WO2020148325A1 - Modulateurs de lxr neutres - Google Patents

Modulateurs de lxr neutres Download PDF

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WO2020148325A1
WO2020148325A1 PCT/EP2020/050895 EP2020050895W WO2020148325A1 WO 2020148325 A1 WO2020148325 A1 WO 2020148325A1 EP 2020050895 W EP2020050895 W EP 2020050895W WO 2020148325 A1 WO2020148325 A1 WO 2020148325A1
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alkyl
alkylene
independently selected
membered
halo
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PCT/EP2020/050895
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Christian Gege
Eva HAMBRUCH
Manfred BIRKEL
Ulrich Deuschle
Claus Kremoser
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Phenex-Fxr Gmbh
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Publication of WO2020148325A1 publication Critical patent/WO2020148325A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel compounds which are Liver X Receptor (LXR) modulators and to pharmaceutical compositions containing same.
  • the present invention further relates to the use of said compounds in the prophylaxis and/or treatment of diseases which are associated with the modulation of the Liver X Receptor.
  • LXRa LXRa
  • LXRb LXRb
  • Both receptors form heterodimeric complexes with Retinoid X Receptor (RXRa, b or g) and bind to LXR response elements (e.g. DR4-type elements) located in the promoter regions of LXR responsive genes.
  • Both receptors are transcription factors that are physiologically regulated by binding ligands such as oxysterols or intermediates of the cholesterol biosynthetic pathways, such as desmosterol.
  • the LXR-RXR heterodimer In the absence of a ligand, the LXR-RXR heterodimer is believed to remain bound to the DR4-type element in complex with co-repressors, such as NCOR1, resulting in repression of the corresponding target genes.
  • co-repressors such as NCOR1
  • an endogenous one such as the oxysterols or steroid intermediates mentioned before or a synthetic, pharmacological ligand
  • the conformation of the heterodimeric complex is changed, leading to the release of corepressor proteins and to the recruitment of coactivator proteins such as NCOA1 (SRC1), resulting in transcriptional stimulation of the respective target genes.
  • SRC1 coactivator proteins
  • LXRb is expressed in most tissues, LXRa is expressed more selectively in cells of the liver, the intestine, adipose tissue and macrophages.
  • the relative expression of LXRa and LXRb at the mRNA or the protein level may vary between different tissues in the same species or between different species in a given tissue.
  • the LXR's control reverse cholesterol transport, i.e. the mobilization of tissue-bound peripheral cholesterol into HDL and from there into bile and feces, through the transcriptional control of target genes such as ABCA1 and ABCG1 in macrophages and ABCG5 and ABCG8 in liver and intestine. This explains the anti-atherogenic activity of LXR agonists in dietary LDLR-KO mouse models.
  • the LXRs do also control the transcription of genes involved in lipogenesis (e.g. SREBF1, SCD, FASN, ACACA) which accounts for the liver steatosis observed following prolonged treatment with LXR agonists.
  • SREBF1, SCD, FASN, ACACA genes involved in lipogenesis
  • the liver steatosis liability is considered a main barrier for the development of non-selective LXR agonists for atherosclerosis treatment.
  • Non-alcoholic fatty liver disease is regarded as a manifestation of metabolic syndrome in the liver and NAFLD has reached epidemic prevalences worldwide (Marchesini et al., Curr. Opin. Lipidol. 2005;16:421).
  • the pathologies of NAFLD range from benign and reversible steatosis to steatohepatitis (nonalcoholic steatohepatitis, NASH) that can develop towards fibrosis, cirrhosis and potentially further towards hepatocellular carcinogenesis.
  • LXR expression was shown to correlate with the degree of fat deposition, as well as with hepatic inflammation and fibrosis in NAFLD patients (Ahn et al., Dig. Dis. Sci. 2014;59:2975). Furthermore, serum and liver desmosterol levels are increased in patients with NASH but not in people with simple liver steatosis. Desmosterol has been characterized as a potent endogenous LXR agonist (Yang et al., J. Biol. Chem.2006;281:27816). NAFLD/NASH patients might therefore benefit from blocking the increased LXR activity observed in the livers of these patients through small molecule antagonists or inverse agonists that shut off LXRs' activity.
  • LXR antagonists or inverse agonists do not interfere with LXRs in peripheral tissues or macrophages to avoid disruption of the anti- atherosclerotic reverse cholesterol transport governed by LXR in these tissues or cells.
  • LXR a is mainly LXR a being responsible for the hepatic steatosis, hence an LXR a-specific antagonist or inverse agonist might suffice or be desirable to treat just hepatic steatosis.
  • LXR a LXR b or double knockout mice with regards to their susceptibility to develop steatosis on a high fat diet. They do not account for a major difference in the relative expression levels of LXR a and LXR b in the human as opposed to the murine liver. Whereas LXR a is the predominant LXR subtype in the rodent liver, LXR b is expressed to about the same if not higher levels in the human liver compared to LXR a.
  • LXR modulator designed to treat NAFLD or NASH for a particular LXR subtype.
  • a certain degree of LXR-subtype selectivity might be allowed if the pharmacokinetic profile of such a compound clearly ensures sufficient liver exposure and resident time to cover both LXRs in clinical use.
  • the treatment of diseases such as NAFLD or NASH would need LXR modulators that block LXRs in a hepato-selective fashion and this could be achieved through hepatotropic pharmacokinetic and tissue distribution properties that have to be built into such LXR modulators.
  • Zuercher et al. describes with the tertiary sulfonamide GSK2033 the first potent, cell-active LXR antagonists (J. Med. Chem. 2010;53:3412). Later, this compound was reported to display a significant degree of promiscuity, targeting a number of other nuclear receptors (Griffett & Burris, Biochem. Biophys. Res. Commun. 2016;479:424). All potent examples (pIC 50 >7.1) have a MeSO 2 -group.
