequently be reacted with compounds of formula (VI), in which R 2 has the meaning as given for general formula (I), and in which LG 2 represents a leaving group as defined herein, preferably a chlorine, bromine, or iodine atom, or a (methylsulfonyl)oxy or [(4-methylphenyl)sulfonyl]oxy group, more preferably a bromine atom, in a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide, at a temperature in the range from 60° C. to 120° C., preferably 80° C. to 100° C., more preferably 90° C., for a time in the range from 30 minutes to 24 hours, preferably from 1 hour to 4 hours, more preferably 2 hours, to give compounds of the present invention, of formula (I-b).
  • LG 2 represents a leaving group as defined herein, preferably a chlorine, bromine, or iodine
  • compounds of formulae (I-c), (I-d), (I-e), (I-f) and (I-g), which constitute various sub-sets of general formula (I) in which R 3 represents an amino group can be prepared from precursors in which the R 4 group is not present from the start (Schemes 3, 4, and 5), or is substituted with a group not covered within the definition of R 4 (such as a carboxy group), which however allows for establishing diverse R 4 groups from a common precursor (Scheme 6)
  • Said intermediate compounds of formula (V-c) can subsequently be reacted with compounds of formula (VI), in which R 2 has the meaning as given for general formula (I), and in which LG 2 represents a leaving group as defined herein, preferably a chlorine, bromine, or iodine atom, or a (methylsulfonyl)oxy or [(4-methylphenyl)sulfonyl]oxy group, more preferably a bromine atom, in the presence of a base such as potassium carbonate, in a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide, at a temperature in the range from 0° C. to 60° C., preferably 10° C.
  • a base such as potassium carbonate
  • intermediate compounds of formula (IX) can be converted into compounds of formula (I-c) by reacting with N-hydroxy imidoyl chlorides of formula (X), in which R 4a has the meaning as given for general formula (I), in a mixture of DMSO, tetrahydrofuran and tert-butanol as a solvent, in the presence of copper(II)sulfate pentahydrate, (+)-ascorbic acid and potassium carbonate, at a temperature in the range from 0° C.
  • Silyl ethynyl ketones of formula (III-a) are largely commercially available or can be prepared using methods known to the person skilled in the art. Also, N-hydroxy imidoyl chorides of formula (X) are known to the person skilled in the art; for a synthesis protocol see Intermediates 41 and 72-76, in the Experimental section below.
  • intermediate compounds of formula (V-e) featuring a carboxylic ester group.
  • Said carboxylic ester group can be reacted subsequently with N-hydroxy amidines of formula (XI), in which R 4b has the meaning as given for general formula (I), to give intermediate compounds of formula (V-f).
  • Said intermediate compounds of formula (V-f) can subsequently be reacted with compounds of formula (VI), in which R 2 has the meaning as given for general formula (I), and in which LG 2 represents a leaving group as defined herein, preferably a chlorine, bromine, or iodine atom, or a (methylsulfonyl)oxy or [(4-methylphenyl)sulfonyl]oxy group, more preferably a bromine atom, in the presence of a base such as potassium carbonate, in a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide, at a temperature in the range from 0° C. to 60° C., preferably 10° C. to 40° C., more preferably at room temperature as defined herein, for a time in the range from 6 hours to 48 hours, preferably from 12 hour to 24 hours, to give compounds of formula (1-d). Specific examples are described in the Experimental Section.
  • compounds of formula (I-e), which constitutes a sub-set of general formula (I) in which R 3 represents an amino group, in which R 4 represents an oxadiazolyl group, and in which R 2 ′ has the meaning as given for R 2 in general formula (I) with the proviso that R 8 represents a group —C( ⁇ O)—NH 2 can be prepared from 2,4-dichlorothiazole (XII) by reacting with a strong base, such as lithium diisopropylamide, followed by an oxalate ester of formula (XIII), in which R A , independently from each other, represents a C 1 -C 4 -alkyl group, preferably methyl or ethyl, in a solvent such as tetrahydrofuran, at a temperature in the range from ⁇ 80° C.