  • WO2014/085453 describes the preparation of small molecule sulfonamide-containing LXR inverse agonists of structure (A) in addition to structure GSK2033 above,
  • R 1 is selected from the group consisting of (halo)alkyl, cycloalkyl, (halo)alkoxy, halo, CN, NO 2 , OR, SO q R , CO 2 R, CONR 2 , OCONR 2 , NRCONR 2 , -SO 2 alkyl, -SO 2 NR-alkyl, -SO 2 -aryl, -SO 2 NR- aryl, heterocyclyl, heterocyclyl-alkyl or N- and C-bonded tetrazoyl;
  • R is selected from H, (halo)alkyl, cycloalkyl, cycloalkyl-alkyl, (hetero)aryl, (hetero)aryl-alkyl, heterocyclyl or heterocyclyl-alkyl;
  • n is selected from 1 to 3 and q is selected from 0 is 2;
  • X is selected from N or CH;
  • R 3 is selected from alkyl, (hetero)aryl or (hetero)aryl-alkyl, wherein all R 3 residues are substituted with 0 to 3 J-groups;
  • J is selected from (halo)alkyl, cycloalkyl, heterocyclyl, (hetero)aryl, haloalkyoxy, halo, CN, NO 2 , OR, SO q R , CO 2 R, CONR 2 , O-CO 2 R, OCONR 2 , NRCONR 2 or NRCO 2 R.
  • SR9238 is described as a liver- selective LXR inverse agonist that suppresses hepatic steatosis upon parenteral administration (Griffett et al., ACS Chem. Biol. 2013;8:559). After ester saponification of SR9238 the LXR inactive acid derivative SR10389 is formed. This compound then has systemic exposure. In addition, it was described, that SR9238 suppresses fibrosis in a model of NASH, again after parenteral administration (Griffett et al., Mol. Metab.2015;4:35).
  • WO2010/039977 describes heteroaryl antagonists of the prostaglandin D2 receptor with general Formula (B),
  • Q 1 is -OH, -OR, -NHSO 2 R, -NR 2 , -NH-OH or -NH-CN;
  • each R 1 is independently selected from H, F, -CH3 and -CH2CH3;
  • ring B is a substituted or unsubstituted heteroaryl
  • R 11 is again selected from a very broad range of substituents and can be an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R 8 is selected from a very broad range of substituents and can be -C 1 -C 4 -alkylene-R 14 , with R 14 is again delected from a very broad range of substituents, e.g. an optionally substituted aryl or heteroaryl;
  • WO2002/055484 describes the preparation of small molecules of structure (C), which can be used to increase the amount of low-density lipoprotein (LDL) receptor and are useful as blood lipid depressants for the treatment of hyperlipidemia, atherosclerosis or diabetes mellitus:
  • a and B represents independently an optionally substituted 5- or 6-membered aromatic ring;
  • R 1 , R 2 and R 3 is independently selected from H, an optionally substituted hydrocarbon group or an optionally substituted heterocycle;
  • X 1 , X 2 , X 3 and X 4 is independently selected from a bond or an optionally substituted divalent hydrocarbon group
  • Y is selected from -NR 3 CO-, -CONR 3 -, -NR 3 -, -SO 2 -, -SO 2 R 3 - or -R 3 -CH2-;
  • Z is selected from -CONH-, -CSNH-, -CO- or -SO 2 -;
  • Ar is selected from an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocycle.
  • G 1 , G 2 , G 3 is independently selected from alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl, alkarylalkyl, alkenylaryl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, alkylamino, alkylaminoaryl, arylamino, aminoalkyl, aminoaryl, alkoxy, alkoxyaryl, aryloxy, alkylamido, alkylcarboxamido, arylcarboxamido, alkoxyoxo, biaryl, alkoxyoxoaryl, amidocycloalkyl, carboxyalkylaryl, carboxyaryl, carboxyamidoaryl, carboxamido, cyanoalkyl, cyanoalkenyl, cyanobiaryl, cycloalkyl, cycloalkyl, cycloal
  • R 1 is selected from a very broad range of substituents and can be -(C1-C6)-alkyl-aryl or -(C1-C6)- alkyl-cycloalkyl, wherein alkyl, cycloalkyl and aryl can be optionally substituted;
  • R 2 is selected from a cycloalkyl or heterocycle, both of them can be optionally substituted;
  • A is selected from a bond, O, NH or S.
  • R 1 and R 2 are independently selected from H or an optionally substituted alkyl, or
  • X 1 can be an optionally alkylated carbon
  • R 3 is an optionally substituted (hetero)cycloalkyl or (hetero)aryl.
  • ITMI0000931485 (or DE4323976) describes N-(tetrahydrofurylalkyl) derivatives with representative structure (H1), wherein the benzyl residue serves as a protecting group for the amine moiety. All structures differ from compounds of the present invention by the fact that ring B in Formula (I) has to be substituted by at least one listed substituent, while compounds in ITMI0000931485 are solely unsubstituted.
  • the present invention relates to compounds according to Formula (I)
  • LXR modulators with hepatoselective properties can be obtained, when the sulfonamide moiety of GSK2033, SR9238 or SR9243 is replaced by a carboxamide or tertiary amine moiety.
  • the compounds of the present invention have a similar or better LXR inverse agonistic, antagonistic or agonistic activity compared to the known LXR-modulators with a sulfonamide moiety.
  • the compounds of the present invention exhibit an advantageous liver/blood-ratio after oral administration so that disruption of the anti-atherosclerotic reverse cholesterol transport governed by LXR in peripheral macrophages can be avoided.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula (I) and at least one pharmaceutically acceptable carrier or excipient.