  • a strong base such as lithium diisopropylamide
  • the ester group present in said compounds of formula (V-g) can be readily converted into a carboxy group, as in compounds of formula (V-h), by well known methods, such as saponification with aqueous alkali hydroxide, such as lithium hydroxide, in a solvent such as methanol, ethanol, or tetrahydrofuran, or mixtures thereof, followed by conversion into an acyl choride, as in compounds of formula (V-i), by well-known methods such a reaction with oxalyl chloride in a solvent such as dichloromethane in the presence of N,N-dimethylformamide.
  • acyl chloride functionality can be reacted subsequently with a N-hydroxy amidine of formula (XI), in which R 4b has the meaning as given for general formula (I), in a solvent such as dichloromethane or N,N-dimethylformamide, in the presence of a base such as trimethylamine, triethylamine or N,N-diisopropylethylamine, at a temperature in the range from 0° C. to 50° C., preferably 20° C.
  • a base such as trimethylamine, triethylamine or N,N-diisopropylethylamine
  • intermediate ester compounds of formula (XVI) Said intermediate ester compounds can be reacted with ammonia, in an aliphatic alcohol C 1 -C 4 -alkyl-OH, preferably methanol or ethanol, as a solvent, at a temperature in the range from 0° C. to 50° C., preferably at room temperature as defined herein, more preferably at 25° C., for a time in the range from 2 hours to 24 hours, preferably from 12 hour to 20 hours, more preferably 16 hours, to give compounds of the present invention, of formula (I-e). Specific examples are described in the Experimental Section.
  • Scheme 6 exemplifies (without any limitation to the invention) the conversions of advanced intermediates of formulae (V-k) and (V-m), which can be prepared using the methods described in the preceding Schemes, in combination with well-established methods such as the saponification of carboxylic esters or the oxidation of primary alcohols, and which are substituted with a group not covered within the definition of R 4 , which however allows for establishing diverse R 4 groups from a common precursor.
  • carboxylic acid derivatives of formula (V-m) can be reacted in well-known amide coupling reactions with amines of formula (XVII), in which R 15 and R 16 have the meanings as given for general formula (I), in the presence of a coupling reagent such as HATU and a tertiary amine such as triethylamine or N,N-diisopropylethylamine, and optionally in the presence of DMAP, in a dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide, at a temperature in the range from 0° C.
  • a coupling reagent such as HATU and a tertiary amine such as triethylamine or N,N-diisopropylethylamine
  • DMAP dipolar aprotic solvent as defined herein, preferably N,N-dimethylformamide
  • aldehydes of formula (V-m) can be reacted in well-known reductive amination reactions with amines of formula (XVIII), in which R 1 ° and R 11 have the meanings as given for general formula (I), in the presence of acetic acid in a mixture of methanol, tetrahydrofuran and N,N-dimethylformamide, followed by the addition of sodium cyanoborohydride, at a temperature in the range from 0° C.
  • aminoalkyl compounds of the invention of formula (I-g). Specific examples are described in the Experimental Section.
  • Amines of formulae (XVII) and (XVIII) are commercially available.
  • the present invention covers methods of preparing compounds of formulae (I-a) and (I-b), which are sub-sets of general formula (I), supra, which when taken together they form.
  • said methods comprise the step of allowing an intermediate compound of formula (V-a):
  • the present invention covers methods of preparing compounds of formulae (I-a) and (I-b), which are sub-sets of general formula (I), supra, which when taken together they form.
  • said methods comprise the step of allowing an intermediate compound of formula (V-a):
  • R 1 , R 2 and R 4 are as defined supra, then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
  • the present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • the present invention covers the use of intermediate 5 compounds for the preparation of the compounds of formulae (I-a) and (I-b), which are sub-sets of general formula (I), supra, which when taken together they form.
  • the present invention covers the intermediate compounds of formula (V-a):
  • the present invention covers intermediate compounds which are disclosed in the Example Section of this text, infra.
  • the present invention covers the use of intermediate compounds which are disclosed in the Example Section of this text, infra.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of formulae (V-a), supra.
  • FIG. 1 DGKz_hu_1 encoding human DGK ⁇ M1 to V928 plus N-terminal Flag-Tag, as described under SEQ ID No. 1.
  • FIG. 2 SIINFEKL amino acid sequence, as described under SEQ ID No. 2.
  • FIG. 3 OVA-30 peptide sequence, as described under SEQ ID No. 3.