  • the present invention is further directed to compounds according to Formula (I) for use in the prophylaxis and/or treatment of diseases mediated by LXRs.
  • the present invention relates to the prophylaxis and/or treatment of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis and hepatitis C virus infection.
  • R 1 , R 2 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 - alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
  • R 1 and R 2 together are a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl, O-halo-C 1-4 -alkyl;
  • R 1 and an adjacent residue from ring C form a 5- to 8-membered saturated or partially unsaturated cycloalkyl or a 5- to 8-membered saturated or partially unsaturated heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 - alkyl;
  • R 3 , R 4 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 - alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
  • R 3 and R 4 together are a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
  • R 3 and an adjacent residue from ring B form a 5- to 8-membered partially unsaturated cycloalkyl or a 5- to 8-membered partially unsaturated heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl; R 5 , R 6 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 - alkyl, halo-C 1-4 -alkyl, O-C 1-4
  • R 5 and R 6 together are oxo, thioxo, a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl; or R 5 and an adjacent residue from ring A form a 5- to 8-membered saturated or partially unsaturated cycloalkyl or a 5- to 8-membered saturated or partially unsaturated heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl or the heterocycloalkyl is unsubsti
  • the 10-membered aryl or 7- to 10-membered heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 61 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 - alkyl-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O)nR 61 , C 0-6 -alkylene-NR 61 S(O) 2 R 61 , C 0-6 -alkylene-S(O) 2 NR 61 R 62 , C 0-6 -alkylene-NR 61 S(O) 2 NR 61 R 62 , C 0-6 -alkylene-CO 2 R 61 , C 0-6 - alkylene
  • C is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteratoms independently selected from N, O and S, 6- or 10-membered aryl and 5- to 10-membered heteroaryl containing 1 to 4 heteratoms independently selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 71 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene- S(O) n R 71 , C 0-6
  • X is selected from
  • Y is selected from O or NR 15 ;
  • R 10 is selected from C 1-4 -alkyl and 3- to 6-membered cycloalkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, O-C 1-4 - alkyl and O-fluoro-C 1-4 -alkyl, or wherein cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, O-C 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, C 1- 4 -alkyl and fluoro-C 1-4 -alkyl;
  • R 11 is selected from H, OH, O-C 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, C 1-4 -alkyl and fluoro-C 1-4 -alkyl;
  • R 12 is selected from H, C 1-4 -alkyl and flu
  • R 11 and R 12 when taken together with the carbon to which they are attached complete a 3- to 6- membered ring containing carbon atoms and optionally containing 1 heteroatom independently selected from O, S or N, wherein the new formed cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, 3- to 6- membered cycloalkyl, fluoro-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, fluoro-(3- to 6-membered heterocycloalkyl), OH, oxo, O-C 1-4 -alkyl and O-fluoro-C 1-4 -alkyl;
  • R 13 and R 14 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituent independently selected from halogen, C 1-4 -alkyl, halo-C 1-4 - alkyl, hydroxy-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, O-C 1-4 -alkyl, O- halo-C 1-4 -alkyl, SO 2 -C 1-4 -alkyl and SO 2 -fluoro-C 1-4 -alkyl; or R 13 and R 14 when taken together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 to 2 heteroatoms independently selected from O
  • R 15 is selected from H, -CN, -NO 2 and C 1-4 -alkyl
  • R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , R 82 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl; or R 51 and R 52 , R 61 and R 62 , R 71 and R 72 , respectively, when taken together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon
  • n is selected from 0 to 2; and m and p is independently selected from 1 and 2.
  • R 1 and R 2 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1- 4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl; or R 1 and R 2 together are a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4
  • R 1 and an adjacent residue from ring C form a 5- to 8-membered saturated or partially unsaturated cycloalkyl or a 5- to 8-membered saturated or partially unsaturated heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 - alkyl.
  • R 1 and R 2 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 - alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl.
  • R 1 and R 2 are both H.
  • R 3 and R 4 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1- 4 -alkyl, O-C 1-4 -alkyl, O-halo-C 1-4 -alkyl;
  • R 3 and R 4 together are a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl, O-halo-C 1-4 -alkyl;
  • R 3 and an adjacent residue from ring B form a 5- to 8-membered partially unsaturated cycloalkyl or a 5- to 8-membered partially unsaturated heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl.
  • R 3 and R 4 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 - alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl, O-halo-C 1-4 -alkyl.
  • R 3 and R 4 are independently selected from H and Me. In a most preferred embodiment in combination with any of the above or below embodiments R 3 and R 4 are both H.
  • R 5 and R 6 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1- 4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl;
  • R 5 and R 6 together are oxo, thioxo, a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl, O- halo-C 1-4 -alkyl;
  • R 5 and an adjacent residue from ring A form a 5- to 8-membered saturated or partially unsaturated cycloalkyl or a 5- to 8-membered saturated or partially unsaturated heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the cycloalkyl or the heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, oxo, C 1-4 -alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 - alkyl.
  • R 5 and R 6 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, OH, oxo, C 1-4 - alkyl, halo-C 1-4 -alkyl, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl; or R 5 and R 6 together are oxo.
  • R 5 and R 6 are independently selected from H and Me.
  • R 5 and R 6 are together oxo.
  • m and p is independently selected from 1 and 2.
  • p is 1 and m is selected from 1 and 2.
  • both m and p are 1.
  • R 1 , R 2 , R 3 and R 4 are independently selected from H or Me
  • R 5 and R 6 are independently selected from H or Me or R 5 and R 6 together are oxo.
  • R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , R 82 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, oxo, O-C 1-4 -alkyl and O-halo-C 1-4 -alkyl; or R 51 and R 52 , R 61 and R 62 , R 71 and R 72 , respectively, when taken together with the nitrogen to which they are attached
  • R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , R 82 are independently selected from H, Me and Et; or R 51 and R 52 , R 61 and R 62 , R 71 and R 72 , respectively, when taken together with the nitrogen to which they are attached complete a ring system independently selected from azetidine, piperidine and morpholine.
  • R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , R 82 are independently selected from H and Me.
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 51 , C 0-6 -alkylene-(3- to 6-membered-cycloalkyl), C 0-6 -alkylene-(3- to 6-membered-heterocycloalkyl), C 0-6 -alkylene- S(
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 - alkylene-OR 51 , C 0-6 -alkylene-(3- to 6-membered-cycloalkyl), C 0-6 -alkylene-(3- to 6-membered- heterocycloalkyl), C 0-6 -alkylene-S(O) n R 51 , C 0-6 -alkylene-NR 51 S(O) 2 R 51 , C 0-6 -alkylene- S(O) 2 NR 51 R 52
  • phenyl in a more preferred embodiment in combination with any of the above or below embodiments is selected from phenyl, pyridyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, pyrazolopyridazinyl, pyrazolopyrimidinyl, naphthyl, benzo[b]thiophenyl, 1,2,3,4-tetrahydronaphthyl, chromanyl, isochromanyl, quinoline, isoquinoline, quinolin-2(1H)-onyl, isoquinolin-2(1H)-onyl, naphthyridinyl, pyridopyrimidinyl, cinnolinyl, phthalazinyl, anthracenyl, acridinyl and 1,2,3,4-tetrahydroanthracenyl, wherein said moiety is unsub
  • R a is selected from H, Cl, CN, Me, Et, CHF 2 , CF 3 , OMe, OCHF 2 and OCF 3 ; and is unsubstituted or substituted with 1 to 3 substituents independently selected from F, Cl, Br, CN, NO 2 , OH, oxo, Me, Et, CHF 2 , CF 3 , OMe, OEt, OCHF 2 and OCF 3 .
  • R a is selected from H, Cl, CN, Me, Et, CHF 2 , CF 3 , OMe, OCHF 2 and OCF 3 ; and is unsubstituted or substituted with 1 to 3 substituents independently selected from F, Cl, Br, CN, NO 2 , OH, oxo, Me, Et, CHF 2 , CF 3 , OMe, OEt, OCHF 2 and OCF 3 .
  • R a and R b is independently selected from H, Cl, CN, Me, Et, cyclopropyl, fluoro- cyclopropyl, CHF 2 , CF 3 , OH, OMe, OCHF 2 and OCF 3 ; and may be further substituted with 1 to 3 additional substituents independently selected from F, Cl, Br, CN, OH, Me, Et, CHF 2 , CF 3 , OMe, OEt, OCHF 2 and OCF 3 .
  • R a is H and R b is selected from Me, Et, cyclopropyl, CHF 2 , CF 3 , OMe, OCHF 2 and OCF 3 ; and may be further substituted with 1 to 3 additional substituents independently selected from F, CN, Me, Et, CHF 2 , CF 3 , OMe, OEt, OCHF 2 and OCF 3 .
  • B is selected from the group consisting of 6- or 10-membered aryl and 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the 6-membered aryl and 5- or 6-membered heteroaryl are substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 - alkylene-OR 61 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkyl-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 61 , C 0-6 -alkylene-NR 61 S(O) 2 R 61 , C 0-6 -alkylene- S(O) 2 NR 61 R
  • substituents in the aryl or heteroaryl moiety form a 5- to 8- membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, oxo, OH, C 1-4 -alkyl, halo-C 1-4 -alkyl, O- C 1-4 -alkyl and O-halo-C 1-4 -alkyl; and
  • the 10-membered aryl or 7- to 10-membered heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 61 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkyl-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 61 , C 0-6 -alkylene-NR 61 S(O) 2 R 61 , C 0-6 - alkylene-S(O) 2 NR 61 R 62 , C 0-6 -alkylene-NR 61 S(O) 2 NR 61 R 62 , C 0-6 -alkylene-CO 2 R 61 , C 0-6 -alky
  • a further more preferred embodiment in combination with any of the above or below embodiments is selected from the group consisting of 6-membered aryl and 5- to 6- membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the 6-membered aryl and 5- or 6-membered heteroaryl are substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 - alkyl, C 0-6 -alkylene-OR 61 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkyl-(3- to 6- membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 61 , C 0-6 -alkylene-NR 61 S(O) 2 R 61 , C 0-6 - alkylene-S(O) 2 NR 61 R 62
  • cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 71 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-alkylene-alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-alkylene-
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 - alkylene-OR 71 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 71 , C 0-6 -alkylene-NR 71 S(O) 2 R 71 , C 0-6 -alkylene- S(O) 2 NR 71 R
  • phenyl, thiophenyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl wherein phenyl, thiophenyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of F, Cl, Br, CN, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, OH, oxo, OC 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, CONH 2 , NH 2 , NHC 1-4 -alkyl and N(C 1-4 -alkyl) 2 ; and wherein the residue -CR 1 R 2 - on ring C
  • phenyl, thiophenyl and pyridinyl is selected from the group consisting of phenyl, thiophenyl and pyridinyl, wherein phenyl, thiophenyl and pyridinyl is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of F, Cl, Br, CN, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, OH, oxo, OC 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, CONH 2 , NH 2 , NHC 1-4 -alkyl and N(C 1- 4 -alkyl) 2 ; and wherein the residue -CR 1 R 2 - on ring C is linked at least with one 1,4-orientation regarding the connection towards ring D.