  • FIG. 4 FLAG-Tag, as described under SEQ ID No. 4.
  • FIG. 5 Kozak sequence for translation initiation, as described under SEQ ID No. 5.
  • FIG. 6 50% thermal ellipsoids of Example 3.1
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration.
  • Chemical names were generated using software programs such as the ACDName batch version 14.05 from ACDLabs and BioVia Draw 2019 Version 19.1 NET, and chemical names were adapted if needed. In some cases generally accepted names of commercially available reagents were used in place of chemical names generated using abovementioned software programs.
  • 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.
  • HATU (7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC high-pressure liquid chromatography LC-MS liquid chromatography coupled with mass spectrometry mL milliliter min minute(s) MTBE methyl tert-butyl ether RP-HPLC reverse-phase high-pressure liquid chromatography Rt retention time rt room temperature sat.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water+0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile+0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 mL/min; temperature: 50° C.; PDA: 220 nm & 254 nm.
  • Optical Rotation Optical rotations were measured with a JASCO Polarimeter 2000 using the solvent and concentration stated in each case at 20° C., wavelength 589 nm, integration time 10 s, layer 5 thickness 100 mm.
  • the example 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.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier system 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. 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.
  • Instrument pump: Labomatic HD-3000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 ⁇ m, 125 ⁇ 30 mm; eluent; gradient; UV-Detection.
  • Eluent solvent A: water+0.1 vol % formic acid (99%; acidic) or 0.2 vol % aqueous ammonia (32%, basic), solvent B: acetonitrile; flow 150 mL/min.
  • Method A 0.00-0.50 min 1% B, 0.50-6.00 min 1-25% B, 6.00-6.10 min 25-100% B, 6.10-8.00 min 100% B
  • Method B 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B, 6.00-6.10 min 50-100% B, 6.10-8.00 min 100% B
  • Method D 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B, 6.00-6.10 min 70-100% B, 6.10-8.00 min 100% B
  • Method E 0.00-0.50 min 40% B, 0.50-6.00 min 40-80% B, 6.00-6.10 min 80-100% B, 6.10-8.00 min 100% B
  • Instrument Biotage Isolera Four; pump: Dual-Piston; flow rate: 1 to 200 mL/min; internal detector: 200-400 nm (variable UV detector); solvent inlets: 4; cartridges: Biotage SNAP UltraTM, sizes: 10 g, 25 g, 50 g, 100 g, 340 g, media: Biotage® HP-Sphere-25 micron 35 spherical silica, resolution: minimum 7000 N/m (plates per meter) typical 10 000 N/m; solvent A: hexane, solvent B: ethyl acetate, solvent C: dichlormethane, solvent D: ethanol; solvent E: methanol; UV collection modes: single/dual/ ⁇ -All wavelengths (variable UV); fractionation modes: volume, threshold, threshold with volume, low slope, medium slope, custom slope or via external detection
  • the reaction mixture was stirred at rt overnight followed by the addition of water and ethyl acetate.
  • the phases were separated and the aqueous phase was extracted three times with ethyl acetate.
  • the combined organic phases were washed with brine and filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness.
  • the crude product was purified by Biotage (method X) to give 26 mg (0.06 mmol, 8% yield) of the title compound.
  • the crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (Biotage, methods X, Y or Z depending on polarity) if necessary. In case of a missing precipitation, the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and evaporated to dryness. The crude product was purified by chromatography as stated in Table 2.
  • 1-fluoro-4-isothiocyanatobenzene 250 mg, 1.63 mmol was dissolved in acetonitrile (15 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (248.5 mg, 1.63 mmol) and cyanamide (82.3 mg, 1.96 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (96 mg, 0.62 mmol) and ethyl 5-(bromoacetyl)-1,2-oxazole-3-carboxylate (124 mg, 0.81 mmol) dissolved in acetonitrile (6 mL) were added.
  • 1,2-difluoro-4-isothiocyanatobenzene (3.27 g, 19 mmol) was dissolved in acetonitrile (60 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (2.9 g, 19 mmol) and cyanamide (0.96 g, 22.9 mmol).