  • phenyl wherein phenyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 71 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -alkylene-S(O) n R 71 , C 0-6 -alkylene-NR 71 S(O) 2 R 71 , C 0-6 - alkylene-S(O) 2 NR 71 R 72 , C 0-6 -alkylene-NR 71 S(O) 2 NR 71 R 72 , C 0-6 -alkylene-CO
  • phenyl is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of F, Cl, Br, CN, C 1-4 - alkyl, fluoro-C 1-4 -alkyl, OH, OC 1-4 -alkyl and O-fluoro-C 1-4 -alkyl; and wherein the residue -CR 1 R 2 - on ring C is linked in para-orientation regarding the connection towards ring D.
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 81 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-S(O)nR 81 , C 0-6 -alkylene-NR 81 S(O) 2 R 81 , C 0-6 -alkylene- S(O) 2 NR 81 R 82 , C 0-6 -alkylene-NR 81 S(O) 2 NR 81 R 82 , C 0-6 -alkylene-NR 81 S(O) 2 NR 81 R 82 , C 0-6 -alkylene-NR 81 S(O) 2 NR 81 R 82 , C 0-6 -alkylene
  • aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, CN, NO 2 , oxo, C 1-4 -alkyl, C 0-6 -alkylene-OR 81 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-S(O) n R 81 , C 0-6 -alkylene-NR 81 S(O) 2 R 81 , C 0-6 -alkylene- S(O) 2 NR 81 R 82 , C 0-6 -alkylene-NR 81 S(O) 2 NR 81 R 82 , C 0-6 -alkylene-NR 81 S(O) 2 NR 81 R 82 ,
  • embodiments is selected from
  • X is selected from or
  • Y is selected from O or NR 15 ;
  • R 10 is selected from C 1-4 -alkyl and 3- to 6-membered cycloalkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, O-C 1-4 - alkyl and O-fluoro-C 1-4 -alkyl, or wherein cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, O-C 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, C 1- 4 -alkyl and fluoro-C 1-4 -alkyl;
  • R 11 is selected from H, OH, O-C 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, C 1-4 -alkyl and fluoro-C 1-4 -alkyl
  • R 12 is selected from H, C 1-4 -alkyl and fluoro-C 1-4 -alkyl; or R 11 and R 12 when taken together with the carbon to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 heteroatom independently selected from O, S or N, wherein the new formed cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, fluoro-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, fluoro-(3- to 6-membered heterocyclo
  • R 13 and R 14 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituent independently selected from halogen, C 1-4 -alkyl, halo-C 1-4 - alkyl, hydroxy-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, O-C 1-4 -alkyl, O- halo-C 1-4 -alkyl, SO 2 -C 1-4 -alkyl and SO 2 -fluoro-C 1-4 -alkyl; or R 13 and R 14 when taken together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 to 2 heteroatoms independently selected from O
  • R 15 is selected from H, -CN, -NO 2 and C 1-4 -alkyl.
  • X is selected from
  • Y is selected from O or NH
  • R 10 is selected from C 1-4 -alkyl and 3- to 6-membered cycloalkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, O-C 1-4 - alkyl and O-fluoro-C 1-4 -alkyl, or wherein cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, CN, OH, O-C 1-4 -alkyl, O-fluoro-C 1-4 -alkyl, C1- 4-alkyl and fluoro-C 1-4 -alkyl;
  • R 11 is selected from H, OH, Me, Et, CHF 2 and CF 3 ;
  • R 12 is selected from H, Me, Et, CHF 2 and CF 3 ; or
  • R 13 and R 14 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituent independently selected from halogen, C 1-4 -alkyl, halo-C 1-4 - alkyl, hydroxy-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, O-C 1-4 -alkyl, O- halo-C 1-4 -alkyl, SO 2 -C 1-4 -alkyl and SO 2 -fluoro-C 1-4 -alkyl; or
  • R 13 and R 14 when taken together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 to 2 heteroatoms independently selected from O, S or N, wherein the new formed cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, CN, C 1-4 -alkyl, fluoro- C 1-4 -alkyl, 3- to 6-membered cycloalkyl, fluoro-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, fluoro-(3- to 6-membered heterocycloalkyl), OH, oxo, O-C 1-4 -alkyl and O- fluoro-C 1-4 -alkyl.
  • X is selected from and .
  • R 13 and R 14 are independently selected from H and C 1-4 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituent independently selected from halogen, C 1-4 -alkyl, halo-C 1-4 - alkyl, hydroxy-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), OH, O-C 1-4 -alkyl, O- halo-C 1-4 -alkyl, SO 2 -C 1-4 -alkyl and SO 2 -fluoro-C 1-4 -alkyl; or R 13 and R 14 when taken together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 to 2 heteroatoms independently selected from O
  • R 1 , R 2 , R 3 and R 4 are independently selected from H and Me;
  • R 5 and R 6 are independently selected from H and Me or R 5 and R 6 together are oxo;
  • R 1 , R 2 , R 3 and R 4 are H;
  • R 5 is selected from H and Me; R 6 is Me; or R 5 and R 6 together are oxo;
  • R a and R b is independently selected from H, Cl, CN, Me, Et, cyclopropyl, fluoro- cyclopropyl, CHF 2 , CF 3 , OH, OMe, OCHF 2 and OCF 3 ; and may be further substituted with 1 to 3 additional substituents independently selected from F, Cl, Br, CN, OH, Me, Et, CHF 2 , CF 3 , OMe, OEt, OCHF 2 and OCF 3 ; is selected from , , , ; is selected from , , ; is selected from X is selected from
  • R 1 , R 2 , R 3 and R 4 are H; and m is 1.