  • 1-fluoro-4-isothiocyanatobenzene (393 mg, 2.56 mmol) was dissolved in acetonitrile (12 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (390 mg, 2.57 mmol) and cyanamide (129.3 mg, 3.1 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (195 mg, 1.28 mmol) and ethyl 3-bromopyruvate (500 mg, 2.56 mmol) dissolved in acetonitrile (4 mL) were added. The reaction mixture was stirred at rt overnight.
  • N-Hydroxyisobutyramidine 14 mg, 0.14 mmol was solved in dry THF (1.5 mL) and treated with sodium hydride (60% in mineral oil, 6.5 mg, 0.16 mmol) for 1 h at rt followed by the addition of ethyl 2-[4-amino-2-(4-fluoroanilino)thiazol-5-yl]-2-oxo-acetate (50 mg, 0.16 mmol, Intermediate 31).
  • the reaction mixture was stirred at 50° C. for 3 h, filtrated and purified by by RP-HPLC (method B, basic) to give 19 mg (34% yield) of the title compound.
  • N-(cyclopentylmethylidene)hydroxylamine (3.00 g, 26.5 mmol, Intermediate 40) in dichloromethane (40 mL) were added N-chlorosuccinimide (3.72 g, 27.8 mmol) and N,N-dimethylformamide (2.0 mL) at 20° C.
  • the reaction mixture was stirred at 20° C. for 3 hours.
  • the reaction mixture was concentrated to give N-hydroxy cyclopentane carboximidoyl chloride (3.00 g, 77% yield) as yellow oil.
  • N-hydroxy-2,3-dimethylbenzene-1-carboximidamide (617 mg, 3.76 mmol) and N,N-diisopropylethylamine (2.18 mL, 12.5 mmol) in N,N-dimethylformamide (11 mL) was added [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (1.00 g, 3.13 mmol, Intermediate 49) at 25° C. The mixture was stirred at 25° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate.
  • N-hydroxy cyclopropane carboximidamide 399 mg, 3.99 mmol
  • dichloromethane 20 mL
  • N,N-diisopropylethylamine 2.89 mL, 16.6 mmol
  • [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride 1.06 g, 3.32 mmol, Intermediate 49
  • reaction mixture was stirred for 3 h, then it was cooled with an ice bath and was diluted with water and a saturated aqueous solution of ammonium chloride. The precipitate was filtered off, washed with water and triturated with hexane, dried at high vacuum to give 810 mg (3.1 mmol, 68%) of the title compound which was employed in the next step without further purification.
  • N-chlorosuccinimide 35 mg, 0.28 mmol was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (176 mg, 1.3 mmol) was added portion wise over few minutes avoiding that the reaction temperature went above 40° C. The reaction mixture was stirred for three hours at room temperature, thin layer chromatography check (hexane:ethyl acetate 7:3) showed complete consumption of starting material and formation of a less polar spot. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.
  • N-chlorosuccinimide 28 mg, 0.23 mmol was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (142 mg, 1.04 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred for three hours at room temperature, thin layer chromatography check (hexane:ethyl acetate 7:3) showed complete consumption of starting material and formation of a less polar spot. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.
  • N-chlorosuccinimide 38 mg, 0.28 mmol was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (170 mg, 1.29 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred for three hours at room temperature. Thin layer chromatography (hexane:ethyl acetate 1:1) showed formation of a less polar spot but still mainly starting material present therefore the reaction was heated to 38° C. overnight. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.
  • N-chlorosuccinimide 38 mg, 0.28 mmol was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (170 mg, 1.29 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred at 36° C. overnight. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.
  • N-chlorosuccinimide 43 mg, 0.32 mmol was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (194 mg, 1.45 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred at 36° C. overnight.
  • N-methoxy-N-methyl-3-phenyl-isothiazole-5-carboxamide (100 mg, 0.40 mmol, Intermediate 80) was dissolved in THF (2 mL) under an inert atmosphere, dibromomethane (0.057 mL, 0.81 mmol) was added to it and the solution was cooled to -78° C. with an acetonedry ice bath. Methyl lithium solution 1.6 M in hexane (0.5 mL, 0.81 mmol) was then added to the cooled solution. After 15 min the reaction mixture was quenched by the addition of acetic acid, diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated and reduced under vacuum. The residue thus obtained was directly used in the next step without further purification.

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