  • the compound is selected from
  • the compound is 1-mesityl-N-((3'-(methylsulfonyl)-[1,1'- biphenyl]-4-yl)methyl)-N-((5-(trifluoromethyl)furan-2-yl)methyl)methanamine and optionally a pharmaceutically acceptable salt thereof.
  • the invention also provides the compound of the invention for use as a medicament.
  • the compound of the invention for use in treating a LXR mediated disease selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hyper- cholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications, and unwanted side-effects of long- term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.
  • the invention further relates to a method for preventing and/or treating diseases mediated by LXRs, the method comprising administering a compound of the present invention in an effective amount to a subject in need thereof.
  • the invention relates to a method for preventing and treating diseases selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hyper- cholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications, and unwanted side-effects of long- term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.
  • diseases selected from non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hyper- cholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications, and unwanted side-effects of long- term glu
  • the invention also relates to the use of a compound according to the present invention in the preparation of a medicament for the prophylaxix and/or treatment of a LXR mediated disease.
  • the invention relates to the use of a compound according to the present invention in the preparation of a medicament for the prophylaxix and/or treatment of a LXR mediated disease, wherein the disease is selected from non-alcoholic fatty liver disease, non- alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome, cardiac steatosis, cancer, viral myocarditis, hepatitis C virus infection or its complications, and unwanted side-effects of long-term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.
  • the disease is selected from non-alcoholic fatty liver disease, non- alcoholic steatohepatitis, liver inflammation, liver fibrosis, obesity, insulin resistance, type II diabetes, familial hypercholesterolemia, hypercholesterolemia in nephrotic syndrome, metabolic syndrome,
  • composition comprising the compound of the invention and a pharmaceutically acceptable carrier or excipient.
  • C 1-6 -alkyl means a saturated alkyl chain having 1 to 6 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl.
  • C 1-4 -alkyl means a saturated alkyl chain having 1 to 4 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • halo-C 1-4 -alkyl means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen.
  • a preferred example thereof is CH 2 F, CHF 2 and CF 3 .
  • A“C 0-6 -alkylene” means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention,“C 0 - alkylene” is meant to represent a bond, whereas C 1 -alkylene means a methylene linker, C 2 - alkylene means a ethylene linker or a methyl-substituted methylene linker and so on. In the context of the present invention, a C 0-6 -alkylene preferably represents a bond, a methylene, a ethylene group or a propylene group. Similarily, a“C 2-6 -alkenylene” and a“C 2-6 -alkinylene” means a divalent alkenyl or alkynyl group which connects two parts of the molecule.
  • a 3- to 10-membered cycloalkyl group means a saturated or partially unsaturated mono-, bi-, spiro- or multicyclic ring system comprising 3 to 10 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octanyl, spiro[3.3]heptyl, bicyclo[2.2.1]heptyl, adamantyl and pentacyclo[4.2.0.0 2,5 .0 3,8 .0 4,7 ]octyl.
  • a 3- to 6-membered cycloalkyl group means a saturated or partially unsaturated mono- bi-, or spirocyclic ring system comprising 3 to 6 carbon atoms
  • a 5- to 8- membered cycloalkyl group means a saturated or partially unsaturated mono-, bi-, or spirocyclic ring system comprising 5 to 8 carbon atoms.
  • a 3- to 10-membered heterocycloalkyl group means a saturated or partially unsaturated 3 to 10 membered carbon mono-, bi-, spiro- or multicyclic ring wherein 1, 2, 3 or 4 carbon atoms are replaced by 1, 2, 3 or 4 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O, S, SO and SO 2 .
  • heterocycloalkyl group can be connected with the remaining part of the molecule via a carbon, nitrogen (e.g. in morpholine or piperidine) or sulfur atom.
  • An example for a S-linked heterocycloalkyl is the cyclic sulfonimidamide .
  • a 5- to 14-membered mono-, bi- or tricyclic heteroaromatic ring system (within the application also referred to as heteroaryl) means an aromatic ring system containing up to 6 heteroatoms independently selected from N, O, S, SO and SO 2 .
  • monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, furanyl, thiophenyl (thienyl), pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl.
  • bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms.
  • heteroatom(s) may be present in one or both rings including the bridgehead atoms.
  • examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl 1,5- naphthyridinyl, 1,7-naphthyridinyl and pyrazolo[1,5-a]pyrimidinyl.
  • tricyclic heteroaromatic rings examples include acridinyl, benzo[b][1,5]naphthyridinyl and pyrido[3,2- b][1,5]naphthyridinyl.
  • the nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heteroaryl system can be connected via a carbon or nitrogen atom.
  • N-linked heterocycles are .
  • a 6- to 14-membered mono-, bi- or tricyclic aromatic ring system (within the application also referred to as aryl) means an aromatic carbon cycle such as phenyl, naphthyl, anthracenyl or phenanthrenyl.
  • N-oxide denotes compounds, where the nitrogen in the heteroaromatic system (preferably pyridinyl) is oxidized. Such compounds can be obtained in a known manner by reacting a compound of the present invention (such as in a pyridinyl group) with H2O 2 or a peracid in an inert solvent.
  • Halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine and most preferably fluorine.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the disclosure also includes“deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g. a human. See, for example, Foster in Trends Pharmacol. Sci.1984:5;524.
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as“H” or“hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of the present invention are partly subject to tautomerism.
  • tautomerism For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following tautomerism can appear: .
  • a cycloalkyl or heterocycloalkyl group can be connected straight or spirocyclic, e.g. when cyclohexane is substituted with the heterocycloalkyl group oxetane, the following structures are possible: .
  • 1,4-orientation means that on a ring the substituents have at least one possibility, where are 4 atoms between the two substituens attached to the ring system:
  • 1,3-orientation means that on a ring the substituents have at least one possibility, where 3 atoms are between the two substituents attached to the ring system, e.g. .
  • the compounds of the present invention can be in the form of a prodrug compound.
  • Prodrug compound means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • prodrug examples include compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • these compounds can be produced from compounds of the present invention according to well-known methods.
  • Metabolites of compounds of the present invention are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • the individual forms like e.g. the keto and enol form, are each within the scope of the invention as well as their mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans-isomers, atropisomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials. Another way to obtain pure enantiomers from racemic mixtures would use enantioselective crystallization with chiral counterions.
  • the compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the present invention which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts.
  • salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the compounds of the present invention may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol.
  • the present invention provides pharmaceutical compositions comprising at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • “Pharmaceutical composition” means one or more active ingredients and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other nuclear receptor modulators.
  • the compositions are suitable for oral, vaginal, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the compounds of the present invention act as LXR modulators.
  • Ligands to nuclear receptors including LXR ligands can either act as agonists, antagonists or inverse agonists.
  • An agonist in this context means a small molecule ligand that binds to the receptor and stimulates its transcriptional activity as determined by e.g. an increase of mRNAs or proteins that are transcribed under control of an LXR response element.
  • Transcriptional activity can also be determined in biochemical or cellular in vitro assays that employ just the ligand binding domain of LXR a or LXR b but use the interaction with a cofactor (i.e. a corepressor or a coactivator), potentially in conjunction with a generic DNA-binding element such as the Gal4 domain, to monitor agonistic, antagonistic or inverse agonistic activity.
  • a cofactor i.e. a corepressor or a coactivator
  • an antagonist is defined as a small molecule that binds to LXRs and thereby inhibits transcriptional activation that would otherwise occur through an endogenous LXR ligand.
  • An inverse agonist differs from an antagonist in that it not only binds to LXRs and inhibits transcriptional activity but in that it actively shuts down transcription directed by LXR, even in the absence of an endogenous agonist. Whereas it is difficult to differentiate between LXR antagonistic and inverse agonistic activity in vivo, given that there are always some levels of endogenous LXR agonist present, biochemical or cellular reporter assays can more clearly distinguish between the two activities. At a molecular level an inverse agonist does not allow for the recruitment of a coactivator protein or active parts thereof whereas it should lead to an active recruitment of corepressor proteins are active parts thereof.
  • LXR antagonist in this context would be defined as an LXR ligand that neither leads to coactivator nor to corepressor recruitment but acts just through displacing LXR agonists. Therefore, the use of assays such as the Gal4-mammalian-two-hybrid assay is mandatory in order to differentiate between coactivator or corepressor-recruiting LXR compounds (Kremoser et al., Drug Discov. Today 2007;12:860; Gronemeyer et al., Nat. Rev. Drug Discov.2004;3:950).
  • LXR modulator Since the boundaries between LXR agonists, LXR antagonists and LXR inverse agonists are not sharp but fluent, the term“LXR modulator” was coined to encompass all compounds which are not clean LXR agonists but show a certain degree of corepressor recruitment in conjunction with a reduced LXR transcriptional activity. LXR modulators therefore encompass LXR antagonists and LXR inverse agonists and it should be noted that even a weak LXR agonist can act as an LXR antagonist if it prevents a full agonist from full transcriptional activation.
  • the compounds are useful for the prophylaxis and/or treatment of diseases which are mediated by LXRs. Preferred diseases are all disorders associated with steatosis, i.e.
  • Such diseases encompass the full spectrum of non-alcoholic fatty liver disease including non-alcoholic steatohepatitis, liver inflammation and liver fibrosis, furthermore insulin resistance, metabolic syndrome and cardiac steatosis.
  • An LXR modulator based medicine might also be useful for the treatment of hepatitis C virus infection or its complications and for the prevention of unwanted side-effects of long-term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma.
  • LXR modulators might be in the treatment of cancer.
  • LXR antagonists or inverse agonists might useful to counteract the so-called Warburg effect which is associated with a transition from normal differentiated cells towards cancer cells (see Liberti et al., Trends Biochem. Sci.2016;41:211; Ward & Thompson, Cancer Cell 2012;21:297–308).
  • LXR is known to modulate various components of the innate and adaptive immune system.
  • Oxysterols which are known as endogenous LXR agonists were identified as mediators of an LXR-dependent immunosuppressive effect found in the tumor microenvironment (Traversari et al., Eur. J. Immunol. 2014;44:1896).
  • LXR antagonists or inverse agonists might be capable of stimulating the immune system and antigen-presenting cells, in particular, to elicit an anti-tumor immune response.
  • the latter effects of LXR antagonists or inverse agonists might be used for a treatment of late stage cancer, in general, and in particular for those types of cancerous solid tumors that show a poor immune response and highly elevated signs of Warburg metabolism.
  • anti-cancer activity of the LXR inverse agonist SR9243 was shown to be mediated by interfering with the Warburg effect and lipogenesis in different tumor cells in vitro and SW620 colon tumor cells in athymic mice in vivo (see Flaveny et al. Cancer Cell. 2015;28:42; Steffensen, Cancer Cell 2015;28:3).
  • LXR modulators preferably LXR inverse agonists
  • LXR modulators may counteract the diabetogenic effects of glucocorticoids without compromising the anti-inflammatory effects of glucocorticoids and could therefore be used to prevent unwanted side-effects of long-term glucocorticoid treatment in diseases such as rheumatoid arthritis, inflammatory bowel disease and asthma (Patel et al. Endocrinology 2017:158:1034).
  • LXR modulators may be useful for the treatment of hepatitis C virus mediated liver steatosis (see Garc ⁇ a-Mediavilla et al. Lab. Invest.2012;92:1191).
  • LXR modulators may be useful for the treatment of viral myocarditis (see Papageorgiou et al. Cardiovasc. Res.2015;107:78). LXR modulators (preferably LXR inverse agonists) may be useful for the treatment of insulin resistance (see Zheng et al. PLoS One 2014;9:e101269).
  • LXR modulators may be useful for the treatment of familial hypercholesterolemia (see Zhou et al. J. Biol. Chem.2008;283:2129).
  • LXR modulators may be useful for the treatment of hypercholesterolemia in nephrotic syndrome (see Liu & Vazizi in Nephrol. Dial. Transplant. 2014;29:538).
  • the compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in WO2018/188795 and in the unpublished international application PCT/EP2018/069515.
  • Abbreviations are described in WO2018/188795 and in the unpublished international application PCT/EP2018/069515.
  • Step 4 1-Mesityl-N-((3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)methyl)-N-((5-(trifluoro- methyl)furan-2-yl)methyl)methanamine (1)
  • Example was prepared similar as described for Example 1 using the appropriate building blocks.
  • Step 1 2-Methyl-1-naphthoyl chloride (2a) To a solution of 2-methyl-1-naphthoic acid (1.86 g, 10.0 mmol) in DCM (30 mL) was added SOCl 2 (10 mL). The mixture was stirred at rt for 2 h and concentrated to give compound 2a as a yellow oil.
  • Step 2 N-(4-Bromobenzyl)-2-methyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1-naphthamide (2b)
  • Step 3 2-Methyl-N-((3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)methyl)-N-((5-(trifluoro- methyl)furan-2-yl)methyl)-1-naphthamide (2)
  • Example 2 was prepared similar as described for Example 2 using the appropriate building block. ⁇ building block structure analytical data
  • Step 2 Methyl 2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfinyl)acetate (3b)
  • Step 3 Methyl 2-((4'-((2-methyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1-naphth- amido)methyl)-[1,1'-biphenyl]-3-yl)sulfinyl)acetate (3c)
  • Step 4 Methyl 2-(4'-((2-methyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1-naphth- amido)methyl)-N-(2,2,2-trifluoroacetyl)-[1,1'-biphenyl]-3-sulfonimidoyl)acetate (3d)
  • Step 5 2-Methyl-N-((3'-(S-methylsulfonimidoyl)-[1,1'-biphenyl]-4-yl)methyl)-N-((5-(trifluoro- methyl)furan-2-yl)methyl)-1-naphthamide (3)
  • Step 1 1-Mesityl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-N-((5-(trifluoro- methyl)furan-2-yl)methyl)methanamine (4a)
  • Step 2 (3-Fluoro-5-(methylsulfonyl)-4'-((((5-(trifluoromethyl)furan-2-yl)methyl)(2,4,6-trimethyl- benzyl)amino)methyl)-[1,1'-biphenyl]-4-yl)methanol (4)
  • Example was prepared similar as described for Example 4 using the appropriate building block.
  • Step 2 3-(Methylsulfonyl)-4'-((((5-(trifluoromethyl)furan-2-yl)methyl)(2,4,6-trimethyl- benzyl)amino)methyl)-[1,1'-biphenyl]-4-carboxamide (5)
  • Step 4 N-(4-Bromobenzyl)-2,3-dimethyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1,5-naph- thyridine-4-carboxamide (6d)
  • Step 5 2,3-Dimethyl-N-((3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)methyl)-N-((5-(trifluoro- methyl)furan-2-yl)methyl)-1,5-naphthyridine-4-carboxamide (6)
  • Step 1 2-((5-Fluoro-4-(hydroxymethyl)-4'-((2-methyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)- 1-naphthamido)methyl)-[1,1'-biphenyl]-3-yl)sulfonyl)acetic acid (7a)
  • Sulfonyl acetic acid derivative 7a was prepared as previously described in PCT/EP2018/069515.
  • Step 2 N-((3'-Fluoro-4'-(hydroxymethyl)-5'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)methyl)-2- methyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1-naphthamide (7)
  • Example 7 The following Examples were prepared similar as described for Example 7 using the appropriate sulfonyl acetic acid educt described in PCT/EP2018/069515.
  • the compound can be prepared by decarboxylation of the sulfonyl acetic acid in a DMSO solution (with optionally adding a base).
  • Step 1 2-(4'-((2,3-Dimethyl-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1,5-naphthyridine-4- carboxamido)methyl)-[1,1'-biphenyl]-3-yl)-2-methylpropanoic acid (8a)
  • Carboxylic acid derivative 8a was prepared as previously described in PCT/EP2018/069515. Step 2: N-((3'-(1-Amino-2-methyl-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-2,3-dimethyl- N-((5-(trifluoromethyl)furan-2-yl)methyl)-1,5-naphthyridine-4-carboxamide (8)
  • the pharmacokinetics of the compounds were assessed in mice after single dosing and oral administrations.
  • the study design was as follows:
  • Animal handling animals were withdrawn from food at least 2 h before administration
  • Bioanalytics LC-MS of liver and blood/plasma samples
  • Hepatic LXR target genes were suppressed. These genes are related to hepatic de-novo lipogenesis. A suppression of these genes will reduce liver fat (liver triglycerides).

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Abstract

La présente invention concerne des composés contenant amine, carboxamide ou thioamide qui se lient au récepteur X du foie (LXRα et/ou LXRβ) et agissent de préférence en tant qu'agonistes inverses de LXR. Les composés sont de formule (I), les cycles A-D, les substituants R1-R6 et X et n étant tels que définis dans la description.
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